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"abstract": "Three male Caucasian patients with ALS were admitted to the hospital due to progressive dysphagia and dysarthria. During two 21-day courses of penicillin G and hydrocortisone, these patients' dysphagia and dysarthria resolved. The patient's other ALS-associated symptoms also improved, including respiratory function, coordination, walking, and muscle strength. This is the first report of a treatment with a protocol for treating dysphagia, dysarthria, respiratory depression and other ALS-related symptoms. Furthermore, the observations are consistent with the recent hypothesis that the successful treatment of ALS symptoms with this treatment course in six patients with syphilitic ALS was not directly due to the treatment of syphilis; but that the administered penicillin G and/or hydrocortisone treated these patients' ALS symptoms due the off-target pharmacological activity of penicillin G and/or hydrocortisone. This report therefore underscores the need to evaluate the efficacy of this treatment course in a clinical trial.",
"affiliations": "Ry Pharma, Hofstraat 1, Willemstad, 4797 AC, Netherlands.;Ry Pharma, Hofstraat 1, Willemstad, 4797 AC, Netherlands.;2-BBB Medicines, J.H. Oortweg 19, Leiden, 2333 CH, Netherlands.",
"authors": "Tuk|Bert|B|;Jousma|Harmen|H|;Gaillard|Pieter J|PJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.12688/f1000research.10534.1",
"fulltext": "\n==== Front\nF1000ResF1000ResF1000ResearchF1000Research2046-1402F1000Research London, UK 2844318710.12688/f1000research.10534.1Clinical Practice ArticleArticlesMotor SystemsTreatment with penicillin G and hydrocortisone reduces ALS-associated symptoms: a case series of three patients [version 1; referees: 2 approved]\n\nTuk Bert a1Jousma Harmen 1Gaillard Pieter J. 2\n1 Ry Pharma, Hofstraat 1, Willemstad, 4797 AC, Netherlands\n2 2-BBB Medicines, J.H. Oortweg 19, Leiden, 2333 CH, Netherlandsa bert.tuk@rypharma.comBT, EW, HJ and PG were responsible for the design of the treatment protocol and contributed to the design and the preparation of the manuscript. All authors were involved in the revision of the draft manuscript and have agreed to the final content.\n\n\nCompeting interests: BT is the inventor listed on a patent application for the treatment of neuromuscular and neurological diseases using the therapies described in this manuscript. BT is also the founder of Ry Pharma, a company that develops the therapy described in the manuscript. HJ is an unsalaried volunteer at Ry Pharma. PG has no competing interests.\n\n3 4 2017 2017 6 41010 2 2017 Copyright: © 2017 Tuk B et al.2017This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Three male Caucasian patients with ALS were admitted to the hospital due to progressive dysphagia and dysarthria.\n\n During two 21-day courses of penicillin G and hydrocortisone, these patients’ dysphagia and dysarthria resolved. The patient’s other ALS-associated symptoms also improved, including respiratory function, coordination, walking, and muscle strength.\n\n This is the first report of a treatment with a protocol for treating dysphagia, dysarthria, respiratory depression and other ALS-related symptoms. Furthermore, the observations are consistent with the recent hypothesis that the successful treatment of ALS symptoms with this treatment course in six patients with syphilitic ALS was not directly due to the treatment of syphilis; but that the administered penicillin G and/or hydrocortisone treated these patients’ ALS symptoms due the off-target pharmacological activity of penicillin G and/or hydrocortisone. This report therefore underscores the need to evaluate the efficacy of this treatment course in a clinical trial.\n\nAmyotrophic lateral sclerosisdysphagiadysarthriapenicillin GhydrocortisoneGABAneuromuscular diseaserespiratory depressionThe author(s) declared that no grants were involved in supporting this work.\n==== Body\nIntroduction\nAmyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) is a rapidly progressive devastating disease with an average life expectancy of only 3–5 years after diagnosis\n1–\n3. The cumulative lifetime risk of ALS is approximately 1:350–400\n3. Moreover, the total cost associated with ALS—excluding the cost of medication—has been estimated to exceed $1.4 million per patient\n4. The clinical manifestations of ALS include progressive wasting of muscle mass, reduced muscle coordination, dysphagia, dysarthria, and fatal respiratory depression\n1–\n3. Several observations regarding the putative pathogenesis of ALS have been reported\n1–\n3; however, although more than 140 years have passed since ALS was first described, its pathogenesis remains poorly understood, and no disease-modifying treatment is available.\n\nDysphagia-associated aspiration pneumonia is the leading cause of death in many neuromuscular and neurological diseases, including ALS, Parkinson’s disease, and Alzheimer’s disease\n5,\n6. Remarkably, however, no effective treatment for dysphagia is currently available.\n\nHere, we report that dysphagia, dysarthria, and other ALS-related symptoms resolved during two 21-day courses of penicillin G and hydrocortisone. This treatment course was previously reported to be efficacious in six patients with so-called syphilitic ALS in which syphilis was hypothesized to cause ALS\n7,\n8. However, we recently proposed that the treatment effect was not due to the treatment of syphilis, but rather was a consequence of the multifaceted pharmacology of penicillin G and/or hydrocortisone\n9. Given that our three patients presented with no evidence of syphilis, our results provide evidence that treating ALS patients with a course of penicillin G and hydrocortisone—regardless of whether they present with syphilitic ALS or non-syphilitic ALS—may effectively treat the symptoms of this rapidly progressive disease. These three cases warrant further study of this treatment course.\n\nCase presentation: Patient 1\nA 42-year-old Caucasian male with ALS was admitted to the hospital with complaints of progressive swallowing and speech difficulties. Three years ago, this patient was diagnosed with limb-onset ALS and presented with other symptoms typical of ALS, including dysphagia, dysarthria, difficulty with coordination, and muscle wasting. The patient had no history of syphilis or other systemic infection, and the diagnosis of ALS was confirmed by the Netherlands National ALS Center.\n\nUpon admission to the hospital, the patient was only able to take a few steps and had been wheelchair-bound for the past four months. In addition, his upper extremities had been paralyzed for over twelve months (see\nFigure 1A). In the preceding months, the patient’s speech had degenerated, and the patient had difficulty swallowing both solid food and liquids, including saliva.\n\nFigure 1. \nA: Upon admission to the hospital, patient 1 was only able to take a few steps and had been wheelchair-bound for the past four months. In addition, his upper extremities had been paralyzed for over twelve months. In the preceding months, the patient’s speech had degenerated, and the patient had difficulty swallowing both solid food and liquids, including saliva.\nB: On the 2\nnd and 3\nrd treatment days, patient 1 reported that he was able to lie in bed without experiencing muscle pain in the neck, shoulders, or back. On day 4, the patient was able to stand from a sitting position. On day 5, the patient was able to walk unaided a distance of approximately 100 meters. During days 76 to 91 the patient experienced increasing muscle pain in the neck, shoulders, or back, his walking ability regressed, and the patient became wheelchair-bound again. His swallowing and speech remained functional.\n\n\nFigure 2 shows the progression of symptoms and the effect of treatment. Dysphagia was confirmed at the time of admission by performing a fiber-optic endoscopic evaluation of swallowing (FEES) examination\n10 (\nMovie 1). Physical examination and laboratory blood analysis revealed no other clinical pathology, and renal function was normal. The patient was not taking any prescription medications.\n\nFigure 2. The clinical progression and effect of treatment in Patient 1.\nThe patient had no history of seizures and was therefore eligible to receive high doses of penicillin G. After confirming that the patient was not allergic to penicillin (by administering a daily dose of amoxicillin for six days), the patient was started on a 21-day course of penicillin G and hydrocortisone (\nTable 1) delivered via midline catheter infusion. This treatment course was recently postulated to be efficacious for treating dysphagia, dysarthria, and other ALS-related symptoms\n9.\n\nTable 1. 21-day course of penicillin G and hydrocortisone consisting of an 8-hour infusion on each treatment day.\n\nTreatment\n\n\nday(s)\n\t\n8-hour continuous infusion\n\t\n1\t1 million units penicillin G + 100 mg hydrocortisone\t\n2\t3 million units penicillin G + 100 mg hydrocortisone\t\n3\t5 million units penicillin G + 100 mg hydrocortisone\t\n4\t10 million units penicillin G + 100 mg hydrocortisone\t\n5 – 14\t20 million units penicillin G + 100 mg hydrocortisone\t\n15 – 21\t20 million units penicillin G\t\nOn the 2\nnd and 3\nrd treatment days, the patient reported that he was able to lie in bed without experiencing muscle pain in the neck, shoulders, or back. On day 4, the patient was able to stand from a sitting position. On day 5, the patient was able to walk unaided a distance of approximately 100 meters (see\nFigure 1B). In addition, the patient’s speech and swallowing improved.\n\nAt the end of the first week, the patient’s dysphagia and dysarthria symptoms had resolved fully, and his walking had improved further. On day 9, the patient was able to move the fourth and fifth fingers on his right hand for the first time in a year, and by day 11 he had regained control of these two fingers (\nMovie 2). On day 11, a repeat FEES examination confirmed that the patient’s dysphagia had resolved. On day 12, the patient was able to move all of the fingers on his right hand (\nMovie 3) and grasp objects with his left hand, and he could once again operate the mouse attached to his computer. Furthermore, the patient’s voice recognition software was able to interpret the speech of the patient for the first time in months. On day 14, it was possible to sample venous blood from the patient’s forearm for the first time since he was admitted to the hospital. On day 18, the patient’s motor function further improved (\nMovie 4).\n\nAt the end of day 21, physiological and FEES examinations revealed that swallowing function remained intact (\nMovie 5), and the patient reported that his breathing and sleep quality had improved markedly during the treatment course. Therefore, in accordance with the defined treatment protocol, the midline catheter was removed and the patient was discharged. Upon discharge, the patient’s speech was restored to nearly pre-ALS levels, and he had regained the ability to stand from his wheelchair and walk unaided. The patient had also regained control over his fingers and had regained the ability to grasp light objects. Overall muscle function and strength were also improved as evidenced by increased power in his arms and legs and his renewed ability to stand, walk, and bend at the waist. Furthermore, his respiratory function had improved. Lastly, the patient reported that his general muscle pain had regressed, and the pain in his shoulder muscles had resolved completely.\n\nAfter returning home, the patient continued to improve. On day 22 (the first day following the end of the treatment course), the patient was able to lie in a dentist’s chair for 40 minutes without muscle pain, which had not been possible prior to receiving the treatment, and the patient was able to complete the dental procedure. On day 25, the patient was able to walk unaided a distance of approximately 650 meters. During the follow-up period from day 25 through day 75, the patient had generally stabilized. During days 76 to 91 the patient experienced increasing muscle pain in the neck, shoulders, or back, he no longer could operate the mouse attached to his computer, his voice recognition software no longer was able to interpret his speech, his walking ability regressed to the point that he not even take a few steps, and the patient became wheelchair-bound again. His swallowing and speech remained functional.\n\nOn day 92, the patient was readmitted to the hospital and started on a second 21-day course of penicillin G and hydrocortisone (\nTable 1) delivered via midline catheter infusion. Physiological and FEES examination on day 92 revealed that swallowing function had remained stable relative to day 21. During the 2\nnd 21-day course (days 92 to 113), the patient reported that he was able to lie in bed without experiencing muscle pain in the neck, shoulders, or back, and that his walking ability had slightly improved. Furthermore, his speech and swallowing function had improved. During days 114 to 150 the patient remained wheelchair-bound. His regained finger movement, swallowing and speech remained functional.\n\nCase presentation: Patient 2\nA 51-year-old Caucasian male with ALS was admitted to the hospital with complaints of progressive swallowing and speech difficulties. One year earlier, this patient was diagnosed with bulbar-onset ALS and presented with symptoms typical of bulbar-onset ALS, including dysphagia and dysarthria. Over the previous year, the patient also developed other symptoms typical of ALS, including fasciculations, coordination problems, and muscle weakness. Furthermore, the patient experienced tremor-like movements when lying in bed and when getting up in the morning. These transient muscle tremors prevented the patient from standing and walking directly after getting out of bed. The patient also experienced bladder control problems for the previous two years, but tested negative for bladder infection. The patient had no history of syphilis or other systemic infection, and the diagnosis of ALS was confirmed by the Netherlands National ALS Center.\n\nIn the year preceding admission to the hospital, the patient’s speech had degenerated, and the patient had difficulty swallowing both solid food and liquids, including saliva, leading to the manifestation of a high frequency of coughing.\nFigure 3 shows the progression of symptoms and the effect of treatment in Patient 2. Dysphagia was confirmed by FEES examination at the time of admission (\nMovie 6), and speech impairment was confirmed by a speech therapist. Physical examination and laboratory blood analysis revealed no other clinical pathology and normal renal function; a test for syphilis was negative. The only prescription medication taken by the patient was Riluzole (100 mg/day).\n\nFigure 3. The clinical progression and effect of treatment in Patient 2.\nThe patient had no history of seizures and was therefore eligible to receive high doses of penicillin G. After confirming that the patient was not allergic to penicillin (as described for Patient 1), the patient was started on a 21-day course of penicillin G and hydrocortisone (\nTable 1) delivered via midline catheter infusion.\n\nOn the 4\nth treatment day, the frequency and severity of coughing had decreased markedly, and a slight improvement in speech was noted. Furthermore, bladder function had improved. On day 5, the patient’s speech further improved, and the patient had stopped coughing completely, indicating improved swallowing function. From day 6 onwards, swallowing and speech function were further improved, as confirmed by FEES examination (\nMovie 7) and evaluation by a speech therapist, both on day 20. Furthermore, respiratory function improved. On days 11–12, the patient’s blood pressure had increased, and the patient reported a severe headache, both of which resolved after starting treatment with a blood pressure medication (nifedipine). After the discontinuation of hydrocortisone on day 15, the patient no longer reported headache symptoms, and his blood pressure had normalized. On days 16 and 17, the patient reported slight muscle weakness in his legs, which resolved within a few days. At the end of day 21, the midline catheter was removed and the patient was discharged. During the follow-up period from day 21 through day 91, the patient had generally stabilized. On day 92, the patient was readmitted to the hospital. Physiological and FEES examination on day 92 revealed that swallowing function had remained stable relative to day 21. The patient was started on a second 21-day course of penicillin G and hydrocortisone (\nTable 1) delivered via midline catheter infusion. Because the observed blood pressure increase during the first course, the patient was administered 30 mg nifedipine retard once daily, starting from the first day of the 2\nnd treatment course. On the 2\nnd day of the 2\nnd 21-day course (day 93), the patient’s blood pressure had increased, which resolved after increasing the nifedipine dose to 90 mg daily. During the second 21-day course, and during the follow-up period from day 112 to 122, the patient remained stable.\n\nCase presentation: Patient 3\nA 65-year-old Caucasian male with ALS was admitted to the hospital with severely impaired swallowing and speech. One year earlier, this patient was diagnosed with bulbar-onset ALS and presented with symptoms typical of bulbar-onset ALS, including dysphagia and dysarthria. Over the course of the disease, the dysphagia had progressed to the level that the patient’s oral intake had become inadequate, and the patient was scheduled to undergo a percutaneous endoscopic gastrostomy (PEG). In the year prior to admission to the hospital, the patient’s speech also had become severely impaired, and the patient developed other symptoms typical of ALS, including coordination problems, muscle weakness, cramps and leg resting tremors. A few months before admission, the patient could no longer walk unaided and began using a walker. The patient had no history of syphilis or other systemic infection, and the diagnosis of ALS was confirmed by the Netherlands National ALS Center.\n\n\nFigure 4 shows this patient’s progression of symptoms and the effect of treatment. Dysphagia was confirmed by FEES examination at the time of admission (\nMovie 8), and the speech impairment was confirmed by a speech therapist. Physical examination and laboratory blood analysis revealed no other clinical pathology and normal renal function. The only prescription medication taken by the patient was losartan (100 mg/day) for high blood pressure.\n\nThe patient had no history of seizures and was therefore eligible to receive high doses of penicillin G. After confirming that the patient was not allergic to penicillin (as described for Patient 1), the patient was started on a 21-day course of penicillin G and hydrocortisone (\nTable 1) delivered via midline catheter infusion.\n\nFigure 4. The clinical progression and effect of treatment in Patient 3.\nOn the 3\nrd treatment day, the patient was able to drink a glass of water for the first time in months. On day 4, swallowing function improved further, and the patient was able to swallow solid food for the first time in months. Furthermore, the patient’s speech improved, his muscle stiffness has diminished, and he no longer experienced cramps or leg rest tremors. Over the following days, both swallowing and speech function continued to improve, as confirmed by FEES examination (\nMovie 9) and evaluation by a speech therapist. From day 7 onwards, the patient’s swallowing function continued to improve to the point that a PEG procedure was no longer necessary, and his speech further improved. On day 8, the patient reported increased muscle strength in arms and legs, and the patient’s walking ability had improved. Furthermore, his weight had increased with 3 kg, and his respiratory function improved. On day 9, the patient’s blood pressure had increased, and the patient reported a headache. He was therefore placed on blood pressure medication (nifedipine), and the hydrocortisone was discontinued on day 10 (rather than on day 14 as indicated in the protocol). After hydrocortisone was discontinued, the patient no longer reported headache symptoms, and blood pressure was normalized. On days 11 and 12, the patient reported slight muscle weakness in his legs, which resolved within a few days. At the end of day 21, the midline catheter was removed and the patient was discharged. During the follow-up period from day 21 through day 90, the patient had generally stabilized. On day 91, the patient was readmitted to the hospital and was started on a second 21-day course of penicillin G and hydrocortisone (\nTable 1) delivered via midline catheter infusion. Because the observed blood pressure increase during the first course, the patient was administered 30 mg nifedipine retard once daily. During the second 21-day course (days 91 to 112) the patient remained stable. \n\nDiscussion\nHere, we report that two 21-day courses of penicillin G and hydrocortisone treated symptoms typical of ALS in three patients with no history of syphilis. After only four days of treatment, Patient 1—who had been wheelchair-bound for four months—was able to walk unaided approximately 100 meters. In addition, this patient rapidly regained movement of his fingers and could grasp items with his left hand, functions that had been completely absent for eight months prior to treatment. Furthermore, the symptoms in Patient 2—who had experienced progressive dysarthria, dysphagia, and bladder dysfunction over the preceding year—also regressed during the first week of treatment. Lastly, in Patient 3—who presented with dysphagia so severe that PEG was indicated—both the dysphagia and dysarthria regressed during the first week of treatment.\n\nThe treatment protocol was generally well tolerated by all three patients. The only side effect observed in Patient 1 was slight, transient edema of the arm and hand at the site where the midline catheter was placed. Patient 2 experienced high blood pressure and a severe headache beginning on day 11; these symptoms can be attributed to the administration of hydrocortisone, and they resolved after the discontinuation of hydrocortisone. Similarly, patient 3 experienced high blood pressure on day 9, which resolved after the discontinuation of hydrocortisone on day 10. During the second course of treatment, the increase in blood pressure in these patients was effectively treated with nifedipine. These observations indicate that blood pressure should be monitored closely during the treatment protocol. Patients 2 and 3 experienced temporary muscle weakness in their legs in the days following the discontinuation of hydrocortisone. Because Patients 2 and 3 are not in the late stages of ALS disease, in which respiratory muscle function is often severely affected, the hydrocortisone withdrawal–induced temporary muscle weakness was well tolerated. However, in late-stage ALS, in which muscle function is often reduced to minimal functional levels, hydrocortisone withdrawal–induced muscle weakness may lead to serious side effects, including respiratory depression.\n\nThe absence of seizure activity in these patients—even on high-dose penicillin G—is consistent with our recent observation that seizures are often absent in patients with ALS\n11. In the treatment of syphilis, for which this treatment protocol was originally developed, increasing doses of penicillin G are given in order to minimize the risk of inducing a Jarisch-Herxheimer reaction. However, this titration of penicillin G is also recommended for use in ALS patients, as these patients may have impaired blood-brain barrier (BBB) function\n12,\n13, potentially resulting in high levels of penicillin G in the CSF, which could induce seizure activity. In this respect, including hydrocortisone in the treatment course may provide additional benefits, as hydrocortisone has been reported to maintain BBB integrity\n14.\n\nFour courses of the 21-day treatment protocol reported here was previously reported to be efficacious in treating six cases of so-called syphilitic ALS\n7,\n8. Syphilitic ALS is an intriguing clinical phenomenon, as it is the only form of ALS ever reported to have been cured\n9. Recently, we proposed that the successful treatment of ALS symptoms in these six patients with syphilitic ALS was not directly due to the treatment of syphilis; specifically, we proposed that the penicillin G and/or hydrocortisone treated these patients’ ALS symptoms due to the off-target pharmacological activity of penicillin G (e.g., as a GABA receptor antagonist) and/or the multifaceted pharmacological activity of hydrocortisone (e.g., as an immunosuppressant)\n9. This notion is supported by the three cases reported here, as our patients had no syphilis-related symptoms or history of syphilis.\n\nIt is important to note that either penicillin G or hydrocortisone—or both—contributed to the observed effects. Penicillin G is a GABA receptor antagonist\n15 that can reduce GABAergic overstimulation. At high doses, penicillin G can also affect other major bodily functions and/or systems, including the immune system, the cardiovascular system, metabolic function, renal function, liver function, the hematological system, and the urogenital system (penicillin G summary of product characteristics, see\nhttps://www.medicines.org.uk/emc/medicine/2962. Accessed July 27, 2016); these pharmacological activities may be associated with the clinical benefits reported here.\n\nHydrocortisone has immunomodulatory and anti-inflammatory properties (hydrocortisone summary of product characteristics.\nhttps://www.medicines.org.uk/emc/medicine/10815, accessed July 27, 2016, and hydrocortisone sodium succinate product monograph.\nhttps://www.drugs.com/monograph/hydrocortisone-sodium-succinate.html, accessed November 16, 2016); therefore, it may also affect systems involved in the pathogenesis of ALS, including the anti-inflammatory system\n1–\n3. Moreover, hydrocortisone has reported efficacy in treating multiple sclerosis and respiratory diseases (hydrocortisone summary of product characteristics.\nhttps://www.medicines.org.uk/emc/medicine/10815, accessed July 27, 2016), conditions that have clinical overlap with ALS. Furthermore, like penicillin G, hydrocortisone can affect several bodily functions and/or systems, including the endocrine system, the immune system, inflammatory function, the respiratory system, the hematological system, and the gastrointestinal system (hydrocortisone summary of product characteristics.\nhttps://www.medicines.org.uk/emc/medicine/10815, accessed July 27, 2016). Furthermore, glucocorticoids have been found to be efficacious in preclinical models of ALS\n16.\n\nOther explanations may account for the observations reported here. First, the patients may have improved due to a placebo effect. However, this may be deemed unlikely, as the full range of ALS symptoms resolved in these patients. Nevertheless, the possibility that the patients improved due to a placebo effect should be investigated in a clinical trial setting. Second, the patients may have been incorrectly diagnosed as having ALS and/or incorrectly diagnosed as not having neurosyphilis. However, this is also unlikely, given that Patient 2 tested negative for syphilis before starting treatment, and given that all three patients were diagnosed at a leading neurology center with extensive experience diagnosing both ALS and neurosyphilis. Furthermore, syphilis has an extremely low prevalence in the Netherlands (present in only 0.15% of the population)\n17, and the symptoms associated with ALS generally do not overlap with the symptoms associated with syphilis\n18. Third, it is possible that the patients’ ALS symptoms were caused by an infection other than syphilis, which was then treated by the penicillin and hydrocortisone. The possible presence of an unidentified infection—and its treatment with penicillin G—may explain the observation that the benefits of treatment remained even after treatment was discontinued. This is an interesting point, as the elimination half-life of penicillin G and hydrocortisone is 0.5–1.0 hour (penicillin G summary of product characteristics, see\nhttps://www.medicines.org.uk/emc/medicine/2962, accessed July 27, 2016) and 1.5–3.5 hours (hydrocortisone sodium succinate product monograph.\nhttps://www.drugs.com/monograph/hydrocortisone-sodium-succinate.html, accessed November 16), 2016, respectively; thus, both compounds would have been cleared from the body within hours after treatment was discontinued. Nevertheless, given the apparent absence of infection in all three patients, we believe that the post-treatment effects were due to the treatment’s effects on ALS rather than its antibacterial activity. Finally, it is formally possible that Patient 2 may have improved because of the concomitant administration of Riluzole. However, this is unlikely, as this patient’s symptoms had been progressing steadily since he was first diagnosed with ALS, and he was on Riluzole since he was diagnosed. Moreover, this patient began to improve only after he started on the penicillin and hydrocortisone protocol.\n\nConclusions\nThis is the first report of a treatment with a protocol for treating dysphagia, dysarthria, and other ALS-related symptoms using a 21-day course of penicillin G and hydrocortisone in three patients with ALS and no history or symptoms of syphilis. This is an important clinical observation, as no treatment is currently available for dysphagia, dysarthria, or ALS. Furthermore, the findings support the recent hypothesis that the successful treatment of ALS symptoms with this treatment course in six patients with syphilitic ALS was not directly due to the treatment of syphilis; but that the administered penicillin G and/or hydrocortisone treated these patients’ ALS symptoms due the off-target pharmacological activity of penicillin G and/or hydrocortisone. In view of the devastating, rapidly progressive nature of ALS, this treatment protocol should be evaluated further in a clinical trial.\n\nConsent\nWritten informed consent for publication was obtained from the patients. The requirement for ethical approval was waived by the Medical Ethics Review Committee of the Academic Medical Center. Patients were treated according to guidelines of the Royal Dutch Medical Association (KNMG) for off-label prescribing (see\nhttps://protect-eu.mimecast.com/s/DdxhBlJkYHQ). Medication was administered under supervision of E.W.J. Wielinga, M.D., Ph.D., consultant ENT-surgeon, who also validated the results regarding swallowing and speech.\n\nAcknowledgments\nThe authors wish to thank Jent Zijlstra, Marc ter Haar, Mikkel Hofstee, and Nico Zandman for their support and critical review of the manuscript.\n\nThe authors also thank SEVBI, a Dutch foundation that promotes the effective use of medications outside of their registered indication, for providing EUR 800 for the cost of making this publication open-access.\n\nSupplementary material\nMovie 1: FEES in Patient 1 prior to the start of the treatment, showing impaired swallowing function while attempting to swallow two pieces of bread.\n\n\nClick here for additional data file.\n\n .\n\nMovie 2: On day 11, Patient 1 had regained movement of the fourth and fifth fingers on his right hand.\n\n\nClick here for additional data file.\n\n .\n\nMovie 3: On day 12, Patient 1 had regained movement of all four fingers on his right hand.\n\n\nClick here for additional data file.\n\n .\n\nMovie 4: On day 18, Patient 1 could grasp objects.\n\n\nClick here for additional data file.\n\n .\n\nMovie 5: FEES in Patient 1 on day 21, showing restored swallowing function. Note that the patient fully swallowed the piece of bread, and the patient could swallow faster than on day 0 (compare with\nMovie 1).\n\n\nClick here for additional data file.\n\n .\n\nMovie 6: FEES in Patient 2 prior to the start of the treatment, showing impaired swallowing function while attempting to swallow two pieces of bread. Note that residue of bread is still present in the vallecula after 4 attempts of swallowing.\n\n\nClick here for additional data file.\n\n .\n\nMovie 7: FEES in Patient 2 on day 20, showing improved swallowing function. After swallowing a piece of bread in one time, no residue can be discerned in the vallecula (compare with\nMovie 6).\n\n\nClick here for additional data file.\n\n .\n\nMovie 8: FEES in Patient 3 prior to the start of the treatment showing that drinking water was impossible without chocking and coughing.\n\n\nClick here for additional data file.\n\n .\n\nMovie 9: FEES in Patient 3 on day 16, showing functional swallowing of a piece of bread (compare with\nMovie 8).\n\n\nClick here for additional data file.\n\n .\n\n10.5256/f1000research.11352.r21581Referee response for version 1 Gill Alan 1RefereeVieira Fernando G. 1Co-refereehttp://orcid.org/0000-0003-2996-6418\n1 ALS Therapy Development Institute, Cambridge, MA, USA\nCompeting interests: No competing interests were disclosed.\n\n5 4 2017 Version 1recommendationapproveInterpreting any therapeutic benefit of Penicillin G plus hydrocortisone on ALS symptom severity and progression does require a careful examination of drug effects that occur outside of the intended general GABA receptor antagonism and anti-inflammatory actions, as well as the effects of additional drugs the patients take, including those needed to offset untoward effects of the primary treatment, e.g., nifedipine. Plasma volume expansion by hydrocortisone might be expected to make venous blood sampling easier, but also to increase blood pressure to levels that need attention. While direct vasodilation by nifedipine increased the size of the circulation’s container enough to permit blood pressure to normalize, both nifedipine and hydrocortisone soon promote additional plasma volume expansion to fill the larger container. The authors do carefully document the application of all drugs in a way that permits therapists to anticipate managing these side-effects.\n\n The authors provide solid safety recommendations about dosing with both the Penicillin G and with the hydrocortisone. These recommendations would be important even without the potential for blood brain barrier leakiness and for adrenal dysregulation that can occur in ALS in order to prevent seizures and unexpected responses by the pituitary-adrenal axis. The authors formally recognize and take these potential risks into account.\n\n We do believe that the apparent therapeutic benefit of treatment shown by patients in the current report is interesting at face value. However, if the objective of the report is to convince ALS clinicians and patients to consider trying this off-label therapeutic approach, then the manuscript would be better served to include typical ALS endpoint data, e.g., ALS FRS scores, forced vital capacity (or slow vital capacity) measurements, and patient body weight, alongside the clinical description and videos. While ALS FRS is subjective, it is familiar to neurologists and patients and could provide important context for the magnitude of benefit observed. FVC/SVC and body weights are more objective measures that would provide indications about the patients’ well-being, although body weights would be influenced in a potentially confounding way by the hydrocortisone during, but perhaps not after, treatment. All of these endpoints are standard in ALS clinics, both in the United States and in Europe.\n\n One can hope that careful clinical testing of the current regimen might encourage efforts to try to identify an even safer, more predictable, therapeutic regimen than PENG/hydrocortisone itself. Such efforts might try to understand which inhibitory interneuron networks require interventions and which do not, and which specific antagonist (or agonist) drugs would optimize our test of the hypothesis. Can specific peptide neuromodulators contribute to improving the regimen? These considerations do not preclude the importance of carefully testing the PENG/hydrocortisone regimen itself. The complexity of this task alone is significant. Refinements of the regimen only add complexity, but could lead to more predictable, safer, and even more effective ALS treatment.\n\nWe have read this submission. We believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.5256/f1000research.11352.r21563Referee response for version 1 Vermeulen Rien 1Referee\n1 Academic Medical Center, Amsterdam, Netherlands\nCompeting interests: No competing interests were disclosed.\n\n5 4 2017 Version 1recommendationapproveThis is a remarkable report on three patients with ALS who improved after treatment with penicillin G and hydrocortisone. This treatment was based on the observed beneficial effects of this treatment in patients with ALS and syphilis. The authors hypothesize, this effect of treatment is a result of reduction of GABAergic overstimulation by penicillin G.\n\n However, all too often neurologists have seen astonishing improvements in uncontrolled studies. Therefore this treatment should be tested in a randomized controlled trial. Before embarking on a large scale trial, I would like to suggest to start with a small efficacy study in patients with ALS in whom the respiratory function is decreasing. The primary outcome in this trial could be the maximal inspiratory pressure which is a well known surrogate marker for disease progression in patients with ALS. In trials in patients with ALS few placebo-effects have been observed, which means that a quick answer is possible to the question whether or not this treatment improves respiratory function. Moreover, there are no safety issue in such a study.\n\n Clinicians owe to their patients with this devastating disease to test the effects of this treatment with high priority, since there are presently no other promising therapies.\n\nI have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n==== Refs\n1 \nKiernan MC Vucic S Cheah BC :\nAmyotrophic lateral sclerosis. \nLancet. \n2011 ;377 (9769 ):942 –55 .\n10.1016/S0140-6736(10)61156-7 \n21296405 \n2 \nSilani V Messina S Poletti B :\nThe diagnosis of Amyotrophic lateral sclerosis in 2010. \nArch Ital Biol. \n2011 ;149 (1 ):5 –27 .\n10.4449/aib.v149i1.1260 \n21412713 \n3 \nTurner MR Hardiman O Benatar M :\nControversies and priorities in amyotrophic lateral sclerosis. \nLancet Neurol. \n2013 ;12 (3 ):310 –22 .\n10.1016/S1474-4422(13)70036-X \n\n23415570 \n4 \nObermann M Lyon M :\nFinancial cost of amyotrophic lateral sclerosis: a case study. \nAmyotroph Lateral Scler Frontotemporal Degener. \n2015 ;16 (1–2 ):54 –7 .\n10.3109/21678421.2014.951946 \n25245119 \n5 \nTjaden K :\nSpeech and Swallowing in Parkinson’s Disease. \nTop Geriatr Rehabil. \n2008 ;24 (2 ):115 –126 .\n10.1097/01.TGR.0000318899.87690.44 \n\n19946386 \n6 \nKalia M :\nDysphagia and aspiration pneumonia in patients with Alzheimer's disease. \nMetabolism. \n2003 ;52 (10 Suppl 2 ):36 –8 .\n10.1016/S0026-0495(03)00300-7 \n14577062 \n7 \nel Alaoui-Faris M Medejel A al Zemmouri K :\n[Amyotrophic lateral sclerosis syndrome of syphilitic origin. 5 cases]. \nRev Neurol (Paris). \n1990 ;146 (1 ):41 –4 .\n2408129 \n8 \nChraa M Mebrouk Y McCaughey C :\nAmyotrophic lateral sclerosis mimic syndrome due to neurosyphilis. \nAmyotroph Lateral Scler Frontotemporal Degener. \n2013 ;14 (3 ):234 .\n10.3109/17482968.2012.727425 \n23020664 \n9 \nTuk B :\nSyphilis may be a confounding factor, not a causative agent, in syphilitic ALS [version 1; referees: 2 approved]. \nF1000Res. \n2016 ;5 :1904 .\n10.12688/f1000research.9318.1 \n\n27830059 \n10 \nNacci A Ursino F La Vela R :\nFiberoptic endoscopic evaluation of swallowing (FEES): proposal for informed consent. \nActa Otorhinolaryngol Ital. \n2008 ;28 (4 ):206 –11 .\n\n18939710 \n11 \nTuk B :\nOverstimulation of the inhibitory nervous system plays a role in the pathogenesis of neuromuscular and neurological diseases: a novel hypothesis [version 2; referees: 2 approved]. \nF1000Res. \n2016 ;5 :1435 .\n10.12688/f1000research.8774.2 \n\n27547379 \n12 \nGarbuzova-Davis S Rodrigues MC Hernandez-Ontiveros DG :\nAmyotrophic lateral sclerosis: a neurovascular disease. \nBrain Res. \n2011 ;1398 :113 –25 .\n10.1016/j.brainres.2011.04.049 \n21632035 \n13 \nEvans MC Couch Y Sibson N :\nInflammation and neurovascular changes in amyotrophic lateral sclerosis. \nMol Cell Neurosci. \n2013 ;53 :34 –41 .\n10.1016/j.mcn.2012.10.008 \n23110760 \n14 \nGaillard PJ van Der Meide PH de Boer AG :\nGlucocorticoid and type 1 interferon interactions at the blood-brain barrier: relevance for drug therapies for multiple sclerosis. \nNeuroreport. \n2001 ;12 (10 ):2189 –93 .\n11447332 \n15 \nRossokhin AV Sharonova IN Bukanova JV :\nBlock of GABA\nA receptor ion channel by penicillin: electrophysiological and modeling insights toward the mechanism. \nMol Cell Neurosci. \n2014 ;63 :72 –82 .\n10.1016/j.mcn.2014.10.001 \n25305478 \n16 \nEvans MC Gaillard PJ de Boer M :\nCNS-targeted glucocorticoid reduces pathology in mouse model of amyotrophic lateral sclerosis. \nActa Neuropathol Commun. \n2014 ;2 :66 .\n10.1186/2051-5960-2-66 \n\n24923195 \n17 \nVan der Ploeg CP van der Pal SM Oomen P :\nProcesmonitoring prenatale screening infectieziekten en erytrocytenimmunisatie 2007–2009. RIVM. Accessed November 1,2016 \nReference Source\n\n18 \nSingh AE Romanowski B :\nSyphilis: Review with Emphasis on Clinical, Epidemiologic, and Some Biologic Features. \nClin Microbiol Rev. \n1999 ;12 (2 ):187 –209 .\n\n10194456\n\n",
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"keywords": "Amyotrophic lateral sclerosis; GABA; dysarthria; dysphagia; hydrocortisone; neuromuscular disease; penicillin G; respiratory depression",
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"pubdate": "2017",
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"title": "Treatment with penicillin G and hydrocortisone reduces ALS-associated symptoms: a case series of three patients.",
"title_normalized": "treatment with penicillin g and hydrocortisone reduces als associated symptoms a case series of three patients"
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"abstract": "Management of pediatric post-transplantation lymphoproliferative disorder (PTLD) after hematopoietic stem cell (HSCT) and solid organ transplantation (SOT) is challenging.\n\n\n\nThis study of 34 PTLD patients up to 19-years old diagnosed in Austria from 2000 to 2018 aimed at assessing initial characteristics, therapy, response, and outcome as well as prognostic markers of this rare pediatric disease.\n\n\n\nA retrospective data analysis was performed. Types of allografts were kidney (n = 12), liver (n = 7), heart (n = 5), hematopoietic stem cells (n = 4), lungs (n = 2), multi-visceral (n = 2), small intestine (n = 1), and vessels (n = 1). Eighteen/34 were classified as monomorphic PTLD, with DLBCL accounting for 15 cases. Polymorphic disease occurred in nine, and non-destructive lesions in six cases. One patient had a non-classifiable PTLD. Thirteen/34 patients are surviving event-free in first remission (non-destructive, n = 4/6; polymorphic, n = 4/9; monomorphic, n = 6/18). Fourteen/34 patients lacked complete response to first-line therapy, of whom seven died. Four/34 patients relapsed, of whom two died. In 3/34 patients, death occurred as a first event. The 5-year overall and event-free survival rates were 64% ± 9% and 35% ± 9% for the whole cohort. Among all parameters analyzed, only malignant disease as the indication for transplantation had a significantly poor influence on survival.\n\n\n\nThis study shows PTLD still to be a major cause of mortality following SOT or HSCT in children. A continued understanding of the molecular biology of the disease shall allow to decrease treatment intensity for lower risk patients and to identify patients who may benefit from newer therapy approaches to improve outcome and decrease morbidity.",
"affiliations": "Department of Pediatric Hematology and Oncology, St. Anna Children's Hospital, Vienna, Austria.;Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Innsbruck, Innsbruck, Austria.;Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria.;Department of Pediatric Hematology and Oncology, St. Anna Children's Hospital, Vienna, Austria.;Division of Pediatric Cardiology, Department of Pediatrics and Adolescent Medicine, Pediatric Heart Center, Medical University of Vienna, Vienna, Austria.;Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.;Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria.;Department of Pediatric Hematology and Oncology, St. Anna Children's Hospital, Vienna, Austria.;Department of Pediatric Hematology and Oncology, St. Anna Children's Hospital, Vienna, Austria.;Division of Pediatric Cardiology, Department of Pediatrics and Adolescent Medicine, Pediatric Heart Center, Medical University of Vienna, Vienna, Austria.;Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.;Department of Pediatric Hematology and Oncology, St. Anna Children's Hospital, Vienna, Austria.;Department of Pathology, Medical University of Vienna, Vienna, Austria.;Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria.;Division of Pediatric Pulmonology, Allergy and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center Pediatrics, Medical University of Vienna, Vienna, Austria.;Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Innsbruck, Innsbruck, Austria.;Department of Pediatric Hematology and Oncology, St. Anna Children's Hospital, Vienna, Austria.",
"authors": "Füreder|Anna|A|;Kropshofer|Gabriele|G|;Benesch|Martin|M|0000-0001-7827-4130;Dworzak|Michael|M|;Greil|Sabine|S|;Huber|Wolf-Dietrich|WD|;Hubmann|Holger|H|;Lawitschka|Anita|A|;Mann|Georg|G|;Michel-Behnke|Ina|I|;Müller-Sacherer|Thomas|T|;Pichler|Herbert|H|;Simonitsch-Klupp|Ingrid|I|;Schwinger|Wolfgang|W|;Szepfalusi|Zsolt|Z|;Crazzolara|Roman|R|;Attarbaschi|Andishe|A|0000-0002-9285-6898;|||",
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"doi": "10.1002/cnr2.1375",
"fulltext": "\n==== Front\nCancer Rep (Hoboken)\nCancer Rep (Hoboken)\n10.1002/(ISSN)2573-8348\nCNR2\nCancer Reports\n2573-8348\nJohn Wiley and Sons Inc. Hoboken\n\n33755341\n10.1002/cnr2.1375\nCNR21375\nOriginal Article\nOriginal Articles\nCharacteristics, management, and outcome of pediatric patients with post‐transplant lymphoproliferative disease—A 20 years' experience from Austria\nFüreder et al.\nFüreder Anna 1 5\nKropshofer Gabriele 2\nBenesch Martin https://orcid.org/0000-0001-7827-4130\n3\nDworzak Michael 1 5\nGreil Sabine 4\nHuber Wolf‐Dietrich 5\nHubmann Holger 6\nLawitschka Anita 1 5\nMann Georg 1\nMichel‐Behnke Ina 4\nMüller‐Sacherer Thomas 5\nPichler Herbert 1 5\nSimonitsch‐Klupp Ingrid 7\nSchwinger Wolfgang 3\nSzepfalusi Zsolt 8\nCrazzolara Roman 2 roman.crazzolara@i-med.ac.at\n\nAttarbaschi Andishe https://orcid.org/0000-0002-9285-6898\n1 5 andishe.attarbaschi@stanna.at\n\nAustrian Society of Pediatric Hematology and Oncology\n1 Department of Pediatric Hematology and Oncology St. Anna Children's Hospital Vienna Austria\n2 Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine Medical University of Innsbruck Innsbruck Austria\n3 Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine Medical University of Graz Graz Austria\n4 Division of Pediatric Cardiology, Department of Pediatrics and Adolescent Medicine, Pediatric Heart Center Medical University of Vienna Vienna Austria\n5 Department of Pediatrics and Adolescent Medicine Medical University of Vienna Vienna Austria\n6 Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine Medical University of Graz Graz Austria\n7 Department of Pathology Medical University of Vienna Vienna Austria\n8 Division of Pediatric Pulmonology, Allergy and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center Pediatrics Medical University of Vienna Vienna Austria\n* Correspondence\nRoman Crazzolara, Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.\nEmail: roman.crazzolara@i-med.ac.at\nAndishe Attarbaschi, Department of Pediatric Hematology and Oncology, St. Anna Children's Hospital, Kinderspitalgasse 6, 1090 Vienna, Austria.\nEmail: andishe.attarbaschi@stanna.at\n\n23 3 2021\n10 2021\n4 5 10.1002/cnr2.v4.5 e137502 3 2021\n14 12 2020\n© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.\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\nBackground\n\nManagement of pediatric post‐transplantation lymphoproliferative disorder (PTLD) after hematopoietic stem cell (HSCT) and solid organ transplantation (SOT) is challenging.\n\nAim\n\nThis study of 34 PTLD patients up to 19‐years old diagnosed in Austria from 2000 to 2018 aimed at assessing initial characteristics, therapy, response, and outcome as well as prognostic markers of this rare pediatric disease.\n\nMethods and results\n\nA retrospective data analysis was performed. Types of allografts were kidney (n = 12), liver (n = 7), heart (n = 5), hematopoietic stem cells (n = 4), lungs (n = 2), multi‐visceral (n = 2), small intestine (n = 1), and vessels (n = 1). Eighteen/34 were classified as monomorphic PTLD, with DLBCL accounting for 15 cases. Polymorphic disease occurred in nine, and non‐destructive lesions in six cases. One patient had a non‐classifiable PTLD. Thirteen/34 patients are surviving event‐free in first remission (non‐destructive, n = 4/6; polymorphic, n = 4/9; monomorphic, n = 6/18). Fourteen/34 patients lacked complete response to first‐line therapy, of whom seven died. Four/34 patients relapsed, of whom two died. In 3/34 patients, death occurred as a first event. The 5‐year overall and event‐free survival rates were 64% ± 9% and 35% ± 9% for the whole cohort. Among all parameters analyzed, only malignant disease as the indication for transplantation had a significantly poor influence on survival.\n\nConclusions\n\nThis study shows PTLD still to be a major cause of mortality following SOT or HSCT in children. A continued understanding of the molecular biology of the disease shall allow to decrease treatment intensity for lower risk patients and to identify patients who may benefit from newer therapy approaches to improve outcome and decrease morbidity.\n\nhematopoietic stem cell transplantation\noutcome\npost‐transplant lymphoproliferative disease\nsolid organ transplantation\ntreatment\nsource-schema-version-number2.0\ncover-dateOctober 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.8 mode:remove_FC converted:28.10.2021\nFüreder A , Kropshofer G , Benesch M , et al. Characteristics, management, and outcome of pediatric patients with post‐transplant lymphoproliferative disease—A 20 years' experience from Austria. Cancer Reports. 2021;4 :e1375. 10.1002/cnr2.1375\n\nAnna Füreder and Gabriele Kropshofer are co‐first authors.\n==== Body\npmcAbbreviations\n\nBM bone marrow\n\nB‐NHL B‐cell non‐Hodgkin lymphoma\n\nCCR continuous complete remission\n\nCHOP cyclophosphamide, doxorubicin, vincristine, and prednisolone\n\nCNS central nervous system\n\nCR complete remission\n\nCSF cerebrospinal fluid\n\nDLBCL diffuse large B‐cell lymphoma\n\nEBER EBV‐encoded RNA\n\nEBV Epstein‐Barr virus\n\nEFS event‐free survival\n\nEPOCH etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin\n\nGIT gastrointestinal tract\n\nHLA human leukocyte antigen\n\nHSCT hematopoietic stem cell transplantation\n\nIPNHLSS International Pediatric Non‐Hodgkin Lymphoma Staging System\n\nLDH lactate dehydrogenase\n\nLPD lymphoproliferative disease\n\nm‐COMP modified ‐ cyclophosphamide, vincristine, methotrexate, and prednisolone\n\nNK‐cells natural killer cells\n\nOS overall survival\n\nPB peripheral blood\n\nPCR polymerase chain reaction\n\nPD progressive disease\n\nPH plasmacytic hyperplasia\n\nPR partial remission\n\nPTLD post‐transplant lymphoproliferative disease\n\nR‐CHOP rituximab‐cyclophosphamide, doxorubicin, vincristine, and prednisolone\n\nRIS reduction of immunosuppression\n\nSD stable disease\n\nSOT solid organ transplantation\n\nWHO World Health Organization\n\n1 INTRODUCTION\n\nIn transplantation medicine prevention and treatment of graft rejection is the primary aim of immunosuppressive medication. Besides this, iatrogenic immunosuppression is accompanied by serious side effects, such as an increased infection susceptibility and a higher risk of developing malignancies due to reduced tumor surveillance. 1 The latter can result in post‐transplant lymphoproliferative disease (PTLD), which is a heterogeneous disorder ranging from benign hyperplasia to malignant lymphomas. 2 , 3 , 4\n\nIn pediatric patients, PTLD represents the most frequent type of malignant diseases secondary to solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT), with the overall risk of developing malignancies being 45‐fold higher than in healthy individuals. 5 , 6 , 7 Epstein‐Barr virus (EBV) infection is detected in most cases of pediatric PTLD. 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 Whereas >90% of the world's adult population already harbor EBV, the infestation rate is comparatively low in children. 16 , 17 Transplantation of grafts from EBV‐seropositive adults results in primary EBV infection of children, thereby explaining a 2‐ to 4‐fold higher risk of PTLD in children compared to adults. 5 , 15 , 18 , 19 , 20 Reflecting the age‐dependent seroprevalence rates, EBV‐positivity occurs in only 50% of adult as compared to 85%‐90% of pediatric PTLD. 15 , 16 , 19 , 21 , 22 , 23 Notably, pediatric EBV‐negative PTLD typically develops late, that is, >1 year after transplantation. 4 , 8 , 11 , 16 , 24\n\nThe World Health Organization (WHO) classification system differentiates between (i) non‐destructive, benign forms, showing polyclonal cell populations only, (ii) polymorphic subtypes, which can present with either polyclonal or monoclonal proliferation patterns, and (iii) monomorphic, monoclonal subtypes, which are genuine malignant lymphomas, mostly of B‐ and, less frequently, of T‐ or NK‐cell origin. 8 , 9\n\nThe incidence of lymphoproliferative diseases (LPD) following transplantations varies between 1% and 30%, depending on the presence of risk factors, 25 , 26 the most important of which are a mismatched EBV serostatus between recipient and donor, 8 , 10 , 11 , 27 , 28 a high‐intensity immunosuppressive regimen, 3 , 11 , 12 , 19 , 29 and the type of allograft. The highest risk for PTLD after SOT results from having an EBV‐positive organ donor and an EBV‐naïve recipient. For PTLD following HSCT, a converse serological EBV constellation of donor and recipient is an established risk factor. Transplantation of intestine or lungs poses the highest risk for PTLD (20%), 12 , 26 , 30 , 31 , 32 followed by cardiac or liver (2%‐10%), 29 , 33 , 34 and kidney transplantations (1%‐4%). 5 , 19 , 29 , 35 , 36 HSCT shows an incidence of 1%‐8%, likewise depending on a range of risk factors, such as transplantation of T‐cell depleted bone marrow (BM) or HLA‐mismatched grafts from unrelated donors, as well as the use of anti‐thymocyte globulin. 37 , 38 , 39 , 40 Concerning the latency period after transplantation, LPDs can be grouped into early‐ and late‐onset diseases, referring to cases within and later than the first year after transplantation. 25\n\nHerein, we describe 34 SOT and HSCT patients with PTLD diagnosed in Austria within a period of nearly 20 years.\n\n2 PATIENTS AND METHODS\n\n2.1 Patients\n\nPatients had to fulfill three inclusion criteria to be enrolled into this retrospective study: (i) diagnosis of PTLD as established by a reference pathologist according to the WHO classification valid at the time of diagnosis, (ii) diagnosis and treatment of PTLD between 2000 and 2018, and (iii) treatment of PTLD carried out at one of the four participating Austrian centers offering performance and aftercare of SOT and/or HSCT. Thirty‐four patients aged <19 years meeting the inclusion criteria were identified and, hence, included in our study.\n\n3 METHODS\n\nClassification of PTLD was based on histopathology according to the contemporary WHO classification system. 41 , 42 EBV‐association was defined by a positive in‐situ hybridization test of EBV‐encoded RNA (EBER) in the tissue(s) analyzed. Patient data included demographics and information on disease, treatment, response, and outcome. Serum analysis was performed to detect EBV in peripheral blood. In dependence of the laboratory, to which the samples were submitted, the threshold for EBV positivity was either ≥5 or ≥ 100 copies/ml. Tumor stage was retrospectively defined according to the International Pediatric Non‐Hodgkin Lymphoma Staging System (IPNHLSS) whenever possible. 43 , 44 Evaluation of response was documented at the end of each therapy line (complete remission, CR; partial remission, PR; stable disease, SD; progressive disease, PD). Accordingly, two subgroups were defined: (i) patients with complete response, including patients with CR at the end of a respective therapy line, and (ii) patients who lacked complete response, including all patients with PR, SD, and PD. Due to the lack of standardized imaging procedures used throughout the therapy and the retrospective nature of our study, our data on response were based on the results documented by the local treating physicians. Fatalities were classified as either (i) PTLD‐related, (ii) therapy of PTLD‐related, or (iii) PTLD‐unrelated deaths.\n\nAll patients were treated after informed consent from the patient, patient's parents or legal guardians had been obtained.\n\n3.1 Statistical analysis\n\nEvent‐free survival (EFS) was calculated from the date of diagnosis to the date of first event. Events considered were lacking complete response at the end of a therapy line, relapse, or death, whichever occurred first. Overall survival (OS) was defined as the time from diagnosis to death from any cause or the date of last follow‐up. EFS and OS were estimated according to the Kaplan‐Meier method; differences between groups were evaluated with the log‐rank test. P‐values ≤0.05 were considered statistically significant.\n\n4 RESULTS\n\n4.1 Initial characteristics\n\nDemographics, histopathological results and EBV‐status are shown in Tables 1 and 2. Among the 34 PTLD patients analyzed, median age was 8.78 years and the male‐to‐female ratio 1:1. Types of allografts were kidney (n = 12), liver (n = 7), heart (n = 5), hematopoietic stem cells (n = 4), lung (n = 2), multi‐visceral (n = 2), small intestine (n = 1), and vessels (n = 1). All patients received one or more immunosuppressive drugs at the time of PTLD onset with 24 receiving ≥2 immunosuppressive drugs.\n\nTABLE 1 Clinical and laboratory characteristics of the 34 patients with PTLD according to the histological subtype\n\n\tNon‐destructive PTLD\tPolymorphic PTLD\tMonomorphic PTLD\tNot classifiable PTLD\t∑\t\nNo. of patients\t6 (18%)\t9 (26%)\t18 (53%)\t1 (3%)\t34\t\nGender\t\t\t\t\t\t\nfemale\t2 (33%)\t5 (56%)\t10 (56%)\t0\t17 (50%)\t\nmale\t4 (67%)\t4 (44%)\t8 (44%)\t1\t17 (50%)\t\nCondition leading to Tx\t\t\t\t\t\t\nmalignant\t0\t0\t3 (17%)\t0\t3 (9%)\t\nnon‐malignant, congenital\t4 (67%)\t5 (56%)\t13 (72%)\t0\t22 (64%)\t\nnon‐malignant, acquired\t2 (33%)\t4 (44%)\t2 (11%)\t1\t9 (27%)\t\nOrgan Tx\t\t\t\t\t\t\nliver a\t3 (50%)\t1 (11%)\t3 (17%)\t0\t7 (21%)\t\nheart\t0\t3 (33%)\t2 (11%)\t0\t5 (15%)\t\nlung\t0\t0\t2 (11%)\t0\t2 (6%)\t\nkidney\t2 (33%)\t3 (33%)\t7 (39%)\t0\t12 (35%)\t\nHSCT\t0\t0\t3 (17%)\t1\t4 (12%)\t\nother\t1 (17%)\t2 (22%)\t1 (5%)\t0\t4 (12%)\t\nTime from Tx to PTLD\t\t\t\t\t\t\nmedian (years)\t1.23\t1.04\t0.63\t/\t0.65\t\nrange (years)\t0.35‐2.56\t0.19‐12.56\t0.06‐11.68\t/\t0.06‐12.56\t\n<1 year\t3 (50%)\t4 (44%)\t11 (61%)\t1\t19 (56%)\t\n≥1 year\t3 (50%)\t5 (56%)\t7 (39%)\t0\t15 (44%)\t\nAge at PTLD onset\t\t\t\t\t\t\nmedian\t3.04\t5.1\t11.69\t/\t8.78\t\nrange\t0.88‐16.63\t2.52‐16.45\t3.07‐21.81\t/\t0.88‐21.81\t\n<10 years\t4 (67%)\t6 (67%)\t9 (50%)\t0\t19 (56%)\t\n≥10 years\t2 (33%)\t3 (33%)\t9 (50%)\t1\t15 (44%)\t\nImmunsuppression at onset of PTLD\t\t\t\t\t\t\ntacrolimus\t6 (100%)\t8 (89%)\t12 (67%)\t0\t26 (77%)\t\nprednisolone\t3 (50%)\t4 (44%)\t11 (61%)\t0\t18 (53%)\t\nmycophenolate mofetil\t2 (33%)\t5 (56%)\t9 (50%)\t0\t16 (47%)\t\ncyclosporin A\t0\t1 (11%)\t5 (28%)\t1\t7 (21%)\t\nother\t1 (17%)\t2 (22%)\t2 (11%)\t0\t5 (15%)\t\n1 drug\t3 (50%)\t1 (11%)\t5 (28%)\t1\t10 (29%)\t\n≥2 drugs\t3 (50%)\t8 (89%)\t13 (72%)\t0\t24 (71%)\t\nB‐Symptoms\t3 (50%)\t5 (56%)\t4 (22%)\t1\t13 (38%)\t\nPre‐therapeutic LDH level\t\t\t\t\t\t\n≥500 U/L\t4 (67%)\t7 (78%)\t13 (72%)\t1\t25 (74%)\t\n<500 U/L\t2 (33%)\t2 (22%)\t5 (28%)\t0\t9 (26%)\t\nAbbreviations: No., number; Tx, transplantation; LDH; lactate dehydrogenase; PTLD, post‐transplant lymphoproliferative disease.\n\na There was one patient included who developed the PTLD after liver transplantation, but had also undergone a previous kidney transplantation.\n\nTABLE 2 Immunohistochemistry, EBV‐status, and site/stage of disease of the 34 patients with PTLD according to the histological subtype\n\n\tNon‐destructive PTLD\tPolymorphic PTLD\tMonomorphic PTLD\tNot classifiable PTLD\t∑\t\nNo. of patients\t6 (18%)\t9 (27%)\t18 (53%)\t1 (3%)\t34\t\nCD20‐expression\t\t\t\t\t\t\npositive\t4 (67%)\t8 (89%)\t15 (83%)\t1\t28 (82%)\t\nnegative\t2 (33%)\t1 (11%)\t3 (17%)\t0\t6 (18%)\t\nEBER status of samples\t\t\t\t\t\t\nEBER‐positive\t4 (67%)\t9 (100%)\t16 (89%)\t1\t30 (88%)\t\nEBER‐negative\t2 (33%)\t0\t2 (11%)\t0\t4 (12%)\t\nEBV‐PCR results of PB\t\t\t\t\t\t\npositive\t5 (83%)\t9 (100%)\t15 (83%)\t1\t30 (88%)\t\nnegative\t1 (17%)\t0\t1 (6%)\t0\t2 (6%)\t\nnot available\t0\t0\t2 (11%)\t0\t2 (6%)\t\n<10.000 copies/ml\t4 (66%)\t4 (44%)\t8 (44%)\t0\t16 (47%)\t\n≥10.000 copies/ml\t1 (17%)\t5 (56%)\t7 (39%)\t1\t14 (41%)\t\nnot available\t1 (17%)\t0\t3 (17%)\t0\t4 (12%)\t\n<100.000 copies/ml\t4 (66%)\t6 (67%)\t11 (61%)\t0\t21 (62%)\t\n≥100.000 copies/ml\t1 (17%)\t3 (33%)\t4 (22%)\t1\t9 (26%)\t\nnot available\t1 (17%)\t0\t3 (17%)\t0\t4 (12%)\t\nStage of disease\t\t\t\t\t\t\nI\t0\t0\t0\t0\t0\t\nII\t1 (17%)\t0\t1 (5%)\t0\t2 (6%)\t\nIII\t1 (17%)\t2 (22%)\t5 (28%)\t0\t8 (24%)\t\nIV/Burkitt leukemia\t0\t1 (11%)\t5 (28%)\t0\t6 (18%)\t\nnot available\t4 (66%)\t6 (67%)\t7 (39%)\t1\t18 (53%)\t\nSite of involvement\t\t\t\t\t\t\nsingle site\t0\t0\t1 (6%)\t0\t1 (3%)\t\ngraft\t0\t2 (22%)\t2 (11%)\t0\t4 (12%)\t\nlungs\t0\t1 (11%)\t3 (17%)\t0\t4 (12%)\t\nlymph nodes regarless of other sites\t5 (83%)\t9 (100%)\t16 (89%)\t1\t31 (91%)\t\nlymph nodes only\t1 (17%)\t3 (33%)\t4 (22%)\t0\t8 (24%)\t\ngastrointestinal tract\t2 (33%)\t2 (22%)\t3 (17%)\t0\t7 (21%)\t\nupper airway\t3 (50%)\t1 (11%)\t6 (33%)\t0\t10 (29%)\t\ncentral nervous system\t0\t0\t2 (11%)\t0\t2 (6%)\t\nbone marrow\t0\t1 (11%)\t4 (22%)\t0\t5 (15%)\t\nothers\t0\t2 (22%)\t6 (33%)\t1\t9 (27%)\t\nAbbreviations: No., number; EBER, EBV‐encoded RNA; EBV, Epstein–Barr virus; PCR, polymerase chain reaction; PB, peripheral blood; PTLD, post‐transplant lymphoproliferative disease.\n\nWe aimed at staging the 34 patients according to the IPNHLSS. In 18 patients staging was incomplete, as pre‐therapeutic bone marrow (BM) and cerebrospinal fluid (CSF) were not assessed. Of the 16 patients evaluable for staging, two showed stage II disease, eight stage III disease, and six stage IV disease or Burkitt's leukemia. The patient with Burkitt's leukemia showed lesions in the CNS, too.\n\nThe most frequently involved sites of disease were the lymph nodes (n = 31/34), however, only in 8/34 patients the disease was solely restricted to the lymph nodes. Other sites of involvement were the gastrointestinal tract (GIT; n = 7/34), upper airways including the Waldeyer's ring (n = 10/34), lungs (n = 4/34), BM (n = 5/34), CNS (n = 2/34), and others (n = 9/34). Graft involvement was diagnosed in four cases (lungs, n = 1; kidney, n = 1; GIT, n = 2). Only 1/34 patients presented with uni‐locular disease (lingula).\n\nEighteen/34 cases were classified as monomorphic PTLD, all of which were of B‐cell origin. Diffuse large B‐cell lymphoma (DLBCL) accounted for the vast majority of this group (n = 15) occurring after SOT in 12/15 and after HSCT in 3/15 cases. The other three patients had a plasmacytoma‐like PTLD, plasmablastic lymphoma, and Burkitt's leukemia, respectively, all occurring after SOT. Polymorphic disease occurred in 9/34 cases, and non‐destructive lesions in 6/34 cases, all occurring after SOT. The latter group included five patients with plasmacytic hyperplasia (PH) and one with mononucleosis‐like PTLD. In 1/34 patients (after HSCT), the PTLD could not be subclassified. In two patients, synchronous detection of different subtypes was seen: one case of polymorphic disease showed elements of mononucleosis‐like PTLD, and one case with PH showed aspects of florid follicular hyperplasia. Twenty‐eight/34 demonstrated CD20‐expression. The CD20‐negative cases included plasmacytic hyperplasia (n = 2), polymorphic PTLD (n = 1), plasmablastic lymphoma (n = 1), and DLBCL (n = 2), respectively.\n\nDepending on the latency period between transplantation and occurrence of PTLD, 19 occurred within the first year after transplantation. The median interval between transplantation and PTLD diagnosis was 0.65 years for all patients. All four cases of PTLD following HSCT occurred within the first year.\n\nIn 32/34 patients, serum PCR analysis was performed for EBV detection at the time of diagnosis with 30/32 being positive. EBV‐positive disease was defined by histological examination of the tumor, showing that 30 were EBER‐positive. Notably, two patients presented with EBER‐positivity of the samples, but had negative EBV‐PCR in PB.\n\nAll nine cases of polymorphic PTLD presented with EBV‐positive PTLD, while this was seen in 4/6 and 16/18 of non‐destructive and monomorphic PTLD, respectively. The patient with non‐classifiable PTLD was EBV‐positive. Of all cases occurring within 1 year after transplantation, all but one patient showed EBER‐positivity (n = 18/19). The remaining patient had a negative EBER‐status of the tumor, but positive EBV‐PCR in PB. Of the four EBV‐negative cases, two had non‐destructive and two monomorphic PTLD, and, interestingly, all were CD20‐negative. In three of the four cases with negative EBER‐reactions, EBV was detectable in PB.\n\n4.2 Treatment and response\n\nA detailed description of the therapy, response and outcome of the 34 patients is given in Figure 1 and Table 3. One/34 patients died from disease before any therapy. Reduction of immunosuppression (RIS) was the first therapeutic step taken in 32 of the remaining 33 individuals. The patient without RIS directly received rituximab followed by chemotherapy, which led to a CR. Three/32 patients with RIS required no further therapy. Two of them achieved a CR, the remaining patient's lesions switched from polymorphic to non‐destructive PTLD (classified as PR). Two/32 patients with RIS, including one with localized disease of the lingula and one with a supraglottic tumor and cervical lymphadenopathy, had a surgical approach of the disease only. Thereby both achieved a CR.\n\nFIGURE 1 Flow chart of the therapy and outcome of the 34 PTLD patients. RIS, reduction of immunosuppression; PR, partial remission; FFH, florid follicular hyperplasia; CCR, continuous complete remission; B‐NHL, B‐cell non‐Hodgkin lymphoma; PTLD, post‐transplant lymphoproliferative disease; CHOP, cyclophosphamide, doxorubicin, vincristine and prednisolone; CR, complete response; R‐CHOP, rituximab‐CHOP; PD, progressive disease; EPOCH, etoposide, prednisolone, vincristine, cyclophosphamide and doxorubicin; m‐COMP, modified ‐ cyclophosphamide, vincristine, methotrexate and prednisone; SD, stable disease; EBV, Epstein–Barr virus\n\nTABLE 3 Response and outcome of the 34 patients with PTLD according to the histological subtype\n\n\tNon‐destructive PTLD\tPolymorphic PTLD\tMonomorphic PTLD\tNot classifiable PTLD\t∑\t\nNo. of patients\t6 (18%)\t9 (27%)\t18 (53%)\t1 (3%)\t34\t\nResponse of initial disease\t\t\t\t\t\t\ncomplete response\t6 (100%)\t5 (56%)\t14 (78%)\t0\t25 (74%)\t\npartial response\t0\t1 (11%)\t1 (6%)\t0\t2 (6%)\t\nstable disease\t0\t1 (11%)\t0\t0\t1 (3%)\t\nprogressive disease\t0\t1 (11%)\t3 (17%)\t1\t5 (15%)\t\nnot evaluable\t0\t1 a (11%)\t0\t0\t1 (3%)\t\nFirst Event\t\t\t\t\t\t\nno event\t4 (67%)\t3 (33%)\t6 (33%)\t0\t13 (38%)\t\nlack of complete response\t2 (33%)\t3 (33%)\t8 (44%)\t1\t14 (41%)\t\nrelapse\t0\t2 (22%)\t2 (11%)\t0\t4 (12%)\t\ndeath\t0\t1\t2\t0\t3 (9%)\t\nResponse of first relapse\t0\t2\t2\t0\t4\t\ncomplete response\t0\t1 (50%)\t1 (50%)\t0\t2 (50%)\t\npartial response\t0\t1 (50%)\t0\t0\t1 (25%)\t\nstable disease\t0\t0\t0\t0\t0\t\nprogressive disease\t0\t0\t0\t0\t0\t\nunknown\t0\t0\t1 (50%)\t0\t1 (25%)\t\nOverall outcome\t\t\t\t\t\t\nmedian follow‐up (years)\t1.27\t7.81\t6.48\t/\t5.68\t\nrange of follow‐up (years)\t0.37‐2.54\t1.45‐16.05\t0.14‐19.56\t/\t0.14‐19.56\t\nCCR\t6 (100%)\t4 (44%)\t11 (61%)\t0\t21 (62%)\t\nFirst CCR\t6 (100%)\t3 (33%)\t10 (56%)\t0\t19 (56%)\t\nSecond CCR\t0\t1 (11%)\t1 (6%)\t0\t2 (6%)\t\ndeath\t0\t4 (44%)\t7 (39%)\t1\t12 (35%)\t\nPTLD‐related\t0\t3 (33%)\t3 (17%)\t0\t6 (18%)\t\ntherapy of PTLD‐related\t0\t0\t0\t1\t1 (3%)\t\nnot‐PTLD‐related\t0\t1 (11%)\t3 (17%)\t0\t4 (12%)\t\ncause of death unknown\t0\t0\t1 (6%)\t0\t1 (3%)\t\nAbbreviations: No., number; CCR, continuous complete remission; PTLD, post‐transplant lymphoproliferative disease.\n\na One patient did not receive any therapy at all.\n\nOf the 27/32 patients with RIS who received further treatment, 15 achieved a CR, while 12 lacked complete response including two progressing during first‐line therapy and dying from the PTLD. Four/15 patients with CR following first‐line therapy relapsed, 2/15 died in first CR due to PTLD‐unrelated causes and 9/15 remained in first continuous CR (CCR). Two of the four relapsed patients achieved a second CCR, the other two died (unknown cause, n = 1; PTLD‐related, n = 1).\n\nOut of the 12 patients who lacked complete response to first‐line therapy, four achieved a first CCR with second‐line therapy, one with stable disease died from a PTLD‐unrelated cause, and five lacked complete response to second‐line therapy. One of the latter achieved a first CCR following third‐line therapy, one attained a PR and died (PTLD‐unrelated), and another patient progressed and died from third‐line therapy‐associated toxicity. The remaining two patients lacking complete response to third‐line therapy proceeded to further chemotherapy, but subsequently succumbed to PTLD.\n\n4.3 Outcome according to therapy\n\nTwenty‐three/27 patients with RIS and further therapy were treated with rituximab as part of their first‐line therapy with or without additional steroids. First‐line therapy in the remaining four consisted of cyclophosphamide and steroids in two, and brentuximab‐vedotin and B‐cell non‐Hodgkin lymphoma (B‐NHL)‐based chemotherapy in each one patient. Fifteen of the 27 patients achieved a CR.\n\nTen/12 patients with RIS and additional treatment, who lacked complete response to first‐line therapy, proceeded to polychemotherapy in nine (R‐CHOP, n = 3; CHOP, n = 2; cyclophosphamide±steroids, n = 3; bendamustine, n = 1) and obinutuzumab in one patient. Five/six patients without complete response to second‐line therapy proceeded to chemotherapy (CHOP, n = 2; B‐NHL therapy, n = 1; EPOCH, n = 1; m‐COMP, n = 1), and two of three patients, who lacked complete response to third‐line therapy, subsequently received other therapies such as etoposide and EBV‐specific T‐cells in one, and cyclophosphamide followed by cytarabine, mitoxantrone, and bortezomib in the other patient.\n\nOf all 14 patients treated with rituximab only (in addition to RIS), 13 achieved a CR, one showed disease progression at the end of therapy, and three patients relapsed. Classical B‐NHL therapies were applied in one case of Burkitt's leukemia as first‐line and in another case of DLBCL as third‐line therapy. The latter achieved a PR and died from a PTLD‐unrelated cause; the former achieved a CCR.\n\n4.4 Outcome according to histology\n\nOf all six patients with non‐destructive disease, four received rituximab±steroids, and two lacked complete response and received second‐line therapy (Table 3). All patients finally achieved a CCR.\n\nAmong the nine patients with polymorphic disease, eight received RIS upfront, and one patient died before having received any therapy. Two/eight patients received RIS only, by which one achieved a CCR. The other patient's lesions regressed from polymorphic to non‐destructive PTLD (classified as PR). Six/8 patients received rituximab±steroids, with four achieving a CR and two who did not (both died). Two of the four patients relapsed, of whom one died from the PTLD, and the other one achieved a second CCR. Of all eight patients with polymorphic disease having received treatment, three achieved a first CCR, and one a second CCR, while one showed a PR and three patients died (PTLD‐related, n = 2; PTLD‐unrelated, n = 1) (Table 3).\n\nMonomorphic PTLD was documented in 18 cases, including the only patient without RIS upfront. One/18 achieved a CCR by RIS and surgery, the other 17 received additional therapy (rituximab±steroids, n = 13; cyclophosphamide±steroids, n = 2; B‐NHL therapy, n = 1; brentuximab‐vedotin, n = 1). Eleven/17 patients received first‐line therapy only, whereby nine achieved a CR, and the other two died of progressive disease. Of the nine patients in CR after first‐line treatment, five remained in CCR, two relapsed (death, n = 1; second CCR, n = 1), and two died from a PTLD‐unrelated cause.\n\nSix/17 patients received second‐line therapy (cyclophosphamide, n = 2; R‐CHOP, n = 2; CHOP, n = 1; bendamustine, n = 1), by which two achieved a CR, whereas four proceeded to third‐line therapy due to lack of complete response (B‐NHL therapy, n = 1; etoposide, n = 1; m‐COMP, n = 1; EPOCH, n = 1). Thereby, one achieved a CCR, and another one died from a PTLD‐unrelated cause. The remaining two patients subsequently received further therapy, by which one patient achieved a CCR, and the other one died from PTLD progression. Overall, 11/18 patients with monomorphic disease achieved a CCR, while 7/18 patients died (PTLD‐related, n = 3, PTLD‐unrelated, n = 3, unknown cause, n = 1).\n\nThe one/34 patients with unclassifiable PTLD received RIS and rituximab+steroids first, to which he lacked response and proceeded to cyclophosphamide and polychemotherapy (CHOP). He died from a treatment‐related complication.\n\nNotably, two/24 patients having received rituximab within first‐line therapy showed CD20‐negative disease. One of them presented with plasmacytic hyperplasia and was treated with RIS + rituximab, and the other one had a DLBCL and received rituximab followed by chemotherapy (cyclophosphamide, etoposide, and CHOP). Both achieved a CR.\n\n4.5 Outcome according to type of transplantation\n\nResponse and outcome of the 4 HSCT as compared to the 30 SOT patients are shown in Supplemental Table 1. Although numbers are small, results suggest a worse response and outcome for the HSCT patients.\n\n4.6 Events\n\nThirteen/34 patients experienced no events and are alive in first CCR. Fourteen/34 patients lacked complete response to first‐line therapy. Out of them, seven died (PTLD‐related, n = 4, PTLD‐unrelated, n = 2, treatment‐related, n = 1). Four/34 patients relapsed, of whom 2 died (PTLD‐related, n = 1; unknown cause, n = 1). Among the remaining 3/34 patients, death occurred as a first event, of which one was PTLD‐related, and the other two were PTLD‐unrelated.\n\nSix/12 deaths were considered PTLD‐related, with five occurring during first‐line treatment (progression, n = 4; EBV‐associated hemophagocytic lymphohistiocytosis, n = 1). The remaining one died from PTLD‐related gastrointestinal perforation during relapse therapy. One patient died amidst relapse therapy due to an unknown cause. One case of candida septicemia was considered a PTLD‐treatment‐related death. The group of 4/12 PTLD‐unrelated deaths consisted of a septicemia, an acute respiratory distress syndrome combined with secondary graft failure following HSCT, a diffuse alveolar hemorrhage syndrome, and a cardiac arrest, respectively.\n\n4.7 Survival rates\n\nMedian follow‐up for surviving patients was 5.68 years as calculated from the time of diagnosis of primary PTLD diagnosis. On the date of last follow‐up 22 of all 34 patients were alive in CCR. The 5‐year OS and EFS rates were 64% ± 9% and 35% ± 9% for the whole study cohort, respectively (Figure 2). When evaluating the 5‐year OS according to the PTLD subtypes, it was 100% for non‐destructive, 53% ± 17% for polymorphic, and 65% ± 12% for monomorphic PTLD. Five‐year EFS according to the PTLD subtypes was 53% ± 25% for non‐destructive, 33% ± 16% for polymorphic, and 36% ± 12% for monomorphic PTLD.\n\nFIGURE 2 5‐year event‐free survival (A) and overall survival (B) of the 34 patients with PTLD. EFS, event‐free survival; OS, overall survival. [Correction added on 12 April 2021, after first online publication: The text “5‐year EFS: 35%±9% (n=34)” has been added in figure 2 A image in this version]\n\nA variety of factors were evaluated concerning their impact on OS and EFS (Supplemental Table 2): Diagnosis indicating transplantation was the only factor having an effect on OS with a significantly poorer survival in cases with malignant diseases (P = 0.002), though numbers were very small. None of the factors analyzed had a significant influence on EFS.\n\n5 DISCUSSION\n\nPTLD represents a heterogenous group of excessive lymphoid proliferation, generally B‐lymphocytes, that occurs in the setting of suppressed T‐cell function, usually after SOT. In HSCT patients, it often represents a fatal risk occurring relatively early after transplantation. EBV infection has long been implicated as a causative factor in the development of PTLD. 8 , 11 , 21 , 45 , 46 , 47 , 48 In our study, 30 of 34 cases showed a positive EBER‐reaction of the tumor, thereby confirming the high rates of association seen in previous pediatric studies. Our data matched previous reports on monomorphic and polymorphic PTLD with 16/18 and 9/9 of the patients being EBER‐positive, while only 4/6 patients with non‐destructive PTLD were EBER‐positive. Interestingly, among the four EBV‐negative cases, median time from transplantation until PTLD was 6.0 years as compared to 2.3 years among the EBV‐positive patients. Accordingly, all four EBER‐negative patients had a CD20‐negative tumor, but no reduced survival.\n\nThe incidence of LPD following transplantations shows a biphasic distribution, with a first peak occurring within 12 months, and another either at 3 to 5 or at 7 to 10 years after transplantation. 11 , 25 , 49 , 50 , 51 , 52 Our study showed that half of the patients presented with early‐onset disease at a median time of 0.44 years and half with late‐onset disease at a median time of 5.61 years after transplantation. In accordance with the literature, all four patients with PTLD after HSCT were diagnosed within the first year after transplantation. 9 , 37 , 53\n\nThe majority of PTLDs present as multi‐locular disease, affecting both nodal and extranodal sites. Virtually every organ can be involved, the graft itself being a common site, whereas the most frequently affected extranodal site is the intestine. 15 , 54 , 55 , 56 We found that the vast majority (n = 33) involved multiple sites and the most frequently affected site were the lymph nodes (n = 31) followed by the upper airways (n = 10) and intestinal tract (n = 7). The graft itself was affected in four of our 34 cases.\n\nSince experience with PTLD in childhood is limited to small case series and studies, treatment is not fully standardized and frequently adjusted to the affected individual, thereby addressing the multitude of clinical and histological presentations. Restoration of the patients' EBV‐specific T‐cell response achieved by RIS is widely accepted as the treatment of first choice independent of the organ graft. However, there is no consensus about the impact of a single immunosuppressive agent and the risk of acute graft‐rejection is assessed differently by the respective organ specialist. 11 , 35 , 57 , 58 Remarkably, none of the 32 patients included in our study who received RIS suffered from graft‐failure or ‐loss due to PTLD‐therapy. Non‐destructive PTLD and low‐risk patients show high response rates to RIS alone, but it is not recommended as a sole therapy in cases of monomorphic PTLD, aggressive disease or patients with a high tumor burden. 11 , 35 Among our cohort, three underwent RIS only (non‐destructive, n = 1; polymorphic, n = 2) and thereby achieved a CCR (n = 2) or PR (n = 1), and another 2 patients achieved CCR by RIS and surgery only (non‐destructive, n = 1; monomorphic, n = 1).\n\nAnother substantial part of PTLD‐therapy is B‐cell depletion due to the use of rituximab. It is recommended as first‐line treatment for all CD20‐positive subtypes sequential or in parallel to RIS. Altogether, treatment with rituximab has led to better overall survival in children and adolescents with PTLD. 22 , 59 , 60 , 61 Eighty‐five percent of our patients having received first‐line treatment required further therapy, with 86% of them having received rituximab±steroids as first‐line therapy. Forty‐six percent of patients lacked response to rituximab, including one patient who died from progressive disease and all others proceeding to chemotherapy. Of the 54% of patients having achieved CR after rituximab‐containing therapy, 23% relapsed.\n\nIn cases of DLBCL non‐responding to RIS and rituximab, as well as “non‐DLBCL” monomorphic PTLD and primary CNS‐lymphoma, polychemotherapy is suggested, mostly consisting of R‐CHOP, CHOP, and COP regimens. 35 , 62 Overall, 56% of our patients with monomorphic disease underwent polychemotherapy at some time, 40% of whom already received it as first‐line therapy, whereas 60% proceeded to chemotherapy after lacking response to rituximab±steroids or brentuximab‐vedotin.\n\nNovel therapeutic approaches include immunotherapies, such as EBV‐specific CTLs and chimeric antigen receptor T‐cells, small molecule inhibitors, such as the mTOR inhibitor everolimus or tyrosine kinase inhibitor ibrutinib, as well as risk‐adapted chemotherapy regimens. Aside from rituximab, targeted therapies such as the anti‐CD30 antibody brentuximab‐vedotin yield promising results. 11 , 35 , 63 Within our cohort, one patient with plasmablastic lymphoma received brentuximab‐vedotin as first‐line therapy, but proceeded to further chemotherapy due to refractory disease.\n\nSeveral factors reportedly influence the prognosis of pediatric patients with PTLD. 13 , 36 , 60 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 Parameters associated with a poor prognosis are a history of malignant disease indicating transplantation, advanced disease, multifocal and extranodal disease, CNS, BM and graft involvement, female gender, B‐symptoms and elevated LDH levels at PTLD onset, high EBV load in PB at the time of diagnosis, CD20‐ and EBV‐negative as well as monomorphic and late‐onset PTLD. Considering the type of allograft, lung, liver, and hematopoietic stem cells were associated with poorer prognosis. None of the factors referred to could be identified as relevant prognostic factors affecting EFS or OS in our patient cohort, which may at least be partially owed to the relatively small number of patients included in our study.\n\nChildren diagnosed with PTLD tend to have a better prognosis compared to adults, which seems to be due to more favorable PTLD‐subtypes (EBV‐positive) and less treatment‐related complications. 15 , 20 The prospective PTLD‐1 trial implemented sequential treatment with rituximab followed by a CHOP‐regimen in adult CD20‐positive patients with mostly monomorphic PTLD, resulting in a median OS of 6.6 years. Considering that response to rituximab predicted favorable OS, another prospective study subsequently treated the patients with CR to 4 weeks of rituximab with further rituximab consolidation, whereas non‐responders switched to R‐CHOP. Thereby, a 3‐year OS of 78% (compared to 69% in PTLD‐1) was achieved. 59 , 61 The prospective Ped‐PTLD 2005 trial treated pediatric patients with CD20‐positive PTLD following SOT with 3 weeks of rituximab followed by either rituximab or chemotherapy (mCOMP) depending on initial response, achieving a 2‐year OS of 86%, and 67% surviving event‐free. 64 According to the literature available, 5‐year survival rates for pediatric PTLD are around 53‐80%. 25 , 61 , 65 , 74 , 75 The 3‐ and 5‐year OS rates in our patient cohort were 69% ± 8% and 64% ± 9%, respectively, fitting well to the hitherto reports.\n\nThe primary aim of this study was to investigate the characteristics and outcome of PTLD in Austrian patients over a period of 20 years. Special attention was paid to factors influencing the patient's prognosis. In childhood and adolescence, PTLD is the largest group of secondary malignant diseases, making it essential to define coherent diagnostic and therapeutic guidelines addressing the heterogeneity of this disease. Considering the absolute number of affected people, it is still defined as an Orphan Disease, and both, a transnational cooperation and a compilation of comprehensive scientific studies, including series like the present one, are essential to optimize the management of PTLD, as it is still a major cause of mortality following transplantation.\n\nCONFLICT OF INTEREST\n\nThe authors declare no competing financial interests.\n\nAUTHORS' CONTRIBUTIONS\n\nA.A., A.F., and R.C. designed and planned the study; A.A., A.F., G.K., and R.C. wrote the manuscript; A.A., A.F., and G.K. collected and analyzed the data; I.S.K. was in charge of the histopathological analyses; M.B., M.D., S.G., W.D.H., H.H., A.L., G.M., I.M.B., T.M.S., H.P., W.S., Z.S., A.A., G.K., and R.C. recruited, treated, and identified the patients. A.F., G.K., M.B., M.D., S.G., W.D.H., H.H., A.L., G.M., I.M.B., T.M.S., H.P., I.S.K., W.S., Z.S., R.C., and A.A. read and approved the final version of the manuscript.\n\nETHICAL STATEMENT\n\nEthical approval for this study (No. 1919/2018) was granted by the Ethics Committee of the Medical University of Vienna on 11th November 2018.\n\nPATIENT CONSENT STATEMENT\n\nThis was a retrospective study involving access to existing medical records, with the research personnel reviewing these records normally having access to these records. Therefore, patient consent was waivered.\n\nSupporting information\n\nSupplemental Table 1 Response and outcome of the 4 HSCT patients as compared to the 30 SOT patients with PTLD\n\nClick here for additional data file.\n\nSupplemental Table 2 Event‐free and overall survival of the 34 patients with PTLD according to prognostic factors analyzed\n\nClick here for additional data file.\n\nACKNOWLEDGEMENTS\n\nWe thank all participating institutions and their physicians, nurses, pathologists, and biologists for their support of the study.\n\nDATA AVAILABILITY STATEMENT\n\nThe data that support the findings of the study are available on request from the corresponding authors.\n==== Refs\nREFERENCES\n\n1 Halloran PF . Immunosuppressive drugs for kidney transplantation. N Engl J Med. 2004;351 :2715‐2729. 10.1056/NEJMra033540.15616206\n2 JK‐C C . Post‐transplant lymphoproliferative disorders: a simplified overview. 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"journal": "Cancer reports (Hoboken, N.J.)",
"keywords": "hematopoietic stem cell transplantation; outcome; post-transplant lymphoproliferative disease; solid organ transplantation; treatment",
"medline_ta": "Cancer Rep (Hoboken)",
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"title": "Characteristics, management, and outcome of pediatric patients with post-transplant lymphoproliferative disease-A 20 years' experience from Austria.",
"title_normalized": "characteristics management and outcome of pediatric patients with post transplant lymphoproliferative disease a 20 years experience from austria"
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"abstract": "The largest health care-associated infection outbreak in the United States occurred during 2012-2013. Following injection of contaminated methylprednisolone, 753 patients developed infection with a dematiaceous mold, Exserohilum rostratum. The long-term outcomes of these infections have not been described.\nThis retrospective cohort study of 440 of a total of 753 patients with proven or probable Exserohilum infection evaluated clinical and radiographic findings, antifungal therapy and associated adverse effects, and outcomes at 6 weeks, 3, 6, 9, and 12 months after diagnosis. Patients were grouped into 4 disease categories: meningitis with/without stroke, spinal or paraspinal infections, meningitis/stroke plus spinal/paraspinal infections, and osteoarticular infections.\nAmong the 440 patients, 223 (51%) had spinal/paraspinal infection, 82 (19%) meningitis/stroke, 123 (28%) both, and 12 (3%) osteoarticular infection. Of 82 patients with meningitis/stroke, 18 (22%) died; among those surviving, 87% were cured at 12 months. Only 7 (3%) of 223 patients with spinal/paraspinal infection died, but at 12 months, 68% had persistent or worsening pain and only 47% were cured. For the 123 patients with both meningitis/stroke and spinal/paraspinal infection, 10 (8%) died, pain persisted in 72%, and 52% were cured at 12 months. Only 37% of those with osteoarticular infection were cured at 12 months. Adverse events from antifungal therapy were noted at 6 weeks in 71% of patients on voriconazole and 81% on amphotericin B.\nFungal infections related to contaminated methylprednisolone injections culminated in death in 8% of patients. Persistent pain and disability were seen at 12 months in most patients with spinal/paraspinal infections.",
"affiliations": "St Joseph Mercy Hospital, Ann Arbor, Michigan, USA.;VA Ann Arbor Healthcare System and University of Michigan Medical School, Ann Arbor, Michigan, USA.;St. Thomas Medical Center and Vanderbilt University School of Medicine, Nashville, Tennessee, USA.;Elkhart General Hospital, Elkhart, Indiana, USA.;Munson Medical Center, Traverse City, Michigan, USA.;Virginia Tech Carilion School of Medicine, Roanoke, Virginia, USA.;Inspira Health Network, Vineland, New Jersey, USA.;University of North Carolina Health Care, High Point, North Carolina, USA.;Vanderbilt University School of Medicine, Nashville, Tennessee, USA.;Vanderbilt University School of Medicine, Nashville, Tennessee, USA.;Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;University of Alabama at Birmingham, Birmingham, Alabama, USA.;Centers for Disease Control and Prevention, Atlanta, Georgia, USA.",
"authors": "Malani|Anurag N|AN|;Kauffman|Carol A|CA|;Latham|Robert|R|;Peglow|Sheree|S|;Ledtke|Christopher S|CS|;Kerkering|Thomas M|TM|;Kaufman|David H|DH|;Triplett|Patricia F|PF|;Wright|Patty W|PW|;Bloch|Karen C|KC|;McCotter|Orion|O|;Toda|Mitsuru|M|;Jackson|Brendan R|BR|;Pappas|Peter G|PG|;Chiller|Tom M|TM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofaa164",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n10.1093/ofid/ofaa164\nofaa164\nMajor Article\nAcademicSubjects/MED00290\nLong-term Outcomes of Patients With Fungal Infections Associated With Contaminated Methylprednisolone Injections\nMalani Anurag N 1 Kauffman Carol A 2 Latham Robert 3 Peglow Sheree 4 Ledtke Christopher S 5 Kerkering Thomas M 6 Kaufman David H 7 Triplett Patricia F 8 Wright Patty W 9 Bloch Karen C 9 McCotter Orion 10 Toda Mitsuru 10 Jackson Brendan R 10 Pappas Peter G 11 Chiller Tom M 10 1 \nSt Joseph Mercy Hospital, Ann Arbor, Michigan, USA\n2 \nVA Ann Arbor Healthcare System and University of Michigan Medical School, Ann Arbor, Michigan, USA\n3 \nSt. Thomas Medical Center and Vanderbilt University School of Medicine, Nashville, Tennessee, USA\n4 \nElkhart General Hospital, Elkhart, Indiana, USA\n5 \nMunson Medical Center, Traverse City, Michigan, USA\n6 \nVirginia Tech Carilion School of Medicine, Roanoke, Virginia, USA\n7 \nInspira Health Network, Vineland, New Jersey, USA\n8 \nUniversity of North Carolina Health Care, High Point, North Carolina, USA\n9 \nVanderbilt University School of Medicine, Nashville, Tennessee, USA\n10 \nCenters for Disease Control and Prevention, Atlanta, Georgia, USA\n11 \nUniversity of Alabama at Birmingham, Birmingham, Alabama, USA\nCorrespondence: Anurag N. Malani, MD, St Joseph Mercy Hospital, 5333 McAuley Drive, Suite 6007, Ypsilanti, MI 48197 (anurag.malani@stjoeshealth.org).\n6 2020 \n09 5 2020 \n09 5 2020 \n7 6 ofaa16418 4 2020 25 4 2020 05 5 2020 06 6 2020 © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2020This 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.comAbstract\nBackground\nThe largest health care–associated infection outbreak in the United States occurred during 2012–2013. Following injection of contaminated methylprednisolone, 753 patients developed infection with a dematiaceous mold, Exserohilum rostratum. The long-term outcomes of these infections have not been described.\n\nMethods\nThis retrospective cohort study of 440 of a total of 753 patients with proven or probable Exserohilum infection evaluated clinical and radiographic findings, antifungal therapy and associated adverse effects, and outcomes at 6 weeks, 3, 6, 9, and 12 months after diagnosis. Patients were grouped into 4 disease categories: meningitis with/without stroke, spinal or paraspinal infections, meningitis/stroke plus spinal/paraspinal infections, and osteoarticular infections.\n\nResults\nAmong the 440 patients, 223 (51%) had spinal/paraspinal infection, 82 (19%) meningitis/stroke, 123 (28%) both, and 12 (3%) osteoarticular infection. Of 82 patients with meningitis/stroke, 18 (22%) died; among those surviving, 87% were cured at 12 months. Only 7 (3%) of 223 patients with spinal/paraspinal infection died, but at 12 months, 68% had persistent or worsening pain and only 47% were cured. For the 123 patients with both meningitis/stroke and spinal/paraspinal infection, 10 (8%) died, pain persisted in 72%, and 52% were cured at 12 months. Only 37% of those with osteoarticular infection were cured at 12 months. Adverse events from antifungal therapy were noted at 6 weeks in 71% of patients on voriconazole and 81% on amphotericin B.\n\nConclusions\nFungal infections related to contaminated methylprednisolone injections culminated in death in 8% of patients. Persistent pain and disability were seen at 12 months in most patients with spinal/paraspinal infections.\n\namphotericin BarachnoiditisExserohilum rostratummeningitismethylprednisolone; paraspinal infectionspinal infectionvoriconazole\n==== Body\nIn September 2012, the Centers for Disease Control and Prevention (CDC) and state public health partners investigated an outbreak of infections caused by the dematiaceous mold Exserohilum rostratum in patients who received injections, primarily epidural, of methylprednisolone acetate. All medications were produced by a single compounding pharmacy, the New England Compounding Center, and had been contaminated during the manufacturing process [1–4].\n\nIn this largest-ever health care–associated outbreak, 753 patients with fungal infections were reported and 64 (8%) patients died [5]. Initially, most patients experienced meningitis, sometimes involving stroke. However, after a few weeks, spinal and paraspinal infections became prominent [6–9]. Among the 753 patients, 325 (43%) had spinal/paraspinal infections, 241 (32%) had meningitis/stroke, 152 (20%) had both spinal/paraspinal infections and meningitis/stroke, 33 (4%) had a peripheral osteoarticular infection, and 2 had both spinal/paraspinal infection and peripheral osteoarticular infection [2, 3].\n\nInitial treatment for most patients involved combination therapy with liposomal amphotericin B and voriconazole or voriconazole monotherapy [9]. Surgical debridement was recommended when feasible for spinal/paraspinal and osteoarticular infection. Most patients received antifungal treatment for 3–6 months, but others required longer therapy.\n\nPreliminary results of follow-up of patients involved in the outbreak were briefly reported [5], but the long-term therapeutic approach, adverse events, and outcomes associated with this outbreak have not been described in detail. The purpose of this study was to examine the clinical course and outcomes for patients who were affected by this outbreak. Outcomes in regard to resolution of the infection and functional status were sought, and adverse effects related to chronic treatment with antifungal agents were evaluated.\n\nMETHODS\nPatients\nThis was a retrospective cohort study of a majority of patients who developed fungal infections following injection of contaminated methylprednisolone and who were cared for by physicians at 8 sites in 6 states (Indiana, Michigan, New Jersey, North Carolina, Tennessee, and Virginia).\n\nInclusion criteria were (1) exposure to a contaminated lot of methylprednisolone acetate; (2) symptoms compatible with meningitis with or without stroke, spinal/paraspinal infection, or osteoarticular infection; (3) laboratory or radiographic evidence of infection; (4) culture, histopathology, or polymerase chain reaction (PCR) evidence of fungal infection. Proven cases met all 4 criteria, and probable cases met the first 3 criteria but lacked confirmatory laboratory evidence of fungal infection.\n\nDefinitions\nCases were classified into 1 of 4 patient categories: meningitis with or without stroke, spinal/paraspinal infection, meningitis/stroke and spinal/paraspinal infection, and nonvertebral osteoarticular infection (Table 1). Disease in patients with spinal/paraspinal infection at or near the site of injection was further classified based on imaging (Table 2). Outcomes were defined based on clinical findings, radiographic evaluations, response to antifungal therapy, pain, and ability to perform activities of daily living (ADLs) (Table 3).\n\nTable 1. Categories of Infection\n\n\nMeningitis with or without stroke: Signs or symptoms of meningitis with cerebrospinal fluid white blood cells ≥5/μL (accounting for the presence of red blood cells) and/or posterior circulation stroke without a cardioembolic source following epidural injection\t\n\nSpinal/paraspinal infection: Abscess, phlegmon, soft tissue, or bony infection in the spinal or paraspinal structures at or near the site of epidural or paraspinal injection\t\n\nMeningitis/stroke and spinal/paraspinal infection: Infection of both central nervous system and spinal/paraspinal tissues, usually with the latter occurring after the former\t\n\nNonvertebral osteoarticular infection: Osteomyelitis or worsening inflammatory arthritis following injection of a joint, bursa, or tendon insertion not contiguous with the spine\t\nTable 2. Classification of Spinal/Paraspinal Infection as Defined by Radiological Criteria\n\n\nArachnoiditis: Enhancement, thickening, or clumping of nerve roots and/or cauda equina\t\n\nEpidural abscess/phlegmon: Epidural fluid collection with or without enhancement\t\n\nVertebral discitis/osteomyelitis/sacroiliac joint infection: Radiological changes indicating infection of vertebrae or sacroiliac joint\t\n\nOther spinal/paraspinal infection: Fluid collection with or without enhancement in the paraspinal space or inflammatory changes, suggesting acute infection in facet joints\t\nTable 3. Outcomes of Infection Associated With Injection of Contaminated Methylprednisolone\n\n\nCure: Improvement or resolution of symptoms and/or signs compared with baseline, defined as the date on which the diagnosis was established, no clinical evidence of active infection, and off antifungal therapy for at least 3 months\t\n\nImproved: Improvement or resolution of symptoms and/or signs compared with baseline; may have clinical evidence of active infection; may or may not be off antifungal therapy\t\n\nStable: Little or no improvement of symptoms and/or signs as compared with baseline; may have clinical evidence of infection; may or may not be off antifungal therapy\t\n\nProgression: Worsening symptoms and/or signs of infection compared with baseline\t\n\nRelapse: Recurrent symptoms and/or signs occurring off antifungal therapy and radiographic or laboratory evidence to support the diagnosis of relapse\t\nData Collection\nRetrospective medical chart reviews were performed at each institution. Data were entered into REDCap, a secure online database (Vanderbilt University, Nashville, TN, USA) at clinical visits corresponding with the following time points after diagnosis: 6 weeks, 3 months, 6 months, 9 months, and 12 months. Data were collected at 18 and 24 months on a subset of patients treated for longer than 12 months and those with a reported relapse. Demographic data, details of the injection of contaminated steroid, underlying medical conditions, symptoms and signs of infection, radiographic data, response to antifungal therapy, adverse effects of antifungal agents, quality of life assessments, and outcomes were collected. The institutional review board at each site and the CDC reviewed and approved the study protocol.\n\nData Analysis\nWe calculated descriptive statistics on demographic and clinical data. Survival functions for all-cause mortality and cumulative incidence of cure (defined in Table 3) of relapse-free patients in the 12-month cohort were estimated for a follow-up period of 450 days. The 450-day cutoff was chosen because <1% of patients had follow-up visits beyond 450 days and visit dates only roughly corresponded with the time points for later visits. The Kaplan-Meier method for all-cause mortality was used to estimate the survival function of relapse-free patients assuming no additional censoring occurred before 450 days. The cumulative incidence was used to estimate patients’ time to cure, while accounting for the competing risk of all-cause mortality during the follow-up period [10]. A Cox proportional hazard model was used to calculate hazard ratio with 95% confidence intervals (CIs). Data cleaning and statistical analysis were performed in SAS, version 9.3 (SAS Institute Inc., Cary, NC, USA), and R, version 3.6.1 (R 2018).\n\nRESULTS\nPatients and Disease Classification\nFour hundred forty patients representing over half (58%) of the 753 patients were entered into the study. The median age (interquartile range [IQR]) was 65 (55–77) years; 58% (n = 257) were women, and most (n = 421, 96%) were non-Hispanic white. Of the 440 patients, 223 (51%) had spinal/paraspinal infection only, 123 (28%) had both spinal/paraspinal infection and meningitis/stroke, 82 (19%) had only meningitis/stroke, and 12 (3%) had nonvertebral osteoarticular infection only. The entire cohort had few underlying illnesses; the most common underlying illness was hypertension in 273 patients (62%), followed by hyperlipidemia in 202 (46%); underlying immunodeficiency was noted in only 26 (6%) patients (Table 4).\n\nTable 4. Characteristics of Patients With Fungal Infections Following Contaminated Methylprednisolone Injections\n\nCharacteristic, No. (%)\tMeningitis/Stroke (n = 82), No. (%)\tSpinal/Paraspinal (n = 223), No. (%)\tSpinal/Paraspinal and Meningitis/Stroke (n = 123), No. (%)\tOsteoarticular (n = 12), No. (%)\tTotal (n = 440), No. (%)\t\nAge, median (IQR), y\t61 (50–77)\t65 (55–75)\t67 (55–75)\t58 (53–65)\t65 (55–75)\t\nSex\t\t\t\t\t\t\n Female\t49 (60)\t128 (57)\t74 (60)\t6 (50)\t257 (58)\t\nRace\t\t\t\t\t\t\n Caucasian\t75 (92)\t217 (97)\t115 (96)\t11 (92)\t421 (96)\t\n African American\t6 (7)\t5 (2)\t4 (3)\t0 (0)\t15 (3)\t\n Other\t1(1)\t1(0.4)\t1 (1)\t1 (8)\t4 (1)\t\nTreatment location (state)\t\t\t\t\t\t\n Indiana\t18 (22)\t18 (8)\t9 (7)\t0 (0)\t45 (10)\t\n Michigan\t10 (12)\t175 (78)\t44 (36)\t12 (100)\t241 (55)\t\n North Carolina\t1 (1)\t14 (6)\t2 (2)\t0 (0)\t17 (4)\t\n New Jersey\t24 (29)\t4 (2)\t9 (7)\t0 (0)\t37 (8)\t\n Tennessee\t11 (13)\t9 (4)\t45 (37)\t0 (0)\t65 (15)\t\n Virginia\t18 (22)\t3 (1)\t14 (11)\t0 (0)\t35 (8)\t\nComorbidities \t\t\t\t\t\t\n Hypertension\t50 (61)\t132 (59)\t80 (65)\t9 (75)\t273 (61)\t\n Dyslipidemia\t39 (46)\t96 (43)\t62 (50)\t5 (42)\t202 (46)\t\n Diabetes mellitus\t17 (21)\t48 (21)\t28 (23)\t3 (25)\t96 (22)\t\n Coronary artery disease\t11 (13)\t37 (16)\t14 (12)\t4 (33)\t66 (15)\t\n Chronic kidney disease\t7 (9)\t20 (9)\t6 (5)\t1 (8)\t34 (8)\t\n Neurologic disease/chronic cognitive disorder\t3 (4)\t15 (7)\t13 (11)\t0 (0)\t31 (7)\t\n Underlying immunodeficiency\t6 (7)\t8 (4)\t11 (9)\t1 (8)\t26 (6)\t\n Cerebrovascular accident\t5 (6)\t11 (5)\t6 (5)\t0 (0)\t22 (5)\t\n Congestive heart failure\t5 (6)\t7 (3)\t3 (3)\t0 (0)\t15 (3)\t\n Chronic liver disease\t1 (1)\t0 (0)\t4 (3)\t0 (0)\t5 (1)\t\nSite of injection associated with infection\t\t\t\t\t\t\n Cervical\t10 (12)\t21 (9)\t7 (6)\t0 (0)\t39 (9)\t\n Thoracic\t0 (0)\t3 (1)\t4 (3)\t0 (0)\t7 (2)\t\n Lumbar\t58 (71)\t160 (72)\t81 (66)\t0 (0)\t299 (68)\t\n Sacral\t6 (7)\t37 (17)\t2 (2)\t0 (0)\t45 (10)\t\n Hip\t0 (0)\t0 (0)\t0 (0)\t4 (33)\t5 (2)\t\n Ankle\t0 (0)\t0 (0)\t0 (0)\t3 (25)\t3 (1)\t\n Shoulder\t0 (0)\t0 (0)\t0 (0)\t5 (42)\t5 (1)\t\n Unknown/missing\t12 (13)\t7 (3)\t30 (24)\t0 (0)\t48 (11)\t\nAbbreviation: IQR, interquartile range.\n\nProven infections were identified in 237 (54%) patients, and probable infections in 203 (46%). The majority of patients received care in Michigan (55%, n = 241). Patients with meningitis predominated at some sites, but at other sites most patients had spinal/paraspinal infections (Figure 1).\n\nFigure 1. Types of infections and site of treatment in patients who received injections of contaminated methylprednisolone acetate.\n\nThe median follow-up time (IQR) was 317 (219–365) days. At the 12-month follow-up, data were available for 328 (75%) of the 440 patients. This decrease was related to the loss of follow-up because patients were cured and off therapy, had died, or had moved. Data were available at 24 months for only 36 (8%) patients.\n\nMeningitis and/or Stroke\nEighty-two patients developed meningitis and/or stroke; 64 (78%) had proven infection, and 18 (22%) had probable infection. Site of epidural injection was known for 71 (87%) patients (Table 4). Of the 82 patients, 73 (89%) had meningitis only, 2 (2%) had a stroke only, and 7 (9%) had both. At 6 months, 10 (16%) of 62 patients were in the hospital or had been hospitalized in the preceding 3 months, 2 (5%) were in long-term care facilities (LTCFs), and 3 (5%) were in long-term acute care hospitals (LTACHs).\n\nProminent symptoms at baseline were headache in 75 (91%), fever in 31 (38%), and decreased cognitive function in 23 (28%). Several patients had severe cognitive dysfunction. By 6 months, cognitive dysfunction was mild–moderate in 10 (16%) of 62 patients and severe in 1 patient, and at 12 months, 4 (11%) of 38 patients had persistent mild–moderate cognitive impairment. At the initial visit, 15 patients (18%) could not walk or needed assistive devices; by 6 and 12 months, 13 (21%) and 6 (16%) patients, respectively, still required assistance to ambulate. Four patients (5%) were aphasic at the initial visit, and 9 (11%) had mild to severe slurring of speech, which persisted for 3 (5%) patients at 6 months.\n\nAll patients received antifungal treatment, except for 2 who had stroke only and died soon after diagnosis (Table 5). Initial treatment was primarily with voriconazole. By the 12-month follow-up, only 2 patients remained on antifungal therapy.\n\nTable 5. Antifungal Treatment for 4 Patient Categories of Infection Over Time\n\nCategory of Disease\tInitial,a No. (%)\t3 Months,a No. (%)\t6 Months,a No. (%)\t12 Months,a No. (%)\t\n\nMeningitis/stroke (No. of patients)\n\t\n(82)\n\t\n(66)\n\t\n(62)\n\t\n(38)\n\t\n Voriconazole\t81 (99)\t56 (85)\t42 (68)\t2 (5)\t\n Amphotericin B\t32 (39)\t4 (6)\t2 (3)\t—\t\n Itraconazole\t3 (4)\t5 (8)\t5 (8)\t—\t\n Posaconazole\t2 (2)\t2 (3)\t1 (2)\t1 (3)\t\n\nSpinal/paraspinal (No. of patients)\n\t\n(223)\n\t\n(210)\n\t\n(206)\n\t\n(148)\n\t\n Voriconazole\t192 (86)\t199 (95)\t171 (83)\t25 (17)\t\n Amphotericin B\t35 (16)\t9 (4)\t12 (6)\t3 (2)\t\n Itraconazole\t4 (2)\t20 (10)\t65 (32)\t37 (25)\t\n Posaconazole\t—\t—\t2 (1)\t7 (5)\t\n\nMeningitis/stroke and spinal/paraspinal (No. of patients)\n\t\n(123)\n\t\n(114)\n\t\n(107)\n\t\n(89)\nb\n\t\n Voriconazole\t113 (92)\t105 (92)\t96 (90)\t13 (15)\t\n Amphotericin B\t42 (34)\t41 (36)\t15 (14)\t6 (7)\t\n Itraconazole\t—\t6 (5)\t23 (21)\t15 (17)\t\n Posaconazole\t8 (7)\t4 (4)\t3 (3)\t2 (2)\t\n\nOsteoarticular infection (No. of patients)\n\t\n(12)\n\t\n(12)\n\t\n(11)\n\t\n(8)\t\n Voriconazole\t12 (100)\t7 (64)\t7 (58)\t—\t\n Itraconazole\t—\t5 (45)\t7 (58)\t4 (50)\t\n Posaconazole\t—\t—\t1 (8)\t—\t\n\naNumbers listed are greater than the total number of patients in each category because many patients received several antifungal agents either in combination or sequentially.\n\n\nbOne patient received isavuconazole.\n\nThirteen (16%) died by the 6-week follow-up and a total of 18 (22%) by the 6-month follow-up. Six (67%) of 9 patients who had a stroke died, 2 before therapy could be started, 3 by 2 weeks, and another by 6 months. Among the 38 patients for whom clinical status was known, 33 (87%) were considered cured at the 12-month follow-up (Table 6).\n\nTable 6. Outcomes at 6 and 12 Months for Each of 4 Patient Categories of Infection\n\nCategory of Disease\tCure, No. (%)\tImproved, No. (%)\tStable, No. (%)\tProgression, No. (%)\t\n\nMeningitis/stroke (n = 82)a\n\t\t\t\t\t\n 6 mo (n = 62)\t9 (15)\t47 (76)\t7 (11)\t1 (2)\t\n 12 mo (n = 38)\t33 (87)\t3 (8)\t1 (3)\t0\t\n\nSpinal/paraspinal (n = 223)b\n\t\t\t\t\t\n 6 mo (n = 206)\t7 (3)\t149 (72)\t39 (19)\t12 (6)\t\n 12 mo (n = 148)\t70 (47)\t57 (39)\t15 (10)\t3 (2)\t\n\nMeningitis/stroke and spinal/paraspinal (n = 123)c\n\t\t\t\t\t\n 6 mo (n = 107)\t1 (1)\t73 (68)\t20 (19)\t13 (12)\t\n 12 mo (n = 89)\t46 (52)\t29 (33)\t13 (15)\t1 (1)\t\n\nOsteoarticular infection (n = 12)\n\t\t\t\t\t\n 6 mo (n = 11)\t0\t8 (73)\t3 (27)\t0\t\n 12 mo (n = 8)\t3 (37)\t5 (63)\t0\t0\t\n\naNot included are 18 patients who died before the 6-month follow-up.\n\n\nbNot included are 7 patients who died before the 6-month follow-up.\n\n\ncNot included are 10 patients who died before the 6-month follow-up.\n\nSpinal/Paraspinal Infections\nA total of 223 patients had localized infection (78 [35%] proven, 145 [65%] probable) at the site of injection, which was known for 216 (97%) patients (Table 4). At 6 months, 28 (14%) of 206 patients were in the hospital or had been hospitalized in the preceding 3 months, 6 (3%) were in LTCFs, and 7 (3%) were in LTACHs. At 12 months, 15 (10%) of 148 patients were in the hospital or had been hospitalized in the preceding 3 months, 1 (1%) was in an LTCF, and 5 (3%) were in LTACHs.\n\nPain was the prominent initial symptom, reported in 213 (96%) patients. By 6 months, pain levels were stable in 101 (49%) of 206 patients and had increased in 26 (13%). Pain was stable or had decreased at the 12-month follow-up in 124 (84%) of 148 patients but had increased in 15 (10%) patients.\n\nPain interfered with ADLs in 88 (39%) patients initially, 61 (30%) of 206 patients at 6 months, and 28 (19%) of 148 patients at 12 months. At 24 months, 7 (30%) of 23 patients were still not able to carry out ADLs. Initially, ambulation was impaired in 76 patients (33%), including 9 who were unable to walk. Of those 9 patients, 4 could not walk at 6 months, and 2 were still unable to walk at 24 months. Moderate impairment requiring use of a cane or walker was present at 6 months in 47 (23%) of 206 patients and at 12 months in 33 (22%) of 148 patients. Bowel and/or bladder dysfunction was present initially in 19 patients (8%) and persisted in 13 of 148 (9%) at 12 months.\n\nAll patients were treated with antifungal agents (Table 5). Initial antifungal therapy was voriconazole alone in 188 (84%) patients. Many patients had changes in their antifungal regimen because of adverse effects of voriconazole. A total of 118 patients (53%) underwent abscess drainage, a washout procedure, or debridement of the infected site. For 11 (9%) patients, multiple debridements were required, and 13 (11%) had a laminectomy.\n\nSeven (3%) patients died. At 6 months, the status was known for 206 patients, of whom only 7 (3%) were reported as cured (Table 6). By 12 months, the status was known for 148 patients, of whom 70 (47%) were considered cured.\n\nMeningitis/Stroke and Spinal/Paraspinal Infections\nBoth meningitis/stroke and spinal/paraspinal infections (92 [75%] proven, 31 [25%] probable) were reported in 123 patients. Only 10 (8%) patients had stroke without meningitis. In most patients, meningitis/stroke was the initial presenting infection, and then symptoms and signs of spinal/paraspinal involvement occurred, usually weeks later. Site of injection was documented for 93 (76%) patients (Table 4). At 6 months, 62 (58%) of 107 patients had been hospitalized in the preceding 3 months, 11 (10%) had been in LTCFs, and 10 (9%) had been in LTACHs. At 12 months, 39 (44%) of 89 patients had been hospitalized within the preceding 3 months, 4 (4%) were in LTCFs, and 3 (3%) were in LTACHs.\n\nThe symptoms and signs were similar to those demonstrated by patients in both of the preceding 2 groups. At the initial visit, 54 patients (44%) had fever and 23 patients (19%) had cognitive impairment. At 6 months, 28 (26%) of 107 patients were cognitively impaired. At the initial visit, pain was present in 120 patients (98%). By 6 months, pain was unchanged or worse in 73 (68%) of 107 patients, and at the 12-month follow-up, 64 (72%) of 89 patients continued to have unchanged or worsening pain. In 33 (28%) patients, pain interfered with ability to complete ADLs, and this continued for 8 patients at 6 months and for 3 patients at 12 months.\n\nInitially, 11 (9%) patients had slurring of speech, and 22 (18%) had problems with bowel and/or bladder function. Thirty-seven (30%) patients had difficulty ambulating, including 5 who could not walk at all. The ability to ambulate worsened by 6 months, when 52 (49%) of 107 patients had difficulty walking. At 12 months, 29 (33%) of 89 patients still had difficulty walking, and 1 patient was unable to walk.\n\nTreatment with antifungal agents was given to 121 (98%) patients; 2 patients died following a stroke before treatment could be initiated (Table 5). Initial treatment was voriconazole alone or combined with amphotericin B in nearly all patients. At 24 months, 5 patients remained on antifungal therapy. Forty patients (40%) had a drainage, washout, or debridement procedure, 6 of whom required a second debridement. Laminectomy was performed in 6 patients.\n\nTen (8%) patients died, 3 of whom had a stroke; 5 patients died within 3 weeks of diagnosis, and another 5 by 6 months. At 6 months, of 107 patients for whom data were available, only 1 patient was cured, and 13 (12%) had progression of disease (Table 6). At the 12-month follow-up for 89 patients, 46 (52%) were cured.\n\nImaging Results for Patients With Spinal/Paraspinal Infection\nMagnetic resonance imaging (MRI) results for the 346 patients who had spinal/paraspinal infection allowed classification of the type of involvement (Table 7). Epidural abscess/phlegmon was found in 173 (50%) of patients, ranging from enhancement in the epidural space to phlegmon to well-circumscribed abscesses. Patients who had epidural disease frequently also had paraspinal disease, and many also had arachnoiditis. Arachnoiditis was found in 117 (34%) patients, with findings ranging from discrete intradural abscesses to clumping and enhancement of nerve roots within the spinal canal (Figure 2). Many patients with arachnoiditis had both epidural and intradural infection, as well as involvement of paraspinal structures. Vertebral osteomyelitis/discitis and sacroiliac joint infection were less common and often seen with epidural abscess/phlegmon.\n\nTable 7. Sites of Infection Determined by Clinical Findings and Magnetic Resonance Imaging in 346 Patients who Had Spinal/Paraspinal Involvement With or Without Meningitis/Strokea\n\nSite of Infection\tNo. (%)b\t\n\nEpidural abscess/phlegmon\n\t\n173 (50)\n\t\n Only\t61 (35)\t\n With arachnoiditis\t53 (31)\t\n With osteomyelitis/sacroiliac disease\t35 (20)\t\n With other spinal/paraspinal disease\t50 (29)\t\n\nArachnoiditis\n\t\n117 (34)\n\t\n Only\t51 (44)\t\n With epidural abscess/phlegmon\t53 (45)\t\n With osteomyelitis/sacroiliac disease\t10 (8)\t\n With other spinal/paraspinal disease\t25 (21)\t\n\nOther spinal/paraspinal disease\n\t\n117 (34)\n\t\n Only\t47 (40)\t\n With arachnoiditis\t25 (21)\t\n With epidural abscess/phlegmon\t50 (43)\t\n With osteomyelitis/sacroiliac disease\t17 (14)\t\n\nOsteomyelitis/sacroiliac disease\n\t\n105 (16)\n\t\n Only\t51 (49)\t\n With arachnoiditis\t12 (11)\t\n With epidural abscess/phlegmon\t41 (39)\t\n With other spinal/paraspinal disease\t23 (22)\t\n\naAs defined in Table 3.\n\n\nbPatients had more than 1 site of infection.\n\nFigure 2. Magnetic resonance images (MRIs) taken 8 months after injection of contaminated methylprednisolone. A, Axial T2-weighted, postcontrast image of the lumbosacral spine showing severe narrowing of the distal thecal sac with thick, multiseptated epidural, dural, and intradural enhancement (arrow) consistent with arachnoiditis. B, Sagittal T1 fat-saturated, postcontrast image of the lumbosacral spine showing epidural, dural, and intrathecal enhancement (arrow) consistent with arachnoiditis and epidural phlegmon. C, Tissue obtained at surgery showing pigmented hyphae (hematoxylin and eosin stain). Polymerase chain reaction on cerebrospinal fluid yielded Exserohilum rostratum.\n\nNonvertebral Osteoarticular Infections\nTwelve patients had osteoarticular involvement, including hip (n = 4), shoulder (n = 4), both hip and shoulder (n = 1), and ankle (n = 3). Three of these infections were proven, and 9 were probable. One patient remained in an LTCF for 6 months.\n\nAt the initial visit, 4 patients were febrile, and all reported pain in the affected joint. Pain decreased in 7 patients by 3 months, but for 5 patients it continued to interfere with ADLs. The most severely affected patient was unable to walk unaided for 9 months. Six other patients had difficulty ambulating, and 2 required a cane or walker at the 12-month follow-up visit. At 24 months, 1 patient reported persistent pain.\n\nInitial treatment of all patients with osteoarticular infections was with voriconazole (Table 5). Debridement or washout procedures were required in 7 patients. All 4 patients with hip infection required revision arthroplasty, and another had resection of the distal clavicle. By 6 months, the infection was improved or stable in all patients. Among 8 patients for whom the status was known at 12 months, 3 (37%) were cured and 5 (63%) were improved (Table 6).\n\nAdverse Effects Associated With Antifungal Agents for All Groups\nAdverse events were common among patients receiving amphotericin B and voriconazole. The prominent side effects of amphotericin B began within the first few weeks of starting therapy and were primarily infusion-related or kidney dysfunction. By the 6-week follow-up visit, 101 patients (61%) had experienced a rising serum creatinine and 104 (62%) had hypokalemia and/or hypomagnesemia.\n\nVoriconazole treatment led to a variety of side effects that were the primary reason for changing from this drug to another azole. By 6 weeks, 292 patients (71%) had experienced a voriconazole-associated adverse event (Figure 3). Changes in liver enzymes had occurred in 191 patients (46%) by 6 weeks, but only rarely did these changes lead to discontinuation of the drug. Photopsia was an early adverse event within the first 6 weeks but was reported infrequently by 12 weeks; however, blurry vision and other visual complaints persisted for as long as 9 months in some patients.\n\nFigure 3. Adverse events experienced by patients taking voriconazole, shown by proportion of patients with specific adverse events in each designated time period.\n\nHallucinations were reported in 144 (35%) patients early in the course of therapy but decreased to <10% at later visits. Trouble focusing on the task at hand and feeling “fuzzy” in the head were still present in almost 20% of patients at 6 months.\n\nOverall Outcomes for All Groups\nAll-cause mortality was 8% (n = 35) (Figure 4A), with the meningitis/stroke-only group having a nearly 8-fold higher likelihood of death compared with the spinal/paraspinal infection-only group (hazard ratio, 7.62; 95% CI, 3.17–18.37). Although more likely to die, patients with meningitis/stroke had a shorter time to cure compared with patients who had spinal/paraspinal infection. Accounting for competing risk of death, the hazard ratio, indicating faster time to cure, was 3.68 (95% CI, 2.64–5.13) (Figure 4B).\n\nFigure 4. A, Kaplan-Maier survival curve for 4 patient disease categories when the event of interest is all-cause-mortality. B, Cumulative incidence curve for 4 patient disease categories accounting for competing risk of all-cause mortality when the event of interest is cure. With respect to cure, censoring (primarily loss to follow-up) occurred in 60% of patients in the spinal/paraspinal infection category, 50% in the meningitis/stroke and spinal/paraspinal infection category, 23% in the meningitis with or without stroke category, and 67% in the nonvertebral osteoarticular infection category.\n\nSeven patients suffered a relapse of infection: 4 with meningitis and spinal/paraspinal infection, 2 with only spinal/paraspinal infection, and 1 with meningitis alone. Four of the 7 had arachnoiditis. The initial course of antifungal therapy was with voriconazole, but therapy in 1 patient was changed to itraconazole after only 1 week. The median length of therapy (range) was 4 (2–9) months; patients ended therapy a median (range) of 3 (1–14) months before relapse occurred. Two of the 4 patients with arachnoiditis had received antifungal therapy for as long as 9 months, but the other 2 had been treated for only 2.5–4 months. One patient who had meningitis, without initial clinical or radiological signs of spine involvement, relapsed with lumbar vertebral osteomyelitis. All patients responded to a second course of prolonged antifungal therapy.\n\nDiscussion\nIn this retrospective review, we report the outcomes of 440 patients with infection caused by injection of methylprednisolone acetate contaminated with E. rostratum. The epidemiology, clinical manifestations, diagnosis, and treatment aspects of this large outbreak and a similar, but much smaller, outbreak have been reported previously [2, 3, 5–9, 11–18]; we report the long-term morbidity and mortality associated with this outbreak.\n\nOutcomes differed based on patient category. Morbidity was especially striking in patients with spinal/paraspinal involvement, and their response to antifungal agents was slow. A year after the injection, many of these patients could not walk without an assistive device. Back pain, which was the primary reason for the injection, became much worse with infection, and persistent pain was noted to interfere with the ability to perform ADLs in 13% of these patients.\n\nWe noted an unexpected dichotomy in outcomes experienced by patients who had meningitis/stroke compared with those who had localized spinal/paraspinal infection. Patients who had only meningitis/stroke had a mortality rate of 22% within 6 months of the diagnosis, but by 12 months, the cure rate for survivors was 89%, and only a handful of patients had residual neurological symptoms. The group with only spinal/paraspinal infection had a mortality rate of 2%; however, the 12-month cure rate was only 48%, and 43% remained on antifungal therapy. At 12 months, a third of patients in both groups that had spinal/paraspinal involvement continued to have symptoms and to require treatment with antifungal agents.\n\nArachnoiditis proved to be exceptionally difficult to treat, which has been noted in prior reports of this condition due to other causes [19]. Several patients with arachnoiditis had prolonged courses of antifungal therapy, as well as operative intervention, but still had persistent pain and bowel and bladder dysfunction. Four of 7 relapses were in patients who had arachnoiditis.\n\nIn comparison with patients who had epidural injections of methylprednisolone, infections associated with osteoarticular injections were less severe, but nevertheless associated with significant morbidity. Three patients had difficulty walking for at least 12 months, and 1 remained in an LTCF for >6 months.\n\nProlonged antifungal therapy contributed to the morbidity experienced by these patients. Voriconazole was the drug of choice because of its in vitro activity against E. rostratum and its ability to achieve adequate concentrations in the central nervous system (CNS). Adverse effects were expected based on prior experience and the need to give higher-than-usual doses of voriconazole initially when treating CNS infection. For example, by 6 weeks, one-third of patients had experienced hallucinations, an adverse effect associated with elevated serum trough concentrations of voriconazole [20–22], but with dose reduction and subsequent decreased serum voriconazole concentrations <5.5 μg/mL, the proportion of patients with hallucinations decreased to <10%.\n\nAlthough not as dramatic as hallucinations, a surprising number of patients complained of feelings of fogginess and slowness in carrying out their day-to-day activities. Family members noted that forgetfulness increased over time and that intermittent confusion and difficulties with word finding were common. These symptoms persisted for months and did not appear to be related to voriconazole serum concentrations. Most patients stated that these symptoms resolved when another azole agent was substituted for voriconazole.\n\nThe limitations of this study include the fact that only 440 (58%) of the 753 patients from only 8 sites were included. Some important events may have been missed because of this selection bias; for example, at least 2 other patients with a relapse were not included in this cohort [23, 24]. An unexpected limitation was that we could not follow the entire cohort because only 75% of patients were actively followed for 12 months and only a small, nonrepresentative proportion could be followed for 24 months. Given the observational nature of the study, patient visits did not correspond precisely with the stated follow-up time points, and retrospective data collection made it difficult to capture all possible treatment-related adverse events experienced by patients. Nevertheless, the study was able to describe the longest follow-up of patients who were affected by this fungal infection.\n\nIn conclusion, we report long-term sequelae associated with a large outbreak of fungal meningitis and spinal/paraspinal infections associated with the injection of contaminated methylprednisolone. Most patients who survived meningitis had total resolution of symptoms with antifungal therapy, whereas many of those who developed localized spinal/paraspinal infection had persistent pain and inability to perform ADLs for at least 12 months.\n\nAcknowledgments\n\nFinancial support. Funding for this study was provided by the Centers for Disease Control and Prevention, Gilead Sciences, and Merck.\n\n\n\nPotential conflicts of interest. A.M. owns shares in Pfizer; C.K. serves on data safety monitoring boards for Laboratoires SMB and Cidara Therapeutics; P.W. serves on the scientific advisory board for Cumberland Pharmaceuticals; P.P. has grant support from Merck, Astellas, Gilead, Scynexis, Amplyx, and Cidara; serves on scientific advisory boards for F2G, Scynexis, Amplyx, and Pfizer; and is on data review committees for Amplyx and Cidara. All others have no conflicts to declare. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1. \nPettit AC , Kropski JA , Castilho JL , et al. \nThe index case for the fungal meningitis outbreak in the United States\n. N Engl J Med 2012 ; 367 :2119 –25\n.23083311 \n2. Centers for Disease Control and Prevention (CDC). Multistate outbreak of fungal infection associated with injection of methylprednisolone acetate solution from a single compounding pharmacy – United States , 2012 \nMMWR Morb Mortal Wkly Rep 2012 ; 61 :839 –42\n.23076093 \n3. \nKainer MA , Reagan DR , Nguyen DB , et al ; Tennessee Fungal Meningitis Investigation Team \nFungal infections associated with contaminated methylprednisolone in Tennessee\n. N Engl J Med 2012 ; 367 :2194 –203\n.23131029 \n4. \nKerkering TM , Grifasi ML , Baffoe-Bonnie AW , et al. \nEarly clinical observations in prospectively followed patients with fungal meningitis related to contaminated epidural steroid injections\n. Ann Intern Med 2013 ; 158 :154 –61\n.23183583 \n5. \nMcCotter OZ , Smith RM , Westercamp M , et al. \nUpdate on multistate outbreak of fungal infections associated with contaminated methylprednisolone injections, 2012-2014\n. MMWR Morb Mortal Wkly Rep 2015 ; 64 :1200 –1\n.26513534 \n6. \nSmith RM , Schaefer MK , Kainer MA , et al ; Multistate Fungal Infection Outbreak Response Team \nFungal infections associated with contaminated methylprednisolone injections\n. N Engl J Med 2013 ; 369 :1598 –609\n.23252499 \n7. \nCenters for Disease Control and Prevention . Spinal and paraspinal infections associated with contaminated methylprednisolone acetate injections – Michigan, 2012–2013\n. MMWR 2013 ; 62 :377 –81\n.23677044 \n8. \nChiller TM , Roy M , Nguyen D , et al ; Multistate Fungal Infection Clinical Investigation Team \nClinical findings for fungal infections caused by methylprednisolone injections\n. N Engl J Med 2013 ; 369 :1610 –9\n.24152260 \n9. \nKauffman CA , Pappas PG , Patterson TF \nFungal infections associated with contaminated methylprednisolone injections\n. N Engl J Med 2013 ; 368 :2495 –500\n.23083312 \n10. \nFine J , Gray R \nA proportional hazards model for the subdistribution of a competing risk\n. J Am Statist Ass 1999 ; 94 :496 –509\n.\n11. \nPettit AC , Malani AN \nOutbreak of fungal infections associated with contaminated methylprednisolone acetate: an update\n. Curr Infect Dis Rep 2015 ; 17 :441 .25416847 \n12. \nLitvintseva AP , Hurst S , Gade L , et al. \nWhole-genome analysis of Exserohilum rostratum from an outbreak of fungal meningitis and other infections\n. J Clin Microbiol 2014 ; 52 :3216 –22\n.24951807 \n13. \nRitter JM , Muehlenbachs A , Blau DM , et al ; Exserohilum Infections Working Group \nExserohilum infections associated with contaminated steroid injections: a clinicopathologic review of 40 cases\n. Am J Pathol 2013 ; 183 :881 –92\n.23809916 \n14. \nLockhart SR , Pham CD , Gade L , et al. \nPreliminary laboratory report of fungal infections associated with contaminated methylprednisolone injections\n. J Clin Microbiol 2013 ; 51 :2654 –61\n.23761142 \n15. \nCenters for Disease Control and Prevention . Interim treatment guidance for central nervous system and parameningeal infections associated with injection of contaminated steroid products. 2012 Available at: http://www.cdc.gov/hai/outbreaks/clinicans/guidance_cns.html.\n16. \nMoudgal V , Singal B , Kauffman CA , et al. \nSpinal and paraspinal fungal infections associated with contaminated methylprednisolone injections\n. Open Forum Infect Dis 2014 ; 1 :XXX–XX .\n17. \nMalani AN , Vandenberg DM , Singal B , et al. \nMagnetic resonance imaging screening to identify spinal and paraspinal infections associated with injections of contaminated methylprednisolone acetate\n. JAMA 2013 ; 309 :2465 –72\n.23780459 \n18. \nCenters for Disease Control and Prevention. \nExophiala infection from contaminated injectable steroids prepared by a compounding pharmacy - United States, July-November 2002\n. MMWR Morb Mortal Wkly Rep 2002 ; 51 :1109 –12\n.12530707 \n19. \nBourne IH \nLumbo-sacral adhesive arachnoiditis: a review\n. J R Soc Med 1990 ; 83 :262 –5\n.2094232 \n20. \nPascual A , Calandra T , Bolay S , et al. \nVoriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes\n. Clin Infect Dis 2008 ; 46 :201 –11\n.18171251 \n21. \nPark WB , Kim NH , Kim KH , et al. \nThe effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial\n. Clin Infect Dis 2012 ; 55 :1080 –7\n.22761409 \n22. \nPascual A , Csajka C , Buclin T , et al. \nChallenging recommended oral and intravenous voriconazole doses for improved efficacy and safety: population pharmacokinetics-based analysis of adult patients with invasive fungal infections\n. Clin Infect Dis 2012 ; 55 :381 –90\n.22610925 \n23. \nSmith RM , Tipple M , Chaudry MN , et al. \nRelapse of fungal meningitis associated with contaminated methylprednisolone\n. N Engl J Med 2013 ; 368 :2535 –6\n.23718153 \n24. \nRenfrow JJ , Frenkel MB , Hsu W \nFungal contamination of methylprednisolone causing recurrent lumbosacral intradural abscess\n. Emerg Infect Dis 2017 ; 23 :552 –3\n.28221116\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "7(6)",
"journal": "Open forum infectious diseases",
"keywords": "Exserohilum rostratum; amphotericin B; arachnoiditis; meningitis; methylprednisolone; paraspinal infection; spinal infection; voriconazole",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofaa164",
"pmc": null,
"pmid": "32528999",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": "24951807;22610925;23131029;23761142;23809916;18171251;24152260;23718153;26513534;23677044;28221116;2094232;23076093;23183583;12530707;22761409;23083311;23083312;23252499;25416847;23780459;25734095",
"title": "Long-term Outcomes of Patients With Fungal Infections Associated With Contaminated Methylprednisolone Injections.",
"title_normalized": "long term outcomes of patients with fungal infections associated with contaminated methylprednisolone injections"
} | [
{
"companynumb": "NVSC2020US275714",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Acquired pure red cell aplasia (PRCA) and autoimmune hemolytic anemia (AIHA) are rare complications of immunosuppression in pediatric solid organ transplant patients. We report a 14-month-old female child who developed Coombs positive hemolytic anemia and reticulocytopenia while on tacrolimus after cardiac transplantation. She was successfully treated with rituximab after failing treatment with corticosteroids and intravenous immunoglobulins. Clinicians should consider PRCA differential diagnosis in a patient presenting with reticulocytopenia and hemolysis. In addition, the coexistence of PRCA with AIHA, and the response to therapy with rituximab, supports a common immune-mediated pathogenesis for both disorders.",
"affiliations": "Division of Pediatric Hematology Oncology, Department of Pediatrics, Loma Linda University, Loma Linda, California.;Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan.;Dayton Children's Hospital, Dayton, Ohio.",
"authors": "Abongwa|Chenue|C|http://orcid.org/0000-0002-9785-3047;Abusin|Ghada|G|;El-Sheikh|Ayman|A|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069283:Rituximab; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.26674",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "64(12)",
"journal": "Pediatric blood & cancer",
"keywords": "AIHA; PRCA; hemolysis; reticulocytopenia; rituximab",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000744:Anemia, Hemolytic, Autoimmune; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D012010:Red-Cell Aplasia, Pure; D000069283:Rituximab; D016559:Tacrolimus",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28598573",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of tacrolimus-related pure red cell aplasia and autoimmune hemolytic anemia with rituximab in a pediatric cardiac transplant patient.",
"title_normalized": "successful treatment of tacrolimus related pure red cell aplasia and autoimmune hemolytic anemia with rituximab in a pediatric cardiac transplant patient"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2017-01213",
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"drug": [
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"activesubstance": {
"activesubstancename": "TACROLIMUS"
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"abstract": "Biologic agents are regarded as an effective treatment for a variety of autoimmune diseases. These drugs have an acceptable safety and tolerability profile, although an increasing number of autoimmune conditions have been reported with their use. Additionally, a variety of cutaneous diseases have been associated with their use. Here we report our experience of adverse cutaneous events with the use of biologic agents. An alternative explanation for patients presenting with adverse cutaneous events including drug interactions must be carefully investigated.",
"affiliations": "Mayo Clinic Health System, Department of Rheumatology, Eau Claire, WI 54702 USA Sehgal.rahul@mayo.edu.;Marshfield Clinic Health System, Department of Dermatology, Marshfield, WI 54449 USA.;Marshfield Clinic Health System, Department of Pathology, Marshfield, WI 54449 USA.",
"authors": "Sehgal|Rahul|R|;Stratman|Erik J|EJ|;Cutlan|Jonathan E|JE|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; C502936:tocilizumab; D000068800:Etanercept; D000068582:Certolizumab Pegol",
"country": "United States",
"delete": false,
"doi": "10.3121/cmr.2017.1364",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1539-4182",
"issue": "16(1-2)",
"journal": "Clinical medicine & research",
"keywords": "Adverse drug events; Anti-TNF therapy; Autoimmune disease; Biologic agents; Cutaneous vasculitis",
"medline_ta": "Clin Med Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015535:Arthritis, Psoriatic; D001172:Arthritis, Rheumatoid; D000068582:Certolizumab Pegol; D004890:Erythema; D000068800:Etanercept; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009504:Neutrophils; D011565:Psoriasis; D013625:Takayasu Arteritis; D018366:Vasculitis, Leukocytoclastic, Cutaneous",
"nlm_unique_id": "101175887",
"other_id": null,
"pages": "41-46",
"pmc": null,
"pmid": "29610119",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15693003;21886723;15468359;20169304;25546688;22515220;15899052;19648274;16197383;24903614;19628303;22383356;20149320;28252861;25110258;19579151;20731650;17149453;21036648;11735706;23891394;23133751;19854301;17823524;22670004;14521689;15853915;17876646;14740451;24942661;17655751",
"title": "Biologic Agent-Associated Cutaneous Adverse Events: A Single Center Experience.",
"title_normalized": "biologic agent associated cutaneous adverse events a single center experience"
} | [
{
"companynumb": "US-MYLANLABS-2018M1070768",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugadditional": null... |
{
"abstract": "Atraumatic spontaneous Achilles tendon ruptures sometimes occur in patients receiving oral corticosteroids. In general, these cases are treated surgically; however, delayed postoperative management can lead to impaired activities of daily living. The modified side-locking loop suture (SLLS) technique is a useful suture method for safe and early active mobilization. Three cases of spontaneous Achilles tendon ruptures were treated with the modified SLLS technique with good clinical results. The modified SLLS technique is a useful method with a short rehabilitation period for treating atraumatic spontaneous Achilles tendon rupture in patients undergoing corticosteroid therapy.",
"affiliations": "Orthopedist, Department of Orthopaedic Surgery, Shimane University Faculty of Medicine, Shimane, Japan.;Assistant Professor, Department of Orthopaedic Surgery, Shimane University Faculty of Medicine, Shimane, Japan. Electronic address: imades@med.shimane-u.ac.jp.;Orthopedist, Department of Orthopaedic Surgery, Shimane University Faculty of Medicine, Shimane, Japan.;Assistant Professor, Department of Orthopaedic Surgery, Shimane University Faculty of Medicine, Shimane, Japan.;Professor, Department of Orthopaedic Surgery, Shimane University Faculty of Medicine, Shimane, Japan.",
"authors": "Ushio|Kiminori|K|;Imade|Shinji|S|;Takuwa|Hiroshi|H|;Kadowaki|Masaru|M|;Uchio|Yuji|Y|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
"country": "United States",
"delete": false,
"doi": "10.1053/j.jfas.2017.10.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1067-2516",
"issue": "57(3)",
"journal": "The Journal of foot and ankle surgery : official publication of the American College of Foot and Ankle Surgeons",
"keywords": "antislip knot; corticosteroid; early rehabilitation; magnetic resonance image; surgical treatment",
"medline_ta": "J Foot Ankle Surg",
"mesh_terms": "D000125:Achilles Tendon; D000305:Adrenal Cortex Hormones; D004434:Early Ambulation; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D019637:Orthopedic Procedures; D010147:Pain Measurement; D011379:Prognosis; D018570:Risk Assessment; D012422:Rupture, Spontaneous; D012494:Sampling Studies; D013536:Suture Techniques; D016896:Treatment Outcome; D014945:Wound Healing",
"nlm_unique_id": "9308427",
"other_id": null,
"pages": "600-604",
"pmc": null,
"pmid": "29398512",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Atraumatic Spontaneous Achilles Tendon Rupture in Patients Receiving Oral Corticosteroids Treated With the Modified Side-Locking Loop Suture Technique.",
"title_normalized": "atraumatic spontaneous achilles tendon rupture in patients receiving oral corticosteroids treated with the modified side locking loop suture technique"
} | [
{
"companynumb": "JP-TEVA-2018-JP-972098",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo describe a case of BK virus encephalitis with attempted direct antiviral therapy, review the reported cases of BK virus in the central nervous system, and report the novel use of intravenous cimetidine in place of oral probenecid to minimize the toxicities of intravenous cidofovir.\n\n\nMETHODS\nA 36-year-old male with acute myelomonocytic leukemia and subsequent myelodysplastic syndrome underwent allogeneic hematopoietic stem cell transplant. His course was complicated by severe graft-versus-host disease involving his skin and gastrointestinal tract. Five weeks after transplantation, he developed fever and confusion. Magnetic resonance imaging was suggestive of limbic encephalitis and cerebrospinal fluid tested positive for BK virus. Therapy with intravenous cidofovir was thought to be indicated. Although probenecid is commonly used to minimize the toxicities of cidofovir, the patient's severe graft-versus-host disease raised concerns about absorption of oral medications. Based on animal models and pharmacokinetic data, intravenous cimetidine was used in place of oral probenecid. Despite these therapies, the patient's mental status did not improve. He developed progressive organ system failure, and care was ultimately withdrawn.\n\n\nCONCLUSIONS\nBK virus is increasingly described as a cause of encephalitis. The majority of reported cases have occurred in immunocompromised patients and have generally had a poor outcome. This case describes attempted antiviral therapy using cidofovir, the antiviral agent used most frequently in other syndromes due to BK virus. Intravenous cimetidine is a novel modality used to minimize ocular and renal toxicities frequently seen with cidofovir, and we believe this warrants further investigation.\n\n\nCONCLUSIONS\nBK virus may be a cause of encephalitis in immunocompromised hosts, and cidofovir represents a possible treatment option. Intravenous cimetidine can be considered to minimize toxicities associated with cidofovir use in patients unable to tolerate or absorb oral probenecid.",
"affiliations": "Beaumont Health System, Royal Oak, MI, USA.",
"authors": "Chittick|Paul|P|;Williamson|John C|JC|;Ohl|Christopher A|CA|",
"chemical_list": "D000998:Antiviral Agents; D063065:Organophosphonates; D003596:Cytosine; D000077404:Cidofovir",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028013500646",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "47(9)",
"journal": "The Annals of pharmacotherapy",
"keywords": "BK virus; cidofovir; cimetidine; encephalitis in immunocompromised hosts",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D001739:BK Virus; D000077404:Cidofovir; D003596:Cytosine; D004660:Encephalitis; D006801:Humans; D008297:Male; D063065:Organophosphonates; D027601:Polyomavirus Infections; D014412:Tumor Virus Infections",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1229-33",
"pmc": null,
"pmid": "24259742",
"pubdate": "2013-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "BK virus encephalitis: case report, review of the literature, and description of a novel treatment modality.",
"title_normalized": "bk virus encephalitis case report review of the literature and description of a novel treatment modality"
} | [
{
"companynumb": "US-MYLANLABS-2021M1057355",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
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"abstract": "Coronavirus disease (COVID-19) has been shown to affect all age groups. The data in the literature usually admit a milder form of disease in infants and newborns than adults. COVID-19 is rarely seen in newborns and an urgent diagnosis should be made in any suspicious situation. A 6-day-old female newborn was admitted to our hospital with fever and dyspnea without cough. A rapid reverse-transcription polymerase chain reaction COVID-19 showed a positive result. Chest computed tomography revealed bilateral and widespread pulmonary involvement. After support therapy, the newborn was successfully discharged. We should carefully consider the new type of coronavirus as an agent for pneumonia in newborns with fever and dyspnea together with non-symptomatic family history. Our case was one of the interesting reported cases of severe pneumonia presenting in the perinatal period.",
"affiliations": "Division of Neonatology, Department of Pediatrics, Health Sciences University, Ankara City Hospital, Ankara, Turkey.;Department of Pediatrics, Health Sciences University, Ankara City Hospital, Ankara, Turkey.;Department of Pediatric Infectious Diseases, Health Sciences University, Ankara City Hospital, Ankara, Turkey.;Division of Neonatology, Department of Pediatrics, Health Sciences University, Ankara City Hospital, Ankara, Turkey.;Division of Neonatology, Department of Pediatrics, Health Sciences University, Ankara City Hospital, Ankara, Turkey.;Division of Neonatology, Department of Pediatrics, Health Sciences University, Ankara City Hospital, Ankara, Turkey.",
"authors": "Cakir|Ufuk|U|0000-0002-9409-185X;Demirel|Merve Akin|MA|;Yuksek|Saliha Kanik|SK|;Tugcu|Ali Ulas|AU|;Tufan|Nihan|N|;Tayman|Cuneyt|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/tropej/fmab023",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0142-6338",
"issue": "67(4)",
"journal": "Journal of tropical pediatrics",
"keywords": "coronavirus; newborn; pneumonia",
"medline_ta": "J Trop Pediatr",
"mesh_terms": "D000328:Adult; D000086382:COVID-19; D003371:Cough; D004417:Dyspnea; D005260:Female; D005334:Fever; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D011247:Pregnancy; D000086402:SARS-CoV-2",
"nlm_unique_id": "8010948",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34471924",
"pubdate": "2021-08-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32304191;32161941;32349772;32233816;33060565;32179660;32285380;32757186;31986264;32065520;32943533;33287880;15165741;31995857;11023764;32134205;32392948;30971386;32115733",
"title": "Case Report of Severe COVID-19 Pneumonia in a Term Newborn.",
"title_normalized": "case report of severe covid 19 pneumonia in a term newborn"
} | [
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"companynumb": "TR-LUPIN PHARMACEUTICALS INC.-2021-22173",
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"abstract": "BACKGROUND\nPatients with CHD-PAH have a limited prognosis. In daily practice, combination therapy is often initiated after a clinical event. Although clinical events have been associated with a poor prognosis in idiopathic PAH, data on this association are limited in CHD-PAH. The aim of this study was to determine whether baseline characteristics and clinical events associate with mortality in patients with pulmonary hypertension (PAH) due to congenital heart disease (CHD).\n\n\nMETHODS\nIn total 91 consecutive adults (42 ± 14 year) with CHD-PAH were referred for therapy between January 2005 and June 2013. Cox proportional hazard analysis was performed to identify determinants of mortality, including clinical events as time dependent covariates.\n\n\nRESULTS\nTwenty-four patients (nine with Down) died during the median follow-up of 4.7 (range 0.1-7.9) years. The one and eight year mortality rates were 7.3% and 37.3%, respectively. Clinical events included admission for heart failure (n=9), arrhythmias (n=9), haemoptysis (n=5), change to a worse NYHA class (n=16), vascular events (n=1), syncope (n=1) and need for red blood cell depletion (n=4). In univariate analysis, both baseline characteristics and clinical events were associated with mortality. In multivariate analysis, only baseline NT-pro-BNP serum level ≥ 500 ng/L and TAPSE<15mm at echocardiography were significant determinants of mortality. None of the clinical events remained significant. Patients with both a NT-pro-BNP serum level ≥ 500 ng/L and TAPSE<15mm at echocardiography have a nine fold higher mortality rate than patients without both risk factors.\n\n\nCONCLUSIONS\nPrognosis is still poor in contemporary patients with CHD-PAH. Both baseline NT-pro-BNP serum level and right ventricular function are superior to clinical events in prognostication. These two baseline characteristics should have a major impact on therapeutic management in patients with CHD-PAH, such as initiation of combination therapy.",
"affiliations": "Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.;Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.;Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands.;Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands.;Department of Cardiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.;Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands.;Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, The Netherlands.;Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands. Electronic address: b.j.mulder@amc.uva.nl.;Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands.",
"authors": "Schuuring|Mark J|MJ|;van Riel|Annelieke C M J|AC|;Vis|Jeroen C|JC|;Duffels|Marielle G|MG|;van Dijk|Arie P J|AP|;de Bruin-Bon|Rianne H A C M|RH|;Zwinderman|Aeilko H|AH|;Mulder|Barbara J M|BJ|;Bouma|Berto J|BJ|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0167-5273",
"issue": "181()",
"journal": "International journal of cardiology",
"keywords": "Congenital heart disease; Mortality; Predictors; Pulmonary hypertension",
"medline_ta": "Int J Cardiol",
"mesh_terms": "D000328:Adult; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006330:Heart Defects, Congenital; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D008875:Middle Aged; D009026:Mortality; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012307:Risk Factors; D016896:Treatment Outcome",
"nlm_unique_id": "8200291",
"other_id": null,
"pages": "270-6",
"pmc": null,
"pmid": "25535690",
"pubdate": "2015-02-15",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "New predictors of mortality in adults with congenital heart disease and pulmonary hypertension: Midterm outcome of a prospective study.",
"title_normalized": "new predictors of mortality in adults with congenital heart disease and pulmonary hypertension midterm outcome of a prospective study"
} | [
{
"companynumb": "NL-ACTELION-A-CH2015-116981",
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"activesubstance": {
"activesubstancename": "SILDENAFIL"
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{
"abstract": "We present a case with co-existing Parkinson's disease and Tourette syndrome. Patient takes aripiprazole for Tourette syndrome, which unfortunately worsens his parkinsonian symptoms. We placed deep brain stimulation targeting the Globus pallidus internus. Strikingly, his parkinsonian motor symptoms and his tics are both well controlled with deep brain stimulation.",
"affiliations": "Department of Neurology, University of Iowa Hospitals and Clinics, 200 Hawkins Dr., Iowa City, IA, United States of America.;Department of Neurology, University of Iowa Hospitals and Clinics, 200 Hawkins Dr., Iowa City, IA, United States of America.",
"authors": "Zhang|Qiang|Q|;Thomsen|Teri R|TR|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.prdoa.2020.100077",
"fulltext": "\n==== Front\nClin Park Relat Disord\nClin Park Relat Disord\nClinical Parkinsonism & Related Disorders\n2590-1125\nElsevier\n\nS2590-1125(20)30045-1\n10.1016/j.prdoa.2020.100077\n100077\nCase Report\nDeep brain stimulation targeting the Globus pallidus internus for Parkinson's disease and Tourette syndrome\nZhang Qiang abc\nThomsen Teri R. teri-thomsen@uiowa.edu\na⁎\na Department of Neurology, University of Iowa Hospitals and Clinics, 200 Hawkins Dr., Iowa City, IA, United States of America\nb Physician Scientist Training Program, University of Iowa School of Medicine, 200 Hawkins Dr., Iowa City, IA, United States of America\nc Clinical NeuroScientist Training Program, University of Iowa Hospitals and Clinics, 200 Hawkins Dr., Iowa City, IA, United States of America\n⁎ Corresponding author at: 200 Hawkins Dr., Iowa City, IA, United States of America. teri-thomsen@uiowa.edu\n16 10 2020\n2020\n16 10 2020\n3 1000775 8 2020\n11 9 2020\n12 10 2020\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/).\nWe present a case with co-existing Parkinson's disease and Tourette syndrome. Patient takes aripiprazole for Tourette syndrome, which unfortunately worsens his parkinsonian symptoms. We placed deep brain stimulation targeting the Globus pallidus internus. Strikingly, his parkinsonian motor symptoms and his tics are both well controlled with deep brain stimulation.\n\nHighlights\n\n• Patients with Tourette syndrome and Parkinson's disease may benefit from GPi DBS.\n\n• Higher frequency (130 Hz) GPi DBS may be helpful for tics.\n\n• Lower pulse width (60 μs) could be beneficial in Tourette syndrome.\n\n• Empirical combinations of pulse width and frequency should be liberally employed to maximize benefit.\n\nKeywords\n\nGlobus pallidus internus (GPi)\ndeep brain stimulation (DBS)\nTourette syndrome\nTics\nTremor\nParkinson's disease\nFrequency\nPulse width\n==== Body\nA 61-year-old right-handed gentleman with Tourette syndrome (TS) presented with tremor. Patient's tics started when he was 10. He had vocal tics with throat clearing, and vocalizations, but he never had coprolalia. He also had motor tics with head shaking, eye blinking, facial grimacing, and occasionally limb movements. He was not diagnosed of TS until he was in his 20s. He developed right-hand resting tremor twenty years ago, after he started taking pimozide for TS. He continued to take pimozide for ten years and switched to risperidone (7 years) then ziprasidone (3 years) until aripiprazole was started 1 year ago. His tremor was mild initially but gradually got worse and did not improve after switching to aripiprazole. At his initial visit, he had unilateral resting right-hand tremor, as well as mild rigidity and bradykinesia only on the right. He also had a slightly flexed posture and reduced arm swing on the right. Of note, his son, father, paternal uncle, and maternal grandfather all had Parkinson's disease (PD). He may have had drug-induced parkinsonism (DIP), however, given the asymmetric tremor predominant nature, along with a strong family history of PD, we favored a diagnosis of PD. His symptoms improved with amantadine, but as the disease continued to progress, we had to add ropinirole and carbidopa\\levodopa, both worsened his tics. Eight years after his initial visit, he was taking aripiprazole at 30 mg twice daily with poorly controlled tics. He was also taking carbidopa/levodopa 25/100 extended-release twice daily, carbidopa/levodopa 50/200 extended-release at bedtime, ropinirole 8 mg three times daily, and amantadine 100 mg three times daily, but his tremor was still debilitating. We did a carbidopa/levodopa OFF/ON test, and his UPDRS motor score improved from 23.5 to 4.5. At this point, we decided to proceed with deep brain stimulation (DBS) targeting the Globus pallidus internus (GPi), in the hope of improving his parkinsonian motor symptoms as well as his tics. For GPi targeting, our surgical team employed a combination of 3D coordinates with MRI/CT, intra-operation microelectrodes recording, and intra-operation stimulation associated symptomatic improvement.\n\nFor his initial GPi DBS programming, we used monopolar settings and achieved adequate tremor control (Table 1.1). The patient also had significant improvement in tics. One month later, we increased the amplitude with further improvement in tremor and tics (Table 1.2). Over time, his parkinsonian motor symptoms continued to progress, however, we were able to manage his symptoms by adjusting the DBS settings. Three years after the DBS placement, patient continues to have good control of his parkinsonian symptoms and tics with double bipolar settings on the left GPi DBS, and mono-bipolar settings on the right GPi DBS (Table 1.3). Interestingly, patient has long standing obsessive-compulsive disorder, and anxiety. Both psychiatric conditions gradually worsened as we titrate up DBS settings, and he required the addition of escitalopram 2 years after DBS placement. It is unclear whether this is associated with DBS (we have gradually increased DBS settings), or PD.Table 1.1 GPi DBS parameters after initial programming (2/2016).\n\nTable 1.1\tElectrode configuration\tVoltage (V)\tPulse width (μs)\tFrequency (Hz)\tTherapeutic effects\t\nLeft GPi\t2-\t1.2\t60\t130\tAdequate tremor control, improved tics\t\nRight GPi\t10-\t0.7\t60\t130\t\n\nTable 1.2 GPi DBS parameters 2nd programming (3/2016).\n\nTable 1.2\tElectrode configuration\tVoltage (V)\tPulse width (μs)\tFrequency (Hz)\tTherapeutic effects\t\nLeft GPi\t2-\t1.5\t60\t130\tImproved tremor control, improved tics\t\nRight GPi\t10-\t0.9\t60\t130\t\n\nTable 1.3 GPi DBS last programming (8/2019).\n\nTable 1.3\tElectrode configuration\tVoltage (V)\tPulse width (μs)\tFrequency (Hz)\tTherapeutic effects\t\nLeft GPi\t3+, 2-, 1-\t4.0\t60\t130\tAdequate control of tremor and tics\t\nRight GPi\t10+, 9-\t4.8\t60\t130\t\nMedtronic DBS device, 4 contacts on the left GPi DBS lead, from top to bottom: 3,2,1,0.\n\n4 contacts on the right GPi DBS lead, from top to bottom: 11, 10, 9, 8.\n\nAlthough aripiprazole may have contributed to parkinsonian motor symptoms, the clinical presentation is most consistent with PD. As a new generation atypical anti-psychotic, aripiprazole is associated with lower rate of adverse effects. However, there has been reports of aripiprazole associated DIP [[1], [2], [3]]. While PD patients usually have asymmetric motor symptoms, DIP tends to be symmetric. Pieters et al., evaluated the frequency of asymmetric parkinsonism among patients with DIP, and found 20.8% of these patients presented with asymmetric features [4]. Interestingly, in this study, the mean symmetry index was 0.16 for bradykinesia items (considered asymmetric above 0.20), and lowest at 0.06 for tremor items. This suggests that asymmetric tremors are the least likely presentation in DIP. Considering the strong family history and the progressive course, PD is most likely. We did not order a DAT scan as this would not have changed our management; therefore, we cannot completely rule out the possibility that the patient does not have PD.\n\nTS can be managed by medication; however, a small group of patients with poor response to medications may benefit from GPi DBS [5,6]. Neuroleptics can be very effective in TS, however, they can cause DIP. In our case, with the progression of PD, the medications used to treat TS (aripiprazole), and PD (ropinirole, levodopa, amantadine) started to counteract each other, to the point that tics and tremors were both out of control. To this end, GPi DBS naturally came up as a possible solution.\n\nTo our knowledge, this is the first case reporting GPi DBS in a patient with co-existing PD and TS. Patel et al., reported a 21 year-old lady with malignant TS and DIP, who benefited from GPi DBS treatment [7]. The authors achieved good clinical outcome with monopolar settings at high pulse width (90–110 μs) and high frequency (150 Hz). Therefore, GPi DBS maybe helpful in DIP as well.\n\nIn summary, we report a patient with co-existing PD and TS, who benefited from GPi DBS. Specifically, with high frequency (130 Hz) and low pulse width (60 μs) stimulation, which is typically used in PD, we not only got parkinsonian motor symptoms well controlled, but also achieved great outcome with his tics (see Video 1, Video 2, Video 3). The conflicting nature of medical treatments for PD and TS makes it very difficult to manage both conditions at the same time. GPi DBS may be an option to consider in these cases.\n\nIn summary, we report a patient with co-existing PD and TS, who benefited from GPi DBS. Specifically, with high frequency (130 Hz) and low pulse width (60 μs) stimulation, which is typically used in PD, we not only got parkinsonian motor symptoms well controlled, but also achieved great outcome with his tics (see videos with DBS ON/OFF). The conflicting nature of medical treatments for PD and TS makes it very difficult to manage both conditions at the same time. GPi DBS may be an option to consider in these cases.\n\nThe following are the supplementary data related to this article.Video 1\n\nDBS ON.\n\nVideo 1\n\nVideo 2\n\nDBS OFF.\n\nVideo 2\n\nVideo 3\n\nDBS OFF short.\n\nVideo 3\n\nSupplementary data to this article can be found online at https://doi.org/10.1016/j.prdoa.2020.100077.\n\nDeclaration of competing interest\n\nQ. Zhang and T. Thomsen report no relevant disclosures.\n\nAcknowledgements\n\nQZ is supported by the 10.13039/100000065 NINDS R25 grant, the 10.13039/100000065 NINDS NeuroNext fellowship, a pilot project grant from the Aging Mind and Brain Initiative at University of Iowa, and the 10.13039/100008893 University of Iowa Carver College of Medicine Physician Scientist Training Pathway. QZ was a trainee of the University of Iowa Clinical Neuroscientist Training Program (CNS-TP).\n==== Refs\nReferences\n\n1 Lopez-Torres E. Salomon J. Vicario F. Penas-Lledo E. Dorado P. Llerena A. Aripiprazole-induced parkinsonism and its association with dopamine and serotonin receptor polymorphisms J. Clin. Psychopharmacol. 28 2008 352 353 18480698\n2 Lua L.L. Zhang L. Development of Parkinsonism following exposure to aripiprazole: two case reports J. Med. Case Rep. 3 2009 6448 19830105\n3 Sharma A. Sorrell J.H. Aripiprazole-induced parkinsonism Int. Clin. Psychopharmacol. 21 2006 127 129 16421466\n4 Pieters L.E. Bakker P.R. van Harten P.N. Asymmetric drug-induced parkinsonism and psychopathology: a prospective naturalistic study in long-stay psychiatric patients Front. Psychiatry 9 2018 18 29459835\n5 Shahed J. Poysky J. Kenney C. Simpson R. Jankovic J. GPi deep brain stimulation for Tourette syndrome improves tics and psychiatric comorbidities Neurology 68 2007 159 160 17210901\n6 Dehning S. Mehrkens J.H. Muller N. Botzel K. Therapy-refractory Tourette syndrome: beneficial outcome with globus pallidus internus deep brain stimulation Mov. Disord. 23 2008 1300 1302 18528896\n7 Patel N. Jimenez-Shahed J. Simultaneous improvement of tics and parkinsonism after pallidal DBS Parkinsonism Relat. Disord. 20 2014 1022 1023 24957594\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2590-1125",
"issue": "3()",
"journal": "Clinical parkinsonism & related disorders",
"keywords": "Frequency; Globus pallidus internus (GPi); Parkinson's disease; Pulse width; Tics; Tourette syndrome; Tremor; deep brain stimulation (DBS)",
"medline_ta": "Clin Park Relat Disord",
"mesh_terms": null,
"nlm_unique_id": "101761473",
"other_id": null,
"pages": "100077",
"pmc": null,
"pmid": "34316655",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "29459835;17210901;24957594;18480698;16421466;19830105;18528896",
"title": "Deep brain stimulation targeting the Globus pallidus internus for Parkinson's disease and Tourette syndrome.",
"title_normalized": "deep brain stimulation targeting the globus pallidus internus for parkinson s disease and tourette syndrome"
} | [
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"abstract": "As the transgender patient population continues to grow, health care providers will need to become aware of elements unique to the transgender community in order to provide the highest quality of care. Neuromuscular blockade with succinylcholine is routinely administered to patients undergoing electroconvulsive therapy (ECT). Decreased amounts or activity of pseudocholinesterase in serum can lead to prolonged duration of muscle paralysis. Causes of reduced action by pseudocholinesterase include genetically abnormal enzymes, reduced hepatic production, pregnancy, and various drug interactions. Estrogen supplementation taken by transitioning patients may affect the duration of neuromuscular blockade.This is a case of a 32-year-old male-to-female transgender patient with prolonged apnea following ECT treatment for severe, refractory depression. Further investigation revealed the patient was on estrogen therapy as a part of her transition and laboratory testing demonstrated reduced serum pseudocholinesterase activity. Further laboratory testing demonstrated reduced serum pseudocholinesterase activity. Succinylcholine dosing was titrated to an appropriate level to avoid prolonged apnea in subsequent ECT treatments. Physicians and other health care providers are faced with a unique population in the transgender community and must be aware of distinctive circumstances when providing care to this group. Of specific interest, many transitioning and transitioned patients can be on chronic estrogen supplementation. Neuromuscular blockade in those patients require attention from the anesthesiology care team as estrogen compounds may decrease pseudocholinesterase levels and lead to prolonged muscle paralysis from succinylcholine.",
"affiliations": "From the Departments of *Anesthesiology, †Pathology and Laboratory Medicine, and ‡Orthopaedics and Rehabilitation, University of Vermont College of Medicine, Burlington, VT.",
"authors": "Tran|Billy K|BK|;O'Donnell|Stephen E|SE|;Balla|Agnes|A|;Adams|David C|DC|;Grondin|Lydia S|LS|;Tsai|Mitchell H|MH|",
"chemical_list": "D000732:Androstanols; D004967:Estrogens; D009467:Neuromuscular Depolarizing Agents; D047408:gamma-Cyclodextrins; D000077122:Sugammadex; D002091:Butyrylcholinesterase; D013390:Succinylcholine; D000077123:Rocuronium",
"country": "United States",
"delete": false,
"doi": "10.1097/YCT.0000000000000371",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1095-0680",
"issue": "33(2)",
"journal": "The journal of ECT",
"keywords": null,
"medline_ta": "J ECT",
"mesh_terms": "D000328:Adult; D000732:Androstanols; D001049:Apnea; D002091:Butyrylcholinesterase; D061218:Depressive Disorder, Treatment-Resistant; D004347:Drug Interactions; D004565:Electroconvulsive Therapy; D004967:Estrogens; D005260:Female; D006801:Humans; D008297:Male; D009467:Neuromuscular Depolarizing Agents; D000077123:Rocuronium; D057829:Sex Reassignment Procedures; D013390:Succinylcholine; D000077122:Sugammadex; D063106:Transgender Persons; D047408:gamma-Cyclodextrins",
"nlm_unique_id": "9808943",
"other_id": null,
"pages": "e14-e16",
"pmc": null,
"pmid": "28009618",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Electroconvulsive Therapy Considerations for Transgendered Patients.",
"title_normalized": "electroconvulsive therapy considerations for transgendered patients"
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"activesubstancename": "SUCCINYLCHOLINE CHLORIDE"
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... |
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"abstract": "BACKGROUND Drug-induced anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) should be suspected in patients on certain medications who present with inflammatory ocular, constitutional, pulmonary, and/or renal manifestations. Here, we present a case of propylthiouracil (PTU)-induced AAV presenting initially with red eye, and review important diagnostic and management considerations for this uncommon disorder. CASE REPORT A 34-year-old woman with hyperthyroidism taking PTU presented with red eye, later followed by fevers and hemoptysis. She was found to have episcleritis, diffuse alveolar hemorrhage, and microhematuria. The infectious diseases workup was unrevealing. Laboratory evaluations were notable for a high-titer perinuclear ANCA and elevated anti-myeloperoxidase antibodies. Renal function was normal. She was ultimately diagnosed with PTU-induced AAV. PTU was promptly discontinued and she was treated with pulse-dose methylprednisolone for 3 days, followed by prednisone 60 mg daily. A kidney biopsy revealed pauci-immune focal segmental necrotizing and crescentic glomerulonephritis. Given an allergy to methimazole, she underwent thyroidectomy and was ultimately treated with rituximab. Her steroid doses are progressively being tapered and she has complete resolution of symptoms. CONCLUSIONS PTU-induced AAV is a rare and serious condition. Our patient presented with ocular symptoms prior to more commonly recognized pulmonary and renal manifestations. Patients may have favorable outcomes if PTU is discontinued promptly, but patients with vital-organ involvement may require treatment with steroids and may need additional immunosuppression.",
"affiliations": "Department of Internal Medicine, Hackensack Meridian Health, Jersey Shore University Medical Center, Neptune, NJ, USA.;Department of Endocrinology, Hackensack Meridian Health, Jersey Shore University Medical Center, Neptune, NJ, USA.;Department of Rheumatology, Hackensack Meridian Health, Jersey Shore University Medical Center, Neptune, NJ, USA.",
"authors": "Alidoost|Marjan|M|;Cheng|Jennifer|J|;Alpert|Deborah R|DR|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D013956:Antithyroid Agents; D011441:Propylthiouracil; D009195:Peroxidase",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.925200",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n33293503\n10.12659/AJCR.925200\n925200\nArticles\nPropylthiouracil-Induced Anti-Neutrophil Cytoplasmic Antibody Vasculitis Presenting with Red Eye Followed by Pulmonary Hemorrhage: Diagnostic and Management Considerations\nAlidoost Marjan EF1 Cheng Jennifer EF2 Alpert Deborah R. ABEF3 \n1 Department of Internal Medicine, Hackensack Meridian Health, Jersey Shore University Medical Center, Neptune, NJ, U.S.A.\n\n2 Department of Endocrinology, Hackensack Meridian Health, Jersey Shore University Medical Center, Neptune, NJ, U.S.A.\n\n3 Department of Rheumatology, Hackensack Meridian Health, Jersey Shore University Medical Center, Neptune, NJ, U.S.A.\nCorresponding Author: Deborah R. Alpert, e-mail: Deborah.Alpert@hmhn.orgAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n09 12 2020 \n21 e925200-1 e925200-5\n16 4 2020 15 10 2020 28 10 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 34-year-old\n\nFinal Diagnosis: Vascuitis\n\nSymptoms: Hemoptysis\n\nMedication:—\n\nClinical Procedure: —\n\nSpecialty: Rheumatology\n\nObjective:\nRare disease\n\nBackground:\nDrug-induced anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) should be suspected in patients on certain medications who present with inflammatory ocular, constitutional, pulmonary, and/or renal manifestations. Here, we present a case of propylthiouracil (PTU)-induced AAV presenting initially with red eye, and review important diagnostic and management considerations for this uncommon disorder.\n\nCase Report:\nA 34-year-old woman with hyperthyroidism taking PTU presented with red eye, later followed by fevers and hemoptysis. She was found to have episcleritis, diffuse alveolar hemorrhage, and microhematuria. The infectious diseases workup was unrevealing. Laboratory evaluations were notable for a high-titer perinuclear ANCA and elevated anti-myeloperoxidase antibodies. Renal function was normal. She was ultimately diagnosed with PTU-induced AAV. PTU was promptly discontinued and she was treated with pulse-dose methylprednisolone for 3 days, followed by prednisone 60 mg daily. A kidney biopsy revealed pauci-immune focal segmental necrotizing and crescentic glomerulonephritis. Given an allergy to methimazole, she underwent thyroidectomy and was ultimately treated with rituximab. Her steroid doses are progressively being tapered and she has complete resolution of symptoms.\n\nConclusions:\nPTU-induced AAV is a rare and serious condition. Our patient presented with ocular symptoms prior to more commonly recognized pulmonary and renal manifestations. Patients may have favorable outcomes if PTU is discontinued promptly, but patients with vital-organ involvement may require treatment with steroids and may need additional immunosuppression.\n\nMeSH Keywords:\nAnti-Neutrophil Cytoplasmic Antibody-Associated VasculitisConjunctivitisHemorrhagePropylthiouracil\n==== Body\nBackground\nVasculitis is characterized by inflammation in blood vessel walls that can cause damage to visceral organs, which may occur via ischemia or necrosis [1]. It is often challenging to diagnose vasculitis, since it may present with a wide variety of symptoms that can potentially affect any organ system. Vasculitis can have numerous presentations, including constitutional symptoms such as fever, arthralgias, and myalgias, as well as various organ manifestations affecting the eyes, skin, nervous system, heart, lungs, gastrointestinal tract, and kidneys [2]. Vasculitis can be classified by size of affected vessels, as well as by primary versus secondary cause. In vasculitis patients, it is estimated that 90% of c-ANCA is directed against proteinase 3 (PR3), while 80-90% of p-ANCA is directed against myeloperoxidase (MPO) [3]. An important subtype of secondary vasculitis is drug-induced vasculitis, which is often an ANCA-associated necrotizing small-vessel vasculitis [2]. Drugs that may be associated with ANCA-associated vasculitis (AAV) include hydralazine, minocycline, ciprofloxacin, phenytoin, levamisole-adulterated cocaine, and propylthiouracil (PTU) [4]. We describe a patient taking PTU for hyperthyroidism who presented initially with episcleritis, prior to a pulmonary-renal syndrome that was diagnosed as PTU-induced vasculitis. Our case highlights the importance of prompt recognition of PTU-induced vasculitis presenting initially with ocular symptoms, cessation of the offending agent, immunosuppressive treatment, and appropriate treatment of the underlying thyroid disease.\n\nCase Report\nA 34-year-old woman with a history of Grave’s hyperthyroidism maintained on PTU for 2 years presented to the Emergency Department with irritated bilateral red eyes for 3 weeks. She denied any visual change or eye discharge. She also reported sneezing and coughing, and denied myalgias, arthralgias, fever, or fatigue. Her ocular symptoms were initially attributed to allergic conjunctivitis, but as they did not improve, she was given a trial of besifloxacin eye drops. A chest X-ray showed a patchy right lower-lobe airspace opacity with air bronchograms (Figure 1). At that time, she was diagnosed with community-acquired pneumonia and discharged with a course of oral levofloxacin. As an outpatient, she was subsequently evaluated by ophthalmology and diagnosed with episcleritis.\n\nOne month later, she presented to the hospital with hemoptysis for 2 weeks, coughing up 20–30 mL of coagulated blood with each episode. At that time, she also reported fevers with a maximum temperature of 38°C, fatigue, arthralgias, and myalgias. She denied decreased urine output, rash, hematuria, or hematochezia. Upon hospital admission, she was found to have severe anemia, with a hemoglobin of 6.1 g/dL, for which she was transfused with 2 units of packed red blood cells (Table 1). A CT angiogram on admission showed symmetric ground-glass opacities in the lungs, suggestive of pulmonary hemorrhage (Figure 2). Her respiratory status remained stable, with a respiratory rate of 14 breaths per minute and oxygen saturation levels of 97% on room air. An infectious diseases workup was negative, including blood and sputum cultures, fungal serologies, and testing for influenza and tuberculosis. Serologic evaluation revealed a negative antinuclear antibody (ANA), but a positive p-ANCA with a titer of 1: 5120. The anti-myeloperoxidase (MPO) level was 168 AU/ml (normal 0–19 AU/mL), and the anti-proteinase 3 (PR3) level was undetectable. Anti-glomerular basement membrane antibody was not detected. Anti-double-stranded DNA and anti-histone antibodies were not detected. Renal function was normal, but urinalysis revealed red blood cells too numerous to count, 15–20 white blood cells, and 3–5 hyaline casts. A kidney biopsy was performed, which revealed a pauci-immune focal segmental necrotizing and crescentic glomerulonephritis (Figure 3).\n\nSince our patient previously had an urticarial reaction with methimazole, she was treated with potassium iodine (SSKI) and cholestyramine in addition to pulse-dose steroids. While her PTU was being held, she was given cholestyramine to increase thyroid hormone excretion via the enterohepatic circulation, and SSKI to block iodine uptake by the thyroid gland to minimize thyroid hormone production. Due to our patient’s intolerance of thionamides, she required a more permanent treatment for Grave’s disease, with either radioactive iodine (RAI) ablation or thyroidectomy. Total thyroidectomy was favored due to the risk for development of Grave’s ophthalmopathy with RAI ablation, and concern for abiding by radiation precautions with young children in the home [5]. She ultimately underwent total thyroidectomy and was later discharged to home on prednisone 60 mg daily, levothyroxine 125 mcg daily, and calcium carbonate with vitamin D supplements.\n\nThe patient was unfortunately lost to rheumatologic follow-up for 4 months. During that time, she continued taking prednisone 60 mg daily, although the steroid taper would have ideally been started sooner. Treatment with 2 doses of intravenous rituximab 1000 mg given 2 weeks apart was ultimately administered as an outpatient, and she is presently undergoing steroid taper. She remains with full resolution of symptoms, and her most recent p-ANCA titer had decreased to 1: 160, with the anti-MPO level decreased to 67 AU/ml (normal 0–19 AU/mL).\n\nDiscussion\nOur patient initially presented with red eye, followed by infiltrate on chest X-ray. The main diagnostic consideration for her lung infiltrate at that time was community-acquired pneumonia.\n\nShe ultimately failed empiric antibiotic treatment for pneumonia and developed hemoptysis. At that point, an autoimmune process was considered. The differential diagnosis for episcleritis is broad, with approximately 20% to 30% of cases being idiopathic [6]. Autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Crohn’s disease, and vasculitis, may also cause episcleritis. Systemic vascular diseases and infections such as hepatitis, syphilis, and Lyme disease are other possible causes of episcleritis [6]. Her serologic workup, including serologies for infections, SLE, and RA, were negative. In the setting of microscopic hematuria, hemoptysis, and a high-titer p-ANCA with anti-myeloperoxidase antibodies, a diagnosis of AAV (specifically, PTU-induced AAV) was strongly suspected. Patients with PTU-induced vasculitis typically have p-ANCA rather than c-ANCA, although they can have a mixed picture with both p-ANCA and c-ANCA [6].\n\nThe pathophysiology of PTU-induced AAV is not entirely clear. One theory is that when PTU binds to MPO, it changes its structure and antigenicity, thus potentially triggering PTU-induced AAV [7]. PTU-induced AAV may develop after initiating PTU treatment or may develop after being on PTU for multiple years [8]. In patients with PTU-induced vasculitis, renal involvement is most common, affecting an estimated 72% of patients, and the pulmonary system is affected in approximately 26% of patients [9]. In patients with pulmonary manifestations, pulmonary hemorrhage is the most common manifestation, which can present as cough, dyspnea, or hemoptysis [10]. Other reported pulmonary sequelae include acute respiratory distress syndrome, hilar lymphadenopathy, and pulmonary infiltrates [11]. Fever and arthralgias are also common, and some patients present with isolated cutaneous findings [12].\n\nOur patient had multiple symptoms of PTU-induced vasculitis. She initially presented with episcleritis, followed by pulmonary hemorrhage and microscopic hematuria. Data from 2 large randomized controlled trials of AAV demonstrated that 17.0% of patients initially presented with ocular involvement. Conjunctivitis and episcleritis were most common, while uveitis and retinal involvement were the rarest. Other ocular findings in AAV include proptosis, scleritis, and retinal hemorrhage [13]. We found 1 report of a 14-year-old girl who was diagnosed with PTU-induced AAV in the setting of anemia, followed by fever, arthritis, and episcleritis [14]. To the best of our knowledge, the present report is the first to describe a patient with PTU-induced AAV presenting initially with episcleritis.\n\nPTU has many well-known adverse effects, ranging from rash to hepatotoxicity [12]. Importantly, PTU can cause drug-induced lupus (DIL), as well as AAV, as seen in our patient. Clinically, patients with DIL usually have more musculoskeletal and gastrointestinal symptoms. With PTU-induced DIL, ANA, anti-double-stranded DNA, and anti-histone antibodies may be positive, with accompanying low complement levels. Our patient did not have serologies consistent with DIL.\n\nThere are no formal guidelines for the treatment of PTU-induced AAV. PTU-induced AAV has classically been treated similarly to primary AAV with cyclophosphamide, rituximab, or, in some cases, plasmapheresis, if clinically indicated [15]. Patients who have no vital-organ involvement may be treated with withdrawal of the causative agent alone and monitored [2]. Those who have vital-organ involvement (e.g., renal or pulmonary involvement) are treated with pulse-dose, followed by oral steroids [1]. Patients with severe organ involvement, such as necrotizing glomerulonephritis and diffuse alveolar hemorrhage, often require treatment with pulse-dose steroids and another immunosuppressive agent such as cyclophosphamide or rituximab. The RAVE trial suggests that rituximab is non-inferior to cyclophosphamide in inducing remission in patients with primary AAV [16]. Some small retrospective studies have suggested that plasmapheresis can benefit patients with massive pulmonary hemorrhage [17]. However, given our patient’s prompt favorable response to PTU discontinuation and pulse-dose steroids, treatment with plasmapheresis was not deemed necessary. Of note, a recent randomized controlled trial with 352 patients comparing plasmapheresis with steroids to steroids alone for the treatment of AAV did not show a decrease in mortality or development of end-stage renal disease [18].\n\nPatients with drug-induced vasculitis (DIV) tend to have better outcomes than those with primary AAV. A 2008 study by Gao et al. reviewed 15 patients with PTU-induced vasculitis, and all but 2 patients went into clinical remission [1]. Prior to use of immunosuppressive agents, primary AAV had a morbidity rate of 93% [19], while fatalities are considered rare for DIV if the offending agent is discontinued [1,19]. Additionally, primary AAV has a higher recurrence rate, estimated at 11–57% [1]. This has been attributed to the fact that DIV has a pathophysiologic trigger that can be removed [20]. Many patients with DIV improve and achieve remission simply with the cessation of the offending drug, whereas patients with primary AAV still require induction and maintenance treatment [19]. However, not all patients with DIV have complete resolution of symptoms with cessation of the offending agent. For instance, in a case series of 19 patients with PTU-induced AAV, 1 of 4 patients not treated with immunosuppressive agents had progression to end-stage renal disease [21]. It is unclear whether patients with DIV need maintenance therapy, but they are often given immunosuppressive therapy for 6-12 months [1]. Since our patient presented with diffuse alveolar hemorrhage and glomerulonephritis, despite improvement with PTU withdrawal and steroid treatment, the clinical decision was made to treat with rituximab to minimize risk of recurrence.\n\nConclusions\nIn this case report we describe a patient with PTU-induced AAV who initially presented with ocular symptoms, which are less common as the initial presentation of AAV and drug-induced AAV. If the suspicion for drug-induced AAV is high, it is important to promptly discontinue the offending medication and confirm the diagnosis. Treatment with high-dose steroids and, possibly, additional immunosuppressive agents may be considered, especially if there is involvement of vital organs. PTU-induced AAV is a rare condition that often has a good prognosis if recognized early. Our case highlights the importance of recognizing both uncommon and common manifestations of drug-induced AAV, to allow for prompt diagnosis and treatment.\n\nConflict of interests\n\nNone.\n\nFigure 1. Chest X-ray on initial presentation, revealing a patchy right lower-lobe opacity with air bronchograms, consistent with pneumonia.\n\nFigure 2. CT angiogram demonstrating symmetrical patchy ground-glass opacification, attributed to diffuse alveolar hemorrhage in this specific clinical context.\n\nFigure 3. Renal biopsy demonstrating a representative necrotic and crescentic glomerulus.\n\nTable 1. Laboratory evaluations. Baseline laboratory values are from 2 months prior to admission.\n\nLaboratory measure\tAdmission values\tBaseline values\tReference range/units\t\nSodium\t139 mmol/L\t137 mmol/L\t136–145 mmol/L\t\nPotassium\t3.9 mmol/L\t4.3 mmol/L\t3.5–5.5 mmol/L\t\nChloride\t103 mmol/L\t104 mmol/L\t96–110 mmol/L\t\nBicarbonate\t27 mmol/L\t27 mmol/L\t24–31 mmol/L\t\nBlood urea nitrogen\t9 mg/dL\t10 mg/dL\t5–25 mg/dL\t\nCreatinine\t0.76 mg/dL\t0.45 mg/dL\t0.61–1.24 mg/dL\t\nGlomerular filtration rate\t>60 mL/min\t>60 mL/min\t>60 mL/min\t\nHemoglobin\t6.1 gm/dL\t12.2 gm/dL\t13.2–17.5 gm/dL\t\nHematocrit\t20.0%\t36.9%\t40.0–53.0%\t\nWhite blood cell (WBC) count\t9.9 K/uL\t7.2 K/uL\t4.5–11.0 K/uL\t\nWBC differential\tNormal\tNormal\tNormal\t\nPlatelets\t492 K/uL\t287 K/uL\t140–450 K/uL\t\nESR\t111 mm/h\tN/A\t0–20 mm/h\t\nCRP\t12.05 mg/dL\tN/A\t0–0.744 mg/dL\t\nTSH\t0.022 iU/mL\t0.329 iU/mL\t0.3–4.5 iU/mL\t\nFree T4\t0.93 ng/dL\t1.0 ng/dL\t0.5–1.6 ng/dL\t\nLDH\t190 iU/L\tN/A\t91–200 iU/L\n==== Refs\nReferences:\n1. Gao Y Chen M Ye H Long-term outcomes of patients with propylthiouracil-induced anti-neutrophil cytoplasmic auto-antibody-associated vasculitis Rheumatology 2008 47 10 1515 20 18676500 \n2. Radic M Martinovic Kaliterna D Radic J Drug-induced vasculitis: A clinical and pathological review Neth J Med 2012 70 1 12 17 22271809 \n3. Radice A Sinico R Antineutrophil cytoplasmic antibodies (ANCA) Autoimmunity 2005 35 1 93 103 \n4. Bossuyt X Tervaert J-WC Arimura Y Revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis Nat Rev Rheumatol 2017 13 11 683 92 28905856 \n5. Walsh JP Dayan CM Potts MJ Radioiodine and thyroid eye disease BMJ 1999 319 7202 68 69 10398607 \n6. Schonberg S Episcleritis StatPearls U.S National Library of Medicine 2019 https://www.ncbi.nlm.nih.gov/books/NBK534796/ \n7. Shikha D Harris J Resta C Park P Antineutrophilic cytoplasmic antibody positive vasculitis associated with methimazole use Case Rep Endocrinol 2015 2015 530319 26060588 \n8. Tetikkurt C Yuruyen M Tetikkurt S Propylthiouracil-induced lupus-like or vasculitis syndrome Multidisciplinary Respiratory Medicine 2012 7 1 14 22958435 \n9. Quax RAM Swaak AJG Baggen MGA Churg-Strauss syndrome following PTU treatment Int J Rheumatol 2009 2009 504105 20107567 \n10. Chen B Yang X Sun S Propylthiouracil-induced vasculitis with alveolar hemorrhage confirmed by clinical, laboratory, computed tomography, and bronchoscopy findings: A case report and literature review Iran Red Crescent Med J 2016 18 4 e23320 27257510 \n11. Pillinger M Staud R Wegeners granulomatosis in a patient receiving propylthiouracil for Graves disease Semin Arthritis Rheum 1998 28 2 124 29 9806373 \n12. Demir M Yaylaci S Tamer A Ayturk S Propylthiouracil induced leukocytoclastic vasculitis: A rare manifestation Indian J Endocrinol Metabol 2013 17 2 339 \n13. Cai S Papaliodis G Lu L Ocular manifestations of ANCA-associated vasculitis [abstract] Arthritis Rheumatol 2016 68 Suppl. 10 Abstract Number: 1947 \n14. Schamp V Verfaillie C Bonroy C Propylthiouracil induced ANCA-associated vasculitis in a 14-year-old girl Acta Clin Belg 2015 70 2 127 29 25937486 \n15. Khan TA Luk FCY Uqdah HT A fatal case of propylthiouracil-induced ANCA-associated vasculitis resulting in rapidly progressive glomerulonephritis, acute hepatic failure, and cerebral angiitis Clin Nephrol 2015 83 5 309 14 25208313 \n16. Stone JH Merkel PA Spiera R RAVE-ITN Research Group Rituximab versus cyclophosphamide for ANCA-associated vasculitis N Engl J Med 2010 363 3 221 32 20647199 \n17. Klemmer PJ Chalermskulrat W Reif MS Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small-vessel vasculitis Am J Kidney Dis 2003 42 6 1149 53 14655185 \n18. Walsh M Merkel PA Peh CA Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis N Engl J Med 2020 382 7 622 31 32053298 \n19. Irani F Elkambergy H Naraharisetty K Jamal R Propylthiouracil-induced leucocytoclastic vasculitis with pulmonary hemorrhage treated with plasmapheresis Am J Med Sci 2009 337 6 470 72 19359981 \n20. Chen Y-X Zhang W Chen X-N Propylthiouracil-induced antineutro-phil cytoplasmic antibody (ANCA)-associated renal vasculitis versus primary ANCA-associated renal vasculitis: a comparative study J Rheumatol 2012 39 3 558 63 22247359 \n21. Chen XC Yu HJ Ni LY Propylthiouracil-associated antinutrophil cytoplasmic autoantibody-positive vasculitis: retrospective study of 19 cases J Rheumatol 2007 34 2451 56 17985400\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "21()",
"journal": "The American journal of case reports",
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"medline_ta": "Am J Case Rep",
"mesh_terms": "D000328:Adult; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D019268:Antibodies, Antineutrophil Cytoplasmic; D013956:Antithyroid Agents; D005260:Female; D006801:Humans; D009195:Peroxidase; D011441:Propylthiouracil",
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"pubdate": "2020-12-09",
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"references": "32053298;22247359;22271809;14655185;25208313;27257510;28905856;9806373;22958435;15804710;19359981;20647199;18676500;23776917;25937486;10398607;17985400;20107567;26060588",
"title": "Propylthiouracil-Induced Anti-Neutrophil Cytoplasmic Antibody Vasculitis Presenting with Red Eye Followed by Pulmonary Hemorrhage: Diagnostic and Management Considerations.",
"title_normalized": "propylthiouracil induced anti neutrophil cytoplasmic antibody vasculitis presenting with red eye followed by pulmonary hemorrhage diagnostic and management considerations"
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"abstract": "Medication-related osteonecrosis of the jaw (MRONJ) is an uncommon but potentially debilitating condition, characterised by nonhealing jawbone, with or without mucosal exposure, in the presence of certain drugs. Those already strongly associated with MRONJ include antiresorptives denosumab and bisphosphonates; however, a growing range of other non-antiresorptive drugs is implicated. The aim of this study was to analyse all case reports of MRONJ submitted to the publicly available Database of Adverse Event Notification from the Therapeutic Goods Administration in Australia.\n\n\n\nThe Therapeutic Goods Administration was contacted on 6 January 2020 and asked for all reports containing the words \"osteonecrosis of the jaw\". This was provided in a spreadsheet of de-identified reports received from commencement of the database in 1971 until 1 October 2019.\n\n\n\nThe drugs implicated in the 419 cases were divided by established drugs with MRONJ and secondary drugs that possibly contribute to MRONJ development. While the majority of cases were associated with denosumab or bisphosphonates (n = 405), there were 14 reports where secondary agents that directly or indirectly affect bone turnover, were also implicated. Some of these secondary drugs, including adalimumab, etanercept, methotrexate and rituximab have previously been associated with MRONJ in published case reports.\n\n\n\nThis study contributes to the sparse but growing literature associating an increasing number of drugs with MRONJ, and underscores the importance of considering all possible drugs that elevate a patient's MRONJ risk.",
"affiliations": "University of Melbourne, Australia.;University of Queensland, Australia.;University of Western Australia, Australia.;University of Melbourne, Australia.",
"authors": "Teoh|Leanne|L|0000-0002-9138-813X;Moses|Geraldine|G|;Nguyen|Amanda P|AP|;McCullough|Michael J|MJ|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004364:Pharmaceutical Preparations",
"country": "England",
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"doi": "10.1111/bcp.14681",
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"issn_linking": "0306-5251",
"issue": "87(7)",
"journal": "British journal of clinical pharmacology",
"keywords": "adverse drug reactions, drug information, medication safety",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D001315:Australia; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D006801:Humans; D004364:Pharmaceutical Preparations",
"nlm_unique_id": "7503323",
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"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Medication-related osteonecrosis of the jaw: Analysing the range of implicated drugs from the Australian database of adverse event notifications.",
"title_normalized": "medication related osteonecrosis of the jaw analysing the range of implicated drugs from the australian database of adverse event notifications"
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"activesubstancename": "DEXAMETHASONE"
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"abstract": "Apparent mineralocorticoid excess (AME) is a genetic disorder causing severe hypertension, hypokalemia, and hyporeninemic hypoaldosteronism owing to deficient 11 beta-hydroxysteroid dehydrogenase type-2 (11βHSD2) enzyme activity. The 11βHSD2 enzyme confers mineralocorticoid receptor specificity for aldosterone by converting cortisol to its inactive metabolite, cortisone and inactivating the cortisol-mineralocorticoid receptor complex. The 20year follow-up of a consanguineous Iranian family with three sibs affected with AME shows the successes and pitfalls of medical therapy with spironolactone. The three sibs, (female, male, female) were diagnosed at the ages of 14, 11, and 4 years, respectively. At diagnosis, hypertensive retinopathy and left ventricular hypertrophy were present in the eldest female and retinopathy was noted in the male sib. Spironolactone treatment resulted in decreased blood pressure and rise in serum potassium levels. The older female, age 36, developed reduced left ventricular function with mitral and tricuspid regurgitation and renal failure after her second pregnancy. She was treated with renal transplantation resulting in cure of AME with decreased blood pressure and weaning from antihypertensives. Her younger sibs, age 34 and 26, do not have end organ damage. Early and vigilant treatment improves morbidity in patients with AME. Mineralocorticoid receptor antagonists normalize blood pressure, correct hypokalemia and reduce hypertensive end-organ damage in patients with AME. Low dose dexamethasone can be considered, though the response may be variable. Future directions of therapy include selective mineralocorticoid antagonists.",
"affiliations": "Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Iran; H. Aliasghar Hospital, Iran University of Medical Sciences, Iran.;Adrenal Steroid Disorder Group, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, United States. Electronic address: mabel.yau@mssm.edu.;Adrenal Steroid Disorder Group, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, United States.;Adrenal Steroid Disorder Group, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, United States.",
"authors": "Razzaghy-Azar|Maryam|M|;Yau|Mabel|M|;Khattab|Ahmed|A|;New|Maria I|MI|",
"chemical_list": "D008901:Mineralocorticoids; D013148:Spironolactone; D042842:11-beta-Hydroxysteroid Dehydrogenases; D012083:Renin",
"country": "England",
"delete": false,
"doi": "10.1016/j.jsbmb.2016.02.014",
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"issn_linking": "0960-0760",
"issue": "165(Pt A)",
"journal": "The Journal of steroid biochemistry and molecular biology",
"keywords": "11β-Hydroxysteroid dehydrogenase type 2; Low renin hypertension; Spironolactone",
"medline_ta": "J Steroid Biochem Mol Biol",
"mesh_terms": "D042842:11-beta-Hydroxysteroid Dehydrogenases; D000293:Adolescent; D000328:Adult; D001794:Blood Pressure; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons; D005192:Family Health; D005260:Female; D006801:Humans; D006973:Hypertension; D007492:Iran; D016030:Kidney Transplantation; D008297:Male; D043204:Mineralocorticoid Excess Syndrome, Apparent; D008901:Mineralocorticoids; D009154:Mutation; D010375:Pedigree; D011110:Polymorphism, Genetic; D011247:Pregnancy; D051437:Renal Insufficiency; D012083:Renin; D013148:Spironolactone",
"nlm_unique_id": "9015483",
"other_id": null,
"pages": "145-150",
"pmc": null,
"pmid": "26892095",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Apparent mineralocorticoid excess and the long term treatment of genetic hypertension.",
"title_normalized": "apparent mineralocorticoid excess and the long term treatment of genetic hypertension"
} | [
{
"companynumb": "IR-MYLANLABS-2017M1003542",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TESTOSTERONE ENANTHATE"
},
"drugadditional": ... |
{
"abstract": "BACKGROUND\nIn North America, 250,000 patients on vitamin K antagonists require surgical procedures each year. Temporary interruption of oral anticoagulation and perioperative bridging therapy with unfractionated heparin or low-molecular-weight heparin are recommended by the American College of Chest Physicians 2012 for select patients.\n\n\nOBJECTIVE\nThe study objectives are to evaluate adherence and nonadherence to the Johns Hopkins clinic guidelines for perioperative management of anticoagulation and identify bleeding or thromboembolic events during perioperative management of anticoagulation.\n\n\nMETHODS\nThis is a retrospective study of patients who required perioperative management of anticoagulation for an invasive procedure from May 2009 to March 2014. Individualized perioperative anticoagulation management plans were prospectively developed for each patient according to the standardized Johns Hopkins perioperative bridging recommendations and documented in the medical record. Adherence to these standardized Johns Hopkins clinic guidelines, the incidence of thromboembolic events, and bleeding and adverse events during perioperative management were retrieved from the medical record.\n\n\nRESULTS\nIn 294 perioperative management cases, there was 1 (0.3%) thromboembolism, 3 (1%) major bleeds, and 21 (7%) minor bleeds. One patient experienced facial swelling after starting enoxaparin. There was no difference in thromboembolic (0 vs 1, P = 1.00), major (1 vs 2, P = 1.00), or minor bleeding (14 vs 7, P = 1.00) events in patients managed by providers who were adherent to guidelines when compared with providers who were nonadherent.\n\n\nCONCLUSIONS\nOur study shows that using a standardized guideline for perioperative management of anticoagulation to inform but not to dictate clinical practice leads to low rates of both thromboembolism and bleeding.",
"affiliations": "1 The Johns Hopkins Hospital, Baltimore, MD, USA.;1 The Johns Hopkins Hospital, Baltimore, MD, USA.;1 The Johns Hopkins Hospital, Baltimore, MD, USA.;3 University of Rhode Island College of Pharmacy, Kingston, RI, USA.;4 Yale School of Medicine, New Haven, CT, USA.;1 The Johns Hopkins Hospital, Baltimore, MD, USA.",
"authors": "Lum|Diane J|DJ|;Ross|Patricia A|PA|;Bishop|Martin A|MA|;Caetano|Michelle L|ML|;Malpani|Rohil|R|;Streiff|Michael B|MB|",
"chemical_list": "D000925:Anticoagulants; D006493:Heparin",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028017719505",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "51(12)",
"journal": "The Annals of pharmacotherapy",
"keywords": "adherence; anticoagulants; anticoagulation; surgery; warfarin",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000328:Adult; D000368:Aged; D000925:Anticoagulants; D005260:Female; D019983:Guideline Adherence; D006470:Hemorrhage; D006493:Heparin; D006801:Humans; D008297:Male; D008875:Middle Aged; D009656:North America; D019990:Perioperative Care; D017410:Practice Guidelines as Topic; D012189:Retrospective Studies; D012307:Risk Factors; D013923:Thromboembolism; D015912:Thrombolytic Therapy",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1077-1083",
"pmc": null,
"pmid": "28677422",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluation of a Standardized Perioperative Management Protocol in the Adult Hematology Anticoagulation Management Service.",
"title_normalized": "evaluation of a standardized perioperative management protocol in the adult hematology anticoagulation management service"
} | [
{
"companynumb": "US-TEVA-2017-US-839717",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ENOXAPARIN"
},
"drugadditional": "3",
... |
{
"abstract": "Hemophagoytic lymphohistiocytosis (HLH) is a rare life-threatening disorder caused by overactivation of the immune system, associated with infections, autoimmune disorders, and malignancies. The pathological hallmark of HLH is phagocytosis of blood cells and platelets by activated macrophages and histiocytes. In this report, we describe the onset of HLH in three children, aged 2, 5 and 7 years old, during the treatment of acute focal bacterial nephritis (AFBN) with an antibiotic, piperacillin-tazobactam (PIPC-TAZ). AFBN is acute localized bacterial infection of the kidney without abscess formation. PIPC-TAZ was chosen for the treatment of AFBN, because it not only has indications for complicated urinary tract infections, but also covers most of the causative bacteria of urinary tract infections, including β-lactamase-producing Escherichia coli. The clinical courses of the three patients were similar, and they were treated with PIPC-TAZ and amikacin (AMK) for AFBN. Fever went down 2 to 5 days later, and AMK was discontinued by day 6. However, fever recurred on 13 to 15 days after introduction of PIPC-TAZ therapy, even though all of the patients had no signs of recurrence of AFBN. The clinical features and laboratory tests of two patients fulfilled the criteria of HLH, whereas the other patient had initiated therapy before fulfilling the criteria. Cessation of PIPC-TAZ combined with corticosteroid therapy improved clinical symptoms. HLH of our patients was probably induced by PIPC-TAZ, as judged by the timing of the onset of HLH and the positivity of the drug-lymphocyte stimulation test. In conclusion, prolonged antibiotic therapy with PIPC-TAZ could be a cause of HLH.",
"affiliations": "Department of Pediatrics, Sendai Medical Center.;Department of Pediatrics, Sendai Medical Center.;Department of Hematology and Oncology, Miyagi Children's Hospital.;Department of Pediatrics, Sendai Medical Center.;Department of Pediatrics, Sendai Medical Center.;Department of Pediatrics, Sendai Medical Center.;Department of Pediatrics, Sendai Medical Center.;Department of Pediatrics, Sendai Medical Center.;Department of Pediatrics, Sendai Medical Center.;Department of Hematology and Oncology, Miyagi Children's Hospital.;Department of Pediatrics, Sendai Medical Center.",
"authors": "Miyabayashi|Hiroki|H|;Kumaki|Satoru|S|;Sato|Atsushi|A|;Onuma|Ryoichi|R|;Noguchi|Rie|R|;Sato|Taiki|T|;Metoki|Takaya|T|;Watanabe|Yohei|Y|;Tazawa|Yusaku|Y|;Imaizumi|Masue|M|;Kitaoka|Setsuko|S|",
"chemical_list": "D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin",
"country": "Japan",
"delete": false,
"doi": "10.1620/tjem.245.55",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-8727",
"issue": "245(1)",
"journal": "The Tohoku journal of experimental medicine",
"keywords": "acute focal bacterial nephritis; antibiotics; computed tomography; hemophagoytic lymphohistiocytosis; piperacillin-tazobactam",
"medline_ta": "Tohoku J Exp Med",
"mesh_terms": "D000208:Acute Disease; D001853:Bone Marrow; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D009393:Nephritis; D010397:Penicillanic Acid; D010878:Piperacillin; D000077725:Piperacillin, Tazobactam Drug Combination; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0417355",
"other_id": null,
"pages": "55-59",
"pmc": null,
"pmid": "29798969",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Onset of Hemophagocytic Lymphohistiocytosis during Piperacillin-Tazobactam Therapy in Three Children with Acute Focal Bacterial Nephritis.",
"title_normalized": "onset of hemophagocytic lymphohistiocytosis during piperacillin tazobactam therapy in three children with acute focal bacterial nephritis"
} | [
{
"companynumb": "JP-PFIZER INC-2018244952",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
},
"dr... |
{
"abstract": "This case report explores the novel use of angiotensin II (Giapreza) for the treatment of vasodilation in the setting of a tricyclic overdose. The purpose of this case is to describe how the use of angiotensin II can improve hemodynamic parameters and result in a dose reduction of other catecholamine vasopressors in vasodilatory shock. The use of angiotensin II is new to clinical practice and has the potential to change outcomes for patients.",
"affiliations": "Jacqueline Ferdowsali, DNP, MSN, BSN, ACNPC-AG, is an assistant professor at the University of Nevada Reno. She is the track coordinator for the adult gerontology acute care nurse practitioner program. Her clinical practice is as an adult gerontology acute care nurse practitioner with a pulmonary and tele-medicine service. Kameron Ferdowsali, MD, is an intensivist at Peace Health Medical Center. He also manages a tele-medicine critical care service. He has vast experience treating individuals with shock states.",
"authors": "Ferdowsali|Jacqueline|J|;Ferdowsali|Kameron|K|",
"chemical_list": "D000929:Antidepressive Agents, Tricyclic; D002395:Catecholamines; D014662:Vasoconstrictor Agents; D000804:Angiotensin II",
"country": "United States",
"delete": false,
"doi": "10.1097/DCC.0000000000000414",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0730-4625",
"issue": "39(3)",
"journal": "Dimensions of critical care nursing : DCCN",
"keywords": null,
"medline_ta": "Dimens Crit Care Nurs",
"mesh_terms": "D000804:Angiotensin II; D000929:Antidepressive Agents, Tricyclic; D002395:Catecholamines; D006801:Humans; D007022:Hypotension; D014662:Vasoconstrictor Agents",
"nlm_unique_id": "8211489",
"other_id": null,
"pages": "140-144",
"pmc": null,
"pmid": "32251161",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Patient With Tricyclic Antidepressant Overdose With Catecholamine-Resistant Hypotension Rescued With Angiotensin II: A Case Report.",
"title_normalized": "a patient with tricyclic antidepressant overdose with catecholamine resistant hypotension rescued with angiotensin ii a case report"
} | [
{
"companynumb": "US-PFIZER INC-202200422962",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXEPIN HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "We report a case of HBV reactivation following belatacept treatment in a patient who underwent kidney transplantation in 2015 for HIV-associated nephropathy (HIVAN). Human immunodeficiency virus viral load was undetectable prior to transplantation, and CD4+ lymphocyte count was greater than 300/mL. Baseline HBV serology at transplantation was HBsAg negative, anti-HBcAb positive, anti-HBsAb 312 UI/L, and HBeAg negative/anti-HBeAb positive. Liver function tests were normal, and viral DNA was undetectable. Two years later, the patient presented with severe acute hepatitis after a progressive disappearance of anti-HbsAb, quickly followed by HBV reactivation. Immunosuppressive treatment was drastically reduced, and treatment with entecavir was started. The outcome was favorable, and HBV DNA became undetectable after 9 weeks of treatment. This is the first report of acute hepatitis related to HBV reactivation in a kidney transplant recipient treated with belatacept. The risk for HBV reactivation in patients treated with belatacept should not be underestimated, especially in those with resolved HBV infection.",
"affiliations": "Department of Nephrology and Dialysis, AP-HP, Hôpital Tenon, Paris, France.;Department of Infectious Disease, AP-HP, Hôpital Tenon, Paris, France.;Department of Virology, AP-HP, Hôpital Tenon, Paris, France.;Department of Kidney Transplantation, AP-HP, Hôpital Tenon, Paris, France.;Department of Kidney Transplantation, AP-HP, Hôpital Tenon, Paris, France.;Department of Nephrology and Dialysis, AP-HP, Hôpital Tenon, Paris, France.",
"authors": "Cambier|Marie-Laure|ML|;Canestri|Ana|A|;Lependeven|Catherine|C|;Peltier|Julie|J|;Mesnard|Laurent|L|;Dahan|Karine|K|https://orcid.org/0000-0003-0323-4673",
"chemical_list": "D000998:Antiviral Agents; D004279:DNA, Viral; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D007166:Immunosuppressive Agents; C413685:entecavir; D006147:Guanine; D000069594:Abatacept",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13170",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "21(6)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "HBV reactivation; hepatitis; kidney transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000069594:Abatacept; D000998:Antiviral Agents; D004279:DNA, Viral; D006084:Graft Rejection; D006147:Guanine; D015658:HIV Infections; D006509:Hepatitis B; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D006515:Hepatitis B virus; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D014775:Virus Activation",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13170",
"pmc": null,
"pmid": "31505095",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hepatitis B virus reactivation during belatacept treatment after kidney transplantation.",
"title_normalized": "hepatitis b virus reactivation during belatacept treatment after kidney transplantation"
} | [
{
"companynumb": "FR-TEVA-2020-FR-1186357",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RALTEGRAVIR"
},
"drugadditional": "3",
... |
{
"abstract": "Cancer and osteoporosis have high incidence rates in older populations. However, the treatment of osteoporosis among cancer patients has not been adequately described. Our purpose was to clarify the current practice patterns of osteoporosis treatment among cancer patients in an academic cancer center, and to analyze the efficacy of treatment interventions. Patient records from April 2009 to March 2018 were retrospectively reviewed, and the study included a total of 316 cancer patients with osteoporosis. After patients' data extraction, the patients were divided into two groups, with (n = 144) or without treatment (n = 172), and compared the outcomes of these groups to evaluate the medication effect. The primary outcome was new radiographic fragility fractures during the study period. The related factors associated with fracture injuries and the rate of adverse events, such as osteonecrosis in the jaw and atypical femoral fractures, were analyzed. The rate of treatment intervention was 45.6% among the patient groups. Among patients in the study group, breast cancer patients (n = 107) were mostly treated (n = 79, 73.8%) with oral bisphosphonate. A significant difference in new fracture rate was observed between the two groups (treatment group, 30.6%; non-treatment group, 54.7%), and the risk of fracture was 42% lower in the treatment group (hazard ratio, 0.58; 95% confidence interval, 0.39-0.86; p<0.05). Previous chemotherapy, steroid use, and older age were significantly associated with increased rate of new fragility fractures. The adverse event rate was 3.5% (presented in five cases). Older cancer patients who receive chemotherapy or steroids are strongly recommended undergo bone quality assessment and appropriate osteoporosis treatment to improve their prognosis.",
"affiliations": "Section of Orthopedic Surgery, Aichi Cancer Center, Nagoya, Japan.;Section of Orthopedic Surgery, Nagoya Ekisaikai Hospital, Nagoya, Japan.;Section of Orthopedic Surgery, Aichi Cancer Center, Nagoya, Japan.;Section of Orthopedic Surgery, Aichi Cancer Center, Nagoya, Japan.;Section of Orthopedic Surgery, Aichi Cancer Center, Nagoya, Japan.",
"authors": "Fujihara|Nasa|N|0000-0002-4197-0586;Fujihara|Yuki|Y|;Hamada|Shunsuke|S|;Yoshida|Masahiro|M|;Tsukushi|Satoshi|S|",
"chemical_list": "D050071:Bone Density Conservation Agents",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0248188",
"fulltext": "\n==== Front\nPLoS One\nPLoS One\nplos\nplosone\nPLoS ONE\n1932-6203\nPublic Library of Science San Francisco, CA USA\n\n10.1371/journal.pone.0248188\nPONE-D-20-33343\nResearch Article\nMedicine and Health Sciences\nOncology\nCancer Treatment\nMedicine and Health Sciences\nOncology\nCancers and Neoplasms\nBreast Tumors\nBreast Cancer\nMedicine and Health Sciences\nRheumatology\nConnective Tissue Diseases\nOsteoporosis\nMedicine and Health Sciences\nEpidemiology\nMedical Risk Factors\nCancer Risk Factors\nMedicine and Health Sciences\nOncology\nCancer Risk Factors\nMedicine and Health Sciences\nCritical Care and Emergency Medicine\nTrauma Medicine\nTraumatic Injury\nBone Fracture\nPhysical Sciences\nChemistry\nChemical Compounds\nOrganic Compounds\nSteroids\nPhysical Sciences\nChemistry\nOrganic Chemistry\nOrganic Compounds\nSteroids\nMedicine and Health Sciences\nOncology\nCancers and Neoplasms\nGenitourinary Tract Tumors\nProstate Cancer\nMedicine and Health Sciences\nUrology\nProstate Diseases\nProstate Cancer\nMedicine and Health Sciences\nGastroenterology and Hepatology\nGastrointestinal Cancers\nCurrent practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center\nOsteoporosis treatment in cancer patients and effects of therapeutic interventions\nhttps://orcid.org/0000-0002-4197-0586\nFujihara Nasa Conceptualization Data curation Formal analysis Investigation Methodology Writing – original draft Writing – review & editing 1*\nFujihara Yuki Conceptualization Data curation Formal analysis Writing – review & editing 2\nHamada Shunsuke Supervision Writing – review & editing 1‡\nYoshida Masahiro Supervision Writing – review & editing 1‡\nTsukushi Satoshi Conceptualization Supervision Writing – review & editing 1\n1 Section of Orthopedic Surgery, Aichi Cancer Center, Nagoya, Japan\n2 Section of Orthopedic Surgery, Nagoya Ekisaikai Hospital, Nagoya, Japan\nBlank Robert Daniel Editor\nMedical College of Wisconsin, UNITED STATES\nCompeting Interests: The authors have declared that no competing interests exist.\n\n‡ These authors also contributed equally to this work.\n\n* E-mail: nfujihara@aichi-cc.jp\n11 3 2021\n2021\n16 3 e024818823 10 2020\n22 2 2021\n© 2021 Fujihara et al\n2021\nFujihara et al\nThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\n\nCancer and osteoporosis have high incidence rates in older populations. However, the treatment of osteoporosis among cancer patients has not been adequately described. Our purpose was to clarify the current practice patterns of osteoporosis treatment among cancer patients in an academic cancer center, and to analyze the efficacy of treatment interventions. Patient records from April 2009 to March 2018 were retrospectively reviewed, and the study included a total of 316 cancer patients with osteoporosis. After patients’ data extraction, the patients were divided into two groups, with (n = 144) or without treatment (n = 172), and compared the outcomes of these groups to evaluate the medication effect. The primary outcome was new radiographic fragility fractures during the study period. The related factors associated with fracture injuries and the rate of adverse events, such as osteonecrosis in the jaw and atypical femoral fractures, were analyzed. The rate of treatment intervention was 45.6% among the patient groups. Among patients in the study group, breast cancer patients (n = 107) were mostly treated (n = 79, 73.8%) with oral bisphosphonate. A significant difference in new fracture rate was observed between the two groups (treatment group, 30.6%; non-treatment group, 54.7%), and the risk of fracture was 42% lower in the treatment group (hazard ratio, 0.58; 95% confidence interval, 0.39–0.86; p<0.05). Previous chemotherapy, steroid use, and older age were significantly associated with increased rate of new fragility fractures. The adverse event rate was 3.5% (presented in five cases). Older cancer patients who receive chemotherapy or steroids are strongly recommended undergo bone quality assessment and appropriate osteoporosis treatment to improve their prognosis.\n\nThe author(s) received no specific funding for this work. Data AvailabilityData are available from the ACC Institutional Data Access / Ethics Committee (contact ortho_tiken@aichi-cc.jp, irb@aichi-cc.jp) for researchers who meet the criteria for access to confidential data.\nData Availability\n\nData are available from the ACC Institutional Data Access / Ethics Committee (contact ortho_tiken@aichi-cc.jp, irb@aichi-cc.jp) for researchers who meet the criteria for access to confidential data.\n==== Body\nIntroduction\n\nTreatment of osteoporosis is essential for maintaining a good quality of life in older individuals [1, 2]. Despite preventative efforts, bone fragility increases with age. Therefore, even older people in good health are required to make a steady effort to avoid problems caused by bone fragility, which can often be challenging [3, 4]. Additionally, cancer is a well-known disease that occurs in older populations. However, the treatment of osteoporosis among cancer patients has not been adequately described, despite the huge risk of developing osteoporosis. The International Society of Geriatric Oncology (ISGO) group reported that classical factors including age, sex, family history of hip fractures, comorbidities, as well as corticosteroid, tobacco, and alcohol consumption are emerging as prevalent risk factors for osteoporosis in cancer patients [5]. Moreover, another study reported that the severity of bone disease and number of lesions help identify patients who are at risk of bone failures, including fragility fractures [6]. However, few studies have examined the incidence of adverse events associated with osteoporosis in cancer patients with such risk factors.\n\nThe ISGO group also reported that even the treatment recommendations are merely a summary of current knowledge and need further discussion because of the lack of study data. Osteoporosis is often misunderstood as a disease that is not fatal, as there are no symptoms in many cases. However, a decrease in the activity levels or immobilization caused by osteoporotic fragility fractures could be a major obstacle associated with cancer chemotherapies and is directly related to the worsening of cancer outcomes [7–10]. Therefore, it is important to prevent osteoporotic fractures in cancer patients. However, few studies have examined the effects of treatment interventions for osteoporosis in cancer patients. Although there is a growing interest in particular fields to preserve bone health, such as bone fragility associated with hormone treatment [3, 11], a comprehensive analysis of the treatment intervention rate for osteoporosis among cancer patients has not been conducted.\n\nThis study aimed to provide an overview of osteoporosis treatment efforts implemented by our center hospital institution for cancer treatment and to identify the effect of preventative medication on new fragility fractures. We expected to observe a higher intervention rate of osteoporosis treatment in patients who received hormone therapy, such as breast or prostate cancer patients. We also hypothesized that the therapeutic intervention would be effective in preventing new fragility fractures, as observed in previous studies [12, 13], and if a similar therapeutic effect is observed in cancer patients, then treating osteoporosis may also improve cancer treatment outcomes.\n\nMaterials and methods\n\nStudy design and participants\n\nThis retrospective study was approved by Aichi Cancer Center institutional ethics committee (approval number 364). After approval, data from our center’s medical records from April 2009 to March 2018 were obtained. As this was a retrospective cohort study, the need for informed consent was waived by our ethics committee, but all participants were given the option to decline participation by way of opting out through the website.\n\nFollowing the Japanese osteoporosis prevention and treatment guidelines of 2015, the inclusion criteria included a history of vertebral or femoral fragility fractures or a dual energy X-ray absorptiometry (DXA)-scanned young adult mean score <70%. This criteria extracted all cancer patients aged >40 years who could be newly diagnosed with osteoporosis in our hospital. The exclusion criteria were history of diagnosis or treatment of osteoporosis before participation, pathological fractures with bone metastasis, age <40 years [14, 15], and follow-up period <6 months.\n\nAfter extracting data from 316 patients who met the criteria, we investigated the patient demographics, cancer type, cancer treatment, and whether osteoporosis was treated or not. The primary outcome was new radiographic fragility fractures during the study period. To detect fragility fractures, data were reviewed from all imaging studies, including conventional lateral spine radiographic photos, computer tomography scans, and spinal magnetic resonance imaging, that were conducted during the follow-up period in each patient. For these techniques, evaluation was performed by two independent orthopedic surgeons, and if the evaluation differed between surgeons, senior orthopedic surgeons judged the results. The average frequency of evaluation in each department was 2–3 months. Treatment intervention of osteoporosis was defined as treatment with anti-osteoporotic agents >6-month period, and steroid use was defined when a patient received prednisolone 7.5 mg/day for more than 3 months [16].\n\nData analysis\n\nWe grouped patients based on whether they received treatment or not. The data of patients treated with oral bisphosphonates (treatment group, n = 101) were compared with the data of those without treatment (non-treatment group, n = 172) to determine the medication effects for preventing new radiographic fragility fractures. The cumulative fracture rate was described using a Kaplan–Meier curve, and a log-rank test was performed to compare the intergroup differences. Additionally, a Cox proportional hazard regression model was applied to evaluate the risk factors associated with new fracture injuries. The factors examined were sex, age, method of diagnosis, cancer type, presence of bone metastases or duplicate cancers, history of chemo/radiotherapy, steroid use, and treatment intervention. Then, a multivariate analysis was conducted with all variables from the univariate analysis. All analyses were performed using STATA/SE version 14.2 (StataCorp, College Station, TX, USA), and the level of significance was set at p<0.05.\n\nResults\n\nIn total, 316 cancer patients (mean age, 70.0 [range 40–93] years; sex, 81 men [25.6%] and 235 women [74.4%]) were diagnosed with osteoporosis during the 10-year study period. The patient demographics are presented in Table 1. Of these, 48 (15.2%) and 29 patients (9.2%) had bone metastasis and double cancers, respectively. Moreover, 188 (59.5%) and 79 patients (25.0%) had previously undergone chemotherapy and radiotherapy, respectively. In relation to chemotherapy, steroid injections were used in 46.8% (n = 148) of patients. The mean follow-up period was 34.2 (range, 6.1 to 114.5) months, and the total number of deaths during the study period was 96 (30.4%).\n\n10.1371/journal.pone.0248188.t001 Table 1 Patient demographics.\n\nCharacteristics\tTotal (n = 316)\tTreatment (n = 144)\tNon-treatment (n = 172)\tp-value\t\nAge, years\t\t\t\t\t\n Mean (range)\t70.0 (40–93)\t67.4 (50–86)\t71.4 (51–84)\t0.06\t\nSex, female\t74.4% (235)\t88.9% (128)\t62.2% (107)\t<0.01\t\nDiagnosis\t\t\t\t\t\n *DXA\t32.9% (104)\t56.3% (81)\t13.4% (23)\t\t\n Vertebral fracture\t60.1% (190)\t38.2% (55)\t78.5% (135)\t\t\n Femoral fracture\t7.0% (22)\t5.6% (8)\t8.1% (14)\t\t\n\t\t\t\t<0.01\t\nCancer\t\t\t\t\t\n Breast\t34.0% (107)\t54.9% (79)\t16.3% (28)\t\t\n Gastrointestinal\t22.8% (72)\t13.9% (20)\t30.2% (52)\t\t\n Lung\t14.9% (47)\t9.7% (14)\t19.2% (33)\t\t\n Blood\t13.3% (42)\t12.5% (18)\t14.0% (24)\t\t\n Head and neck\t7.9% (25)\t2.7% (4)\t12.2% (21)\t\t\n Others\t7.3% (23)\t6.3% (9)\t8.1% (14)\t\t\n\t\t\t\t<0.01\t\nDouble cancer\t9.2% (29)\t5.8% (10)\t11.0% (19)\t0.21\t\nBone metastasis\t15.2% (48)\t19.4% (28)\t11.6% (20)\t0.05\t\nPrevious radiotherapy\t25% (79)\t19.4% (28)\t29.7% (51)\t0.04\t\nPrevious chemotherapy\t59.5% (188)\t56.2% (81)\t62.2% (107)\t0.28\t\nSteroid use\t46.8% (148)\t47.2% (68)\t46.5% (80)\t0.9\t\nAdverse effect\t\t\t\t<0.01\t\n Additional fracture\t43.7% (138)\t30.6% (44)\t54.7% (94)\t\t\n Jawbone necrosis\t\t2.1% (3)\t0% (0)\t\n Atypical femoral fracture\t\t1.4% (2)\t0% (0)\t\n*DXA: dual energy X-ray absorptiometry.\n\nPatients were mostly diagnosed with breast cancer (n = 107, 34.0%), followed by gastrointestinal (n = 72, 22.8%), lung (n = 47, 14.9%), and blood cancer (n = 42, 13.3%). Contrary to our expectation, prostate cancer patients were almost undiagnosed (<2%). The total rate of medications was 45.6% (n = 144), with 70.1% (n = 101) of patients receiving oral bisphosphonate, followed by 9.7% (n = 14) of receiving zoledronic acid injections. An active vitamin D3 form, the one most commonly prescribed in general practice, was used in 9% of all cases. Denosumab was used in 6.9% of the treatment-group participants. Apart from the healthy population, only one participant (0.7%) received a teriparatide injection at another clinic (Fig 1). Osteoporosis was most frequently treated in breast cancer patients (n = 79, 73.8%), followed by blood (n = 18, 42.9%), lung (n = 14, 29.8%), and gastrointestinal cancer patients (n = 20, 27.8%). However, only 16.0% of head and neck cancer patients received medication for osteoporosis (Fig 2).\n\n10.1371/journal.pone.0248188.g001 Fig 1 Key drugs used for osteoporosis treatment and frequency of anti-osteoporotic agents.\n\nOf the oral bisphosphonates, 54.9% were alendronate and the rest were risedronate. The active form of vitamin D3 included eldecalcitol and alfacalcidol.\n\n10.1371/journal.pone.0248188.g002 Fig 2 Treatment intervention rate.\n\nThe total rate of treatment intervention was 45.6%, and if breast cancer patients were excluded, it reduced to 31.0%. Approximately 73.8% of breast cancer patients were treated. In contrast, only 16.0% of head and neck cancer patients were treated.\n\nThe total rate of new fragility fractures during the study period was 43.7% (n = 138) (i.e., 30.6% [n = 44] and 54.7% [n = 94] in the treatment and non-treatment groups, respectively). Although there was clearly a statistically significant difference, only the statistics of the oral bisphosphonate group (n = 101) were examined because of the need for uniformity in the treatment agents. The Nelson-Aalen cumulative hazard estimate showed a great difference in the risk of new radiological fragility fractures between the treatment (n = 101) and non-treatment groups (n = 172), and the log-rank test demonstrated a significant difference among these groups (p<0.001) (Fig 3). However, the greater percentage of DXA-diagnosed patients could be a bias for the treatment group. We also performed the analysis after excluding the DXA-diagnosed patients, but it presented similar results (Fig 4). Although the difference between the two groups was small, the log-rank test also showed a significant difference between the two groups (p<0.05).\n\n10.1371/journal.pone.0248188.g003 Fig 3 Cumulative risk of fracture (treatment vs non-treatment group).\n\nThe Nelson-Aalen cumulative hazard estimate showing the difference in the risk of additional fragility fractures between the two groups. The log-rank test showed a significant difference between these two groups (p<0.001).\n\n10.1371/journal.pone.0248188.g004 Fig 4 Cumulative risk of fracture without DXA-diagnosed patients (treatment vs non-treatment group).\n\nWhen patients diagnosed by DXA were excluded, the difference between the two groups narrowed. However, the log-rank test still showed a significant difference between these groups (p = 0.047). DXA, dual energy X-ray absorptiometry.\n\nThe multivariate analysis revealed that previous chemotherapy (hazard ratio [HR], 1.78; p = 0.019; 95% confidence interval [CI], 1.10–2.89), steroid use (HR, 1.68; p = 0.018; 95% CI, 1.09–2.58), and older age (HR, 1.03; p = 0.007; 95% CI, 1.01–1.05) were positively related to the increase in the rate of getting another fracture. Treatment intervention (HR, 0.58; p = 0.007; 95% CI, 0.39–0.86) and DXA diagnosis (HR, 0.29; p<0.001; 95% CI, 0.15–0.51) showed an inverse result (Table 2).\n\n10.1371/journal.pone.0248188.t002 Table 2 Factors related to the risk of new radiological fragility fractures.\n\nFactors\tHazard ratio\tp-value\t95% CI\t\nPrevious chemotherapy\t1.78\t0.019\t1.10–2.89\t\nSteroid use\t1.68\t0.018\t1.09–2.58\t\nOlder age\t1.03\t0.007\t1.01–1.05\t\nDiagnosed with DXA\t0.29\t<0.001\t0.15–0.51\t\nTreatment intervention\t0.58\t0.007\t0.39–0.86\t\nCI: confidence interval; DXA: dual energy X-ray absorptiometry.\n\nThe most prevalent new radiological fragility fractures were vertebral (76.8%, n = 106) and femoral fractures (11.6%, n = 16). An adverse effect from using anti-osteoporotic drugs was observed in five cases (3.5%). This included two cases (1.4%) of atypical femoral fractures with long-term use of zoledronic acid, and three cases (2.1%) of jawbone necrosis in relation to the use of zoledronic acid or denosumab injections. Patients with fractures underwent open reduction and internal fixation at our department without any complications. Jawbone necrosis patients were treated at the dental department of our hospital, and all patients recovered during the follow-up period.\n\nDiscussion\n\nAlthough the prognosis of cancer patients has improved, it is necessary to treat osteoporosis to maintain the performance status (PS) for chemotherapies [5, 17]. With this perspective, we found that medication had a significant influence on osteoporosis even in cancer patients. The use of anti-osteoporotic agents could reduce the risk of new radiological fragility fractures by 42%. However, the treatment rate itself was below 50%, despite the existence of the national guidelines. These results were fairly better than those of the general population (i.e., approximately 20% in Japan) [18, 19].\n\nDisparities in treatment interventions between departments were large, with well-conducted interventions in breast and hematology departments, but not in lung, gastrointestinal, or head and neck surgery departments. This may stem from the differences in the cancer treatment itself, although we have not studied the exact reasons for this issue. For example, breast cancer treatment is directly related to bone metabolism with the use of hormone treatment, such as tamoxifen or aromatase inhibitors. There are several guidelines that have already been published for bone-directed treatment, and Hadji et al. [11] have updated the treatment algorithm for better assessment of fracture risk. In addition, Colzani et al. [20] reported an increased risk of fragility fracture in patients using aromatase inhibitors compared with patients using tamoxifen (HR, 1.48; 95% CI, 0.98–2.22). Therefore, in such cases, a treatment intervention should be provided. In these cases, physicians and patients may easily accept osteoporosis treatment because it is already included in the cancer treatment.\n\nConcerning risk factors, chemotherapy and associated steroid use had an obvious effect on the development of new radiological fragility fractures. Although chemotherapy itself is a risk factor for osteoporosis, a certain amount of steroid is often used as an antiemetic in chemotherapy, and this may worsen the patient’s comorbidities, which were not considered fatal. Many cancer patients are prescribed more steroids than the diagnosis criteria of steroid-induced osteoporosis [16], and the risk of developing this condition is dose dependent [21, 22]. In this study, patients who received chemotherapy and used steroids were at an increased risk of developing additional fractures, indicating that more careful interventions are needed for these patient groups.\n\nAfter considering these results, we propose some suggestions for individual physicians who are engaged in cancer treatments. First, as the use of osteoporotic drugs has an evident effect on preventing new fragility fractures, physicians should take osteoporosis seriously to provide an efficient cancer treatment. Indeed, the treatment of osteoporosis is a time-consuming process, as oral bisphosphonates are sometimes not fully effective in patients who have difficulty with oral intake or are unable to receive oral medication. However, in recent years, several new anti-osteoporotic agents, such as annual zoledronic acid, semi-annual denosumab, or newly developed romosozumab injections have been released and are gradually being used. These new drugs are potentially therapeutically beneficial and cost effective for cancer patients who must undergo multiple medical treatments [23–25]. The use of appropriate drugs for osteoporosis may also reduce the use of unnecessary analgesics, such as opioids or morphine, which can ultimately lead to a worsened PS. Second, as aforementioned, an increased rate of anti-osteoporotic agent usage can be attained as long as it can be linked to the cancer treatment itself. For example, when the diagnostic criteria for steroid osteoporosis are correctly applied to all cancer patients receiving chemotherapy, osteoporosis treatment could be included in their cancer treatment and physicians may prevent the decrease of the PS by avoiding fragility fractures caused by osteoporosis. Finally, there is an urgent need to correct disparities among medical departments. Common criteria are needed for initiating osteoporosis treatment in an institution. Moreover, establishing a cancer board that includes all departments may also help improve the rate of treatment interventions.\n\nRegarding the adverse effects of using anti-osteoporotic drugs, jawbone necrosis and atypical femoral fracture were observed in 1.4%, and 2.1% of patients, respectively. This was similar to those previously reported by Edwards et al. [26] and Lipton et al. [27]. Our institution routinely requires dental consultations for screening oral conditions before starting anti-osteoporotic agent administration, and patients who were diagnosed with a high risk of jawbone necrosis underwent dental treatment before using these agents [28]. In addition, there were three cases of atypical femoral fractures in our study group, and all were treated surgically at our orthopedic department without any complications.\n\nIn this study, we had few patients who used teriparatide, which is rarely used for osteoporosis treatment in recent years. After Subbiah et al. [29] reported the risk of teriparatide-induced osteosarcoma, the use of teriparatide is avoided for cancer patients. However, recent research has provided new evidence concerning the use of teriparatide [25, 30, 31]. Interestingly, Gilsenan et al. reported that the incidence of osteosarcoma associated with teriparatide use during a 15-year period was not different than what was expected based on the background incidence rate of osteosarcoma after examining data from a US database [30]. Besides, other new agents, such as romosozumab, humanized IgG2 monoclonal antibody, or annual zoledronic acid, were allowed to be used for the treatment of cancer patients. These relatively new drugs will be used more aggressively for such patients in the future.\n\nHowever, this study had several limitations. First, there were differences between the two groups. Although we conducted the analysis without factors that could affect the results, the potential difference may have affected the study results. Additionally, we had no detailed data on cancers and chemo/radiotherapies, and these unknown factors may also have affected the results. Second, we applied Japanese national guidelines for the prevention and diagnosis of osteoporosis, which are slightly different from the World Health Organization guidelines. This may have affected treatment interventions in particular for patients from different departments, such as the breast oncology department. Third, we defined treatment interventions as those provided for more than 6 months, as cancer patients often have poor prognoses. However, most related studies set this intervention period as over 1 year; therefore, some may doubt the effect of treatment interventions.\n\nDespite these limitations, the current study provided a sound analysis of the effect of osteoporosis treatment among cancer patients in our tertiary center. We found that the medication effect was quite substantial, while the incidence of adverse events was low. Therefore, older cancer patients who receive chemotherapy or use steroids are strongly recommended to use anti-osteoporotic drugs to maintain their PS. However, there is still a need to study the effect of osteoporotic treatment in terms of specific cancer types or agents, as related research is lacking. From these viewpoints, further research is required to improve the quality-of-life associated with cancer treatment of patients to achieve better prognoses.\n\nSupporting information\n\nS1 Data (XLSX)\n\nClick here for additional data file.\n\nS1 Checklist (DOCX)\n\nClick here for additional data file.\n\nThe authors thank Hidemi Ito and Kenichi Yoshimura for their statistical support.\n\n10.1371/journal.pone.0248188.r001\nDecision Letter 0\nBlank Robert Daniel Academic Editor\n© 2021 Robert Daniel Blank\n2021\nRobert Daniel Blank\nThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nSubmission Version0\n2 Nov 2020\n\nPONE-D-20-33343\n\nCurrent practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center\n\nPLOS ONE\n\nDear Dr. Fujihara,\n\nThank you for submitting your manuscript to PLOS ONE. 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For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols\n\nWe look forward to receiving your revised manuscript.\n\nKind regards,\n\nRobert Daniel Blank, MD, PhD\n\nAcademic Editor\n\nPLOS ONE\n\nAdditional Editor Comments:\n\nThere are several important issues that you must address before I send this MS to other reviewers.\n\n1. Please check your MS against STROBE standards for cohort studies and add the STROBE checklist to your MS.\n\n2. Please show p-values for table 1. My inspection of the table suggests that the treated/untreated groups differ. This should be checked explicitly, as it is an important potential source of confounding in your subsequent analysis.\n\n3. Date of entry into study should be explicitly defined, and survival curves plotted based on study entry, not diagnosis of osteoporosis. It is necessary to unpack those who were already being treated prior to cancer diagnosis.\n\n4. What about osteoporosis based on other low trauma fractures beside vertebral or femoral?\n\nJournal Requirements:\n\nWhen submitting your revision, we need you to address these additional requirements.\n\n1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at\n\nhttps://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and\n\nhttps://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf\n\n2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. 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Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.\n\nb) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.\n\nWe will update your Data Availability statement on your behalf to reflect the information you provide.\n\n[Note: HTML markup is below. Please do not edit.]\n\n[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link \"View Attachments\". If this link does not appear, there are no attachment files.]\n\nWhile revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.\n\n10.1371/journal.pone.0248188.r002\nAuthor response to Decision Letter 0\nSubmission Version1\n8 Dec 2020\n\nNovember, 30, 2020\n\nDear Editor:\n\nThank you for checking the manuscript. We have summarized the corrections below based on your review. Thank you in advance for your kind help.\n\nBest regards,\n\nNasa Fujihara\n\nAdditional Editor Comments:\n\n1. Please check your MS against STROBE standards for cohort studies and add the STROBE checklist to your MS.\n\n⇒ The checklist is attached at the end of the manuscript.\n\n2. Please show p-values for table 1. My inspection of the table suggests that the treated/untreated groups differ. This should be checked explicitly, as it is an important potential source of confounding in your subsequent analysis.\n\n⇒ We have included it because it affects the results of the analysis as you pointed out. Although there were fewer women in the untreated group, which may lead to a lower risk of fracture, the results actually showed a higher risk of fracture.\n\n3. Date of entry into study should be explicitly defined, and survival curves plotted based on study entry, not diagnosis of osteoporosis. It is necessary to unpack those who were already being treated prior to cancer diagnosis.\n\n⇒As you pointed out, the starting point was the time of participation in the study, and we have corrected this to include the notation in the graph.\n\nAlso, patients with a diagnosis of osteoporosis prior to the start of the study were excluded and this has been noted.\n\n4. What about osteoporosis based on other low trauma fractures beside vertebral or femoral?\n\n⇒ To clarify the definition, we only included the cases with vertebral or low-energy femoral fractures, or less than 70% of YAM value according to the Japanese diagnostic criteria of osteoporosis. So as you pointed out, the other low trauma fracture with high YAM value cases are not included. However, results includes all fragility fractures caused from low energy trauma.\n\nJournal Requirements:\n\n1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at\n\n⇒Done\n\n2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information.\n\n⇒ I have changed the manuscript following above.\n\n3. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.\n\nIn your revised cover letter, please address the following prompts:\n\nb) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers.\n\n⇒Done\n\nAttachment Submitted filename: Responce to Reviewer.docx\n\nClick here for additional data file.\n\n10.1371/journal.pone.0248188.r003\nDecision Letter 1\nBlank Robert Daniel Academic Editor\n© 2021 Robert Daniel Blank\n2021\nRobert Daniel Blank\nThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nSubmission Version1\n23 Dec 2020\n\nPONE-D-20-33343R1\n\nCurrent practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center\n\nPLOS ONE\n\nDear Dr. Fujihara,\n\nThank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.\n\nReviewer 1 wishes a few additional details regarding drug treatment. Reviewer 2 wishes a higher standard of English syntax and usage. Editor agrees with both reviewers.\n\nPlease submit your revised manuscript by Feb 06 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.\n\nPlease include the following items when submitting your revised manuscript:\n\nA rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.\n\nA marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.\n\nAn unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.\n\nIf you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.\n\nIf applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols\n\nWe look forward to receiving your revised manuscript.\n\nKind regards,\n\nRobert Daniel Blank, MD, PhD\n\nAcademic Editor\n\nPLOS ONE\n\n[Note: HTML markup is below. Please do not edit.]\n\nReviewers' comments:\n\nReviewer's Responses to Questions\n\nComments to the Author\n\n1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your \"Accept\" recommendation.\n\nReviewer #1: (No Response)\n\nReviewer #2: (No Response)\n\n**********\n\n2. Is the manuscript technically sound, and do the data support the conclusions?\n\nThe manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n3. Has the statistical analysis been performed appropriately and rigorously?\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n4. Have the authors made all data underlying the findings in their manuscript fully available?\n\nThe PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n5. Is the manuscript presented in an intelligible fashion and written in standard English?\n\nPLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.\n\nReviewer #1: Yes\n\nReviewer #2: No\n\n**********\n\n6. Review Comments to the Author\n\nPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)\n\nReviewer #1: The result is somehow expected where those being treated should have a lower incidence of fragility fracture. It is supported by this piece of research. 9% of the patients were being treated with Vitamin D. Many current studies showed the important role of Vitamin D in patients with cancer especially breast cancer. Is Vitamin D considered a treatment for osteoporosis in patient with cancer in your centre? What kind of Vitamin D was being used? Was it single therapy or in combination with anti-osteoporosis medicines? Did you look at the vitamin D level of your patients, both baseline and after treatment?\n\nAlthough it was mentioned in your document that there might be a role of teriparatide in treating cancer patients with osteoporosis, it is clearly stated in the teriparatide product information that it should not be used in cancer patients with skeletal metastatic lesion. What is your view on this?\n\nReviewer #2: The paper is scientifically sound and presents useful information. However, the written language used in the manuscript is not appropriate for a scientific publication (For example: first person used not be in scientific manuscript.\n\nEditing of the paper by an individual scientist with English as their language would aid in acceptance of the paper.\n\n**********\n\n7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.\n\nIf you choose “no”, your identity will remain anonymous but your review may still be made public.\n\nDo you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.\n\nReviewer #1: No\n\nReviewer #2: No\n\n[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link \"View Attachments\". If this link does not appear, there are no attachment files.]\n\nWhile revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.\n\n10.1371/journal.pone.0248188.r004\nAuthor response to Decision Letter 1\nSubmission Version2\n3 Feb 2021\n\nFebruary 3, 2021\n\nDear Dr. Blank,\n\nAcademic Editor\n\nPLOS ONE\n\nDear Editor:\n\nWe would like to thank you for your response and for giving us the opportunity to improve and resubmit our manuscript (PONE-D-20-33343R1) entitled \"Current practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center.\" We are hereby resubmitting a revised manuscript conforming to all of the reviewers’ comments. In particular, we have addressed all the reviewers’ comments in a point-by-point manner and revisions are indicated in red font in the revised manuscript. We hope that the revised manuscript is now suitable for publication in your journal.\n\nThank you for your consideration. I look forward to hearing from you.\n\nSincerely,\n\nNasa Fujihara,\n\nSection of Orthopedic Surgery, Aichi Cancer Center\n\n1-1 Kanokoden Tikusa-ku,\n\nNagoya City, Aichi, Japan 464-8681\n\nEmail: nfujihara@aichi-cc.jp\n\nPhone: 052-762-6111\n\nFAX: 052-762-6111\n\nReviewer #1: The result is somehow expected where those being treated should have a lower incidence of fragility fracture. It is supported by this piece of research. 9% of the patients were being treated with Vitamin D. Many current studies showed the important role of Vitamin D in patients with cancer especially breast cancer. Is Vitamin D considered a treatment for osteoporosis in patient with cancer in your centre? What kind of Vitamin D was being used? Was it single therapy or in combination with anti-osteoporosis medicines? Did you look at the vitamin D level of your patients, both baseline and after treatment?\n\nAlthough it was mentioned in your document that there might be a role of teriparatide in treating cancer patients with osteoporosis, it is clearly stated in the teriparatide product information that it should not be used in cancer patients with skeletal metastatic lesion. What is your view on this?\n\nResponse\n\nWe would like to thank the reviewer for evaluating our manuscript and for these constructive comments.\n\nFirst, regarding vitamin D, we did use not the natural form of vitamin D that is often discussed nowadays. “Vitamin D” described in this study was actually “eldecalcitol” or “alfacalcidol,” which is an active vitamin D3 prodrug. Besides, we do not have a specific hospital or medical department protocol for applying Vitamin D drugs. Probably, the use of Vitamin D has been reported in some cases of breast cancer, as the reviewer stated.\n\nHowever, in Japan, “eldecalcitol” or “alfacalcidol” is often prescribed as an initial drug for osteoporosis treatment. Please note that we have edited the text and figures to make it clear that we used an active vitamin D3 prodrug. Especially, we have added the following sentences in the revised manuscript:\n\n“An active vitamin D3 form, the one most commonly prescribed in general practice, was used in 9% of all cases.” (Lines 137–138)\n\n“The active form of vitamin D3 included eldecalcitol and alfacalcidol.” (Line 147)\n\nMoreover, teriparatide's contraindication for cancer patients with skeletal metastatic lesion is mainly based on past studies showing that teriparatide increased osteosarcoma in rats. However, in this study on rats, the used doses were dozens of times higher and provided for a longer period of time than those given to humans. Therefore, there are many arguments regarding whether it can directly apply to humans. In fact, as a recent study that analyzed the data of patients from a US database did not show any evidence concerning the role of teriparatide in increasing osteosarcoma or malignant bone tumors, we believe that the indications for teriparatide will be expanded in the future. Alternatively, another new osteoporosis drug, romosozumab, is indicated for cancer patients and may be a useful treatment option. Please note that we have included these issues in the discussion of the revised manuscript as follows: “However, recent research has provided new evidence concerning the use of teriparatide (25, 30, 31). Interestingly, Gilsenan et al. reported that the incidence of osteosarcoma associated with teriparatide use during a 15-year period was not different than what was expected based on the background incidence rate of osteosarcoma after examining data from a US database (30). Besides, other new agents, such as romosozumab, humanized IgG2 monoclonal antibody, or annual zoledronic acid, were allowed to be used for the treatment of cancer patients. These relatively new drugs will be used more aggressively for such patients in the future.”\n\n(Lines 256–263)\n\nReviewer #2: The paper is scientifically sound and presents useful information. However, the written language used in the manuscript is not appropriate for a scientific publication (For example: first person used not be in scientific manuscript.\n\nResponse\n\nWe would like to thank the reviewer for evaluating our manuscript and for this comment. Please note that we have sent our manuscript to an English editing company (Editage) for English proofreading. We hope that the level of English has significantly improved in the revised manuscript.\n\nAttachment Submitted filename: Responce_to_Reviewers_0203.docx\n\nClick here for additional data file.\n\n10.1371/journal.pone.0248188.r005\nDecision Letter 2\nBlank Robert Daniel Academic Editor\n© 2021 Robert Daniel Blank\n2021\nRobert Daniel Blank\nThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nSubmission Version2\n22 Feb 2021\n\nCurrent practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center\n\nPONE-D-20-33343R2\n\nDear Dr. Fujihara,\n\nWe’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.\n\nWithin one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.\n\nAn invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.\n\nIf your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.\n\nKind regards,\n\nRobert Daniel Blank, MD, PhD\n\nAcademic Editor\n\nPLOS ONE\n\nAdditional Editor Comments (optional):\n\nReviewers' comments:\n\nReviewer's Responses to Questions\n\nComments to the Author\n\n1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your \"Accept\" recommendation.\n\nReviewer #1: All comments have been addressed\n\nReviewer #2: All comments have been addressed\n\n**********\n\n2. Is the manuscript technically sound, and do the data support the conclusions?\n\nThe manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n3. Has the statistical analysis been performed appropriately and rigorously?\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n4. Have the authors made all data underlying the findings in their manuscript fully available?\n\nThe PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n5. Is the manuscript presented in an intelligible fashion and written in standard English?\n\nPLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n6. Review Comments to the Author\n\nPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)\n\nReviewer #1: Change all DEXA to DXA. The question about the use of vitamin D has been well explained. Agreed with the input on the role of teriparatide.\n\nReviewer #2: (No Response)\n\n**********\n\n7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.\n\nIf you choose “no”, your identity will remain anonymous but your review may still be made public.\n\nDo you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.\n\nReviewer #1: No\n\nReviewer #2: No\n\n10.1371/journal.pone.0248188.r006\nAcceptance letter\nBlank Robert Daniel Academic Editor\n© 2021 Robert Daniel Blank\n2021\nRobert Daniel Blank\nThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\n1 Mar 2021\n\nPONE-D-20-33343R2\n\nCurrent practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center\n\nDear Dr. Fujihara:\n\nI'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.\n\nIf your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.\n\nIf we can help with anything else, please email us at plosone@plos.org.\n\nThank you for submitting your work to PLOS ONE and supporting open access.\n\nKind regards,\n\nPLOS ONE Editorial Office Staff\n\non behalf of\n\nProfessor Robert Daniel Blank\n\nAcademic Editor\n\nPLOS ONE\n==== Refs\nReferences\n\n1 Hagino H , Soen S , Sugimoto T , Endo N , Okazaki R , Tanaka K , et al . Changes in quality of life in patients with postmenopausal osteoporosis receiving weekly bisphosphonate treatment: a 2-year multicenter study in Japan. J Bone Miner Metab. 2019;37 (2 ):273–81. 10.1007/s00774-018-0914-3 29523963\n2 Hu Z , Man GCW , Kwok AKL , Law SW , Chu WWC , Cheung WH , et al . Global sagittal alignment in elderly patients with osteoporosis and its relationship with severity of vertebral fracture and quality of life. Arch Osteoporos. 2018;13 (1 ):95. 10.1007/s11657-018-0512-y 30194552\n3 Hernlund E , Svedbom A , Ivergård M , Compston J , Cooper C , Stenmark J , et al . Osteoporosis in the European Union: medical management, epidemiology and economic burden. Archives of Osteoporosis. 2013;8 (1–2 ).\n4 Reginster JY , Burlet N . Osteoporosis: a still increasing prevalence. Bone. 2006;38 (2 Suppl 1 ):S4–9. 10.1016/j.bone.2005.11.024 16455317\n5 Body JJ , Terpos E , Tombal B , Hadji P , Arif A , Young A , et al . Bone health in the elderly cancer patient: A SIOG position paper. Cancer Treat Rev. 2016;51 :46–53. 10.1016/j.ctrv.2016.10.004 27863287\n6 Miceli TS , Colson K , Faiman BM , Miller K , Tariman JD , International Myeloma Foundation Nurse Leadership B. Maintaining bone health in patients with multiple myeloma: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board. Clin J Oncol Nurs. 2011;15 Suppl :9–23. 10.1188/11.S1.CJON.9-23 21816707\n7 Khanfir A , Lahiani F , Bouzguenda R , Ayedi I , Daoud J , Frikha M . Prognostic factors and survival in metastatic breast cancer: A single institution experience. Rep Pract Oncol Radiother. 2013;18 (3 ):127–32. 10.1016/j.rpor.2013.01.001 24416543\n8 Koo DH , Ryoo BY , Kim HJ , Ryu MH , Lee SS , Moon JH , et al . A prognostic model in patients who receive chemotherapy for metastatic or recurrent gastric cancer: validation and comparison with previous models. Cancer Chemother Pharmacol. 2011;68 (4 ):913–21. 10.1007/s00280-011-1561-8 21290247\n9 Takamatsu H , Honda S , Miyamoto T , Yokoyama K , Hagiwara S , Ito T , et al . Changing trends in prognostic factors for patients with multiple myeloma after autologous stem cell transplantation during the immunomodulator drug/proteasome inhibitor era. Cancer Sci. 2015;106 (2 ):179–85. 10.1111/cas.12594 25530023\n10 Winter WE 3rd , Maxwell GL , Tian C , Carlson JW , Ozols RF , Rose PG , et al . Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2007;25 (24 ):3621–7. 10.1200/JCO.2006.10.2517 17704411\n11 Hadji P , Aapro MS , Body JJ , Gnant M , Brandi ML , Reginster JY , et al . Management of Aromatase Inhibitor-Associated Bone Loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: Joint position statement of the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG. J Bone Oncol. 2017;7 :1–12. 10.1016/j.jbo.2017.03.001 28413771\n12 Khosla S , Bilezikian JP , Dempster DW , Lewiecki EM , Miller PD , Neer RM , et al . Benefits and risks of bisphosphonate therapy for osteoporosis. J Clin Endocrinol Metab. 2012;97 (7 ):2272–82.22523337\n13 Cosman F , de Beur SJ , LeBoff MS , Lewiecki EM , Tanner B , Randall S , et al . Clinician’s Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int. 2014;25 (10 ):2359–81. 10.1007/s00198-014-2794-2 25182228\n14 Orimo H , Nakamura T , Hosoi T , Iki M , Uenishi K , Endo N , et al . Japanese 2011 guidelines for prevention and treatment of osteoporosis—executive summary. Arch Osteoporos. 2012;7 :3–20. 10.1007/s11657-012-0109-9 23203733\n15 Prieto-Alhambra D , Premaor MO , Aviles FF , Castro AS , Javaid MK , Nogues X , et al . Relationship between mortality and BMI after fracture: a population-based study of men and women aged >/ = 40 years. J Bone Miner Res. 2014;29 (8 ):1737–44. 10.1002/jbmr.2209 24615695\n16 Suzuki Y , Nawata H , Soen S , Fujiwara S , Nakayama H , Tanaka I , et al . Guidelines on the management and treatment of glucocorticoid-induced osteoporosis of the Japanese Society for Bone and Mineral Research: 2014 update. J Bone Miner Metab. 2014;32 (4 ):337–50. 10.1007/s00774-014-0586-6 24818875\n17 Ottanelli S . Prevention and treatment of bone fragility in cancer patient. Clinical Cases in Mineral and Bone Metabolism. 2015;12 :116–29. 26604936\n18 Kataoka Y , Luo Y , Chaimani A , Onishi A , Kimachi M , Tsujimoto Y , et al . Cumulative network meta-analyses, practice guidelines, and actual prescriptions for postmenopausal osteoporosis: a meta-epidemiological study. Arch Osteoporos. 2020;15 (1 ):21. 10.1007/s11657-020-0697-8 32088774\n19 Iki M . [Epidemiology of osteoporosis in Japan]. Clin Calcium. 2012;22 (6 ):797–803. 22653016\n20 Colzani E , Clements M , Johansson AL , Liljegren A , He W , Brand J , et al . Risk of hospitalisation and death due to bone fractures after breast cancer: a registry-based cohort study. Br J Cancer. 2016;115 (11 ):1400–7. 10.1038/bjc.2016.314 27701383\n21 Frieze DA . Musculoskeletal pain associated with corticosteroid therapy in cancer. Curr Pain Headache Rep. 2010;14 (4 ):256–60. 10.1007/s11916-010-0120-z 20490741\n22 Nawata H , Soen S , Takayanagi R , Tanaka I , Takaoka K , Fukunaga M , et al . Guidelines on the management and treatment of glucocorticoid-induced osteoporosis of the Japanese Society for Bone and Mineral Research (2004). J Bone Miner Metab. 2005;23 (2 ):105–9. 10.1007/s00774-004-0596-x 15750687\n23 Moriwaki K , Mouri M , Hagino H . Cost-effectiveness analysis of once-yearly injection of zoledronic acid for the treatment of osteoporosis in Japan. Osteoporos Int. 2017;28 (6 ):1939–50. 10.1007/s00198-017-3973-8 28265718\n24 Fardellone P , Cortet B , Legrand E , Bresse X , Bisot-Locard S , Vigneron AM , et al . Cost-effectiveness model of using zoledronic acid once a year versus current treatment strategies in postmenopausal osteoporosis. Joint Bone Spine. 2010;77 (1 ):53–7. 10.1016/j.jbspin.2009.04.009 20034831\n25 Cosman F , Crittenden DB , Adachi JD , Binkley N , Czerwinski E , Ferrari S , et al . Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N Engl J Med. 2016;375 (16 ):1532–43. 10.1056/NEJMoa1607948 27641143\n26 Edwards BJ , Sun M , West DP , Guindani M , Lin YH , Lu H , et al . Incidence of Atypical Femur Fractures in Cancer Patients: The MD Anderson Cancer Center Experience. J Bone Miner Res. 2016;31 (8 ):1569–76. 10.1002/jbmr.2818 26896384\n27 Lipton A , Fizazi K , Stopeck AT , Henry DH , Brown JE , Yardley DA , et al . Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer. 2012;48 (16 ):3082–92. 10.1016/j.ejca.2012.08.002 22975218\n28 Lindsay BR , Olufade T , Bauer J , Babrowicz J , Hahn R . Patient-reported barriers to osteoporosis therapy. Arch Osteoporos. 2016;11 :19. 10.1007/s11657-016-0272-5 27129487\n29 Subbiah V , Madsen VS , Raymond AK , Benjamin RS , Ludwig JA . Of mice and men: divergent risks of teriparatide-induced osteosarcoma. Osteoporos Int. 2010;21 (6 ):1041–5. 10.1007/s00198-009-1004-0 19597911\n30 Andrews EB , Gilsenan AW , Midkiff K , Sherrill B , Wu Y , Mann BH , et al . The US postmarketing surveillance study of adult osteosarcoma and teriparatide: study design and findings from the first 7 years. J Bone Miner Res. 2012;27 (12 ):2429–37. 10.1002/jbmr.1768 22991313\n31 Gilsenan A , Midkiff K , Harris D , Kellier-Steele N , McSorley D , Andrews EB . Teriparatide Did Not Increase Adult Osteosarcoma Incidence in a 15-Year US Postmarketing Surveillance Study. J Bone Miner Res. 2020.\n\n",
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"title": "Current practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center.",
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"abstract": "The administration of cyproterone acetate (CPA) and estradiol is a common regimen used by male-to-female transsexuals (transwoman) to adjust their body to their gender identity. Major adverse events are uncommon in these subjects in spite of long-term, high dose cross-sex steroid treatments. We describe the occurrence of a meningioma in a transwoman treated with estrogens and CPA over a period of nine years. The meningioma was revealed during a magnetic resonance imaging (MRI) scan performed as follow-up of a previous surgery for ganglioglioma. CPA intake was discontinued and tumor resection was performed. Histological diagnosis confirmed a strong progesterone receptor-positive and slight estrogen positive meningioma. After surgery, the patient continued her treatment with leuprorelina acetate and estradiol. At one-year follow-up, the MRI scan reveals no recurrence of the tumor. This is the ninth case in literature of a meningioma in a transwoman treated with estrogens and CPA, confirming a possible association between female sex steroids and meningioma. Although there is no still strong evidence of an association between meningioma and CPA, this report may suggest use of alternative treatment for transwomen. This report highlights the importance to record all the cases of meningiomas in high dose CPA-users, in order to improve data.",
"affiliations": "a DIMEC , University of Bologna , Bologna , Italy.;b Department of Surgery , Operative Unit of Neurosurgery, Hospital of Padua , Padua , Italy.;c Department of Medicine (DIMED) , Surgical Pathology Unit, University of Padua , Padua , Italy.;a DIMEC , University of Bologna , Bologna , Italy.;a DIMEC , University of Bologna , Bologna , Italy.;a DIMEC , University of Bologna , Bologna , Italy.",
"authors": "Mancini|Ilaria|I|;Rotilio|Antonino|A|;Coati|Irene|I|;Seracchioli|Renato|R|;Martelli|Valentina|V|;Meriggiola|Maria Cristina|MC|",
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"title": "Presentation of a meningioma in a transwoman after nine years of cyproterone acetate and estradiol intake: case report and literature review.",
"title_normalized": "presentation of a meningioma in a transwoman after nine years of cyproterone acetate and estradiol intake case report and literature review"
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"abstract": "DRESS (drug reaction with eosinophilia and systemic symptoms) is a rare, severe multiorgan adverse drug reaction. Antiepileptic age's and antibiotics are the most frequently reported causative agents. Compared with other drug reactions, DRESS demonstrates a long latency period thus complicating recognition and diagnosis. DRESS is defined as presence of fever, skin eruption, hematologic abnormalities and systemic involvement, especially liver injury. Withdrawal of the culprit drug, commencement of systemic corticosteroid and supportive care are the mainstay of treatment. The majority of patients recover completely after drug withdrawal and appropriate therapy. Some patients suffer from chronic sequelae or even death.",
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"title": "How to identify DRESS, drug reaction with eosinophilia and systemic symptoms?",
"title_normalized": "how to identify dress drug reaction with eosinophilia and systemic symptoms"
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"abstract": "Although, both bisphosphonates and denosumab are effective in reducing the risk of skeletal-related events in patients with metastatic bone disease, many concerns were being raised about the possible association between their use and atypical femoral fractures. A case of an atypical femoral fracture in a metastatic bone disease patient, six months after discontinuation of long-term zoledronic acid therapy and sequential treatment with denosumab is reported. After extensive laboratory and imaging examination, the fracture was classified as atypical and it was finally treated with discontinuation of denosumab, long cephalomedullary interlocking nailing and vitamin D administration. Sequential treatment with bisphosphonates and denosumab in patients with metastatic bone disease, may lead to an overlapping treatment effect, increasing bone suppression and the risk of atypical femoral fracture. In addition, discontinuation of denosumab may activate bone remodeling units in an area with microdamage accumulation in cortical bone caused by the previous bone suppression from the antiresorptive treatment. The activation of bone remodeling units may accelerate the occurrence of the atypical femoral fractures.",
"affiliations": "4th Orthopaedic Department and Osteoporosis Department, Asclepieion Voulas General Hospital, Athens, Greece.;Computed Tomography Department and Osteoporosis Department, Asclepieion Voulas General Hospital, Athens, Greece.;2nd Orthopaedic Department, Asclepieion Voulas General Hospital, Athens, Greece.;6th Orthopaedic Department and Osteoporosis Department, Asclepieion Voulas General Hospital, Athens, Greece.;Radiology Department, Georgios Gennimatas General Hospital and Osteoporosis Department, Asclepieion Voulas General Hospital, Athens, Greece.;6th Orthopaedic Department and Osteoporosis Department, Asclepieion Voulas General Hospital, Athens, Greece.",
"authors": "Georgiadis|George F|GF|;Balanika|Alexia P|AP|;Vasilakis|Alexandros Ε|AΕ|;Begkas|Dimitrios G|DG|;Baltas|Christos S|CS|;Pastroudis|Alexandros P|AP|",
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"fulltext": "\n==== Front\nJ Musculoskelet Neuronal Interact\nJ Musculoskelet Neuronal Interact\nJournal of Musculoskeletal & Neuronal Interactions\n1108-7161\nInternational Society of Musculoskeletal and Neuronal Interactions Greece\n\n34465683\nJMNI-21-429\nCase Report\nAtypical femoral fracture in a metastatic bone disease patient six months after discontinuation of denosumab received sequentially to previous bisphosphonate therapy - A case report\nGeorgiadis George F. 1\nBalanika Alexia P. 2\nVasilakis Alexandros Ε. 3\nBegkas Dimitrios G. 4\nBaltas Christos S. 5\nPastroudis Alexandros P. 4\n1 4th Orthopaedic Department and Osteoporosis Department, Asclepieion Voulas General Hospital, Athens, Greece\n2 Computed Tomography Department and Osteoporosis Department, Asclepieion Voulas General Hospital, Athens, Greece\n3 2nd Orthopaedic Department, Asclepieion Voulas General Hospital, Athens, Greece;\n4 6th Orthopaedic Department and Osteoporosis Department, Asclepieion Voulas General Hospital, Athens, Greece\n5 Radiology Department, Georgios Gennimatas General Hospital and Osteoporosis Department, Asclepieion Voulas General Hospital, Athens, Greece\nCorresponding author: George Georgiadis, 1 Vasileos Pavlou Street, Voula, 166 73, Athens, Greece E-mail: gegeorgiades@yahoo.com\n2021\n21 3 429433\n13 4 2021\nCopyright: © Journal of Musculoskeletal and Neuronal Interactions\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 4.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nAlthough, both bisphosphonates and denosumab are effective in reducing the risk of skeletal-related events in patients with metastatic bone disease, many concerns were being raised about the possible association between their use and atypical femoral fractures. A case of an atypical femoral fracture in a metastatic bone disease patient, six months after discontinuation of long-term zoledronic acid therapy and sequential treatment with denosumab is reported. After extensive laboratory and imaging examination, the fracture was classified as atypical and it was finally treated with discontinuation of denosumab, long cephalomedullary interlocking nailing and vitamin D administration. Sequential treatment with bisphosphonates and denosumab in patients with metastatic bone disease, may lead to an overlapping treatment effect, increasing bone suppression and the risk of atypical femoral fracture. In addition, discontinuation of denosumab may activate bone remodeling units in an area with microdamage accumulation in cortical bone caused by the previous bone suppression from the antiresorptive treatment. The activation of bone remodeling units may accelerate the occurrence of the atypical femoral fractures.\n\nAtypical Femoral Fracture\nBisphosphonates\nDenosumab\nMetastatic Bone Disease\nZoledronic Acid\n==== Body\npmcIntroduction\n\nBisphosphonates (BPs) and denosumab are commonly used in patients with metastatic bone disease (MBD) to reduce the risk of skeletal-related events (SRE) like pathological fractures, spinal cord compression, and hypercalcemia of malignancy[1,2]. However, many concerns were being raised about the possible association between prolonged and high-dose of both BPs and denosumab for MBD and atypical femoral fractures (AFFs)[3-7]. We present a case of an AFF in a MBD patient six months after discontinuation of an eleven-months oncologic dose denosumab administration which was received sequentially to a long-term zoledronic acid therapy.\n\nCase presentation\n\nIn March 2020, a 76-year-old woman with a past medical history of MBD from breast cancer presented to the emergency department of our hospital with a spontaneous left femur fracture. The breast cancer was diagnosed in 1985 and treated with partial mastectomy, chemotherapy and hormonotherapy with Tamoxifen for five years. In 1997 the patient underwent total mastectomy due to local recurrence of the cancer and she was administered chemotherapy and hormonotherapy with Tamoxifen for another five years. Bone metastases were found in January 2012 and she received zoledronic acid (4 mg monthly) until April 2015 when she presented acute renal failure. She continued receiving zoledronic acid in lower dose (5 mg every two months) until October 2018 when BPs were switched to denosumab in oncologic dose (120 mg monthly) due to MBD recurrence. She received eleven doses of denosumab until September 2019 when she underwent hysterectomy with the suspicion of endometrial cancer. Although the histopathology was negative, she presented serious wound infection. Additionally, the patient was suffered from diabetes mellitus and psoriatic arthritis.\n\nUpon her arrival at the emergency department, she reported that was experienced continuous pain in her left thigh, for a period of eight months. Although an initial frontal radiograph of the left hip showed localized thickening of the lateral cortex in the subtrochanteric region of the left femur, the examination was misinterpreted as normal (Figure 1). Moreover, bone scan obtained in November 2019, two months since the patient discontinued denosumab, showed increased tracer uptake at the subtrochanteric area, while the previous bone scan obtained in July 2018 was negative (Figure 2).\n\nFigure 1 Anteroposterior radiograph of both femurs performed one month before the occurrence of the complete AFF showing a localized periosteal thickening in the lateral cortex of the left femur (arrow).\n\nFigure 2 The three-phase bone scintigraphy obtained after eleven doses of denosumab showing increased tracer uptake in the lateral aspect of the proximal femur (arrow), while the three-phase bone scintigraphy obtained before the initiation of denosumab was negative.\n\nThe recent serial hip radiographs revealed a complete non-comminuted transverse subtrochanteric fracture at the left femur with focal lateral cortical thickening and a small medial spike (Figure 3), while radiographs at the contralateral femur were negative. At the time of fracture, the following blood test results were found: urine (47mg/dl, normal range 10-50 mg/dl), creatinine (0,9 mg/dl, normal range 0,5-1,5 mg/dl), alkaline phosphatase (52 U/L normal range 25-130 U/L), blood calcium (8,2 mg/dl, normal range 8,2-10,4 mg/dl), blood phosphate (2,5 mg/dl, normal range 2,5-4,5 md/dl) and parathyroid hormone (69 pg/ml, normal range 15-69 pg/ml) were in normal ranges, while 25-hydroxy-vitamin D level was low (12,6 ng/ml, normal range 20-40 ng/ml). No bone turnover markers obtained at the time of fracture or at any point during the course of the patient. Patient underwent DXA scan only twice in her life, the first one five years before and the second one nine months after AFF, with normal BMD values.\n\nFigure 3 Anteroposterior radiograph of left femur shows a non-comminuted transverse subtrochanteric fracture with lateral cortical hypertrophy and medial spiking. Note the generalized increase in lateral cortical thickness (arrow).\n\nMultidetector computed tomography (MDCT) of pelvis and femurs was performed for exclusion of a MBD fracture. The MDCT scan demonstrated imaging features suggesting stress fracture such as complete transverse fracture line at the subtrochanteric region of left femur with focal lateral cortical thickening of the shaft, no aggressive periosteal reaction, no endosteal scalloping or soft tissue mass (Figures 4a-b).\n\nFigures 4 Sagittal and coronal MDCT scan of the left femur revealed a non-comminuted transverse subtrochanteric fracture with localized periosteal thickening in the lateral cortex (arrow).\n\nLong cephalomedullary interlocking nailing was performed and histopathology showed no evidence of malignancy. The fracture healed in a normal time period of 5 months with callus formation (Figure 5). Postoperatively, vitamin D was commenced. Denosumab was given again in oncologic dose 120 mg monthly, six months after the fracture occurrence in order to prevent SRE and since there was no evidence of AFF in the contralateral femur.\n\nFigure 5 Anteroposterior radiograph of left femur 5 months after the operation, showing healing of the fracture with callus formation.\n\nDiscussion\n\nBPs given in high doses, usually at frequent of monthly interval, intravenously or orally, seemed to delay the time of first SRE and to decrease the incidence of SRE[1]. Oncologic dosing of denosumab comparing with BPs in MBD patients was proved to reduce the risk and to delay the time of the first SRE even more[2]. Despite the proven efficacy of both BPs and denosumab in preventing SRE, their use in long-term, high-doses and sequential manner in MBD patients is reported to be associated with increased risk for AFFs[3-7].\n\nThe American Society for Bone and Mineral Research (ASBMR) task force described major and minor defining features of AFF[8]. Our case had all of the major features: the location was the subtrochanteric region, the fracture was transverse with a small medial spike, there was no trauma, there was no comminution, and there was a focal periosteal reaction of the lateral cortex. Regarding the minor features, there was generalized lateral cortical thickening and prodromal pain, but not bilaterality.\n\nPathological fractures are excluded from ASBMR definition for AFF[8]. In the setting of complicated patients with advanced cancer, AFF may be confused with a pathological fracture. First of all, it should be noted that cortical bone metastases are very rare. Secondary, additional cross-sectional imaging with MDCT or MRI should be used for the distinction of pathological fractures from the insufficiency fractures like AFF[9]. MDCT scan in our case revealed features such as focal callus formation and endosteal thickening around a fracture site which are suggestive of a stress fracture. It didn’t reveal features like aggressive periosteal reaction, bone marrow pattern of destruction, endosteal scalloping, mineralized matrix and a large soft tissue mass which are present in pathological fractures. Additionally, histopathology of tissues obtained during surgery showed no evidence of malignancy.\n\nThe current consensus is that AFFs are stress or insufficiency fractures that develop over time[8]. Since, antiresorptive agents like BPs and denosumab inhibit osteoclast function[10,11], (osteoclast inhibitors) and cause a reduction of bone turnover, long-term use or high doses are associated with an altered bone structure and biomechanics. Microcracks within femoral lateral cortex are not adequately repaired due to severely bone suppression, accumulate and over the time these can precipitate a fracture. Moreover, BPs and denosumab inhibit osteoclast function through different pharmacological pathways and BPs are retained in bone for several months to years[10,11]. Sequential treatment with BPs and denosumab might lead to an overlapping treatment effect and increased bone suspension, due to the addition of the effect of denosumab on the residual BPs effect. A multi-center retrospective study found that the incidence rate of AFF was 1.8% among 277 cancer patients who had received monthly denosumab treatment[7]. In the same study long-term denosumab treatment and prior zoledronic acid treatment were identified as risk factors for the development of AFF. Our patient was treated sequentially with zoledronic acid and denosumab in high doses for more than 8 years. Major limitations in the supporting of the overlapping effect in the present patient are the lack of BMD values, bone turnover markers and histological indexes of bone turnover at the end of both zoledronic and denosumab treatments.\n\nOn the other hand it is well documented that discontinuation of denosumab therapy may be followed by rebound-associated vertebral fractures in a period of 3 to 12 months due to the synergy of rapid bone resorption and accelerated microdamage accumulation in trabecular bone[12]. In the same way, the activation of bone remodeling units at the time of loss of denosumab effect, in an area with microdamage accumulation due to failure of microdamage repair in cortical bone caused by the previous bone suppression from the antiresorptive treatment, may accelerate the occurrence of the AFFs. Again, major limitations in the supporting of this hypothesis in the present patient are the lack of bone turnover markers values as well as the lack of histological indexes of bone turnover and microdamage accumulation. In our case, denosumab was given monthly for eleven doses sequentially after a long-term BPs therapy and it was discontinued for six months before complete AFF occurred due to serious wound infection after hysterectomy although wound infection is not an indication for denosumab discontinuation. The rebound phenomenon six months after denosumab discontinuation was not mitigated from zoledronic acid retained to bones because its effect was decreased seventeen months after its discontinuation. Moreover, in a period of eight months before AFF occurrence, patient continued to walk bearing full weight although she experienced pain in the left thigh.\n\nIn addition, stress concentration on the lateral cortex of the femur especially in curved femur is considered to be possible contributing factor[13-16]. Multiple other factors associated with deterioration of bone quality such as certain medications use (glucocorticoids, proton pump inhibitors)[17,18], certain comorbid conditions (diabetes, rheumatoid arthritis and other autoimmune diseases)[16,18], and conditions with impaired mineralization caused by osteomalacia or vitamin D deficiency[8], are considered as risk factors for AFF. Our patient presented diabetes mellitus, psoriatic arthritis and vitamin D deficiency.\n\nThe presence of prodromic symptoms and subclinical imaging changes in the lateral femoral cortex should be assessed among patients with MBD treated with BPs or denosumab[4,7]. In our case, the incomplete AFF went unrecognized despite the thigh pain lasting for eight months and the focal cortical thickening along the lateral cortex of the proximal femur until it proceeded to a complete AFF.\n\nStatic intramedullary nailing is the first-line treatment for AFF in patients with MBD. Although, stopping of denosumab or BPs therapy, as well as the prescribing of calcium and vitamin D are mandatory in order to avoid AFF bilaterally and to improve the fracture healing, they must be accurately weighted in patients with MBD. Moreover, teriparatide treatment although found to reduce the time to union of AFFs treated with intramedullary nails[9], is unsuitable for patients with MBD.\n\nConclusions\n\nIn conclusion, sequential treatment with zoledronic acid and denosumab in patients with MBD leads to an overlapping treatment effect and increases bone suspension, due to the addition of the effect of denosumab on the residual bisphosphonates effect, increasing the risk of AFF. Additionally, discontinuation of denosumab may activate bone remodeling units at the time of loss of its effect in an area with microdamage accumulation, due to failure of microdamage repair in cortical bone caused by the previous bone suppression from the antiresorptive treatment and may accelerate the occurrence of the AFF.\n\nEthics approval and consent to participate\n\nInstitutional Review Board of Asclepieion Voulas General Hospital approved the case report presentation.\n\nConsent for publication\n\nInformed consent was given by the patient.\n\nAuthors’ contributions\n\nGeorge F. Georgiadis was responsible for the design, collection of data and writing of the manuscript, Alexia P. Balanika evaluated the radiological findings, Alexandros E. Vasilakis operated and followed the patient, Dimitrios G. Begkas collected clinical data and participated in the design and revision of the manuscript, Christos S. Baltas participated in radiological data analysis, and Alexandros P. Pastroudis coordinated the manuscript.\n\nThe authors have no conflict of interest.\n\nEdited by: G. Lyritis\n==== Refs\n1 Van Acker HH Anguille S Willemen Y Smits EL Van Tendeloo VF Bisphosphonates for cancer treatment:mechanisms of action and lessons from clinical trials Pharmacol Ther 2016 158 24 40 26617219\n2 Lipton A Fizazi K Stopeck AT Henry DH Brown JE Yardley DA Richardson GE Siena S Maroto P Clemens M Bilynskyy B Charu V Beuzeboc P Rader M Viniegra M Saad F Ke C Braun A Jun S Superiority of denosumab to zoledronic acid for prevention of skeletal-related events:A combined analysis of 3 pivotal, randomized, phase 3 trials Eur J Cancer 2012 48 16 3082 92 22975218\n3 Edwards BJ Sun M West DP Guindani M Lin YH Lu H Hu M Barcenas C Bird J Feng C Saraykar S Tripathy D Hortobagyi GN Gagel R Murphy WA Jr Incidence of atypical femur fractures in cancer patients:the MD Anderson Cancer Center experience J Bone Miner Res 2016 31 8 1569 76 26896384\n4 Puhaindran ME Farooki A Steensma MR Hameed M Healey JH Boland PJ Atypical subtrochanteric femoral fractures in patients with skeletal malignant involvement treated with intravenous bisphosphonates J Bone Jt Surg Am 2011 93 13 1235 42\n5 Chang ST Tenforde AS Grimsrud CD O'Ryan FS Gonzalez JR Baer DM Chandra M Lo JC Atypical femur fractures among breast cancer and multiple myeloma patients receiving intravenous bisphosphonate therapy Bone 2012 51 3 524 27 22634175\n6 Yang SP Kim TWB Boland PJ Farooki A Retrospective review of atypical femoral fracture in metastatic Bone disease patients receiving Denosumab therapy Oncologist 2017 22 4 438 44 28275116\n7 Takahashi M Ozaki Y Kizawa R Masuda J Sakamaki K Kinowaki K Umezu T Kondoh C Tanabe Y Tamura N Miura Y Shigekawa T Kawabata H Baba N Iguchi H Takano T Atypical femoral fracture in patients with bone metastasis receiving denosumab therapy:a retrospective study and systematic review BMC Cancer 2019 19 1 980 90 31640606\n8 Shane E Burr D Abrahamsen B Adler RA Brown TD Cheung AM Cosman F Curtis JR Dell R Dempster DW Ebeling PR Einhorn TA Genant HK Geusens P Klaushofer K Lane JM McKiernan F McKinney R Ng A Nieves J O'Keefe R Papapoulos S Howe TS van der Meulen MC Weinstein RS Whyte MP Atypical subtrochanteric and diaphyseal femoral fractures:second report of a task force of the American Society for Bone and Mineral Research J Bone Miner Res 2014 29 1 1 23 23712442\n9 Fayad LM Kamel IR Kawamoto S Blumke DA Frassica FJ Fishman EK Distinguishing stress fractures from pathologic fractures:A multimodality approach Skeletal Radiol 2005 34 5 245 59 15838703\n10 Russell RG Watts NB Ebetino FH Rogers MJ Mechanisms of action of bisphosphonates:similarities and differences and their potential influence on clinical efficacy Osteoporos Int 2008 19 6 733 59 18214569\n11 Dempster DW Lambing CL Kostenuik PJ Grauer A A Role of RANK ligand and denosumab, a targeted RANK ligand inhibitor, in bone health and osteoporosis:a review of preclinical and clinical data Clin Ther 2012 34 3 521 36 22440513\n12 Cummings SR Ferrari S Eastell R Gilchrist N Jensen JEB McClung M Roux C Torring O Valter I Wang AT Brown JP Vertebral fractures after discontinuation of denosumab:a post hoc analysis of the randomized placebo-controlled FREEDOM Trial and its extension J Bone Miner Res 2018 33 2 190 98 29105841\n13 Yoo H Cho Y Park Y Ha S Lateral femoral bowing and the location of atypical femoral fractures Hip Pelvis 2017 29 2 127 32 28611964\n14 Mahjoub Z Jean S Leclerc JT Brown JP Boulet D Pelet S Grondin C Dumont J Belzile EL Michou L Incidence and characteristics of atypical femoral fractures:clinical and geometrical data J Bone Miner Res 2016 31 4 767 76 26588590\n15 Hagen JE Miller AN Ott SM Gardner M Morshed S Jeray K Alton T Ren D Abblit WP Krieg JC Association of atypical femoral fractures with bisphosphonate use by patients with varus hip geometry J Bone Joint Surg Am 2014 96 22 1905 9 25410509\n16 Lim SJ Yeo I Yoon PW Yoo JJ Rhyu KH Han SB Lee WS Song JH Min BW Park YS Incidence, risk factors and fracture healing of atypical femoral fractures:a multicenter case-control study Osteoporos Int 2018 29 11 2427 35 30039251\n17 Koh JH Myong JP Yoo J Lim YW Lee J Kwok SK Park SH Ju JH Predisposing factors associated with atypical femur fracture among postmenopausal Korean women receiving bisphosphonate therapy:8 years'experience in a single center Osteoporos Int 2017 28 11 3251 59 28748389\n18 Kim D Sung YK Cho SK Han M Kim YS Factors associated with atypical femoral fracture Rheumatol Int 2016 36 1 65 71 26202894\n19 Yeh WL Su CY Chang CW Chen CH Fu TS Chen LH Lin TY Surgical outcome of atypical subtrochanteric and femoral fracture related to bisphosphonates use in osteoporotic patients with or without teriparatide treatment BMC Musculoskelet Disord 2017 18 1 527 29237448\n\n",
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"title": "Atypical femoral fracture in a metastatic bone disease patient six months after discontinuation of denosumab received sequentially to previous bisphosphonate therapy - A case report.",
"title_normalized": "atypical femoral fracture in a metastatic bone disease patient six months after discontinuation of denosumab received sequentially to previous bisphosphonate therapy a case report"
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"affiliations": "Ernie Wilkins Vej 27, 1. tv, 2450 København SV. julie.steen.ped@gmail.com.",
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"mesh_terms": "D000293:Adolescent; D018687:Antidepressive Agents, Second-Generation; D003866:Depressive Disorder; D062787:Drug Overdose; D017809:Fatal Outcome; D005260:Female; D006333:Heart Failure; D006801:Humans; D013405:Suicide; D000069470:Venlafaxine Hydrochloride",
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"abstract": "A spinal intramedullary abscess is a rare clinical entity in which patients classically present with a subacute myelopathy and progressive paraplegia, sensory deficits, and/or bowel and bladder dysfunction. We report the second case of spinal intramedullary abscess caused by Candida albicans to ever be published and the first case of its kind to be surgically managed.\nA 44-year-old female presented with severe lumbar pain associated with paraparesis, incontinence, and paraplegia. She reported multiple hospital admissions and had a history of seizures, having already undergone treatment for neurotuberculosis and fungal infection of the central nervous system unsuccessfully. Nevertheless, no laboratory evidence of immunosuppression was identified on further investigation. Magnetic resonance imaging showed a D10-D11, well-circumscribed, intramedullary mass within the conus, which was hypointense on T1-weighted imaging and hyperintense on T2/STIR weighted. The patient underwent surgery for removal and biopsy of the lesion, which provided the diagnosis of an intramedullary abscess caused by C. albicans, a very rare condition with only one case reported in literature so far.\nC. albicans intramedullary abscess is a very rare clinical entity, especially in immunocompetent patients. We highlight C. albicans as an important etiology that must be considered in differential diagnosis. Critical evaluation of every case, early diagnosis, timely referral and surgical management of the abscess is essential to improve neurological outcome.",
"affiliations": "Department of Medicine, Catanduva Medical School (FAMECA-UNIFIPA), Catanduva, São Paulo, Brazil.;Department of Medicine, Pontifical Catholic University of Goiás, Goiânia, Brazil.;Department of Medicine, Faculty of Medicine of ABC, Santo André, São Paulo, Brazil.;Department of Medicine, Faculty of Medicine of ABC, Santo André, São Paulo, Brazil.;Department of Medicine, School of Medicine of Pontifical Catholic University of São Paulo, Sorocaba, São Paulo, Brazil.;Department of Neurosurgery, Santa Paula Hospital, São Paulo, Brazil.;Department of Pathology, DASA, São Paulo, Brazil.;Department of Neurology and Neurosurgery, University of Caxias do Sul, Caxias do Sul, Rio Grande do Sul, Brazil.;Department of Neurosurgery, Santa Paula Hospital, São Paulo, Brazil.;Department of Medicine, Division of Neurology, Catholic Pontifical University of São Paulo, Sorocaba, São Paulo, Brazil.",
"authors": "Raffa|Paulo Eduardo Albuquerque Zito|PEAZ|;Vencio|Rafael Caiado Caixeta|RCC|;Ponce|Andre Costa Corral|ACC|;Malamud|Bruno Pricoli|BP|;Vencio|Isabela Caiado|IC|;Pacheco|Cesar Cozar|CC|;Costa|Felipe D'Almeida|FD|;Franceschini|Paulo Roberto|PR|;Medeiros|Roger Thomaz Rotta|RTR|;Aguiar|Paulo Henrique Pires|PHP|",
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"doi": "10.25259/SNI_435_2021",
"fulltext": "\n==== Front\nSurg Neurol Int\nSurg Neurol Int\nSurgical Neurology International\n2229-5097\n2152-7806\nScientific Scholar USA\n\n10.25259/SNI_435_2021\n10.25259/SNI_435_2021\nCase Report\nSpinal intramedullary abscess due to Candida albicans in an immunocompetent patient: A rare case report\nRaffa Paulo Eduardo Albuquerque Zito 1pauloeduardoazr@gmail.com\n\nVencio Rafael Caiado Caixeta 2rcvencio@gmail.com\n\nPonce Andre Costa Corral 3andre.ponce@aluno.fmabc.net\n\nMalamud Bruno Pricoli 3bruno.malamud@gmail.com\n\nVencio Isabela Caiado 4belacvencio@gmail.com\n\nPacheco Cesar Cozar 5cesarpacheco.md@gmail.com\n\nCosta Felipe D’Almeida 6felipedalmeida@yahoo.com.br\n\nFranceschini Paulo Roberto 7prfrance@yahoo.com.br\n\nMedeiros Roger Thomaz Rotta 5roger.rotta@hotmail.com\n\nAguiar Paulo Henrique Pires 8phpaneurocir@gmail.com\n\n1 Department of Medicine, Catanduva Medical School (FAMECA-UNIFIPA), Catanduva, São Paulo, Brazil.\n2 Department of Medicine, Pontifical Catholic University of Goiás, Goiânia, Brazil.\n3 Department of Medicine, Faculty of Medicine of ABC, Santo André, São Paulo, Brazil.\n4 Department of Medicine, School of Medicine of Pontifical Catholic University of São Paulo, Sorocaba, São Paulo, Brazil.\n5 Department of Neurosurgery, Santa Paula Hospital, São Paulo, Brazil.\n6 Department of Pathology, DASA, São Paulo, Brazil.\n7 Department of Neurology and Neurosurgery, University of Caxias do Sul, Caxias do Sul, Rio Grande do Sul, Brazil.\n8 Department of Medicine, Division of Neurology, Catholic Pontifical University of São Paulo, Sorocaba, São Paulo, Brazil.\n* Corresponding author: Paulo Eduardo Albuquerque Zito Raffa, Catanduva Medical School (FAMECA-UNIFIPA), Catanduva, São Paulo, Brazil. pauloeduardoazr@gmail.com\n2021\n14 6 2021\n12 27530 4 2021\n18 5 2021\nCopyright: © 2021 Surgical Neurology International\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This 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.\nBackground:\n\nA spinal intramedullary abscess is a rare clinical entity in which patients classically present with a subacute myelopathy and progressive paraplegia, sensory deficits, and/or bowel and bladder dysfunction. We report the second case of spinal intramedullary abscess caused by Candida albicans to ever be published and the first case of its kind to be surgically managed.\n\nCase Description:\n\nA 44-year-old female presented with severe lumbar pain associated with paraparesis, incontinence, and paraplegia. She reported multiple hospital admissions and had a history of seizures, having already undergone treatment for neurotuberculosis and fungal infection of the central nervous system unsuccessfully. Nevertheless, no laboratory evidence of immunosuppression was identified on further investigation. Magnetic resonance imaging showed a D10-D11, well-circumscribed, intramedullary mass within the conus, which was hypointense on T1-weighted imaging and hyperintense on T2/STIR weighted. The patient underwent surgery for removal and biopsy of the lesion, which provided the diagnosis of an intramedullary abscess caused by C. albicans, a very rare condition with only one case reported in literature so far.\n\nConclusion:\n\nC. albicans intramedullary abscess is a very rare clinical entity, especially in immunocompetent patients. We highlight C. albicans as an important etiology that must be considered in differential diagnosis. Critical evaluation of every case, early diagnosis, timely referral and surgical management of the abscess is essential to improve neurological outcome.\n\nAbscess\nCandida albicans\nCentral nervous system\nConus medullaris\nIntramedullary\n==== Body\nINTRODUCTION\n\nInvolvement of the central nervous system (CNS) by Candida sp. usually leads to meningitis and cerebral microabscesses, especially in immunocompromised individuals or when anatomic barriers are breached by surgery or implanted devices.[17] However, CNS involvement in immunocompetent patients represents an even rarer entity.[7] To the best of our knowledge, Candida albicans intramedullary abscesses had only been reported once in an immunocompetent who did not need neurosurgery.[39] Here, we report a cauda equina C. albicans intramedullary abscess, representing the second report in literature and the first case approached surgically.\n\nCASE REPORT\n\nA 44-year-old female patient sought the neurosurgery service at Hospital Santa Paula with a complaint of lower back pain associated with paraparesis for 2 years with progressive worsening of the condition between crises. She reported development of paraplegia in the past year.\n\nIn an investigation of multiple hospital admissions, she previously underwent treatment for CNS fungal infection and neurotuberculosis in late 2020 with amphotericin B (for 6 weeks) followed by voriconazole (for 4 weeks) with an ineffective result. The cerebrospinal fluid (CSF) contained 43 cells (75% lymphocytes, monocytes 22%, macrophages 3%), protein 175 mg/dL; glucose 26 mg/dL; lactic acid 42 mg/dL; lactate dehydrogenase 30 U/L; adenosinedeaminase 6.2 U/L; gamma globulin 31.62%; microbiology negative; antibodies for syphilis, Borrelia burgdorferi, toxoplasmosis, cytomegalovirus (CMV), herpes simplex 1 and 2, herpes zoster, cysticercosis, human immunodeficiency virus (HIV), and human T-lymphotropic virus were not reactive; no cancerous cells were identified. She also presented a history of seizures and meningitis.\n\nOn neurological examination, the patient presented with dysarthria, horizontal nystagmus with preservation of extrinsic eye movement, Grade III strength in upper limbs with wrist spasticity, plegia in lower limbs, and anesthesia from the T12 level without proprioception. She also presented with bicipital, tricipital, and styloradial hyperreflexia in upper limbs, with bilateral exaltation points and positive Hoffmann’s sign, besides patellar and aquilean areflexia, and negative Babinski’s sign.\n\nFor better evaluation, magnetic resonance imaging (MRI) images of the brain and spine were requested. Brain MRI showed thickening and leptomeningeal impregnation by gadolinium compromising both lateral fissures, insula, and frontotemporal operculum, evidencing diffuse pachymeningitis [Figure 1]. The MRI of the spine showed marked diffuse leptomeningeal enhancement along the anterior and posterior pial surfaces of all medullary segments, as well as medullary cone, marked segmental narrowing of the medulla at T10-T11 levels with hypersignal in the weighted sequences at T1 and T2/STIR associated with the tumefactive effect of the cone spinal cord with intramedullary lesion at this level, hypointense in T1-weighted image and hyperintense in T2/STIR weighted [Figure 2].\n\nFigure 1: Preoperative magnetic resonance imaging. (a) Coronal gadolinium-enhanced image, (b) sagittal gadolinium-enhanced image, (c) axial T2/FLAIR-weighted image showing a slight reduction in the thickness of the leptomeningeal impregnation of the lateral fissures and frontotemporal operculum on both sides suggestive of diffuse pachymeningitis.\n\nFigure 2: Preoperative magnetic resonance imaging. (a) Axial T2/STIR-weighted image, sagittal T1 and T2/STIR-weighted image, (c) sagittal T2/STIR-weighted showing the intramedullary abscess hypointense on images (a and b) and hyperintense on image (c).\n\nFrom the imaging findings and their relationship with the clinic, the patient underwent surgery and biopsy of the lesion. A T10-T11 laminectomy was performed and, after straight opening of the dura mater, a whitish lesion was found in the intramedullary region, suggestive of an abscess, being, therefore, drained and biopsied for analysis [Figure 3].\n\nFigure 3: Intramedullary abscess drainage surgery.\n\nThe culture of the surgical specimen tested positive for C. albicans and the histopathological evaluation of the lesion revealed extensive fibrinoid material and presence of hyaline septate pseudohyphae and fungal spores, with strong impregnation by Grocott methenamine silver stain [Figure 4]. These findings are consistent with intramedullary abscess due to C. albicans infection, being the second case report in the literature.\n\nFigure 4: Histopathology revealed numerous septate pseudohyphae and fungal spores embedded in fibrinoid material (a, H and E, ×400). There was intense silver impregnation by Grocott methenamine silver stain, suggestive of Candida albicans (b, GMS, ×400).\n\nDISCUSSION\n\nCandida spp. are considered opportunistic commensal pathogens that promote infection under host predisposing conditions.[55] When the CNS is involved in patients with systemic candidiasis, several clinical manifestations can be overlooked due to the severity of the patient’s situation. It is primarily found in immunocompromised hosts[56] or when anatomic barriers are breached by surgery, implanted devices, nonpenetrating blunt trauma to the back, or intermittent systemic corticosteroid,[17] typically leading to decrease in the level of consciousness, meningitis, and cerebral microabscesses.[7] However, other manifestations such as macroabscesses, sometimes suggestive of spinal tumors, are a more rare entity, especially when intramedullary.[56] Nevertheless, infection by Candida spp. has also been reported in immunocompetent individuals, as in this case report, but it is a rare event.[35,38,39,53]\n\nThere are a wide array of infectious causes of intramedullary myelitis, most of them caused by B. burgdorferi, Treponema pallidum, Mycobacterium tuberculosis, HIV, herpes simplex virus, varicella-zoster virus, CMV, Epstein-Barr virus), rabies, and schistosomiasis.[22] When the infection leads to an intramedullary spinal cord abscess, it is usually associated with high mortality and neurological morbidity and rarely encountered in modern neurosurgical practice.[10] We reviewed all cases of spinal intramedullary abscesses in the past 10 years [Table 1].[12-73] We found that approximately 68% of patients were male and 32% of female, the median age was 25, 86 years old (4 months – 82 years old), the main location was at thoracic level and the most frequent pathogen was from a tubercular source. Among all the reports, none of them identified an intramedullary abscess caused by C. albicans, which demonstrates the rarity of this entity once again.\n\nTable 1: Studies published in the past 10 years reporting intramedullary abscess.\n\nC. albicans spinal infection still configures a challenging diagnostic. MRI is useful in diagnosing medullary abscesses, but those infections may mimic a neoplastic process as myxopapillary ependymoma or leptomeningeal carcinomatosis.[7] Besides, the albuminocytologic dissociation often present may come from Guillain–Barré syndrome, cerebral meningitis, malignant lymphoma, spinal hemangioma, multiple sclerosis, central hemorrhagic disease, myelitis, and cerebrospinal infarction, making diagnosis more difficult.[53] However, the CSF of patients with candidal CNS abscesses generally presents no biochemical or cytologic abnormalities. Proteins are usually discreetly high, and a discreet pleocytosis with polymorphonuclear or lymphocytic predominance can be equally frequent,[56] which increases the suspicion of a Candida infection, especially when the diagnosis is uncertain, as in the case presented. In addition, some studies still highlight genes related to candidiasis.[23] Colony-stimulating factor 2, Ras protein-specific guanine nucleotide-releasing factor 1, and phospholipase C gamma 2 are examples related to increased susceptibility to CNS Candida infection, but functional and bioinformatic studies are needed to identify possible variants that could have influenced Candida spp. infection reported in this article. As we have discussed, there are cases with no laboratory evidence of immunodeficiency or no identifiable cause of immunosuppression,[7] as we observed in this case report.\n\nCONCLUSION\n\nC. albicans intramedullary abscess represents a very rare clinical entity, especially in immunocompetent patients. It must, however, be considered as an important etiology for spinal intramedullary abscesses and as a differential diagnosis in intramedullary pathologies. Critical evaluation of every case, early diagnosis, timely referral and surgical management of the abscess is essential to improve neurological outcome.\n\nDeclaration of patient consent\n\nPatient’s consent not required as patients identity is not disclosed or compromised.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n\nHow to cite this article: Raffa PE, Vencio RC, Ponce AC, Malamud BP, Vencio IC, Pacheco CC, et al. Spinal intramedullary abscess due to Candida albicans in an immunocompetent patient: A rare case report. 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"journal": "Surgical neurology international",
"keywords": "Abscess; Candida albicans; Central nervous system; Conus medullaris; Intramedullary",
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"title": "Spinal intramedullary abscess due to Candida albicans in an immunocompetent patient: A rare case report.",
"title_normalized": "spinal intramedullary abscess due to candida albicans in an immunocompetent patient a rare case report"
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"abstract": "Goodpasture's syndrome is a rare vasculitis associated with anti-glomerular basement membrane (anti-GBM) autoantibodies that target type IV collagen found in the basement membranes of glomeruli and alveoli. We present a case of a 79-year-old man with seronegative Goodpasture's syndrome with predominant respiratory symptoms and mild acute kidney injury that initially improved. Final diagnosis was made by immunofluorescent staining on open lung biopsy which also revealed concomitant organising pneumonia. The patient underwent treatment with corticosteroids, cyclophosphamide, haemodialysis and plasmapheresis. This was an atypical presentation wherein the patient only exhibited pulmonary symptoms early in the course of illness in the setting of negative anti-GBM antibody serum testing, which made diagnosis challenging. With this case, we emphasise that clinicians should have a high suspicion for Goodpasture's syndrome in the setting of unexplained severe pulmonary or renal disease despite negative anti-GBM antibody testing.",
"affiliations": "Internal Medicine, Greenwich Hospital/Yale-New Haven Health, Greenwich, Connecticut, USA.;Medical Education, Greenwich Hospital/Yale-New Haven Health, Greenwich, Connecticut, USA khalil.hussein@ynhh.org.;Pulmonary/Critical Care, Greenwich Hospital/Yale-New Haven Health, Greenwich, Connecticut, USA.;Internal Medicine, Greenwich Hospital/Yale-New Haven Health, Greenwich, Connecticut, USA.",
"authors": "Bae|Ju Young|JY|;Hussein|Khalil Ian|KI|http://orcid.org/0000-0001-9095-0103;Leibert|Eric|E|;Archer|Herbert M|HM|",
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"issue": "14(2)",
"journal": "BMJ case reports",
"keywords": "acute renal failure; cardiothoracic surgery; interstitial lung disease; pathology; vasculitis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D019867:Anti-Glomerular Basement Membrane Disease; D000890:Anti-Infective Agents; D015415:Biomarkers; D001999:Bronchoscopy; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D006801:Humans; D007442:Intubation, Intratracheal; D008297:Male; D010956:Plasmapheresis; D011014:Pneumonia; D006435:Renal Dialysis; D013256:Steroids",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33563667",
"pubdate": "2021-02-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Seronegative Goodpasture's syndrome associated with organising pneumonia.",
"title_normalized": "seronegative goodpasture s syndrome associated with organising pneumonia"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-072581",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "APIXABAN"
},
"drugaddit... |
{
"abstract": "Light Chain Deposition Disease (LCDD) is a monoclonal immunoglobulin deposition disease that commonly affects kidneys among other organs. It leads to end-stage renal disease and has a high disease recurrence rate after kidney transplantation. This has led some authors to advise against transplantation in view of the poor long-term graft and patient outcomes. Recent literature has shown improvement/stabilization of native kidney disease following the use of bortezomib. We present 2 cases of LCDD after transplantation with graft dysfunction. They were both treated with different therapeutic agents to induce remission. Because sustained remission was not achieved they received bortezomib following which they have experienced a prolonged period of stable renal function with no clinically detectable disease. These unique cases highlight the possibility to achieve long-term stable graft function and disease remission after renal transplantation for LCDD.",
"affiliations": "Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA. Electronic address: sarat-kuppachi@uiowa.edu.;Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.;Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA; Department of Internal Medicine, VA Medical Center, Iowa City, Iowa, USA.",
"authors": "Kuppachi|S|S|;Holanda|D|D|;Thomas|C P|CP|",
"chemical_list": "D000970:Antineoplastic Agents; D007147:Immunoglobulin Light Chains; D000069286:Bortezomib",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "48(1)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D000069286:Bortezomib; D006085:Graft Survival; D006801:Humans; D007147:Immunoglobulin Light Chains; D007668:Kidney; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010265:Paraproteinemias; D011183:Postoperative Complications; D012074:Remission Induction; D019737:Transplants",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "255-8",
"pmc": null,
"pmid": "26915878",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Light Chain Deposition Disease After Kidney Transplantation With Long Graft Survival: Case Report.",
"title_normalized": "light chain deposition disease after kidney transplantation with long graft survival case report"
} | [
{
"companynumb": "PHHY2016US026065",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Despite advances in supportive care and novel antifungal agents, mortality caused by invasive Candida infection is high. A 3-year-old boy with disseminated Candida dubliniensis infection during induction chemotherapy for acute lymphoblastic leukemia deteriorated despite resolution of neutropenia and appropriate antifungal treatment. Monocyte human leukocyte antigen-DR expression was extremely low, suggesting immunoparalysis. Adjuvant immunotherapy with interferon-gamma restored the immune response, which was accompanied by clinical and radiographic recovery.",
"affiliations": "From the *Department of Pediatrics, Division of Infectious Diseases and Immunology, Sophia Children's Hospital, §Department of Pediatric Oncology, and ¶Laboratory of Medical Immunology, Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands; and Departments of †Internal Medicine and ‡Intensive Care Medicine, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences (RILMS), Nijmegen, The Netherlands.",
"authors": "Buddingh|Emilie P|EP|;Leentjens|Jenneke|J|;van der Lugt|Jasper|J|;Dik|Willem A|WA|;Gresnigt|Mark S|MS|;Netea|Mihai G|MG|;Pickkers|Peter|P|;Driessen|Gertjan J|GJ|",
"chemical_list": "D007371:Interferon-gamma",
"country": "United States",
"delete": false,
"doi": "10.1097/INF.0000000000000909",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0891-3668",
"issue": "34(12)",
"journal": "The Pediatric infectious disease journal",
"keywords": null,
"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D001921:Brain; D002177:Candidiasis; D002675:Child, Preschool; D006801:Humans; D060828:Induction Chemotherapy; D007371:Interferon-gamma; D007938:Leukemia; D008279:Magnetic Resonance Imaging; D008297:Male",
"nlm_unique_id": "8701858",
"other_id": null,
"pages": "1391-4",
"pmc": null,
"pmid": "26379166",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Interferon-gamma Immunotherapy in a Patient With Refractory Disseminated Candidiasis.",
"title_normalized": "interferon gamma immunotherapy in a patient with refractory disseminated candidiasis"
} | [
{
"companynumb": "NL-HORIZON-ACT-0145-2016",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INTERFERON GAMMA-1B"
},
"drugadditional": "1",... |
{
"abstract": "We describe a case of ventricular fibrillation occurring in a patient with multi-vessel coronary spasm after the initiation of an oral beta-blocker. A 56-year-old man began to experience chest discomfort and his computed tomography revealed intermediate coronary stenoses. He was administered medications including an oral beta-blocker but suddenly collapsed while walking 4 days later. An automated external defibrillator detected ventricular fibrillation and delivered successful electrical cardioversion. An acetylcholine provocation test after stabilization of the status revealed triple-vessel coronary spasm. Beta-blockers may provoke exacerbation of coronary spasm and result in lethal arrhythmia.\nBeta-blockers which have a vasoconstrictive effect may occasionally provoke exacerbation of coronary spasm.Coronary spasm should be considered as a cause of lethal ventricular arrhythmia or cardiac arrest.",
"affiliations": "Division of Cardiology, Yokohama City Minato Red Cross Hospital, Yokohama City, Japan.;Division of Cardiology, Yokohama City Minato Red Cross Hospital, Yokohama City, Japan.;Division of Cardiology, Yokohama City Minato Red Cross Hospital, Yokohama City, Japan.;Division of Cardiology, Yokohama City Minato Red Cross Hospital, Yokohama City, Japan.;Division of Cardiology, Yokohama City Minato Red Cross Hospital, Yokohama City, Japan.",
"authors": "Kurabayashi|Manabu|M|;Suzuki|Hidetoshi|H|;Shimura|Tsukasa|T|;Yamauchi|Yasuteru|Y|;Okishige|Kaoru|K|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2016_000439",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2016_000439439-1-2861-1-10-20160630ArticlesVentricular Fibrillation in a Patient with Multi-Vessel Coronary Spasm Four Days after the Initiation of an Oral Beta-blocker Kurabayashi Manabu Suzuki Hidetoshi Shimura Tsukasa Yamauchi Yasuteru Okishige Kaoru Division of Cardiology, Yokohama City Minato Red Cross Hospital, Yokohama City, Japan2016 06 7 2016 3 5 00043913 5 2016 26 5 2016 © EFIM 20162016This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseWe describe a case of ventricular fibrillation occurring in a patient with multi-vessel coronary spasm after the initiation of an oral beta-blocker. A 56-year-old man began to experience chest discomfort and his computed tomography revealed intermediate coronary stenoses. He was administered medications including an oral beta-blocker but suddenly collapsed while walking 4 days later. An automated external defibrillator detected ventricular fibrillation and delivered successful electrical cardioversion. An acetylcholine provocation test after stabilization of the status revealed triple-vessel coronary spasm. Beta-blockers may provoke exacerbation of coronary spasm and result in lethal arrhythmia.\n\nLEARNING POINTS\nBeta-blockers which have a vasoconstrictive effect may occasionally provoke exacerbation of coronary spasm.\n\nCoronary spasm should be considered as a cause of lethal ventricular arrhythmia or cardiac arrest.\n\nCoronary spasmventricular fibrillationbeta-blockeracetylcholine provocation test\n==== Body\nINTRODUCTION\nBeta-blockers have a vasoconstrictive effect and may provoke exacerbation of coronary spasm[1]. It is known that coronary spasm can cause serious arrhythmias and consequently sudden cardiac death[2]. We herein describe a case of ventricular fibrillation occurring in a patient with multi-vessel coronary spasm 4 days after the initiation of an oral beta-blocker.\n\nCASE REPORT\nA 56-year-old man with a history of dyslipidaemia began to experience chest discomfort on effort and at rest. He presented to a local hospital where coronary computed tomography revealed intermediate stenoses in the mid portion of the left anterior descending artery (LAD) and the first diagonal branch. The patient was prescribed medications including low-dose aspirin, a statin and a beta-blocker (atenolol 25 mg once daily), but his symptoms worsened.\n\nFour days later he took his medications and went shopping on foot. At 10 am, he suddenly collapsed while walking. Cardiac massage was immediately performed by bystanders and after 5 min of resuscitation effort, an automated external defibrillator (AED) was attached. It detected ventricular fibrillation and delivered a successful electrical cardioversion (Fig. 1A). The AED electrocardiogram (ECG) record just after successful cardioversion showed ST-segment elevation (Fig. 1B), which disappeared promptly (Fig. 1C). After the return of spontaneous circulation, the patient was brought to the emergency department of our hospital.\n\nAt presentation to the emergency department, his ECG and chest x-ray showed almost normal findings. Laboratory analysis revealed normal values for complete blood cell counts, electrolytes and cardiac biomarkers. We performed emergency coronary angiography (CAG) (Fig. 2A–C), which showed intermediate stenoses in the mid portion of the LAD and the first diagonal branch (Fig. 2B, black arrow) and normal coronary flow in each coronary artery. Based on the cardiac catheterization findings, we ruled out acute coronary syndrome due to coronary plaque rupture as the cause of the ventricular fibrillation. After CAG, we performed intensive care including targeted temperature management and intravenous injection of nicorandil for the prevention of coronary spasm. Following treatment, the patient regained a stable cardiopulmonary status and had no serious ventricular arrhythmias. His neurological status gradually improved and he did not experience any residual neurological deficits.\n\nEight days after the episode of ventricular fibrillation, we performed an acetylcholine provocation test for coronary spasm after a 48 h drug holiday from vasodilators. After baseline coronary angiography (Fig. 2D–F), intracoronary injection of 20 μg of acetylcholine into the right coronary artery (RCA) and left coronary artery (LCA) provoked coronary spasm of the RCA (Fig. 2G, black arrow head), LAD (Fig. 2H, white arrow head) and left circumflex coronary artery (LCX) (Fig.2I, black arrow). Next, we measured fractional flow reserve, which was 0.85 for the distal LAD, and 0.92 for the first diagonal branch. The patient was diagnosed as having multi-vessel coronary spasm, and the intermediate stenotic lesions of the LAD and the first diagonal branch were not considered to be significant. We prescribed an oral calcium antagonist (nifedipine sustained released tablet, 20 mg twice daily). Fifteen days after the ventricular fibrillation event, we performed a cardiac electrophysiological study while the patient was on an oral calcium antagonist. Programmed ventricular stimulation did not induce reproducible ventricular arrhythmia even with triple extra-stimuli from the right ventricular apex and outflow tract. We therefore attributed the patient’s cardiopulmonary arrest to coronary spasm, and continue to prescribe an oral calcium antagonist. Since the initiation of calcium antagonist, the patient has been free from any angina symptoms and ventricular arrhythmias.\n\nDISCUSSION\nBeta-blockers reduce heart rate and contractility, resulting in relief of myocardial ischaemia. However, blockade of the vasodilatory β2-adrenergic effect even with β1-selective agents[3] and relative enhancement of the vasoconstrictive α1-adrenergic effect[1] can result in exacerbation of coronary spasm and provoke lethal arrhythmia. In this case, the patient had experienced ventricular fibrillation 4 days after the initiation of an oral β1-selective adrenergic blocker, and was ultimately diagnosed as having multi-vessel coronary spasm. The fact that multi-vessel spasm was provoked by intracoronary injection of low-dose acetylcholine indicates that this patient’s baseline coronary artery tone may be high. To our knowledge, there are few cases of the initiation of oral beta-blocker therapy resulting in ventricular fibrillation in patients with coronary spastic angina.\n\nCoronary spasm can cause critical ischaemic heart disease. In particular, multi-vessel spasm is often complicated by lethal ventricular arrhythmias[4], similar to our case. A previous study reported that reperfusion after coronary spasm, rather than coronary spasm itself, correlated with the onset of ventricular arrhythmia in some cases[4]. Those patients may not be diagnosed as having coronary spasm following emergency coronary angiography just after resuscitation. Physicians should perform a spasm provocation test after the patient has stabilized and emergency coronary angiography had not revealed any likely cardiac lesions, because coronary spasm was detected in 11% of patients who survived cardiac arrest without structural heart disease[5]. Coronary spasm is a more common cause of lethal ventricular arrhythmia or cardiac arrest than one might expect.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nFigure 1 The electrocardiogram record of the automated external defibrillator\n\nFigure 2 Emergency coronary angiography (A–C) and elective acetylcholine provocation test (D–F: baseline coronary angiography, G–I: acetylcholine provocation test)\n==== Refs\nREFERENCES\n1 Robertson RM Wood AJ Vaughn WK Robertson D Exacerbation of vasotonic angina pectoris by propranolol Circulation 1982 65 281 285 6797752 \n2 Takagi Y Yasuda S Tsunoda R Ogata Y Seki A Sumiyoshi T Clinical characteristics and long-term prognosis of vasospastic angina patients who survived out-of-hospital cardiac arrest: multicenter registry study of the Japanese Coronary Spasm Association Circ Arrhythm Electrophysiol 2011 4 295 302 21406685 \n3 Kaplan NM Kaplan’s Clinical Hypertension 8th ed. Philadelphia Lippincott Williams & Wilkins 2002 261 267 \n4 Myerburg RJ Kessler KM Mallon SM Cox MM deMarchena E Interian A Jr Life-threatening ventricular arrhythmias in patients with silent myocardial ischemia due to coronary-artery spasm N Engl J Med 1992 326 1451 1455 1574091 \n5 Krahn AD Healey JS Chauhan V Birnie DH Simpson CS Champagne J Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER) Circulation 2009 120 278 285 19597050\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2284-2594",
"issue": "3(5)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Coronary spasm; acetylcholine provocation test; beta-blocker; ventricular fibrillation",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "000439",
"pmc": null,
"pmid": "30755884",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "1574091;19597050;21406685;6797752",
"title": "Ventricular Fibrillation in a Patient with Multi-Vessel Coronary Spasm Four Days after the Initiation of an Oral Beta-blocker.",
"title_normalized": "ventricular fibrillation in a patient with multi vessel coronary spasm four days after the initiation of an oral beta blocker"
} | [
{
"companynumb": "JP-PFIZER INC-2016604500",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATENOLOL"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo compare the two different 'in situ' methods of corneal trephination technique under morgue condition (morgue trephination technique, MTT) and classic scleracorneal removal technique (SRT).\n\n\nMETHODS\nA total of 1179 cases were evaluated for cornea donation at Gazi University Faculty of Medicine mortuary between the years 2008 and 2013 and were included to the study. Suitable donor corneas were retrieved with in situ trephination technique under morgue condition (group 1, MTT) or with in situ classic SRT (group 2, SRT). The two different 'in situ' methods were compared in terms of donor corneal biological quality (endothelial cell count, ECC) and functional outcome (presence of infection and primary graft failure).\n\n\nRESULTS\nOne hundred and fifty-two of 1179 cases were suitable for corneal donation. Two hundred and twenty-nine corneas of 152 cases were transplanted, 108 corneas were obtained with MTT and 121 corneas were obtained with SRT. Pretransplant and post-transplant ECCs were 2402.5 ± 115.6 and 2108.3 ± 108.23 (p = 0.065) in MTT, respectively, and 2512.7 ± 130.4 and 2235.4 ± 201.8 (p = 0.059) in SRT, respectively. The incidence of primary graft failure and infection was not statistically significantly different between two method [2.7% and 1.6% (p = 0.223), 0.9% and 0.8% (p = 0.115)].\n\n\nCONCLUSIONS\nThe two different 'in situ' methods, MTT and SRT, were similar in terms of donor ECC, presence of infection and primary graft failure. Cornea excision performed through the technique described herein may increase the corneal donation rates as result of reduced disfigurement to donor body and offer important contributions during surgery with good anatomic adaptation of tissues.",
"affiliations": "Deparment of Ophthalmology, Faculty of Medicine, Gazi University, Ankara, Turkey.;Ophthalmology Clinic, Ataturk Training and Research Hospital, Ankara, Turkey.;Deparment of Ophthalmology, Faculty of Medicine, Gazi University, Ankara, Turkey.",
"authors": "Yuksel|Erdem|E|;Yuksel|Nilay|N|;Akata|Fikret|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/aos.12692",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1755-375X",
"issue": "93(7)",
"journal": "Acta ophthalmologica",
"keywords": "corneal transplantation; donor cornea; eye banking; in situ corneal donation; morgue trephination",
"medline_ta": "Acta Ophthalmol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002452:Cell Count; D003315:Cornea; D004728:Endothelium, Corneal; D005125:Eye Banks; D015817:Eye Infections; D005260:Female; D006084:Graft Rejection; D006801:Humans; D015948:Keratoplasty, Penetrating; D008297:Male; D008875:Middle Aged; D012590:Sclera; D014019:Tissue Donors; D020858:Tissue and Organ Harvesting; D009927:Tissue and Organ Procurement; D055815:Young Adult",
"nlm_unique_id": "101468102",
"other_id": null,
"pages": "e573-7",
"pmc": null,
"pmid": "25913383",
"pubdate": "2015-11",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Comparison of two in situ corneal donation technique: morgue trephination or scleracorneal removal technique.",
"title_normalized": "comparison of two in situ corneal donation technique morgue trephination or scleracorneal removal technique"
} | [
{
"companynumb": "ALCN2015TR007157",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
"d... |
{
"abstract": "Bone-modifying agents (BMAs), including bisphosphonate and anti-receptor activator of NF-κB ligand (RANKL) antibodies, are effective in treating bone metastases. The present study is a case report on the efficacy and side effects of long-term treatment with zoledronic acid, a BMA, in a 57-year-old woman. The patient was diagnosed with concurrent stage IV triple-negative breast cancer and stage II colon cancer. The patient experienced complete remission of both these cancers following chemotherapy, zoledronic acid treatment and irradiation for breast cancer and surgery for colon cancer. The patient received long-term zoledronic acid treatment and has survived >7 years after her initial diagnosis. The patient subsequently reported bilateral hip pain that was diagnosed as osteonecrosis of the femoral head, after the presence of bone metastases was ruled out using magnetic resonance imaging. The patient underwent bilateral artificial hip joint replacements. After orthopedic surgery, the multiple distant metastases, including a brain metastasis, remained in complete remission. It is well established that BMAs, such as zoledronic acid, increase the risk of osteonecrosis of the jaw, but it is not well understood if they can increase this risk in other anatomical locations. The findings of the present case study suggested that while long-term use of BMAs may be effective in managing bone metastases, it may increase the risk of osteonecrosis in anatomical locations other than the jaw.",
"affiliations": "Department of Breast Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama 350-1298, Japan.;Department of Breast Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama 350-1298, Japan.;Department of Palliative Medicine, Saitama Medical University International Medical Center, Hidaka, Saitama 350-1298, Japan.;Department of Orthopaedic Oncology and Surgery, Saitama Medical University International Medical Center, Hidaka, Saitama 350-1298, Japan.;Department of Orthopedic Surgery, Saitama Medical University Hospital, Hidaka, Saitama 350-0495, Japan.;Department of Breast Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama 350-1298, Japan.;Department of Breast Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama 350-1298, Japan.",
"authors": "Matsuura|Kazuo|K|;Saeki|Toshiaki|T|;Takahashi|Takao|T|;Torigoe|Tomoaki|T|;Watarai|Keisuke|K|;Osaki|Akihiko|A|;Hojyo|Takashi|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2021.2328",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-9450",
"issue": "15(2)",
"journal": "Molecular and clinical oncology",
"keywords": "bilateral femoral head osteonecrosis; breast cancer; case report; zoledronic acid",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "166",
"pmc": null,
"pmid": "34194744",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": "25900167;29035643;29154968;18214569;31673791;32060705;22169965;31823174;26406544;26178889;16750501;24485975;26762348;30032243;20844158;17878149;31640606",
"title": "Bilateral femoral head osteonecrosis in a patient with metastatic breast cancer receiving long-term zoledronic acid treatment: A case report.",
"title_normalized": "bilateral femoral head osteonecrosis in a patient with metastatic breast cancer receiving long term zoledronic acid treatment a case report"
} | [
{
"companynumb": "JP-INFO-001279",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPIRUBICIN"
},
"drugadditional": "3",
"drugadm... |
{
"abstract": "BACKGROUND\nIn transplant recipients, due to the use of immunosuppressive therapy, it is occasionally difficult to distinguish between an infection and malignancy, especially in the case of a lung lesion. Here, we report a case of isolated pulmonary cryptococcosis after kidney transplantation that was difficult to distinguish from a lung tumor.\n\n\nMETHODS\nA 52-year-old man underwent a kidney transplant from his mother when he was 44 years old. Immunosuppression was maintained with tacrolimus, methylprednisolone, and mycophenolate mofetil. His post-transplant course was uneventful and serum creatinine levels were maintained. Five years post-transplantation, a non-contrast computed tomography (CT) examination revealed a nodule measuring 3 mm in diameter in the middle lobe of the right lung. The nodule gradually increased to 12 mm in 2 years. Positron emission tomography/CT examination showed a maximum standardized uptake value of 0.5 for the nodule. Biochemical examination revealed no elevation in total leucocyte count and C-reactive protein levels. However, tumor markers were elevated: serum carcinoembryonic antigen, 5.9 ng/mL; pro-gastrin-releasing peptide, 84.6 pg/mL. Furthermore, the serum cryptococcus antigen was negative. Therefore, thoracoscopic partial lung resection was performed. Pathologically, a number of spherical fungi from the necrotic substance of the tumor were confirmed positive by periodic acid-Schiff and Grocott-Gomori staining. The patient was therefore diagnosed with pulmonary cryptococcosis. Two years later, the patient is alive and has shown no evidence of recurrence.\n\n\nCONCLUSIONS\nIn lung nodules after kidney transplantation, even if serum cryptococcus antigen is not identified, it is necessary to keep in mind the possibility of pulmonary cryptococcosis.",
"affiliations": "Department of Artificial Organs, Akane-Foundation, Tsuchiya General Hospital, Hiroshima, Japan. Electronic address: m-banshodani@tsuchiya-hp.jp.;Department of Artificial Organs, Akane-Foundation, Tsuchiya General Hospital, Hiroshima, Japan.;Department of Artificial Organs, Akane-Foundation, Tsuchiya General Hospital, Hiroshima, Japan.;Department of Artificial Organs, Akane-Foundation, Tsuchiya General Hospital, Hiroshima, Japan.;Department of Artificial Organs, Akane-Foundation, Tsuchiya General Hospital, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institution of Biomedical & Health Sciences, Hiroshima, Japan.;Department of Artificial Organs, Akane-Foundation, Tsuchiya General Hospital, Hiroshima, Japan.",
"authors": "Banshodani|M|M|;Marubayashi|S|S|;Shintaku|S|S|;Moriishi|M|M|;Tsuchiya|S|S|;Ohdan|H|H|;Kawanishi|H|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2018.12.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "51(2)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D003453:Cryptococcosis; D006801:Humans; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D016030:Kidney Transplantation; D008172:Lung Diseases, Fungal; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "561-564",
"pmc": null,
"pmid": "30879590",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Isolated Pulmonary Cryptococcosis Confused with Lung Tumor 5 Years After Kidney Transplantation: A Case Report.",
"title_normalized": "isolated pulmonary cryptococcosis confused with lung tumor 5 years after kidney transplantation a case report"
} | [
{
"companynumb": "JP-PFIZER INC-2019145867",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Background: Intentional overdose is the commonest form of self-harm in adolescents globally. We explored temporal trends in intentional overdose among youth.Methods: Using multiple linked healthcare databases, we conducted a population-based cohort study in Ontario, Canada, from 2002 to 2015. We included all patients aged 8 to 19 years who presented to an emergency department (ED) or were hospitalized for intentional overdose, stratifying by age and agent(s) consumed. We determined the annual rate of intentional overdose over time. For context, we contrasted these data against the annual rate of select unintentional injuries (laceration of face or scalp, upper extremity fracture, and accidental burn) in the same group over the same period.Results: We identified 31,419 unique intentional overdose events in youth, with a striking U-shaped trend apparent over the study period. From 2002 to 2010, hospital presentations for intentional overdose gradually declined. However, from 2010 to 2015, ED visits increased by 75% and hospital admissions doubled. The sharpest increases were observed in adolescents aged 14 to 17 years, and the most commonly implicated substances were acetaminophen, antidepressants and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Over the study period, intentional overdoses involving antidepressants nearly doubled and those involving acetaminophen increased by 50%. In contrast, we observed steady and sustained declines in rates of hospital care for unintentional injuries in the same population over the same period.Conclusions: Since 2010, intentional overdoses have increased among youth, while other forms of unintentional injury have continued to decline. Further research is needed to understand the reasons for the unexpected rise in intentional overdose in adolescents, and strategies developed to mitigate this phenomenon.",
"affiliations": "Department of Pediatrics, University of British Columbia, Vancouver, Canada.;Departments of Emergency Medicine, and of Biomedical & Molecular Sciences, Queen's University, Kingston, Canada.;ICES, Toronto, Canada.;ICES, Toronto, Canada.;ICES, Toronto, Canada.;ICES, Toronto, Canada.",
"authors": "Gilley|Meghan|M|;Sivilotti|Marco L A|MLA|;Juurlink|David N|DN|;Macdonald|Erin|E|;Yao|Zhan|Z|;Finkelstein|Yaron|Y|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2019.1687900",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "58(7)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Adolescents; intentional; overdose",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000059:Accidents; D000293:Adolescent; D002648:Child; D015331:Cohort Studies; D016208:Databases, Factual; D062787:Drug Overdose; D004636:Emergency Service, Hospital; D005260:Female; D006760:Hospitalization; D006801:Humans; D008297:Male; D009864:Ontario; D016728:Self-Injurious Behavior; D013406:Suicide, Attempted; D055815:Young Adult",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "711-715",
"pmc": null,
"pmid": "31760804",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Trends of intentional drug overdose among youth: a population-based cohort study.",
"title_normalized": "trends of intentional drug overdose among youth a population based cohort study"
} | [
{
"companynumb": "CA-JNJFOC-20200617253",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nWhile clindamycin-induced acute kidney injury (AKI) is uncommon, it has occurred more frequently in recent years.\n\n\nCONCLUSIONS\nWe investigated 24 patients diagnosed with clindamycin-induced AKI retrospectively. The dosage of clindamycin was 1.0-1.5 g/day. Fifteen patients had episodes of gross hematuria, but fever, skin rash and eosinophilia were rare. Urine analysis revealed mild proteinuria and severe tubular dysfunction. Twenty-three patients were diagnosed with AKI stage 3 upon admission. The clindamycin lymphocyte transformation assay was positive for 63.2% of the patients. Acute interstitial nephritis (AIN) and acute tubular necrosis (ATN) were proven by renal biopsy, and renal insufficiency appeared to result from tubular toxicity and drug crystals. In the majority (87.5%) of the patients, AKI was severe and required renal replacement therapy, but all of their renal function recovered significantly 2 months after discharge. Clindamycin-induced AKI is largely reversible and has episodes of gross hematuria. Renal biopsies confirmed AIN or ATN in these patients.",
"affiliations": "Research Institute of Nephrology, Jinling Hospital, Nanjing University Clinical School of Medicine, Nanjing, PR China.",
"authors": "Xie|Honglang|H|;Chen|Huiping|H|;Hu|Yangling|Y|;Xu|Shutian|S|;He|Qunpeng|Q|;Liu|Jing|J|;Hu|Weixin|W|;Liu|Zhihong|Z|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002981:Clindamycin",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000354088",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-8095",
"issue": "38(3)",
"journal": "American journal of nephrology",
"keywords": null,
"medline_ta": "Am J Nephrol",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000818:Animals; D000900:Anti-Bacterial Agents; D001706:Biopsy; D002981:Clindamycin; D005260:Female; D006417:Hematuria; D006801:Humans; D007684:Kidney Tubules; D008214:Lymphocytes; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D009395:Nephritis, Interstitial; D011507:Proteinuria; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "8109361",
"other_id": null,
"pages": "179-83",
"pmc": null,
"pmid": "23941896",
"pubdate": "2013",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Clindamycin-induced acute kidney injury: large biopsy case series.",
"title_normalized": "clindamycin induced acute kidney injury large biopsy case series"
} | [
{
"companynumb": "CN-BAUSCH-BL-2015-012841",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLINDAMYCIN\\CLINDAMYCIN PHOSPHATE"
},
"drugad... |
{
"abstract": "Portal vein embolization (PVE) is a pre-operative treatment modality in adults undergoing hepatectomy with concerns of post-operative liver failure from insufficient future liver remnant (FLR). PVE induces growth in the FLR. The success of this technique is well described in adults, but not in young children with hepatoblastoma.",
"affiliations": "Department of Pediatric Surgery, Children's Mercy Hospital, 2401 Gillham Rd, Kansas City, MO, 64108, USA.;Department of Pediatric Surgery, Children's Mercy Hospital, 2401 Gillham Rd, Kansas City, MO, 64108, USA.;Department of Pediatric Surgery, Children's Mercy Hospital, 2401 Gillham Rd, Kansas City, MO, 64108, USA.;Department of Pediatric Surgery, Children's Mercy Hospital, 2401 Gillham Rd, Kansas City, MO, 64108, USA.;Department of Pediatric Surgery, Children's Mercy Hospital, 2401 Gillham Rd, Kansas City, MO, 64108, USA.;University of Kansas Medical Center, Kansas City, KS, USA.;Department of Pediatric Surgery, Children's Mercy Hospital, 2401 Gillham Rd, Kansas City, MO, 64108, USA. rjhendrickson@cmh.edu.",
"authors": "Le|Nhatrang|N|;Rivard|Douglas C|DC|;Rentea|Rebecca M|RM|;Manalang|Michelle|M|;Andrews|Walter|W|;Kane|Bartholomew|B|;Hendrickson|Richard J|RJ|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00383-018-4250-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0179-0358",
"issue": "34(5)",
"journal": "Pediatric surgery international",
"keywords": "Future liver remnant; Hepatectomy; Hepatoblastoma; Portal vein embolization",
"medline_ta": "Pediatr Surg Int",
"mesh_terms": "D004621:Embolization, Therapeutic; D006498:Hepatectomy; D018197:Hepatoblastoma; D006801:Humans; D007223:Infant; D008113:Liver Neoplasms; D008297:Male; D011169:Portal Vein; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8609169",
"other_id": null,
"pages": "573-578",
"pmc": null,
"pmid": "29600326",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article; D016427:Technical Report",
"references": "19564288;27283892;26391943;10898314;11905674;11218918;23369559;15747030;26357620;18074355;26942331;18166449;21165999;20678021;17583900;24129824;22806245;21415193;2333592;26835349;23600968;16447274;22692949;15862752;19333540;25158914",
"title": "Right trisegmentectomy after portal vein embolization in a high-risk toddler with hepatoblastoma.",
"title_normalized": "right trisegmentectomy after portal vein embolization in a high risk toddler with hepatoblastoma"
} | [
{
"companynumb": "US-BAUSCH-BL-2018-013609",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThe role of streptozocin-based chemotherapy (STZ CTx) in advanced, well-differentiated pancreatic neuroendocrine tumours (PanNET) and the best sequence of treatments in advanced PanNET are unclear. We examined the outcomes after STZ CTx in patients who had been selected according to the current therapeutic guidelines.\n\n\nMETHODS\nData from 50 PanNET patients consecutively treated with STZ CTx between 2010 and 2018 were analysed. The endpoints of the study were the objective-response rate (ORR), progression-free survival (PFS), and overall survival (OS).\n\n\nRESULTS\nSTZ CTx was the first-line treatment in 54% of patients. The PanNET grades were as follows: 6% G1, 88% G2, and 6% well-differentiated G3. The ORR was 38%. Stable disease was the best response in 38% of patients and 24% showed progressive disease. Treatment was discontinued because of toxicity in one patient. Median PFS and OS were 12 (95% confidence interval (CI), 8.5-15.5) and 38 months (95% CI, 20.4-55.6), respectively. In the Kaplan-Meier analysis, the median OS was 89 months (95% CI, 34.9-143.1) for STZ CTx as first-line therapy compared with 22 months (95% CI, 19.3-24.7; p = 0.001, log-rank test) for subsequent lines. Bone metastases negatively impacted survival (HR, 2.71, p = 0.009, univariate analysis, HR, 2.64, p = 0.015, multivariate analysis, and Cox regression).\n\n\nCONCLUSIONS\nIn patients selected according to current guidelines, PFS, and OS after STZ CTx were lower than previously reported, whereas ORR was unchanged. First-line treatment was positively associated with OS and the presence of bone metastases was negatively associated with OS. Pre-treatment with targeted or peptide-receptor radionuclide therapy did not alter ORR, PFS, or OS.",
"affiliations": "Department of Endocrinology, Diabetes and Metabolism and Division of Laboratory Research, Endocrine Tumor Center at WTZ/ Comprehensive Cancer Center and ENETS Center of Excellence, University of Duisburg-Essen, Essen, Germany. harald.lahner@uk-essen.de.;Department of Endocrinology, Diabetes and Metabolism and Division of Laboratory Research, Endocrine Tumor Center at WTZ/ Comprehensive Cancer Center and ENETS Center of Excellence, University of Duisburg-Essen, Essen, Germany.;Department of Endocrinology, Diabetes and Metabolism and Division of Laboratory Research, Endocrine Tumor Center at WTZ/ Comprehensive Cancer Center and ENETS Center of Excellence, University of Duisburg-Essen, Essen, Germany.;Department of Endocrinology, Diabetes and Metabolism and Division of Laboratory Research, Endocrine Tumor Center at WTZ/ Comprehensive Cancer Center and ENETS Center of Excellence, University of Duisburg-Essen, Essen, Germany.;Institute of Diagnostic and Interventional Radiology and Neuroradiology, University of Duisburg-Essen, Essen, Germany.;Institute of Medical Informatics, Biometry, and Epidemiology, University of Duisburg-Essen, Essen, Germany.;Institute of Medical Informatics, Biometry, and Epidemiology, University of Duisburg-Essen, Essen, Germany.;Institute of Pathology, University of Duisburg-Essen, Essen, Germany.;Institute of Pathology, University of Duisburg-Essen, Essen, Germany.;Department of Nuclear Medicine, University of Duisburg-Essen, Essen, Germany.;Department of Endocrinology, Diabetes and Metabolism and Division of Laboratory Research, Endocrine Tumor Center at WTZ/ Comprehensive Cancer Center and ENETS Center of Excellence, University of Duisburg-Essen, Essen, Germany.",
"authors": "Lahner|Harald|H|;Mathew|Annie|A|;Klocker|Anna Lisa|AL|;Unger|Nicole|N|;Theysohn|Jens|J|;Rekowski|Jan|J|;Jöckel|Karl-Heinz|KH|;Theurer|Sarah|S|;Schmid|Kurt Werner|KW|;Herrmann|Ken|K|;Führer|Dagmar|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s12020-021-02859-y",
"fulltext": "\n==== Front\nEndocrine\nEndocrine\nEndocrine\n1355-008X\n1559-0100\nSpringer US New York\n\n34480724\n2859\n10.1007/s12020-021-02859-y\nOriginal Article\nStreptozocin/5-fluorouracil chemotherapy of pancreatic neuroendocrine tumours in the era of targeted therapy\nLahner Harald harald.lahner@uk-essen.de\n\n1\nMathew Annie 1\nKlocker Anna Lisa 1\nUnger Nicole 1\nTheysohn Jens 2\nRekowski Jan 3\nJöckel Karl-Heinz 3\nTheurer Sarah 4\nSchmid Kurt Werner 4\nHerrmann Ken 5\nFührer Dagmar 1\n1 grid.5718.b 0000 0001 2187 5445 Department of Endocrinology, Diabetes and Metabolism and Division of Laboratory Research, Endocrine Tumor Center at WTZ/ Comprehensive Cancer Center and ENETS Center of Excellence, University of Duisburg-Essen, Essen, Germany\n2 grid.5718.b 0000 0001 2187 5445 Institute of Diagnostic and Interventional Radiology and Neuroradiology, University of Duisburg-Essen, Essen, Germany\n3 grid.5718.b 0000 0001 2187 5445 Institute of Medical Informatics, Biometry, and Epidemiology, University of Duisburg-Essen, Essen, Germany\n4 grid.5718.b 0000 0001 2187 5445 Institute of Pathology, University of Duisburg-Essen, Essen, Germany\n5 grid.5718.b 0000 0001 2187 5445 Department of Nuclear Medicine, University of Duisburg-Essen, Essen, Germany\n4 9 2021\n4 9 2021\n2022\n75 1 293302\n14 5 2021\n26 8 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.\nPurpose\n\nThe role of streptozocin-based chemotherapy (STZ CTx) in advanced, well-differentiated pancreatic neuroendocrine tumours (PanNET) and the best sequence of treatments in advanced PanNET are unclear. We examined the outcomes after STZ CTx in patients who had been selected according to the current therapeutic guidelines.\n\nMethods\n\nData from 50 PanNET patients consecutively treated with STZ CTx between 2010 and 2018 were analysed. The endpoints of the study were the objective-response rate (ORR), progression-free survival (PFS), and overall survival (OS).\n\nResults\n\nSTZ CTx was the first-line treatment in 54% of patients. The PanNET grades were as follows: 6% G1, 88% G2, and 6% well-differentiated G3. The ORR was 38%. Stable disease was the best response in 38% of patients and 24% showed progressive disease. Treatment was discontinued because of toxicity in one patient. Median PFS and OS were 12 (95% confidence interval (CI), 8.5–15.5) and 38 months (95% CI, 20.4–55.6), respectively. In the Kaplan-Meier analysis, the median OS was 89 months (95% CI, 34.9–143.1) for STZ CTx as first-line therapy compared with 22 months (95% CI, 19.3–24.7; p = 0.001, log-rank test) for subsequent lines. Bone metastases negatively impacted survival (HR, 2.71, p = 0.009, univariate analysis, HR, 2.64, p = 0.015, multivariate analysis, and Cox regression).\n\nConclusions\n\nIn patients selected according to current guidelines, PFS, and OS after STZ CTx were lower than previously reported, whereas ORR was unchanged. First-line treatment was positively associated with OS and the presence of bone metastases was negatively associated with OS. Pre-treatment with targeted or peptide-receptor radionuclide therapy did not alter ORR, PFS, or OS.\n\nKeywords\n\nStreptozocin\n5-fluorouracil\nPancreatic neuroendocrine tumor\nObjective response\nSurvival\nissue-copyright-statement© Springer Science+Business Media, LLC, part of Springer Nature 2022\n==== Body\npmcIntroduction\n\nPancreatic neuroendocrine tumours (PanNET) are rare neoplasms with an annual incidence of 0.48/100,000 [1]. Surgical removal is the only curative therapy. At presentation, 60%–80% of patients have unresectable disease due to local extension or metastases. Hence, only palliative interventions can be offered [2]. Streptozocin-based chemotherapy (STZ CTx) has been an established first-line treatment since 1980. Initially, response rates (RR) exceeding 60% and a sustained median progression-free survival (PFS) of 36 months were reported [3]. Subsequent series found very heterogeneous results with RR between 6% and 55% and PFS of 4–23 months [4]. These conflicting results are attributed to heterogeneous patient cohorts and classification systems.\n\nIn 2010, a unified PanNET assessment was established and novel treatment options have been developed since then. The World Health Organisation (WHO) introduced a new classification system that abolished the distinction between well-differentiated endocrine tumours of benign behaviour and endocrine carcinomas, highlighting the malignant potential of all neuroendocrine tumours (NET) based on the proliferation marker, Ki-67 [5]. The validity of this grading system was confirmed in several studies [6].\n\nSunitinib, a multikinase inhibitor, approved by the European medicines agency (EMA) in 2010 and the food and drug administration (FDA) in 2011, was the first licensed therapeutic alternative to STZ CTx for progressive, well-differentiated PanNET. Approval of sunitinib was based on a double-blind, randomised study demonstrating an increase in PFS from 5.5 to 11.4 months [7]. In the same year, everolimus, an oral mTOR inhibitor, was also approved by the EMA and FDA for the treatment of progressive, well-differentiated PanNET. Approval of everolimus was also based on double-blind, randomised data [8]; PFS increased from 4.6 to 11.0 months in this study.\n\nSince their approval, sunitinib and everolimus have competed with STZ CTx in the treatment of well-differentiated PanNET. However, the importance of the individual substances within the therapy algorithm has not been established because of the lack of comparative studies. Furthermore, peptide receptor radionuclide therapy (PRRT) is commonly used in PanNET, but whether prior PRRT influences the outcome of STZ-CTx is currently unknown [9, 10]. In the current guidelines, STZ CTx is one of the standard therapies [11–13]. The length of practical experience supports this approach. However, there are no studies in which the current therapeutic alternatives have been available. Tumour classification, therapeutic thresholds, and alternatives differ considerably in published studies [4, 14–17]. In addition, grading based on Ki-67 has only been established as a mandatory part of NET baseline classification since 2010.\n\nThe aims of the present study were thus (1) to determine the outcome of STZ CTx in a well-defined patient population, treated according to current guidelines, in which the current therapeutic alternatives are available; (2) to assess the influence of previous targeted therapy and PRRT on objective response rate (ORR), PFS, and overall survival (OS), and (3) to detect factors influencing therapeutic outcomes.\n\nMaterials and methods\n\nPatients\n\nPatients with histologically confirmed, well-differentiated and locally advanced or metastatic PanNET, who received STZ CTx between January 2010 and January 2018, were identified from our prospective database at the European Neuroendocrine Tumour Society (ENETS) Centre of Excellence at the University Hospital of Essen. The follow-up period was extended until April 2020. Patients with hereditary tumours (multiple endocrine neoplasia type 1 or von Hippel–Lindau disease) were excluded. To ensure consistency, indication for therapies was determined according to ENETS guidelines by an experienced, multidisciplinary tumour board (MTB) [11, 12]. All therapies were administered in-house at our centre.\n\nChemotherapy\n\nThe STZ CTx consisted of 500 mg/m² of streptozocin in 100 ml of 0.9% NaCl IV infusion given over 30 min, followed after 1 h by 400 mg/m² of fluorouracil (5-FU) infusion in 100 ml of 0.9% NaCl given over 30 min. Adequate peri-interventional hydration was ensured by administering at least 1000 ml of 0.9% NaCl IV infusion. A 5-hydroxytryptamine (5-HT3) antagonist was administered 30 min before the start of therapy. Dexamethasone (8 mg) was administered per os at the beginning of each chemotherapy day. The therapy was implemented over five consecutive days, with a cycle length of 42 days. In case of impaired performance status or toxicity, a delay of up to 2 weeks was provided. The first staging was performed using computed tomography (CT) after three cycles. Patients who did not show progression received the intended number of six cycles, unless unacceptable toxicity occurred.\n\nFollow-up and evaluation of tumour response\n\nA baseline CT scan was performed within 4 weeks before starting STZ CTx. After three completed treatment courses, the first evaluation of therapeutic response (history, physical examination, CT or MRI scan, and laboratory investigations) was scheduled. In case of stable disease (SD) or remission, STZ CTx was continued until the planned number of six cycles. Within 4 weeks after the last cycle and at 3-month intervals, follow-up examinations (CT or MRI) were performed. Hybrid imaging (68Ga DOTATOC positron emission tomography (PET)/CT) was included at the initial presentation and at least every 12 months within the surveillance schedule. After 1 year of SD, partial remission (PR) or complete remission (CR), follow-up intervals were extended from 3 to a maximum of 6 months, according to the MTB decision. Response to treatment was evaluated using the international criteria proposed by the Response evaluation criteria in solid tumours (RECIST) committee. At each scheduled time point, chromogranin A (CgA), hematologic, renal, hepatic, endocrine, and coagulation parameters were measured and clinical symptoms were recorded according to common terminology criteria for adverse events (CTCAE), version 3.0.\n\nPathology of the tumours\n\nThe presence of PanNET was confirmed morphologically and immunohistochemically in all patients. The Ki-67 index was indicated using the MIB-1 antibody, taking into consideration the area of highest activity. Tumour grading was performed according to the WHO/ENETS criteria [18, 19]. Low-grade (G1) PanNET were defined as tumours having a Ki-67 index of ≤2% and intermediate-grade (G2) PanNET was defined as tumours having a Ki-67 index between 3% and 20%. Three patients had well-differentiated, high proliferative PanNET with a Ki-67 index of >20%. The analyses were performed by one pathologist with expertise in endocrine and pancreatic tumours. The pathologist was blinded to the patients’ history.\n\nStatistical methods\n\nResponse and tumour characteristics were compared using Fisher’s exact test. PFS was recorded as the time between the start of treatment and radiological progression (based on RECIST 1.1) or death. Survival rates were calculated using the Kaplan-Meier method. OS from diagnosis was defined as the time between PanNET diagnosis and death or the last follow-up. OS from the start of chemotherapy was defined as the time between the start of treatment and death or the last follow-up. Univariate and multivariate Cox regression analyses were performed to identify prognostic factors. Statistical differences in PFS and OS between patient groups were estimated using the log-rank test. A p-value of <0.05 was considered significant. All statistical calculations were performed using IBM SPSS Statistics for Windows, Version 25.0 (IBM Corp., Armonk, NY).\n\nResults\n\nGeneral characteristics\n\nThe cohort consisted of 50 consecutive PanNET patients with well-differentiated morphology. All patients were accessible for analysis (Table 1). Forty-one tumours (82%) were non-functioning and nine tumours (18%) were functioning. Three tumours were graded as G1 and the majority (88%) were G2 neoplasms, according to the WHO 2017 classification. Three patients had well-differentiated tumours, with elevated Ki-67-proliferation rates of 25% (n = 2) and 30% (n = 1), corresponding to NET G3. Stage-IV disease was present in 96% of patients and the majority of these patients had liver metastases. Distant organs (≥2) were involved in 50% of patients.Table 1 Patient characteristics\n\n\tn (%)\t\nSex\t\nMale\t26 (52)\t\nFemale\t24 (48)\t\nAge at treatment start (years)\t61 (28–82)\t\nDisease duration at treatment start (months)\t6.5 (1–159)\t\nFunctionality\t\nNon-functioning\t41 (82)\t\nGastrinoma\t4 (8)\t\nInsulinoma\t3 (6)\t\nVIPoma\t1 (2)\t\nPTHrP producing\t1 (2)\t\nTumour grade (WHO 2017)\t\nG1\t3 (6)\t\nG2\t44 (88)\t\nG3\t3 (6)\t\nKi-67 index (%)\t\n≤5%\t17 (34)\t\n>5%–10%\t13 (26)\t\n>10%–20%\t17 (34)\t\n>20%–30%\t3 (6)\t\nWell-differentiated morphology\t50 (100)\t\nOrgan tumour involvement\t\nNo distant disease site\t2 (4)\t\n1 distant disease site\t23 (46)\t\n2 distant disease sites\t15 (30)\t\n≥3 distant disease sites\t10 (20)\t\nMetastases\t\nLymph node involvement only\t2 (4)\t\nLiver metastases\t48 (96)\t\nDistant metastases other than liver\t25 (50)\t\nBone metastases\t19 (38)\t\nTreatment line\t\n1st line\t27 (54)\t\n2nd line\t13 (26)\t\n>2nd line\t10 (20)\t\nPrior treatment\t\nNone\t27 (54)\t\nSomatostatin analogues\t16 (32)\t\nSunitinib or everolimus\t7 (14)\t\nPRRT\t13 (26)\t\nInterferon\t1 (2)\t\nOther CTx (Tem/Capa, Carbo/Etob)\t4 (8)\t\nPrevious resection of primary tumour\t23 (46)\t\nECOG PS at STZ CTx start\t\n0\t19 (38)\t\n1\t24 (48)\t\n2\t7 (14)\t\nBaseline status\t\nRadiologically progressive ≤12 months\t33 (66)\t\nClinically progressive ≤6 months\t17 (34)\t\nAge and disease duration at treatment start are given as median (range), categorical parameters as absolute and relative frequencies (n = 50)\n\naTem/Cap temozolomide/ capecitabine, bCarbo/Eto carboplatin/ etoposide\n\nThe median age at the start of therapy was 61 years (range, 28–82 years). Approximately half of the patients (n = 27, 54%) were administered STZ CTx as the first-line treatment. The median time from diagnosis to the onset of chemotherapy was 6.5 months (range, 1–159). Of those patients with prior systemic treatments (n = 23), the majority had received long-acting somatostatin analogs (SSA, n = 16) or PRRT (n = 13); nine of the PRRT-treated patients received combination treatment with SSA. Seven patients were pretreated with targeted therapy (n = 4 sunitinib, n = 3 everolimus). Four patients received other CTx (temozolomide-based or carboplatin/etoposide) and one patient received prior treatment with interferon. Twenty-three patients underwent surgery of the primary tumour (46%). At baseline, 66% of patients had radiologically proven progressive disease (PD). Another 17 subjects (34%) had clinically PD, characterized by new-onset or worsened abdominal pain (n = 15), nausea (n = 5), or ascites (n = 3). Four patients showed radiological signs of peritoneal carcinomatosis.\n\nObjective response\n\nCR and PR as best responses were observed in 1 (2%) and 18 (36%) patients, respectively, corresponding to an ORR of 38%. SD as the best response, including mixed response in one case, was documented in 19 cases (38%), accounting for an overall disease control rate (DCR; CR + PR + SD) of 76%. PD was noted in 24% of all cases. Among the functional syndromes, the ORR was 22.2% (2/9), and the DCR was 77.8% (7/9). The four patients with gastrinomas each had SD and PD twice, and the three subjects with insulinomas showed PR once and SD twice. At PTHrPoma PR and at VIPoma SD was the best response. In 47 patients, the complete biochemical course of the tumour marker CgA was evaluated before, during and after STZ CTx. A decrease of CgA levels of more than 30% during therapy was associated with a significantly superior ORR (69% vs. 23%, p = 0.004, Fisher’s exact test). Prior targeted therapy, previous PRRT, SSA, Ki-67 index, number of distant metastases, or the progression status at baseline did not significantly affect ORR. A detailed analysis of the response to STZ CTx is summarised in Table 2.Table 2 Response to STZ CTx\n\n\tObjective response No. (%)\tp*\tStable disease No. (%)\tProgressive disease No. (%)\t\nAll patients (n = 50)\t19 (38.0)\t\t19 (38.0)\t12 (24.0)\t\nTreatment line\t\t0.387\t\t\t\n1st line (n = 27)\t12 (44.4)\t\t10 (37.0)\t5 (18.5)\t\n2nd or higher line (n = 23)\t7 (30.4)\t\t9 (39.1)\t7 (30.4)\t\nPrevious SSA therapy\t\t>0.99\t\t\t\nYes (n = 16)\t6 (37.5)\t\t5 (31.3)\t5 (31.3)\t\nNo (n = 34)\t13 (38.2)\t\t14 (41.2)\t7 (20.1)\t\nPrevious targeted therapy\t\t0.229\t\t\t\nYes (n = 7)\t1 (14.3)\t\t3 (42.9)\t3 (42.9)\t\nNo (n = 43)\t18 (41.9)\t\t16 (37.2)\t9 (20.9)\t\nPrevious PRRTa\t\t0.742\t\t\t\nYes (n = 13)\t4 (30.8)\t\t4 (30.8)\t5 (38.5)\t\nNo (n = 37)\t15 (40.5)\t\t15 (40.5)\t7 (18.9)\t\nTumour type\t\t0.452\t\t\t\nFunctioning (n = 9)\t2 (22.2)\t\t5 (55.6)\t2 (22.2)\t\nNon-functioning (n = 41)\t17 (41.5)\t\t14 (34.2)\t10 (24.4)\t\nAffected organ systems\t\t0.244\t\t\t\n≤1 (n = 25)\t12 (48.0)\t\t9 (36.0)\t4 (16.0)\t\n≥2 (n = 25)\t7 (28.0)\t\t10 (40.0)\t8 (32.0)\t\nBone metastases\t\t0.237\t\t\t\nYes (n = 19)\t5 (26.3)\t\t6 (31.6)\t8 (42.1)\t\nNo (n = 31)\t14 (45.2)\t\t13 (41.9)\t4 (12.9)\t\nECOG PSb at start\t\t0.695\t\t\t\n≤1 (n = 43)\t17 (39.5)\t\t16 (37.2)\t10 (23.3)\t\n2 (n = 7)\t2 (28.6)\t\t3 (42.9)\t2 (28.6)\t\nGrading\t\t>0.99\t\t\t\nKi-67 ≤ 15% (n = 32)\t12 (37.5)\t\t13 (40.6)\t7 (21.9)\t\nKi-67 > 15% (n = 18)\t7 (38.9)\t\t6 (33.3)\t5 (27.8)\t\nProgression status at start\t\t0.767\t\t\t\nRadiologically (n = 33)\t12 (36.4)\t\t11 (33.3)\t10 (30.3)\t\nTumour burden/symptoms (n = 17)\t7 (41.2)\t\t8 (47.1)\t2 (11.8)\t\nTime from initial diagnosis\t\t0.773\t\t\t\n≤1 year (n = 27)\t11 (40.7)\t\t10 (37.0)\t6 (22.2)\t\n>1 year (n = 23)\t8 (34.8)\t\t9 (39.1)\t6 (26.1)\t\nCgAc decrease\t\t0.004\t\t\t\n0–30% (n = 31)\t7 (22.6)\t\t15 (48.4)\t9 (29.0)\t\n>30% (n = 16)\t11 (68.8)\t\t3 (18.8)\t2 (12.5)\t\nAll p-values have been specified as italicized values and all values showing statistical significance were highlighted using bold characters\n\naPRRT peptide receptor radionuclide therapy, bECOG PS Eastern Cooperative Oncology Group performance status, cCgA Chromogranin A\n\n*p-value by Fisher’s exact test (objective response vs. stable disease or progression).\n\nProgression-free survival and overall survival\n\nAt the time of analysis, 49 of the 50 patients had radiologically proven PD. The median PFS after treatment with STZ CTx was 12.0 months, according to Kaplan–Meier analysis (95% confidence interval (CI), 8.5–15.5 months; Fig. 1). Four patients (8%) had a long-term response of more than 2 years. The mean previous staging interval at the time point of progression was 3.52 months (95% CI, 3.15–3.90 months).Fig. 1 PFS, expressed in months (n = 50)\n\nThe median survival from the start of treatment with STZ CTx was 38 months in the whole patient group (95% CI, 20.4–55.6 months). The OS rate was 57.6% (95% CI, 43.9–71.3%) at 2 years and 33.9% (95% CI, 19.8–48.0%) at 5 years, according to Kaplan-Meier analysis (Fig. 2). The overall median survival from diagnosis was 64 months (95% CI, 35.6–92.5 months). At the time of analysis, 33 cohort patients (66%) had died.Fig. 2 Survival from the start of treatment, expressed in months (n = 50)\n\nParameters that could affect PFS and OS are shown in Table 3. Univariate and multivariate analyses were performed using the Cox regression model. First-line treatment and the presence of bone metastases had a significant impact on survival. In Kaplan–Meier analyses, median survival from the start of treatment was 89 (95% CI, 34.9–143.1) vs. 22 (95% CI, 19.3–24.7) months in patients with first vs. later therapy lines (p = 0.001, log-rank test) (Fig. 3). The presence of bone metastases was associated with a shorter OS of 24 (95% CI, 20.8–27.2) vs. 46 (95% CI, 26.3–65.7) months (p = 0.006, log-rank test) (Fig. 4). PFS was not influenced by previous targeted therapy, PRRT, bone metastases or therapy line.Table 3 Clinical parameters and their impact on PFS and OS based on univariate and multivariate analyses\n\nVariable\tUnivariate\tMultivariate\t\nHR\t95% CI\tp-value\tHR\t95% CI\tp-value\t\nPFS\t\nPrevious targeted therapya Yes (n = 7) vs. no (n = 43)\t0.650\t0.273–1.547\t0.330\t0.554\t0.220–1,392\t0.209\t\nPrevious PRRT Yes (n = 13) vs. no (n = 37)\t1.724\t0.886–3.357\t0.109\t1.919\t0.956–3,855\t0.067\t\nResection of primary tumour (n = 23) vs. no resection (n = 27)\t0.969\t0.541–1.736\t0.915\t0.985\t0.524–1,849\t0.961\t\nBone metastases Yes (n = 19) vs. no (n = 31)\t1.144\t0.625–2.093\t0.663\t1.123\t0.608–2,074\t0.711\t\nOS from STZ CTx\t\nPrevious targeted therapya Yes (n = 7) vs. no (n = 43)\t1.324\t0.544–3.220\t0.537\t1.464\t0.543–3.946\t0.452\t\nPrevious PRRT Yes (n = 13) vs. no (n = 37)\t1.609\t0.773–3.353\t0.204\t1.429\t0.581–3.516\t0.437\t\nResection of primary tumour (n = 23) vs. no resection (n = 27)\t0.771\t0.386–1.543\t0.463\t0.614\t0.279–1.352\t0.226\t\nBone metastases Yes (n = 19) vs. no (n = 31)\t2.710\t1.285–5.716\t0.009\t2.637\t1.205–5.772\t0.015\t\nAll p-values have been specified as italicized values and all values showing statistical significance were highlighted using bold characters\n\naEverolimus and/ or sunitinib\n\nFig. 3 Survival from the start of treatment (months) according to therapy line (n = 50)\n\nFig. 4 Survival from the start of treatment (months) according to bone metastases (n = 50)\n\nToxicity\n\nAdverse effects were documented in 49 of the 50 patients. The most common side effect reported was constipation in 28 patients (57%). This could be controlled with laxatives and enemas without restricting the activities of daily living (ADL). Fatigue occurred in 11 patients (22%) without limiting the ADL. Nausea and vomiting occurred in eight patients (16%) and were mild to moderate. In two patients (4%), hospitalisation was prolonged by persistent nausea despite adequate therapy. At the onset of chemotherapy, 19 patients (39%) had anaemia with haemoglobin (Hb) levels between the specific lower limit of normal and 10 g/dl; eight patients (16%) had anaemia with Hb values between 10 and 8 g/dl. A decrease in the initial Hb value, corresponding to CTCAE grade 1, was found in 11 patients (22%) during STZ CTx. No patient showed a Hb-level decrease of grade 2 or higher. In two patients (4%), leukopenia occurred, one case of leukopenia led to discontinuation of STZ CTx after four cycles owing to persistent fever. Eight patients had pre-therapeutic thrombocytopenia. In two patients (4%), thrombocytopenia first appeared on therapy (CTCAE grade 2). Liver enzymes (aspartate aminotransferase, alanine aminotransferase and gamma-glutamyltransferase) increased in 21 patients (43%) while on therapy, corresponding to CTCAE grades 1 and 2. Renal function could be assessed in 48 patients using creatinine levels and glomerular filtration rate (GFR) calculated according to the Modification of Diet in Renal Disease (MDRD) formula. Prior to STZ CTx, 41 patients had normal renal function and seven patients had a slightly reduced function. Chemotherapy resulted in a mostly mild deterioration of renal function in 13 patients (27%) (Table 4). Additionally, decreased renal function parameters 6 and 12 months after cessation of chemotherapy were reported in 35 and 27 patients, respectively. GFR decreased in the first 6 months after cessation of STZ CTx and then remained stable (Table 5). No treatment-related deaths were observed.Table 4 Toxic reaction to chemotherapy\n\nReaction\tAll grades No. (%)\tGrade 3 or 4 No. (%)\t\nConstipation\t28 (56)\t0\t\nAltered liver enzymes\t21 (43)\t2 (4)\t\nRenal insufficiency\t13 (27)\t1 (2)\t\nAnaemia\t11 (22)\t0\t\nFatigue\t11 (22)\t0\t\nNausea/vomiting\t8 (16)\t2 (4)\t\nLeukopenia\t2 (4)\t1 (2)\t\nThrombocytopenia\t2 (4)\t0\t\n\nTable 5 Renal function (GFRa, MDRDb formula) before and after STZ CTx\n\n\tStart STZ CTx n (%)c\tStop STZ CTx n (%)c\t6 months after the end of STZ CTx n (%)d\t12 months after the end of STZ CTx n (%)e\t\n>60 ml/min\t41 (85)\t35 (73)\t20 (57)\t14 (52)\t\n60–30 ml/min\t7 (15)\t12 (25)\t14 (40)\t11 (41)\t\n29–15 ml/min\t0 (0)\t1 (2)\t1 (3)\t2 (7)\t\n<15 ml/min\t0\t0\t0\t0\t\naGFR glomerular filtration rate.\n\nbMDRD Modification of Diet in Renal Disease.\n\ncGFR available in 48 patients.\n\ndGFR available in 35 patients.\n\neGFR available in 27 patients.\n\nDiscussion\n\nIn this study, the efficacy of STZ CTx in patients selected according to current guidelines was investigated [13, 20, 21]. Since the introduction of STZ CTx in the 1970s, the therapy threshold has risen from the mere detection of residual disease to the clinical or radiological progression of an incurable condition [3, 13, 22]. In 2010, competing targeted therapies with sunitinib and everolimus were approved and PRRT became widely available [7, 8, 11]. Since then, STZ CTx has been used competitively with these new therapies, preferably in short-term progressive PanNET with multiple-organ manifestations. This study indicates a persistent ORR of 38% with a lower PFS at 12 months and lower OS of 38 months compared with previous studies (Table 6).Table 6 Patient characteristics and outcome of STZ CTx in PanNET\n\n\tRegimen, implementation (duration)\tn\tRadiologic response assessable, n (%)\tLocalisation\tWHO tumour grading G1 (% of cohort)\tStage IV\tSTZ CTx 1st line\tTime from initial diagnosis to therapy start (months)\tProgressive disease at baseline\tORR\tDCR\tmPFS/TTP (months)\tmOS (months)\tMarkers of response\tPrognostic factors PFS/TTP\tPrognostic factors OS\t\nClewemar et al. [15]\tSTZ/5-FU 1981–2014\t133\t100 (75.2%)\t100% pancreas\t36%\t88%\t63.2%\tn.ra\t32%\t28%\t92%\t23\t51.9\tCgA decrease > 50%\tGrading Stage IV\tGrading Previous surgery\t\nDilz et al. [13]\tSTZ/5-FU 1998–2014\t96\t93 (96.8%)\t100% pancreas\t12%\t93.8%\t56.3%\t11.8\t74%\t42.7%\t83.3%\t19.4\t54.8\tCgA decrease >30%\tKi-67 > 15%\tKi-67 > 15% Metastatic sites ≥2\t\nKrug et al. [14]\tSTZ/Dox/5-FU 1995–2013\t77\t64 (83.1%)\t84.4% pancreas (+bronchial, duodenal, CUP-NEN)\t12%\t90.9%\t19.5%\t33\tn.ra\t34%\t72%\t16\t28\tCgA decrease >30%, positive Octreo-Scan\tKi-67 > 10%\t—b\t\nSchrader et al. [16]\tSTZ/5-FU 2002–2018\t30\t28 (93.3%)\t100% pancreas\tn.ra\t92.9%\t61%\tn.ra\tn.ra\t36%\t86%\t21\t69\t—b\tPrevious surgery\t—b\t\nLahner et al.\tSTZ/5-FU 2010–2018\t50\t50 (100%)\t100% pancreas\t6%\t96%\t54%\t6.5\t100%\t38%\t76%\t12\t38\tCgA decrease >30%\t—b\tBone metastases Therapy line\t\nan.r. not reported\n\nb— not found\n\nBaseline characteristics of our cohort confirmed a shift toward a more aggressive clinical course compared with published data [14–17]. The median duration of illness from the first diagnosis to the beginning of STZ CTx was considerably shorter in our investigation (6.5 months) than in recent studies from Berlin and Marburg (11.8 and 33.0 months, respectively) [15, 16]. At the same time, 50% of our patients had a tumour spread to two or more distant organ systems; in a previous study, tumours spread in only 33% of patients [15]. The proportion of patients with a low proliferative G1 PanNET, corresponding to a Ki-67 index of ≤2%, was significantly smaller in our cohort (6%) compared with that in previous studies, with G1 PanNET of 12%–36% [14–16]. Finally, when commencing STZ CTx, all of our patients were morphologically and/or clinically progressive. Taken together, our cohort illustrates the influence of the guidelines, treating preferably short-term progressive PanNET G2 or G3 with multiple-organ manifestations.\n\nDespite this selection, we observed an ORR in 38% of the patients, which is in line with the results of 34%, 36%, and 42.7% in previous studies [15–17]. In contrast, 24% of our patients progressed during therapy, corresponding to a DCR of 76%, which is lower than previous reports [14–17]. Interestingly, the highest DCR of STZ CTx (92%) was found in a study that had a uniquely high proportion of low proliferative G1 PanNET patients (36%), possibly reflecting the natural course of the disease rather than anti-tumour activity [14]. With a decreasing proportion of G1 differentiated PanNET, the DCR also decreased [15, 17]. Even progression status at baseline may play a relevant role. In previous reports focused on STZ CTx, progression status was rarely reported. However, in two prospective, placebo-controlled PanNET studies with sunitinib and everolimus in progressive patients, the DCRs of 72% and 73% match the 76% DCR of our STZ CTx study [7, 8]. Compared with targeted therapy, our results show a superior ORR with a similar DCR. As shown before, the biochemical response (CgA decrease >30%) was associated with significantly higher ORR. However, while there was a trend toward better response of STZ–CTx without preceding therapy with targeted therapy or PRRT, this difference was not statistically significant as the sample size might lack the power to reliably detect a difference.\n\nThe median PFS of 12 months and median OS of 38 months were considerably shorter in our cohort than in recent analyses. Clewemar et al. reported a much higher PFS of 23 months with an OS of 51.9 months in patients treated between 1981 and 2014 [14]. Dilz et al. showed a time to progression (TTP) of 19.4 months with an OS of 54.8 months in patients treated between 1998 and 2014 [15]. Krug et al. and Schrader et al. reported similar results; the OS was exceptionally short in the first study, most likely because of the inclusion of bronchial and CUP-NET [16, 17] (Table 6). PFS and OS in our study reflected the performance of STZ CTx in progressive PanNET patients with multiple-organ manifestations.\n\nPrevious lines of therapy, including surgery, had no measurable impact on PFS. However, data on targeted therapy were limited to seven patients and on PRRT to 13 patients. The impact of prior treatments, therefore, needs to be further elucidated in a larger cohort.\n\nInterestingly, we could not find any influence of the Ki-67 marker on PFS, as described in other studies. However, only three of our patients (6% of the cohort) had a WHO G1 tumour; thus, a much smaller proportion of our patients had G1 tumours than that in the other studies (Table 6). Again, this demonstrates the influence of patient selection according to the current guidelines from 2010 onwards. The G1 PanNET patients whose biologically slow course ultimately shows the influence of the Ki-67 marker are only rarely treated with STZ CTx nowadays.\n\nSTZ CTx as the first-line therapy was associated with a significantly longer median OS in this study. Thus, beginning the therapy sequence with STZ CTx may result in a more favourable outcome for dynamically growing PanNET. On the other hand, available therapy alternatives may have an impact. Everolimus, sunitinib, PRRT, or temozolomide/capecitabine may be administered in subsequent lines of therapy to our patients. First-line therapy may be associated with the longest survival in this setting. In contrast, no reliable therapy alternatives were available for patients in past decades.\n\nAnother key finding in this study is the prognostic importance of bone metastases. In this study, 38% of our patients had bone metastases, which was significantly higher than would have been expected. An analysis of 14,685 GI-NEN patients in the Surveillance, Epidemiology, and End Results database (SEER-9 registry) from 1973 to 2015 showed a bone metastases rate of 5.7% in stage-IV patients [23]. In contrast, the rate of bone metastases in an analysis by a tertiary referral centre in Germany was 26% in stage-IV patients [24]. Notably, a significant increase in bone metastases was detected after the introduction of 68Ga-DOTATOC PET/CT. In our study, all patients had received hybrid imaging before beginning STZ CTx and at least once a year thereafter, so the increased incidence of bone metastases in our study may have been due to improved detection corresponding to true incidence. In addition, the selection of patients with a more aggressive course may have also impacted the bone metastasis rate. Overall, the significant influence of bone metastases on the median OS is remarkable; the OS was reduced to nearly half in patients with bone metastases compared with that in patients without bone metastases (24 vs. 46 months) (Fig. 4).\n\nIn contrast to previous studies, we detected no effects of primary tumour resection, the Ki-67 index, or the number of metastatic sites on median OS [14, 15]. Surgical removal of the primary tumour, as a prognostic factor, is prone to selection bias, because patients with a smaller tumour burden, lower grading and better performance status may be more likely to undergo surgery. A higher Ki-67 index and more affected organs, which were previously mentioned as prognostic parameters, are statistically included in our collective as an initial finding and, therefore, are no longer detectable. Interestingly, neither preceding targeted therapy nor PRRT showed a significant correlation with median PFS or OS. It should be noted that the number of patients with targeted therapy prior to STZ CTx was small in our analysis. The ongoing phase-3 SEQTOR study (NCT 02246127), which compares the STZ CTx followed by everolimus upon progression with the reverse sequence, will further elucidate the optimal therapy sequencing.\n\nThe safety profile of STZ CTx in our study was consistent with the previous experience in advanced PanNET. The most frequent toxic reactions were of grade 1 or 2 severity and included renal insufficiency, anaemia, fatigue, and nausea; the frequencies were similar to those reported previously [14–16].\n\nConclusion\n\nThe majority of patients with dynamically progressive PanNET benefit from STZ CTx. The toxicity is low. Compared with those in targeted therapies or PRRT, remissions occur more frequently. First-line STZ CTx is associated with prolonged survival. Patients with bone metastases require intensive therapy.\n\nAuthor contribution\n\nHL and DF were responsible for the study concept, planning, and design. HL, JR, and KHJ carried out the statistical analysis. HL drafted the paper. All authors contributed to the acquisition, analysis, or interpretation of data and critical revision of the paper. All authors read and approved the final paper.\n\nFunding\n\nOpen Access funding enabled and organized by Projekt DEAL.\n\nCompliance with ethical standards\n\nConflict of interest\n\nHL reports personal fees and grants from Novartis and personal fees from Ipsen and AAA, outside the submitted work. KH reports personal fees from Bayer, personal fees, and others from Sofie Biosciences, personal fees from SIRTEX, non-financial support from ABX, personal fees from Adacap, personal fees from Curium, personal fees from Endocyte, grants, and personal fees from BTG, personal fees from IPSEN, personal fees from Siemens Healthineers, personal fees from GE Healthcare, personal fees from Amgen, personal fees from Novartis, personal fees from ymabs, outside the submitted work. AM, LK, NU, JT, JR, KHJ, ST, KWS, and DF have no relevant financial or non-financial interests to disclose.\n\nEthical approval\n\nWritten informed patient consent and approval for data collection and analysis was obtained upon admission to our institution. The study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the medical faculty of the University Duisburg-Essen (18-8367-BO).\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Dasari A Shen C Halperin D Zhao B Zhou S Xu Y Shih T Yao JC Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States JAMA Oncol. 2017 3 1335 1342 10.1001/jamaoncol.2017.0589 28448665\n2. Yao JC Hassan M Phan A Dagohoy C Leary C Mares JE Abdalla EK Fleming JB Vauthey JN Rashid A Evans DB One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States J. Clin. Oncol. 2008 26 3063 3072 10.1200/jco.2007.15.4377 18565894\n3. Moertel CG Hanley JA Johnson LA Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma N. Engl. 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Clewemar Antonodimitrakis P Sundin A Wassberg C Granberg D Skogseid B Eriksson B Streptozocin and 5-Fluorouracil for the treatment of pancreatic neuroendocrine tumors: efficacy, prognostic factors and toxicity Neuroendocrinology 2016 103 345 353 10.1159/000439086 26279284\n15. Dilz LM Denecke T Steffen IG Prasad V von Weikersthal LF Pape UF Wiedenmann B Pavel M Streptozocin/5-Fluorouracil chemotherapy is associated with durable response in patients with advanced pancreatic neuroendocrine tumours Eur. J. Cancer. 2015 51 1253 1262 10.1016/j.ejca.2015.04.005 25935542\n16. Krug S Boch M Daniel H Nimphius W Muller D Michl P Rinke A Gress TM Streptozocin-based chemotherapy in patients with advanced neuroendocrine neoplasms-predictive and prognostic markers for treatment stratification PLoS. One 2015 10 e0143822 10.1371/journal.pone.0143822 26630134\n17. Schrader J Henes FO Blaeker M Zimmermann-Fraedrich K Pace A Perez D Izbicki JR Lohse AW Benten D Extended cycle streptozotocin/5-FU chemotherapy for maintenance therapy in pancreatic neuroendocrine tumors Endocrine 2019 65 460 467 10.1007/s12020-019-01941-w 31037707\n18. R.V. Lloyd, R.Y. Osamura, G. Kloppel, J. Rosai: WHO Classification of Tumours of the Endocrine Organs. IARC Publications, Lyon (2017)\n19. Rindi G Kloppel G Alhman H Caplin M Couvelard A de Herder WW Erikssson B Falchetti A Falconi M Komminoth P Korner M Lopes JM McNicol AM Nilsson O Perren A Scarpa A Scoazec JY Wiedenmann B TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system Virchows Arch. 2006 449 395 401 10.1007/s00428-006-0250-1 16967267\n20. O’Toole D Kianmanesh R Caplin M ENETS 2016 consensus guidelines for the management of patients with digestive neuroendocrine tumors: an update Neuroendocrinology 2016 103 117 118 10.1159/000443169 26731186\n21. Rinke A Wiedenmann B Auernhammer C Bartenstein P Bartsch D Begum N Faiss S Fottner C Gebauer B Goretzki P Lynen Jansen P Pöpperl G Scherübl H Weber M Gress T Pavel M Albert J Alfke H Amthauer H Anlauf M Arnold R Baum RP Denecke T Ezziddin S Fendrich V Gniffke S Haug A Hörsch D Kegel T Knoefel W Knösel T Kratochwil C Lahner H Lordick F Luster M Mahnken A Mellar K Mönig H Musholt T Nothacker M Pape U Pascher A Pöppel T Prasad V Probst A Scheidhauer K Schneider D Schott M Schrader J Seufferlein T Sipos B Spitzweg C Steinmüller T Trumm C Wurst C Zorger N [Practice guideline neuroendocrine tumors - AWMF-Reg. 021-27] Z. Gastroenterol. 2018 56 583 681 10.1055/a-0604-2924 29890561\n22. Steinmuller T Kianmanesh R Falconi M Scarpa A Taal B Kwekkeboom DJ Lopes JM Perren A Nikou G Yao J Delle Fave GF O’Toole D Frascati consensus conference p. consensus guidelines for the management of patients with liver metastases from digestive (neuro)endocrine tumors: foregut, midgut, hindgut, and unknown primary Neuroendocrinology 2008 87 47 62 10.1159/000111037 18097131\n23. Zheng Z Chen C Jiang L Zhou X Dai X Song Y Li Y Incidence and risk factors of gastrointestinal neuroendocrine neoplasm metastasis in liver, lung, bone, and brain: a population-based study Cancer Med. 2019 8 7288 7298 10.1002/cam4.2567 31609098\n24. Scharf M Petry V Daniel H Rinke A Gress TM Bone metastases in patients with neuroendocrine neoplasm: frequency and clinical, therapeutic, and prognostic relevance Neuroendocrinology 2018 106 30 37 10.1159/000457954 28152537\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1355-008X",
"issue": null,
"journal": "Endocrine",
"keywords": "5-fluorouracil; Objective response; Pancreatic neuroendocrine tumor; Streptozocin; Survival",
"medline_ta": "Endocrine",
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"nlm_unique_id": "9434444",
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"pmid": "34480724",
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"title": "Streptozocin/5-fluorouracil chemotherapy of pancreatic neuroendocrine tumours in the era of targeted therapy.",
"title_normalized": "streptozocin 5 fluorouracil chemotherapy of pancreatic neuroendocrine tumours in the era of targeted therapy"
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"abstract": "OBJECTIVE\nTo report the effects of aflibercept on eyes with large retinal pigment epithelial detachment (PED) associted with polypoidal choroidal vasculopathy (PCV).\n\n\nMETHODS\nWe reviewed the medical records of patients with PEDs associated with PCV that were treated with aflibercept after intravitreal ranibizumab had failed.\n\n\nRESULTS\nThree eyes of patients aged 72, 79, and 80 years were studied. Reflective material was seen in the PED along the outer surface of the retinal pigment epithelium (RPE) by spectral-domain optical coherence tomography (SD-OCT). A complete resolution of the serous PEDs was found after two aflibercept injections; however, all eyes had a fibrovascular PED. In addition, one eye developed a retinal hemorrhage and a recurrent PED just after the third injection of aflibercept. The visual acuity in this eye decreased from 10/20 to 2/20.\n\n\nCONCLUSIONS\nThe reflective material below the outer surface of the RPE in serous PED suggests the presence of neovascularization. Intravitreal aflibercept could be considered for large PEDs in eyes with PCV but should be carefully applied.",
"affiliations": "Department of Ophthalmology, Nara Medical University, Kashihara, Nara, Japan.;Department of Ophthalmology, Nara Medical University, Kashihara, Nara, Japan.;Department of Ophthalmology, Nara Medical University, Kashihara, Nara, Japan.;Department of Ophthalmology, Nara Medical University, Kashihara, Nara, Japan.",
"authors": "Yamashita|Mariko|M|;Nishi|Tomo|T|;Hasegawa|Taiji|T|;Ogata|Nahoko|N|",
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"fulltext": "\n==== Front\nClin OphthalmolClin OphthalmolClinical OphthalmologyClinical Ophthalmology (Auckland, N.Z.)1177-54671177-5483Dove Medical Press 10.2147/OPTH.S56539opth-8-343Case ReportResponse of serous retinal pigment epithelial detachments to intravitreal aflibercept in polypoidal choroidal vasculopathy refractory to ranibizumab Yamashita Mariko Nishi Tomo Hasegawa Taiji Ogata Nahoko Department of Ophthalmology, Nara Medical University, Kashihara, Nara, JapanCorrespondence: Nahoko Ogata, Department of Ophthalmology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan, Tel +81 744 298 884, Fax +81 744 238 032, Email ogata@naramed-u.ac.jp2014 02 3 2014 8 343 346 © 2014 Yamashita et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2014The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Purpose\nTo report the effects of aflibercept on eyes with large retinal pigment epithelial detachment (PED) associted with polypoidal choroidal vasculopathy (PCV).\n\nMethods\nWe reviewed the medical records of patients with PEDs associated with PCV that were treated with aflibercept after intravitreal ranibizumab had failed.\n\nResults\nThree eyes of patients aged 72, 79, and 80 years were studied. Reflective material was seen in the PED along the outer surface of the retinal pigment epithelium (RPE) by spectral-domain optical coherence tomography (SD-OCT). A complete resolution of the serous PEDs was found after two aflibercept injections; however, all eyes had a fibrovascular PED. In addition, one eye developed a retinal hemorrhage and a recurrent PED just after the third injection of aflibercept. The visual acuity in this eye decreased from 10/20 to 2/20.\n\nConclusion\nThe reflective material below the outer surface of the RPE in serous PED suggests the presence of neovascularization. Intravitreal aflibercept could be considered for large PEDs in eyes with PCV but should be carefully applied.\n\nKeywords\nage-related macular degenerationretinal pigment epithelial detachmentpolypoidal choroidal vasculopathyaflibercept\n==== Body\nIntroduction\nIntravitreal injections of pegaptanib or bevacizumab have been reported to be efficacious and safe treatments for retinal pigment epithelial detachments (PEDs) associated with occult choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD).1 Aflibercept, a recombinant fusion protein, has a higher binding affinity for vascular endothelial growth factor (VEGF), and it has been shown to be beneficial for patients with AMD who were refractory to multiple injections of either bevacizumab or ranibizumab.2,3 In addition, a recent study showed that intravitreal aflibercept may be an effective treatment for serous PEDs in which bevacizumab and ranibizumab were not effective.4\n\nWe report three cases of polypoidal choroidal vasculopathy (PCV) with a large PED that was refractory to ranibizumab but responded to intravitreal aflibercept. We present our spectral domain optical coherence tomographic (SD-OCT) findings, which provided some evidence on the development of the PED.\n\nCase reports\nCase 1\nA 79-year-old man presented with a large serous PED. Fluorescein angiography (FA) displayed an occult CNV, and indocyanine green (IA) images showed a PCV. At the initial visit, his best-corrected visual acuity (BCVA) was 2/20 oculus sinister (OS). Three monthly injections of ranibizumab slightly flattened the PED and reduced the subretinal fluid (SRF), but a recurrence developed. Three additional monthly injections of ranibizumab (total of six injections) did not improve the PED, and there was an increase of the highly reflective material beneath the outer surface of the RPE in the SD-OCT images.\n\nWe switched to aflibercept and, after one intravitreal injection, the PED was slightly flattened; two additional injections of aflibercept were given, which flattened the PED over the hyper-reflective material observed by SD-OCT. The BCVA remained at 2/20 OS (Figure 1).\n\nCase 2\nA 72-year-old man presented with a large serous PED in his right eye associated with a PCV. His BCVA was 14/20 OD. He had received six ranibizumab injections over a 10-month period, but the PED worsened and the SRF recurred. Hyper-reflective materials were seen beneath the outer surface of the RPE in the SD-OCT images. The BCVA decreased to 8/20 OD.\n\nTwo monthly injections of aflibercept resulted in a complete resolution of the serous PED; however, the flattened PED contained fibrovascular material beneath the RPE layer in the SD-OCT images.\n\nCase 3\nAn 80-year-old man presented with a large serous PED. FA displayed an occult CNV, and IA images showed a PCV. His BCVA was 10/20 OS. Three monthly injections of ranibizumab slightly flattened the PED, but a recurrence was observed after 3 months. Three additional monthly injections of ranibizumab (total of six injections) failed to reduce the PED, and hyper-reflective materials were seen beneath the outer surface of the RPE in the SD-OCT images. We switched to aflibercept, and after the two additional monthly injections, an exudative CNV lesion was observed instead of the serous PED. OCT showed a loss of optical free space and highly reflective materials, suggesting the formation of fibrovascular PED. One day after the third monthly injection of aflibercept, a subretinal hemorrhage and recurrent PED were observed. BCVA was reduced to 2/20 (Figure 2).\n\nDiscussion\nWe found from three cases that intravitreal injections of aflibercept reduced or flattened large serous PEDs associated with PCV that were refractory to ranibizumab. Bird and Marshall5 and Casswell et al6 proposed that an interaction between the RPE and the Bruch membrane was central to the development of a PED, and they were not mutually exclusive.7 Alternatively, Gass8 proposed that PEDs in eyes with AMD occurred by neovascular ingrowth with subsequent exudation from the new vessels.\n\nIt is well known that PCVs frequently accompany PEDs.9 We found highly reflective materials within the serous PED beneath the outer surface of the RPE in all three cases. After aflibercept treatment, all of our cases had an apparent contracture of the accumulated material. This suggested the presence of fibrovascular tissues within the flattened PED. This is supported by the findings of Spaide,10 who examined the internal structure of PEDs in eyes with AMD and found that PEDs frequently have reflective materials on the back surface of the RPE, suggestive of CNV. These findings can be explained by the hypothesis presented by Gass8 on PED formation.\n\nWe found a sudden subretinal hemorrhage and recurrent PED in case 3. Following anti-VEGF therapy, a contracture of fibrovascular tissue has been reported in eyes with proliferative diabetic retinopathy.11 We suggest that aflibercept therapy may have enhanced fibrosis of neovascular tissues and caused a traction of the vessels, which then resulted in a sudden subretinal hemorrhage and a recurrence of the PED.\n\nIn conclusion, the reflective material below the outer surface of the RPE in serous PEDs suggests the presence of neovascularization. Intravitreal aflibercept could be considered for large PEDs in eyes with PCV but should be carefully applied.\n\nDisclosure\n\nThe authors have no conflict of interest to declare in this work.\n\nFigure 1 Findings from case 1, a 79-year-old Japanese man with a large PED in the left eye with PCV.\n\nNotes: (A) Fundus photograph of the left eye at the initial examination showing a large serous retinal PED. His BCVA was 2/20 OS. (B) FA image of the left eye at the initial visit showing late leakage at the base of the PED suggestive of occult CNV and pooling of dye within the serous PED. (C) IA images at the initial visit showing hyperfluorescent spots in the choroidal circulation at the base of the PED suggesting the presence of polyps and hypofluorescence in the serous PED lesion. (D) Fundus photograph taken after three monthly aflibercept injections. The large serous PED is not present. (E) SD-OCT images of the left eye at the initial examination showing a large serous PED with SRF. The PED appears to be optically empty. Reflective material beneath the RPE layer (white arrow) suggestive of an occult CNV was detected that corresponded to the lesion of late leakage by FA. (F) SD-OCT image 6 months after three monthly injections of ranibizumab. Three monthly injections of ranibizumab slightly flattened the PED and reduced the SRF. However 6 months later, recurrent SRF and PED were observed. Hyper-reflective materials (white arrowhead) beneath the outer surface of the RPE can be seen. (G) SD-OCT image showing near resolution of the PED with complete resolution of the SRF after three additional monthly injections of ranibizumab (total of six injections). Sub-RPE materials (white arrowhead) can be seen even though the PED is collapsed. (H) One month after the last injection of ranibizumab, a recurrent large PED can be seen. (I) Flattened PED 2 weeks after a single aflibercept injection. Sub-RPE materials (white arrowhead) can be seen. (J) A complete resolution of the PED after the second injection of aflibercept, although reflective materials (white arrowhead), suggesting fibrovascular tissue, can be seen within the PED beneath the RPE layer. (K) SD-OCT image of (D). After three monthly injections of aflibercept, complete resolution of PED had a fibrovascular PED. BCVA remained 2/20 OS.\n\nAbbreviations: BCVA, best-corrected visual acuity; CNV, choroidal neovascularization; FA, fluorescein angiography; IA, indocyanine green; OS, oculus sinister; PCV, polypoidal choroidal vasculopathy; PED, pigment epithelial detachment; RPE, retinal pigment epithelium; SD-OCT, spectral domain optical coherence tomographic; SRF, subretinal fluid.\n\nFigure 2 Images from case 3, an 80-year-old Japanese man with a large PED associated with a PCV in the left eye.\n\nNotes: (A–C and G). Images at the initial visit. (A) Fundus photograph of the left eye at the initial visit shows a large serous PED. His BCVA was 10/20 OS. (B) FA images of the left eye at the initial visit showing late leakage at the base of the PED suggestive of an occult CNV and pooling of dye within the serous PED. (C) IA image showing hyperfluorescent spots from the choroidal circulation at the base of the PED suggestive of polyps and hypofluorescence in the PED lesion. (D) Fundus photograph after a single injection of aflibercept. The large serous PED is still present. (E) After two monthly injections of aflibercept, an exudative lesion with small hemorrhages can be seen instead of the serous PED. Yellowish precipitates are faintly seen in the subretinal space. (F) One day after the third monthly injection of aflibercept. The patient reported a central dark spot, a scotoma, in his left eye. Fundus photograph shows the presence of a subretinal hemorrhage and a recurrent PED. The PED was hemorrhagic. The BCVA was reduced to 2/20. (G–M) SD-OCT images of the left eye. (G) SD-OCT shows a large serous PED with SRF at the initial examination. The PED is optically empty but hyper-reflective materials (white arrowheads) can be seen beneath the outer surface of the RPE. Hyper-reflective materials located at the base of the temporal side of the PED, corresponding to the late leakage by FA, suggesting an occult CNV lesion, can be seen beneath the RPE layer. (H) SD-OCT image showing that three monthly injections of ranibizumab slightly flattened the PED and reduced the SRF. (I) Three months after the last injection of ranibizumab, a recurrence of the SRF and PED are observed. Hyper-reflective materials (white arrowhead) can be seen along the outer surface of the RPE. (J) SD-OCT shows that the PED with SRF enlarged despite three additional monthly ranibizumab injections (total of six injections). Hyper-reflective materials (white arrowhead) from the back surface of the RPE layer were increased. (K) SD-OCT image of (D). A single aflibercept injection did not resolve the PED and SRF but worsened. (L) SD-OCT image of (E). After two monthly injections of aflibercept, a near resolution of PED with complete resolution of SRF can be seen. However, hyper-reflective materials, suggesting the existence of fibrovascular PED, are present beneath the RPE layer. (M) SD-OCT image of (F). After three monthly injections of aflibercept, a recurrent large PED with SRF can be seen. Hyper-reflective materials reflecting hemorrhages in the subretinal space and PED space were detected. BCVA was reduced to 2/20.\n\nAbbreviations: BCVA, best-corrected visual acuity; CNV, choroidal neovascularization; FA, fluorescein angiography; IA, indocyanine green; OS, oculus sinister; PCV, polypoidal choroidal vasculopathy; PED, pigment epithelial detachment; RPE, retinal pigment epithelium; SD-OCT, spectral domain optical coherence tomographic; SRF, subretinal fluid.\n==== Refs\nReferences\n1 Arias L Treatment of retinal pigment epithelial detachment with antiangiogenic therapy Clin Ophthalmol 2010 4 369 374 20463807 \n2 Bakall B Folk JC Boldt HC Aflibercept therapy for exudative age-related macular degeneration resistant to bevacizumab and ranibizumab Am J Ophthalmol 2013 156 1 15 22 23706500 \n3 Cho H Shah CP Weber M Heier JS Aflibercept for exudative AMD with persistent fluid on ranibizumab and/or bevacizumab Br J Ophthalmol 2013 97 8 1032 1035 23766432 \n4 Patel KH Chow CC Rathod R Rapid response of retinal pigment epithelial detachments to intravitreal aflibercept in neovascular age-related macular degeneration refractory to bevacizumab and ranibizumab Eye (Lond) 2013 27 5 663 667 23558214 \n5 Bird AC Marshall J Retinal pigment epithelial detachments in the elderly Trans Ophthalmol Soc U K 1986 105 Pt 6 674 682 3310342 \n6 Casswell AG Kohen D Bird AC Retinal pigment epithelial detachments in the elderly: classification and outcome Br J Ophthalmol 1985 69 6 397 403 2408659 \n7 Singerman LJ Stockfish JH Natural history of subfoveal pigment epithelial detachments associated with subfoveal or unidentifiable choroidal neovascularization complicating age-related macular degeneration Graefes Arch Clin Exp Ophthalmol 1989 227 6 501 507 2483142 \n8 Gass JD Drusen and disciform macular detachment and degeneration Trans Am Ophthalmol Soc 1972 70 409 436 4663679 \n9 Saito M Iida T Nagayama D Cross-sectional and en face optical coherence tomographic features of polypoidal choroidal vasculopathy Retina 2008 28 3 459 464 18327139 \n10 Spaide RF Enhanced depth imaging optical coherence tomography of retinal pigment epithelial detachment in age-related macular degeneration Am J Ophthalmol 2009 147 4 644 652 19152869 \n11 Arevalo JF Maia M Flynn HW Jr Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy Br J Ophthalmol 2008 92 2 213 216 17965108\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1177-5467",
"issue": "8()",
"journal": "Clinical ophthalmology (Auckland, N.Z.)",
"keywords": "aflibercept; age-related macular degeneration; polypoidal choroidal vasculopathy; retinal pigment epithelial detachment",
"medline_ta": "Clin Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101321512",
"other_id": null,
"pages": "343-6",
"pmc": null,
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"pubdate": "2014",
"publication_types": "D002363:Case Reports",
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"title": "Response of serous retinal pigment epithelial detachments to intravitreal aflibercept in polypoidal choroidal vasculopathy refractory to ranibizumab.",
"title_normalized": "response of serous retinal pigment epithelial detachments to intravitreal aflibercept in polypoidal choroidal vasculopathy refractory to ranibizumab"
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"abstract": "OBJECTIVE\nPhenytoin is an effective anticonvulsant for focal epilepsy. Its use can be associated with long-term adverse effects including cerebellar ataxia. Whilst phenytoin is toxic to Purkinje cells in vitro; the clinical and radiological phenotype and mechanism of cerebellar degeneration in vivo remain unclear. We describe the prevalence, clinical and radiological characteristics of phenytoin-related ataxia.\n\n\nMETHODS\nPatients with epilepsy receiving treatment with phenytoin were recruited from the Epilepsy clinics at Royal Hallamshire Hospital, Sheffield, UK. Neurological examination was performed on all patients after recruitment. Patients were categorised into those with and without ataxia. We determined the severity of ataxia clinically (SARA score) and the pattern of cerebellar involvement by neuroimaging (MRI volumetry and MR spectroscopy).\n\n\nRESULTS\nForty-seven patients were recruited. Median duration of epilepsy was 24 years, median duration of phenytoin treatment was 15 years and current median phenytoin daily dose was 325 mg. Fifty-five percent of patients complained of poor balance. Clinical evidence of ataxia was seen in 40% patients. Gait, stance and heel-shin slide were the predominant features of cerebellar dysfunction. MRI demonstrated structural, volumetric and functional deficits of the cerebellum. Only one patient with ataxia had phenytoin levels above the normal range.\n\n\nCONCLUSIONS\nCerebellar ataxia is present in 40% of patients with epilepsy and chronic exposure to phenytoin. Patients on long-term phenytoin have reduced cerebellar volume even if they have no clinical evidence of ataxia. Evidence of structural deficits on imaging suggests a predilection for vermian involvement.",
"affiliations": "Academic Department of Neurosciences, Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK. Electronic address: p.d.shanmugarajah@sheffield.ac.uk.;Academic Unit of Radiology, University of Sheffield, Sheffield, UK. Electronic address: n.hoggard@sheffield.ac.uk.;Matrix Biology & Tissue Repair Research Unit, College of Biomedical and Life Sciences, School of Dentistry, Cardiff University, Cardiff, UK. Electronic address: AeschlimannDP@Cardiff.ac.uk.;Matrix Biology & Tissue Repair Research Unit, College of Biomedical and Life Sciences, School of Dentistry, Cardiff University, Cardiff, UK. Electronic address: aeschlimannpc@cardiff.ac.uk.;Academic Department of Neurosciences, Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK. Electronic address: gary.dennis@sth.nhs.uk.;Academic Department of Neurosciences, Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK. Electronic address: stephen.howell@sth.nhs.uk.;Academic Department of Neurosciences, Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK. Electronic address: m.reuber@sheffield.ac.uk.;Academic Department of Neurosciences, Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK. Electronic address: r.a.grunewald@sheffield.ac.uk.;Academic Department of Neurosciences, Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK. Electronic address: m.hadjivassiliou@sheffield.ac.uk.",
"authors": "Shanmugarajah|Priya D|PD|;Hoggard|Nigel|N|;Aeschlimann|Daniel P|DP|;Aeschlimann|Pascale C|PC|;Dennis|Gary J|GJ|;Howell|Stephen J|SJ|;Reuber|Markus|M|;Grünewald|Richard A|RA|;Hadjivassiliou|Marios|M|",
"chemical_list": "D000906:Antibodies; D000927:Anticonvulsants; D010672:Phenytoin; D005903:Gliadin; D005492:Folic Acid; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins",
"country": "England",
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"keywords": "Ataxia; Cerebellar degeneration; Cerebellum; Epilepsy; Phenytoin",
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"mesh_terms": "D000906:Antibodies; D000927:Anticonvulsants; D001259:Ataxia; D001921:Brain; D004827:Epilepsy; D005260:Female; D005492:Folic Acid; D019204:GTP-Binding Proteins; D005903:Gliadin; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D059906:Neuroimaging; D009460:Neurologic Examination; D010672:Phenytoin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012678:Sensation Disorders; D011503:Transglutaminases",
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"title": "Phenytoin-related ataxia in patients with epilepsy: clinical and radiological characteristics.",
"title_normalized": "phenytoin related ataxia in patients with epilepsy clinical and radiological characteristics"
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"abstract": "The metronomic therapy concept uses low doses of continuously applied chemotherapeutic, anti-angiogenetic, and immunomodulating drugs. Twenty patients with recurrent and 3 with refractory high-risk neuroblastoma were treated by the metronomic concept using celecoxib, cyclophosphamide, vinblastine, and etoposide for up to 24 months. The outcome was compared to 274 matched patients with a first recurrence from stage 4 neuroblastoma using the variables time from diagnosis to first recurrence, number of organs involved, and MYCN amplification. All were treated with dose-intensive conventional chemotherapy. The study patients experienced 1-3 recurrences and had 1-3 sites involved (osteomedullary, primary tumor, central nervous system, lymph nodes, liver, lungs) before the metronomic therapy started. Two patients in complete remission and three with active refractory disease following recurrence treatment were excluded from the outcome analysis. The curves for secondary event-free and overall survival demonstrated no significant differences. The toxicity was minimal except for ≥3 grade thrombocytopenia and leukopenia (all heavily pretreated). The treatment was realized in an outpatient setting. The metronomic approach is similarly effective as standard treatment in recurrent high-risk neuroblastoma, has low toxicity, and is applicable in an outpatient setting. A prospective study including propranolol as a fifth drug is underway.",
"affiliations": "a Department of Pediatric Oncology and Hematology , University of Cologne , Germany.;a Department of Pediatric Oncology and Hematology , University of Cologne , Germany.;b Department of Pediatric Oncology and Hematology , University of Minsk , Belarus.;c Department of Pediatric Oncology and Hematology , University of Brno , Czech Republic.;d Department of Pediatric Oncology and Hematology , University of Cologne , St. Petersburg , Russia.;e Institute of Medical Statistics, Informatics, and Epidemiology , University of Cologne , Germany.;c Department of Pediatric Oncology and Hematology , University of Brno , Czech Republic.",
"authors": "Berthold|Frank|F|;Hömberg|Marc|M|;Proleskovskaya|Inna|I|;Mazanek|Pavel|P|;Belogurova|Margarita|M|;Ernst|Angela|A|;Sterba|Jaroslav|J|",
"chemical_list": "D014747:Vinblastine; D005047:Etoposide; D003520:Cyclophosphamide; D000068579:Celecoxib",
"country": "England",
"delete": false,
"doi": "10.1080/08880018.2017.1373314",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0888-0018",
"issue": "34(5)",
"journal": "Pediatric hematology and oncology",
"keywords": "Angiogenesis; dose-intense chemotherapy; immunomodulation; metronomic therapy; neuroblastoma",
"medline_ta": "Pediatr Hematol Oncol",
"mesh_terms": "D059250:Administration, Metronomic; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068579:Celecoxib; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D005047:Etoposide; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009364:Neoplasm Recurrence, Local; D009447:Neuroblastoma; D010865:Pilot Projects; D015996:Survival Rate; D014747:Vinblastine",
"nlm_unique_id": "8700164",
"other_id": null,
"pages": "308-319",
"pmc": null,
"pmid": "29148865",
"pubdate": "2017-08",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "Metronomic therapy has low toxicity and is as effective as current standard treatment for recurrent high-risk neuroblastoma.",
"title_normalized": "metronomic therapy has low toxicity and is as effective as current standard treatment for recurrent high risk neuroblastoma"
} | [
{
"companynumb": "DE-CIPLA LTD.-2017DE23022",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CELECOXIB"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe purpose of the present study was to determine the relatedness of Staphylococcus aureus strains successively isolated over a 7-day period from a single bacteraemic patient undergoing antibiotic treatment with vancomycin.\n\n\nMETHODS\nThe S. aureus strains had been isolated and sequenced previously. Antibiotic susceptibility testing, population analysis profiling, and lysostaphin sensitivity and phagocytic killing assays were used to characterize these clonal isolates.\n\n\nRESULTS\nThe seven isolates (MEH1-MEH7) were determined to belong to a common multilocus sequence type (MLST) and spa type. Within the third and fifth day of vancomycin treatment, mutations were observed in the vraS and rpsU genes, respectively. Population analysis profiles revealed that the initial isolate (MEH1) was vancomycin-susceptible S. aureus (VSSA), while those isolated on day 7 were mostly heteroresistant vancomycin-intermediate S. aureus (hVISA). Supporting these findings, MEH7 was also observed to be slower in growth, to have an increase in cell wall width and to have reduced sensitivity to lysostaphin, all characteristics of VISA and hVISA strains. In addition, MEH7, although phagocytosed at numbers comparable to the initial isolate, MEH1, survived in higher numbers in RAW 264.7 macrophages. Macrophages infected with MEH7 also released more TNF-α and IFN-1β.\n\n\nCONCLUSIONS\nWe report an increasing resistance to vancomycin coupled with daptomycin that occurred within approximately 3 days of receiving vancomycin and steadily increased until the infection was cleared with an alternative antibiotic therapy. This study reiterates the need for rapid, efficient and accurate detection of hVISA and VISA infections, especially in high-bacterial load, metastatic infections like bacteraemia.",
"affiliations": "1 Division of Microbiology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas, USA.;2 Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.;3 Division of Molecular and Genetic Toxicology, NCTR, Food and Drug Administration, Jefferson, Arkansas, USA.;3 Division of Molecular and Genetic Toxicology, NCTR, Food and Drug Administration, Jefferson, Arkansas, USA.;1 Division of Microbiology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas, USA.;1 Division of Microbiology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas, USA.;2 Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.;1 Division of Microbiology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas, USA.",
"authors": "Basco|M D S|MDS|;Kothari|A|A|;McKinzie|Page B|PB|;Revollo|J R|JR|;Agnihothram|S|S|;Azevedo|M P|MP|;Saccente|M|M|;Hart|M E|ME|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin; D008248:Lysostaphin; D017576:Daptomycin",
"country": "England",
"delete": false,
"doi": "10.1099/jmm.0.000988",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-2615",
"issue": "68(6)",
"journal": "Journal of medical microbiology",
"keywords": "Staphylococcus aureus; hVISA; resilence to immunoclearance; vancomycin resistance",
"medline_ta": "J Med Microbiol",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D002473:Cell Wall; D017576:Daptomycin; D006801:Humans; D008248:Lysostaphin; D008264:Macrophages; D008297:Male; D008826:Microbial Sensitivity Tests; D058885:Multilocus Sequence Typing; D009154:Mutation; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus; D014640:Vancomycin; D020713:Vancomycin Resistance",
"nlm_unique_id": "0224131",
"other_id": null,
"pages": "848-859",
"pmc": null,
"pmid": "31136294",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Reduced vancomycin susceptibility and increased macrophage survival in Staphylococcus aureus strains sequentially isolated from a bacteraemic patient during a short course of antibiotic therapy.",
"title_normalized": "reduced vancomycin susceptibility and increased macrophage survival in staphylococcus aureus strains sequentially isolated from a bacteraemic patient during a short course of antibiotic therapy"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2019SP005860",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional... |
{
"abstract": "Sinusoidal obstruction syndrome (SOS) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT). Traditional ultrasound (US) has poor sensitivity and specificity. US shear wave elastography (SWE) is a newer technology that measures liver stiffness. This is a single-institution, prospective cohort study evaluating SWE in patients younger than 21 years who received HSCT from December 2015 through June 2017. SOS was defined using the modified Seattle criteria. Subjects had US with SWE at three scheduled time points. t-tests were used to assess for difference between the groups and ROC curves were generated. Twenty-five patients were included. Five subjects developed SOS. At day +5 HSCT, SOS patients had SWE velocities that increased by 0.25 ± 0.21 m/s compared to 0.02 ± 0.18 in patients without SOS (p = 0.020). At day +14, SOS patients had SWE velocities that significantly increased by 0.91 m/s ± 1.14 m/s compared to 0.03 m/s ± 0.23 m/s in patients without SOS (p = 0.010). SWE SOS diagnosis occurred on average 9 and 11 days before clinical and conventional US diagnosis, respectively. Patients who develop SOS have increased liver stiffness compared to patients who do not develop SOS. SWE changes occur before other imaging and clinical findings of SOS.",
"affiliations": "Banner Children's Hospital, Mesa, AZ, USA.;Children's Mercy Hospital, Kansas City, MO, USA.;Children's Mercy Hospital, Kansas City, MO, USA.;Children's Mercy Hospital, Kansas City, MO, USA.;UH Rainbow Babies and Children's Hospital, Cleveland, OH, USA.;Children's Mercy Hospital, Kansas City, MO, USA.;Children's Mercy Hospital, Kansas City, MO, USA. sschan@cmh.edu.",
"authors": "Reddivalla|Naresh|N|;Robinson|Amie L|AL|;Reid|Kimberly J|KJ|;Radhi|Mohamed A|MA|;Dalal|Jignesh|J|;Opfer|Erin K|EK|;Chan|Sherwin S|SS|http://orcid.org/0000-0002-2393-8355",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1038/s41409-017-0064-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "55(3)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D002648:Child; D054459:Elasticity Imaging Techniques; D018380:Hematopoietic Stem Cell Transplantation; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D011446:Prospective Studies",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "523-530",
"pmc": null,
"pmid": "29335626",
"pubdate": "2020-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Using liver elastography to diagnose sinusoidal obstruction syndrome in pediatric patients undergoing hematopoetic stem cell transplant.",
"title_normalized": "using liver elastography to diagnose sinusoidal obstruction syndrome in pediatric patients undergoing hematopoetic stem cell transplant"
} | [
{
"companynumb": "US-OTSUKA-2017_018044",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": "3",
"dr... |
{
"abstract": "OBJECTIVE\nTo evaluate daily life management and functional outcome of Idarucizumab administration in case of emergency situations in patients with Dabigatran treatment.\n\n\nMETHODS\nMulticenter observational registry study.\n\n\nMETHODS\nAll hospitals with full neurological departments (n = 6) in Munich, Germany INCLUDED PATIENTS: All patients treated with Idarucizumab from 01/2016 to 03/2019.\nIndication and application of Idarucizumab, demographics and clinical parameters, and further interventions and treatments; clinical outcome was assessed with the modified Rankin scale (mRS) at 3 months after Idarucizumab administration RESULTS: Idarucizumab was administered to 32 patients for severe bleeding complications and ischemic strokes, more precisely for the following specific indications: intracranial bleeding (17 patients, 53%), ischemic stroke (8 patients, 25%), gastrointestinal bleeding (3 patients, 9%), femoral fracture, aortic dissection, and abdominal trauma and ileus (1 patient each, 3%). Additional coagulation management was performed in 7 patients (22%). Nine patients (28%) underwent emergency surgery. Seven patients (22%) received Idarucizumab before intravenous thrombolysis due to ischemic stroke and 4 of these 7 patients (13%) received mechanical thrombectomy in addition. Indication was mainly based on the history of Dabigatran intake and was irrespective of laboratory testing. At follow-up, 25% of the investigated patients had a mRS 0-2, while 25% had an unfavorable outcome (mRS 4-5). Mortality was 31%.\n\n\nCONCLUSIONS\nIn our study, we have shown that the administration of Idarucizumab is a rare intervention and restricted to patients with severe bleeding complications or ischemic stroke. The clinical outcome of patients who received Idarucizumab in emergency situations was poor.",
"affiliations": "Department of Neurology, Ludwig Maximilians University, Campus Großhadern, Marchioninistraße 15, 81377, Munich, Germany. Clemens.Kuepper@med.uni-muenchen.de.;Department of Neurology, Ludwig Maximilians University, Campus Großhadern, Marchioninistraße 15, 81377, Munich, Germany.;Department of Neurology, Ludwig Maximilians University, Campus Großhadern, Marchioninistraße 15, 81377, Munich, Germany.;Department of Neurology, Ludwig Maximilians University, Campus Großhadern, Marchioninistraße 15, 81377, Munich, Germany.;Department of Neurology Bogenhausen, Munich Hospital, Munich, Germany.;Department of Neurology Bogenhausen, Munich Hospital, Munich, Germany.;Department of Neurology Harlaching, Munich Hospital, Munich, Germany.;Department of Neurology, Helios Hospital Munich West, Munich, Germany.;Department of Neurology, Kbo-Isar-Amper-Hospital Munich East, Munich, Germany.;Department of Neurology, Kbo-Isar-Amper-Hospital Munich East, Munich, Germany.;Department of Neurology, University Hospital rechts der Isar, Technical University, Munich, Germany.;Department of Neurology, University Hospital rechts der Isar, Technical University, Munich, Germany.;Department of Neurology Bogenhausen, Munich Hospital, Munich, Germany.;Department of Neurology, Ludwig Maximilians University, Campus Großhadern, Marchioninistraße 15, 81377, Munich, Germany.;Department of Neurology, Ludwig Maximilians University, Campus Großhadern, Marchioninistraße 15, 81377, Munich, Germany.",
"authors": "Küpper|Clemens|C|http://orcid.org/0000-0003-3919-639X;Feil|Katharina|K|;Klein|Matthias|M|;Feuerecker|Regina|R|;Lücking|Marc|M|;Thanbichler|Florian|F|;Dietrich|Dennis|D|;Zerkaulen|Irene|I|;Jandl|Mitja|M|;Marziniak|Martin|M|;Poppert|Holger|H|;Wunderlich|Silke|S|;Topka|Helge|H|;Dieterich|Marianne|M|;Kellert|Lars|L|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C000594745:idarucizumab; D000069604:Dabigatran",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00415-019-09492-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-5354",
"issue": "266(11)",
"journal": "Journal of neurology",
"keywords": "Acute stroke; Dabigatran; Emergency; Emergency surgery; Idarucizumab; Intracerebral hemorrhage; Ischemic stroke; Oral anticoagulation",
"medline_ta": "J Neurol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D002545:Brain Ischemia; D000069604:Dabigatran; D004632:Emergency Medical Services; D005858:Germany; D006470:Hemorrhage; D006801:Humans; D012042:Registries; D020521:Stroke",
"nlm_unique_id": "0423161",
"other_id": null,
"pages": "2807-2811",
"pmc": null,
"pmid": "31375990",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": "28728489;24344086;28494694;29122465;30339226;30032118;29807757;28693366;27412905;19717844",
"title": "Idarucizumab administration in emergency situations: the Munich Registry of Reversal of Pradaxa® in clinical routine (MR REPAIR).",
"title_normalized": "idarucizumab administration in emergency situations the munich registry of reversal of pradaxa in clinical routine mr repair"
} | [
{
"companynumb": "DE-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-031758",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "OBJECTIVE\nPaclitaxel (Taxol) is a microtubule-stabilizing agent and belongs to the taxane group of chemotherapeutic drugs. It is used to treat numerous malignancies, such as breast and lung cancers. A rare side effect of this drug includes cystoid macular edema (CME), which is presumed to resolve after cessation of Paclitaxel. We present a case of topical Dorzolamide 2% (Trusopt) having a possible successful effect in the treatment of Paclitaxel-related nonresolving CME. By highlighting this rare ocular side effect of a common chemotherapeutic agent, which fails to resolve upon cessation of the drug alone, we suggest a possible treatment that may help other ophthalmologists in their management of similar cases.\n\n\nMETHODS\nA retrospective case report.\n\n\nRESULTS\nA 74-year-old female, with no previous ocular history, presented to eye clinic complaining of bilateral gradual painless reduction in vision for the past 1 month. Medical history included left-sided breast carcinoma with bone and pulmonary metastases. She was on three chemotherapeutic agents-Herceptin, Denosumab, and Paclitaxel. On examination, her best corrected visual acuities were 6/12 in the right eye and 6/18 in the left eye. Fundus examination revealed bilateral CME, which was confirmed on ocular coherence tomography scan. Central macular thickness was 378 μm in the right eye and 354 μm in the left eye. Fundus fluorescein angiography did not reveal any leakage of fluid. Electrodiagnostic tests helped exclude carcinoma-associated retinopathy. Paclitaxel-related CME was suspected, and after discussions with the oncologist, this medication was stopped. After 4 weeks, the patient's vision had deteriorated (best corrected visual acuities = 6/18 right eye and 6/36 left eye) with increased CME (central macular thickness = 397 μm right eye and 356 μm left eye). Hypertrophic retinal pigment epithelial changes started to develop. Because of the nonresolving CME, the patient was started on topical Dorzolamide 2% (Trusopt) three times daily to both eyes. Four weeks later, her vision had improved (best corrected visual acuities = 6/12 right eye and 6/18 left eye). Ocular coherence tomography scan showed near-complete resolution of CME in both eyes (central macular thickness = 287 μm right eye and 282 μm left eye). At the last follow-up visit (3 months after starting topical Dorzolamide), CME had resolved completely and best corrected visual acuities improved to 6/9 in both eyes.\n\n\nCONCLUSIONS\nCystoid macular edema is a rare side effect of the chemotherapeutic drug Paclitaxel. Imaging in Paclitaxel-related CME reveals fluid on ocular coherence tomography scan without leakage on fundus fluorescein angiography, which is in keeping with our findings. There are no recommended treatment guidelines for this condition because of the unclear mechanism of pathology. Treatment strategies have focused on Paclitaxel cessation, which appears to result in spontaneous resolution of CME and improvement in visual acuity. In our patient's case, worsening vision combined with persistent CME and development of retinal pigment epithelial changes after the initial 4 weeks of Paclitaxel cessation indicated that irreversible reduction in vision was a real possibility if we persisted with the drug cessation treatment plan alone. However, a combination of Paclitaxel cessation and topical Dorzolamide 2% TDS (Trusopt) appeared to be effective in reducing her nonresolving CME with no adverse side effects. We can thus postulate that Dorzolamide 2% TDS might have helped to accelerate the resolution of CME, resulting in improved visual acuity, and could be considered as an early treatment option helping to avoid possible irreversible pigmentary changes at the macula that may lead to reduction in vision. Although further research is required, our case report displays a promising treatment strategy and outcome for this rare nonresolving Paclitaxel-related side effect.",
"affiliations": "Southport & Ormskirk Hospitals NHS Trust, Southport, Merseyside, United Kingdom.",
"authors": "Dwivedi|Rahul|R|;Tiroumal|Sambath|S|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D002257:Carbonic Anhydrase Inhibitors; D009883:Ophthalmic Solutions; D013449:Sulfonamides; D013876:Thiophenes; C062765:dorzolamide; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000433",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "12(1)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D000287:Administration, Topical; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic; D001943:Breast Neoplasms; D002257:Carbonic Anhydrase Inhibitors; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D006801:Humans; D008269:Macular Edema; D009883:Ophthalmic Solutions; D017239:Paclitaxel; D013449:Sulfonamides; D013876:Thiophenes; D041623:Tomography, Optical Coherence; D014792:Visual Acuity",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "75-79",
"pmc": null,
"pmid": "27749791",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "POSSIBLE EFFICACY OF TOPICAL DORZOLAMIDE IN THE TREATMENT OF PACLITAXEL-RELATED CYSTOID MACULAR EDEMA.",
"title_normalized": "possible efficacy of topical dorzolamide in the treatment of paclitaxel related cystoid macular edema"
} | [
{
"companynumb": "GB-FRESENIUS KABI-FK201803273",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": null,
... |
{
"abstract": "High-dose cisplatin (Cis) is a preferred systemic agent for concurrent chemoradiation (CRT) in locally advanced head and neck squamous cell cancer (LAHNSCC) patients. As some patients are unable to tolerate Cis, this study compares the toxicity and efficacy of weekly cisplatin-paclitaxel (CP) regimen with Cis.\n\n\n\nPatients with LAHNSCC receiving definitive chemoradiation either with Cis (Cisplatin-100 mg/m2 q3w x 3) or CP (Cisplatin-20 mg/m2 ; Paclitaxel-30 mg/m2 qw x7) were included.\n\n\n\nCis and CP groups were comprised of 114 and 111 subjects, respectively. Complete response for Cis versus CP groups was 88% versus 88%, respectively. Median follow-up for the study was 58.5 months. After adjusting for potential treatment selection bias, no significant differences were evident between Cis and CP groups for overall survival (hazard ratios [HR] 0.85, 95% CI 0.59-1.21, P = 0.36), progression free survival (HR 0.88, 95% CI 0.62-1.24, P = 0.46), locoregional control (HR 0.77, 95% CI 0.52-1.15, P = 0.21), and distant control (HR 0.87, 95% CI 0.61-1.23, P = 0.42). Patients in the CP group had less acute and chronic toxicities.\n\n\n\nWeekly CP regimen can serve as an alternative systemic therapy with radiation in patients with LAHNSCC who are not fit for Cis.",
"affiliations": "Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa.;Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa.;Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa.;Biostatistics Core, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, Iowa.;Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa.;Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, Iowa.;Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, Iowa.;Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, Iowa.;Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa.",
"authors": "Furqan|Muhammad|M|0000-0003-3137-2053;Snyders|Travis P|TP|;Saqlain|Mohammed U|MU|;Mott|Sarah L|SL|;Laux|Douglas|D|;Snow|Anthony|A|;Anderson|Carryn M|CM|;Watkins|John M|JM|;Clamon|Gerald H|GH|",
"chemical_list": "D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1002/cam4.2139",
"fulltext": "\n==== Front\nCancer MedCancer Med10.1002/(ISSN)2045-7634CAM4Cancer Medicine2045-7634John Wiley and Sons Inc. Hoboken 3096860410.1002/cam4.2139CAM42139Original ResearchClinical Cancer ResearchOriginal ResearchComparing high‐dose cisplatin with cisplatin‐based combination chemotherapy in definitive concurrent chemoradiation setting for locally advanced head and neck squamous cell carcinoma (LAHNSCC) FURQAN et al.Furqan Muhammad https://orcid.org/0000-0003-3137-2053Muhammad-furqan@uiowa.edu \n1\nSnyders Travis P. \n1\nSaqlain Mohammed U. \n1\nMott Sarah L. \n2\nLaux Douglas \n1\nSnow Anthony \n3\nAnderson Carryn M. \n4\nWatkins John M. \n4\nClamon Gerald H. \n1\n\n1 \nDepartment of Internal Medicine\nUniversity of Iowa Hospitals and Clinics\nIowa City\nIowa\n\n2 \nBiostatistics Core\nHolden Comprehensive Cancer Center\nUniversity of Iowa Hospitals and Clinics\nIowa City\nIowa\n\n3 \nDepartment of Pathology\nUniversity of Iowa Hospitals and Clinics\nIowa City\nIowa\n\n4 \nDepartment of Radiation Oncology\nUniversity of Iowa Hospitals and Clinics\nIowa City\nIowa\n* Correspondence\n\nMuhammad Furqan, Division of Hematology, Oncology, Marrow and Blood Transplant, Dept. of Medicine University of Iowa, Iowa City, IA.\n\nEmail: Muhammad-furqan@uiowa.edu\n09 4 2019 6 2019 8 6 10.1002/cam4.2019.8.issue-62730 2739 05 12 2018 15 3 2019 18 3 2019 © 2019 The Authors. Cancer Medicine 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.Abstract\nBackground\nHigh‐dose cisplatin (Cis) is a preferred systemic agent for concurrent chemoradiation (CRT) in locally advanced head and neck squamous cell cancer (LAHNSCC) patients. As some patients are unable to tolerate Cis, this study compares the toxicity and efficacy of weekly cisplatin‐paclitaxel (CP) regimen with Cis.\n\nMethods\nPatients with LAHNSCC receiving definitive chemoradiation either with Cis (Cisplatin—100 mg/m2 q3w x 3) or CP (Cisplatin—20 mg/m2; Paclitaxel—30 mg/m2qw x7) were included.\n\nResults\nCis and CP groups were comprised of 114 and 111 subjects, respectively. Complete response for Cis versus CP groups was 88% versus 88%, respectively. Median follow‐up for the study was 58.5 months. After adjusting for potential treatment selection bias, no significant differences were evident between Cis and CP groups for overall survival (hazard ratios [HR] 0.85, 95% CI 0.59‐1.21, P = 0.36), progression free survival (HR 0.88, 95% CI 0.62‐1.24, P = 0.46), locoregional control (HR 0.77, 95% CI 0.52‐1.15, P = 0.21), and distant control (HR 0.87, 95% CI 0.61‐1.23, P = 0.42). Patients in the CP group had less acute and chronic toxicities.\n\nConclusions\nWeekly CP regimen can serve as an alternative systemic therapy with radiation in patients with LAHNSCC who are not fit for Cis.\n\nchemotherapyHead and neck cancerradiation therapyThe Holden Comprehensive Cancer Center at The University of Iowa and its National Cancer InstituteP30CA086862The Holden Comprehensive Cancer Center Gift Funds source-schema-version-number2.0component-idcam42139cover-dateJune 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.5 mode:remove_FC converted:10.07.2019\n\n\nFurqan \nM \n, \nSnyders \nTP \n, \nSaqlain \nMU \n, et al. Comparing high‐dose cisplatin with cisplatin‐based combination chemotherapy in definitive concurrent chemoradiation setting for locally advanced head and neck squamous cell carcinoma (LAHNSCC) . Cancer Med . 2019 ;8 :2730 –2739 . 10.1002/cam4.2139 \n30968604 \n\n\n\nFunding information\n\n\nThis project is supported by The Holden Comprehensive Cancer Center at The University of Iowa and its National Cancer Institute Award P30CA086862 and The Holden Comprehensive Cancer Center Gift Funds.\n==== Body\n1 INTRODUCTION\nHead and neck squamous cell carcinoma (HNSCC) accounts for approximately 3%‐4% of all new cancer cases in the Unites States.1 Around 60% of these patients present with locally advanced disease. Meta‐Analysis of Chemotherapy in Head and Neck Cancer (MACH‐NC) has shown improvement in absolute survival by 4.5% with systemic therapy when utilized concurrently with radiation. Therefore these patients are primarily treated with concurrent chemotherapy and radiotherapy (CRT) to preserve organ function. However, an optimal systemic therapy is not well defined. Regimens that were associated with benefit include platinum‐based monotherapy or polychemotherapy regimens containing platinum or fluorouracil (5‐FU) or both.2 Due to lack of prospective data, high‐dose cisplatin 100 mg/m2 (Cis) monotherapy on days 1, 22, and 43 has been considered the preferred systemic treatment with concurrent radiation. It is an intensive regimen with considerable acute and chronic toxicities including mucositis, nausea, vomiting, myelosuppression, ototoxicity, nephrotoxicity, and neuropathy. A fair number of patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC) are considered “not suitable” for this regimen. Even 30%‐40% of so called “fit” subjects from phase III randomized studies of high‐dose cisplatin could not complete the intended 3 cycles of chemotherapy with radiation.3, 4, 5 Traditionally, alternative platinum‐based regimens or cetuximab have been prescribed to patients who are unfit for high‐dose cisplatin. Wide variation and preference in utilization of these alternative regimens exist among oncologists in the United States as demonstrated by Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN) analysis.6 The 2 most common substituted regimens are weekly cetuximab and low‐dose cisplatin (30‐40 mg/m2). Cetuximab has been found to be inferior to high‐dose cisplatin 7, 8 whereas weekly cisplatin is compared to high‐dose in only small prospective studies or retrospectively.9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22\n\n\nCombination of weekly cisplatin and paclitaxel can be a potential substitute for high‐dose cisplatin and this regimen was developed by RTOG. Weekly cisplatin‐paclitaxel (CP) was effective in a randomized phase II study (RTOG 97‐03) with high rates of compliance.23 Despite the fact that combination chemotherapy might be better compared to single agent chemotherapy from neoadjuvant trials of HNSCC,24 the combination of CP is significantly underutilized.6 In this study, we retrospectively explored the efficacy and toxicity of weekly CP regimen and compared it with Cis when given concurrently with radiation for the treatment of HNSCC.\n\n2 MATERIALS AND METHODS\nPatients with LAHNSCC who received curative‐intent concurrent chemoradiation from 1 January 1998 to 31 December 2013 were identified from University of Iowa Oncology Registry, a prospectively maintained database of cancer patients. Intended chemotherapy regimen had to be either high‐dose cisplatin 100 mg/m2 (Cis) on day 1, 22, and 43 or the combination of cisplatin 20 mg/m2—paclitaxel 30 mg/m2 (CP) weekly x 7. Patients were excluded if: age <18, nasopharyngeal or salivary gland as the primary site of tumor, 2 different synchronous primaries, presence of distant metastases, and receipt of induction chemotherapy. Study protocol was approved by the Institutional Review Board of University of Iowa. Per institution policy, individual patient consent was not required as this study was retrospective in nature and did not involve any intervention.\n\nDemographic, disease‐, and treatment‐related data were captured through chart review by one of the authors. Comorbidities were scored using the Charlson Comorbidity Index (CCI). Smoking history was defined as “never” smoker if patient smoked <100 cigarette/life time, “former” smoker if quit before development of symptoms from index tumor otherwise regarded as “current” smoker. All patients underwent a thorough staging work‐up which at a minimum included endoscopic examination of aero‐digestive tract, contrast‐enhanced neck CT, and CT of the chest or PET/CT prior to initiation of definitive therapy. Disease sites were categorized as oral, oropharyngeal, hypopharyngeal, larynx, and other primaries based on location of index primary tumor. Toxicities were graded per CTCAE v4.0. Toxicities occurring in the first 90 days from the date of initiation of treatment were considered as acute, and recurrent toxicities were documented only once with highest grade. Late toxicities were recorded at 6, 12, and 24 months from the start of treatment. These included chronic kidney disease, impaired hearing affecting routine activities of daily life, inability to eat solid food, aspiration pneumonia, and neuropathy.\n\nA minimum follow‐up time of 16 months was available for all surviving patients. All patients underwent response assessment after completion of treatment by endoscopic examination and neck imaging either through CT or PET/CT. Complete response (CR) was defined as no evidence of tumor at the site of primary tumor and in the regional nodes. Regional node had to be normal by size criteria or have no increase in FDG uptake on PET/CT at 3 months from treatment completion. Patients undergoing salvage neck dissection for possible residual tumor within 5 months of treatment completion were not considered to have regional recurrence. Loco‐regional failure/recurrence was defined as histologic identification of tumor at site of index tumor at any time after completion of therapy or 5 months after therapy in the regional nodes or death due to index cancer. This definition was adopted from RTOG1016 protocol (NCT NCT01302834). Treatment failure was defined as persistent disease at the site of index tumor after therapy.\n\nTo investigate differences in the demographic, clinicopathologic, and outcome variables between intended chemotherapy groups, chi‐squared (Fisher's exact test were appropriate), and Wilcoxon rank sum tests were used. Survival probabilities were estimated and plotted using the Kaplan‐Meier method. For locoregional control, time was calculated from diagnosis to treatment failure, loco‐regional recurrence, or death due to cancer. For distant control, time was calculated from diagnosis to distant recurrence or death due to any cause. For progression free survival, time was calculated from diagnosis to treatment failure, locoregional or distant recurrence, or death due to any cause. For overall survival, time was calculated from diagnosis to death due to any cause. To adjust for potential treatment selection bias, inverse probability score weighted Cox regression models were fit to evaluate differences in outcomes by intended treatment group. Propensity scores were derived from a logistic regression model adjusting for age, smoking status and exposure, ECOG performance status, Charlson Comorbidity Index, baseline laboratory values, primary site, and TN stage. Estimated effects are reported as hazard ratios (HR) along with 95% confidence intervals. All statistical testing was 2‐sided and assessed for significance at the 5% level using SAS v9.4 (SAS Institute, Cary, NC).\n\n3 RESULTS\nOut of 516 patients treated during the study period, 225 cases met the eligibility criteria of the study. Reasons for exclusion were adjuvant chemoradiation for high risk LAHNSCC (n = 180), receipt of induction chemotherapy (n = 45), use of alternative systemic therapy (n = 50), and others (n = 16). Cis group included 114 patients while CP group composed of 111 patients. Three patients had stage II disease (2 in Cis group and 1 CP group), while remaining patients had stage III or higher disease.\n\nBaseline demographic and clinical data for all patients are summarized in Table 1. Patients prescribed Cis were younger (P < 0.01) and more likely to be an active cigarette smoker (P < 0.01); however, overall extent of exposure to tobacco was less compared to patients receiving CP (P < 0.01). Distribution of patients was balanced with regard to performance status but subjects with higher morbidity (CCI) were more likely to receive CP (P = 0.01). Oropharynx was the most common site for the index tumor (75%) in both groups (P = 0.35). The mean dose of cisplatin received in Cis and CP groups was 239.0 mg/m2 (79.7% of intended) and 120.2 mg/m2 (85.8% of intended), respectively. Fifty‐nine (51.8%) patients in the Cis group and 68 (61.3%) in the CP group could not receive all the intended cycles or weeks of chemotherapy (P = 0.15). Switch to a different regimen was required in 13.2% versus 2.7% in patients receiving Cis versus CP, respectively. All patients received intensity modulated radiation therapy and completed the intended course of radiation (66‐70Gy) except for 3 patients in Cis and 2 in CP group. Table 2 summarized intended versus delivered therapy.\n\nTable 1 Patient characteristics\n\nVariables\t\nCisplatin (Cis)\n\nn = 114 (%)\n\t\nCisplatin + Paclitaxel (CP)\n\nn = 111 (%)\n\t\nP‐Value\t\nAge (median)\t53.0\t57.0\t\n<0.01\n\t\nSex\t\nMale\t84 (73.7)\t84 (75.7)\t0.73\t\nFemale\t30 (26.3)\t27 (24.3)\t \t\nSmoking\t\nCurrent\t63 (55.3)\t38 (34.2)\t\n<0.01\n\t\nFormer\t30 (26.3)\t51 (45.9)\t \t\nNever\t21 (18.4)\t22 (19.8)\t \t\nExtent of smoking (only smokers were included)\t\n≥20 pack‐year\t74 (79.6)\t87 (97.8)\t\n<0.01\n\t\n<20 pack‐year\t19 (20.4)\t2 (2.3)\t \t\nECOG performance status\t\n≤1\t108 (94.7)\t110 (99.1)\t0.12\t\n≥2\t6 (5.3)\t1 (0.9)\t \t\nCharlson comorbidity index (mean)\t0.3\t0.5\t\n0.01\n\t\nPrimary site of SCC\t\nOral\t2 (1.8)\t4 (3.6)\t0.35\t\nOropharynx\t85 (74.6)\t84 (75.7)\t \t\nHypopharynx\t3 (2.6)\t5 (4.5)\t \t\nLarynx\t24 (21.1)\t16 (14.4)\t \t\nOthers\t0 (0.0)\t2 (1.8)\t \t\nPrimary site T staging\t\nT2\t64 (56.1)\t53 (47.7)\t0.33\t\nT3\t28 (24.6)\t28 (25.2)\t \t\nT4\t22 (19.3)\t30 (27.0)\t \t\nTNM staging\t\nII‐III\t21 (18.4)\t19 (17.1)\t0.80\t\nIVa‐Ivb\t93 (81.6)\t92 (82.9)\t \t\nJohn Wiley & Sons, LtdTable 2 Intended vs received therapy\n\nVariables\t\nCisplatin (Cis)\n\nn = 114 (%)\n\t\nCisplatin + Paclitaxel (CP)\n\nn = 111 (%)\n\t\nP‐value\t\nCompletion of prescribed chemotherapy\t\nNo\t59 (51.8)\t68 (61.3)\t0.15\t\nYes\t55 (48.2)\t43 (38.7)\t \t\nMean cisplatin‐dose received\t239.0 mg/m2\t120.2 mg/m2\t\n<0.01\n\t\nMean % of intended cisplatin dose delivered\t79.7%\t85.8%\t0.12\t\nSwitch to a different systemic regimen\t\nNo\t99 (86.8)\t108 (97.3)\t\n<0.01\n\t\nYes\t15 (13.2)\t3 (2.7)\t \t\nCarboplatin‐paclitaxel\t7\t3\t \t\nCisplatin‐Paclitaxel\t8\tNA\t \t\nReceipt of intended radiation dose\t\nNo\t3 (2.6)\t2 (1.8)\t1.00\t\nYes\t111 (97.4)\t109 (98.2)\t \t\nBreak in radiation therapy (≥5 days)\t\nNo\t113 (99.1)\t107 (96.4)\t0.24\t\nYes\t1 (0.9)\t3 (2.7)\t \t\nJohn Wiley & Sons, LtdAll of the 225 patients were included in the efficacy analysis. CR was observed in 100 (87.7%) versus 98 (88.3%) patients in Cis versus CP groups, respectively. Complete response by primary site and nodes in Cis versus CP groups was 104 (91.2%) versus 100 (90%) and 99 (86.8%) versus 96 (86.5%), respectively. Salvage neck node dissection was performed in 1 patient in Cis group and 2 in CP group for residual disease. In Cis group persistent disease was noted in 9 subjects, (primary site only [n = 3], regional nodes only [n = 3], and at both sites [n = 3]). In CP group, 10 subjects had persistent disease (primary site only [n = 2] and at both sites [n = 8]). Response to therapy could not be determined in 5 subjects due to death prior to assessment (n = 4 in Cis group; n = 1 in CP group).\n\nMedian length of follow‐up was 58.5 months (2.1‐186.7 months) for the study. In the Cis group, 12 patients had a locoregional recurrence, 13 patients had a distant recurrence, and 41 patients died. Similarly in the CP group, 13 patients developed locoregional recurrence, 16 patients had a distant recurrence, 48 patients died. Unadjusted Kaplan‐Meier curves along with 2‐ and 5‐year estimates are presented in Figures 1 and 2 and Table 3. After adjusting potential treatment selection bias, no significant differences between the high‐dose cisplatin and CP regimens for overall survival (HR 0.85, 95% CI 0.59‐1.21, P = 0.36), progression free survival (HR 0.88, 95% CI 0.62‐1.24, P = 0.46), locoregional control (HR 0.77, 95% CI 0.52‐1.15, P = 0.21), and distant control (HR 0.87, 95% CI 0.61‐1.23, P = 0.42) were evident.\n\nFigure 1 Overall and progression free survival by intended chemotherapy\n\nFigure 2 Locoregional and distant control by intended chemotherapy\n\nTable 3 2‐ and 5‐year efficacy outcomes according to intended chemotherapy assignment\n\nOutcome\tIntended regimen\t2 years (95% CI)\t5 years (95% CI)\t\nOverall survival\tCisplatin\t89% (82%‐94%)\t74% (65%‐82%)\t\nCisplatin‐Paclitaxel\t83% (74%‐89%)\t65% (55%‐73%)\t\nProgression free survival\tCisplatin\t77% (68%‐84%)\t68% (58%‐76%)\t\nCisplatin‐Paclitaxel\t75% (66%‐82%)\t61% (51%‐69%)\t\nLocoregional control\tCisplatin\t79% (70%‐85%)\t74% (65%‐81%)\t\nCisplatin‐Paclitaxel\t76% (67%‐83%)\t69% (60%‐77%)\t\nDistant control\tCisplatin\t83% (75%‐89%)\t73% (63%‐80%)\t\nCisplatin‐Paclitaxel\t65% (55%‐73%)\t65% (55%‐73%)\t\nJohn Wiley & Sons, LtdToxicities of chemotherapy regimens were assessed according to Common Toxicity Criteria of Adverse Events (CTCAE) version 4.0. Due to the retrospective nature of the study, mucositis could not be assessed reliably from patient's electronic records. Among the acute toxicities, patients receiving high‐dose cisplatin had higher incidence of grade ≥ 3 nausea, acute kidney injury (AKI), and presence of ototoxicity, whereas more patients in combination chemotherapy group required feeding tube placement. Distribution of grade 3 or higher vomiting, neuropathy, febrile neutropenia, and any hospitalization was similar between the 2 groups. Assessment of chronic toxicities during 6‐24 months after treatment revealed statistically higher incidence of chronic kidney disease, ototoxicity, and aspiration pneumonia in patients who received high‐dose cisplatin whereas feeding tube dependency was more common in combination chemotherapy group (Table 4).\n\nTable 4 Acute and chronic toxicities of treatment\n\nToxicities\t\nCisplatin (Cis)\n\nn = 114 (%)\n\t\nCisplatin‐Paclitaxel\n\n(CP) n = 111 (%)\n\t \t\nP‐Value\t\nAcute\tHospitalization\t\n \tNo\t69 (60.5)\t60 (54.1)\t0.33\t\n \tYes\t45 (39.5)\t51 (45.9)\t \t\n \tFebrile neutropenia\t\n \tNo\t104 (91.2)\t104 (93.7)\t0.48\t\n \tYes\t10 (8.8)\t7 (6.3)\t \t\n \tAcute kidney injury\t\n \tGrade ≤ 2\t107 (93.9)\t111 (100.0)\t\n0.01\n\t\n \tGrade ≥ 3\t7 (6.1)\t0 (0.0)\t \t\n \tNausea\t\n \tGrade ≤ 2\t85 (74.6)\t95 (85.6)\t\n0.04\n\t\n \tGrade ≥ 3\t29 (25.4)\t16 (14.4)\t \t\n \tVomiting\t\n \tGrade ≤ 2\t93 (81.6)\t96 (86.5)\t0.32\t\n \tGrade ≥ 3\t21 (18.4)\t15 (13.5)\t \t\n \tNeuropathy\t\n \tGrade ≤ 2\t114 (100.0)\t110 (100.0)\t \t\n \tOtotoxicity (any)\t\n \tNo\t94 (82.5)\t105 (94.5)\t\n<0.01\n\t\n \tYes\t20 (17.5)\t5 (4.6)\t \t\n \tNeutropenia\t\n \tGrade ≤ 2\t102 (89.5)\t106 (95.5)\t0.09\t\n \tGrade ≥ 3\t12 (10.5)\t5 (4.5)\t \t\n \tThrombocytopenia\t\n \tGrade ≤ 2\t114 (100.0)\t109 (98.2)\t0.24\t\n \tGrade ≥ 3\t0 (0.0)\t2 (1.8)\t \t\n \tAnemia\t\n \tGrade ≤ 2\t110 (96.5)\t104 (93.7)\t0.33\t\n \tGrade ≥ 3\t4 (3.5)\t7 (6.3)\t \t\n \tFeeding tube required\t\n \tNo\t35 (30.7)\t6 (5.4)\t\n<0.01\n\t\n \tYes\t79 (69.3)\t105 (94.6)\t \t\nChronic\tChronic kidney disease\t\n \tNo\t93 (84.3)\t107 (98.2)\t\n<0.01\n\t\n \tYes\t16 (14.7)\t2 (1.8)\t \t\n \tOtotoxicity\t\n \tNo\t86 (80.4)\t105 (96.3)\t\n<0.01\n\t\n \tYes\t21 (19.6)\t4 (3.7)\t \t\n \tNeuropathy\t\n \tNo\t102 (95.3)\t108 (99.1)\t0.12\t\n \tYes\t5 (4.7)\t1 (0.9)\t \t\n \tAspiration pneumonia\t\n \tNo\t94 (87.9)\t107 (99.1)\t\n<0.01\n\t\n \tYes\t13 (12.1)\t1 (0.9)\t \t\n \tFeeding tube dependency\t\n \tNo\t61 (57.0)\t34 (31.2)\t\n<0.01\n\t\n \tYes\t46 (43.0)\t77 (68.8)\t \t\nJohn Wiley & Sons, Ltd4 DISCUSSION\nThe goal of this study was to compare low‐dose‐cisplatin‐based combination chemotherapy with high‐dose cisplatin in definitive concurrent chemoradiation setting for patients with LAHNSCC. Our findings suggest higher compliance, comparable efficacy, and significantly less acute toxicity with low‐dose CP combination chemotherapy.\n\nThree‐weekly single agent high‐dose cisplatin is considered as the standard of care systemic therapy for definitive concurrent chemoradiation setting. Despite the irrefutable benefits, higher incidence of severe acute toxicities (16%‐47%) and relatively low compliance rates (60%‐70%) raise significant concern regarding tolerability of this regimens in the minds of treating physicians and patients.3, 4, 5, 25 In addition, long‐term follow‐up of RTOG91‐11 discovered significantly higher non‐cancer‐related mortality in patients who received high‐dose cisplatin concomitantly with radiation.26 Consequently, there has been an effort to reduce the treatment‐related complications without compromising anticancer activity. Weekly low dose cisplatin (30‐40mg/m2) is considered an alternative option to high dose cisplatin as it offers similar dose intensity, reduces chemotherapy‐related acute adverse events, and facilitates dose adjustments according to changes in patient's condition with relatively similar survival benefit as suggested by a meta‐analysis.25 Nevertheless, other studies have questioned this finding. Only randomized study comparing low (30 m/m2) versus high dose (100 mg/m2) cisplatin prospectively found inferior locoregional disease control with low dose cisplatin. While other studies revealed inferior overall survival with low‐dose cisplatin compare to high‐dose cisplatin.20, 27, 28 Despite the controversy of high and low dose cisplatin, 15% of LAHNSCC patients in the United States receive weekly low‐dose cisplatin with radiation according to LORHAN analysis. Cetuximab, an epidermal growth factor receptor monoclonal antibody, is another alternative option to high or low‐dose cisplatin as it is considered to have better side‐effect profile.29 However, recent studies have confirmed that it is inferior to high‐dose cisplatin even in HPV positive oropharyngeal LAHNSCC which is a considered as good prognostic disease.7, 8, 10, 12, 14\n\n\nOther substitutes to high‐dose cisplatin include combinatorial chemotherapy regimens involving multiple radiosensitizing agents. Combinatorial regimens could disturb varying aspect of tumor biology along with providing systemic effects. Since, survival benefit associated with concurrent chemoradiation is mainly due to improvement in locoregional control; multiagent radiosensitizing regimens may actually do better than single agent cisplatin. This is supported by the reversal in pattern of failure from locoregional recurrences to distant disease as seen in some of the studies that utilized multiagent regimens.30, 31, 32, 33, 34 MACH‐NC meta‐analysis on the use of chemotherapy also concluded that polychemotherapy either with platin or 5‐FU was not inferior to mono‐platin.2, 35 However, data comparing combination of relatively newer chemotherapeutic agents with high‐dose cisplatin monotherapy is regrettably lacking. Many centers have attempted to look at weekly carboplatin‐paclitaxel combination in concomitant chemoradiation setting. Not surprisingly, compliance was better and overall outcomes were comparable to historical control.36, 37, 38, 39, 40, 41 But these studies did not directly compare the combination therapy with single agent high‐dose cisplatin (Table 5).\n\nTable 5 Outcomes of studies utilizing platinum‐taxol regimens\n\nPrimary sites of disease\tRetrospective vs prospective\tChemotherapy regimen\tNumber Of Patients\tOverall Survival (OS)\tProgression Free Survival (PFS)\tComplete response rate (CR)\tRef\t\nAll HNSCC\t\nProspective\n\nSingle arm\n\t\nCarboplatin 100\n\nPaclitaxel 40\n\t55\t\n3y‐45%\n\n5y‐35%\n\t\n3y‐36%\n\n5y‐36%\n\t52%\t35\t\nAll HNSCC\t\nProspective\n\nSingle arm\n\t\nCarboplatin AUC1\n\nPaclitaxel 60mg/m2\n\t43\t\nNA\n†\n\n\n\n5y‐40%\n\t\nNA\n†\n\n\n\n5y‐70%\n\t65%\t36\t\nAll HNSCC\tProspective (UMC0221)\t\nCarboplatin AUC1\n\nPaclitaxel 30 mg/m2\n\t35\t\n3y‐88%\n\nNA\n†\n\n\t\nNA\n†\n\n\n\nNA\n†\n\n\tNA\n†\n\n\t37\t\nAll HNSCC\t\nRetrospective\n\n(two groups –High dose Cis group data nor shown)\n\t\nCisplatin 20mg/m2\n\nPaclitaxel 30 mg/m2\n\t111\t\n2y‐83%\n\n5y‐65%\n\t\n2y‐77%\n\n5y‐61%\n\t\n88%\n\tCurrent study\t\nOropharyngeal (OP) only\t\nRetrospective\n\n(one group)\n\t\nCarboplatin AUC2\n\nPaclitaxel 40\n\t160\t\n3y‐81%\n\n5y‐70%\n\t\nNA\n†\n\n\n\n5y‐64%\n\t\nNA\n†\n\n\t39\t\nAll HNSCC\t\nRetrospective\n\n(one group)\n\t\nCarboplatin 100 mg/m2\n\nPaclitaxel 45 mg/m2\n\t60\t3y‐48%\t3y‐48%\t75%\t34\t\nHPV + OP\t\nRetrospective\n\n(3 groups, weekly Cis, and Cetuximab data not shown)\n\t\nCarboplatin\n\nPaclitaxel\n\t59\t\n3y‐88%\n\n5y‐78%\n\t\n3y‐84%\n\n5y‐80%\n\tNA\n†\n\n\t38\t\n† NA: Not available or applicable due to difference in methodology.\n\nJohn Wiley & Sons, LtdOur study aimed to compare a multiagent combination of 2 strong radiosensitizing chemotherapies, cisplatin and paclitaxel, against high‐dose cisplatin to minimize toxicity and improve compliance without jeopardizing tumor control. Outcomes of patients who received CP combination chemotherapy with definitive radiation seems to be numerically inferior at 5‐year time‐point but these differences were not significant. One of the common concerns over low‐dose chemotherapy is their limited efficacy toward eradicating micrometastases affecting distant failure. However, distant control in our study was similar in both the groups. All acute and chronic toxicities that were different between the 2 groups were seen less frequently with combination chemotherapy except for requirement and dependency on feeding tube. Due to retrospective nature of the study, it is unclear why patients in combination chemotherapy group required feeding tube to be placed more often but this may be to prevent malnutrition as patients in this group were old, had higher co‐morbidity and larger primary (T4) tumor compare to high‐dose cisplatin group. Another explanation is patients in combination chemotherapy group had higher degree of swallowing dysfunction. This could suggest higher radiosensitizing potential of the CP regimen. Nonetheless, dependency on feeding tube was different only till 6 months, after that both groups were similar with regards to requiring feeding tube to maintain adequate nutrition.\n\nOur study has several limitations. Due to retrospective nature of the study there is inherent selection bias toward intended chemotherapy assignment for patients. Data pertaining to HPV or p‐16 positivity was lacking for most patients. Since, frequency of oropharyngeal squamous cell carcinoma is similar in both group therefore we believe this should not have affected the results. Toxicity data in our study were captured from patients’ electronic health records and due to differences in documentation among treating physicians, there could be more differences which could not be captured.\n\n5 CONCLUSIONS\nIn patients with LAHNSCC who are not fit for high‐ or low‐dose cisplatin, weekly CP regimen can serve as an alternative systemic therapy with radiation. Our data suggest that it is well tolerated, easy to deliver and have similar efficacy. Our findings need further evaluation through prospective studies.\n\nCONFLICT OF INTEREST\nThe authors have no conflict of interest to declare.\n\nACKNOWLEDGMENT\nNone.\n==== Refs\nREFERENCES\n1 \n\nSiegel \nRL \n, \nMiller \nKD \n, \nJemal \nA \n. Cancer statistics, 2018 . CA Cancer J Clin . 2018 ;68 :7 ‐30 .29313949 \n2 \n\nPignon \nJ‐P \n, \nMaître \nAl \n, \nMaillard \nE \n, \nBourhis \nJ \n. Meta‐analysis of chemotherapy in head and neck cancer (MACH‐NC): an update on 93 randomised trials and 17,346 patients . 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Cancer . 2011 ;117 :1679 ‐1686 .21472715 \n7 \n\nMehanna \nH \n, \nRobinson \nM \n, \nHartley \nA \n, et al. Radiotherapy plus cisplatin or cetuximab in low‐risk human papillomavirus‐positive oropharyngeal cancer (De‐ESCALaTE HPV): an open‐label randomised controlled phase 3 trial . Lancet . 2019 ;393 :51 -60 .30449623 \n8 \n\nGillison \nML \n, \nTrotti \nAM \n, \nHarris \nJ \n, et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus‐positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non‐inferiority trial . Lancet . 2019 ;393 :40 -50 .30449625 \n9 \n\nKoutcher \nL \n, \nSherman \nE \n, \nFury \nM \n, et al. Concurrent cisplatin and radiation versus cetuximab and radiation for locally advanced head‐and‐neck cancer . Int J Radiat Oncol Biol Phys . 2011 ;81 :915 ‐922 .20947269 \n10 \n\nLevy \nA \n, \nBlanchard \nP \n, \nBellefqih \nS \n, et al. Concurrent use of cisplatin or cetuximab with definitive radiotherapy for locally advanced head and neck squamous cell carcinomas . Strahlenther Onkol . 2014 ;190 :823 ‐831 .24638267 \n11 \n\nShapiro \nLQ \n, \nSherman \nEJ \n, \nRiaz \nN \n, et al. Efficacy of concurrent cetuximab vs. 5‐fluorouracil/carboplatin or high‐dose cisplatin with intensity‐modulated radiation therapy (IMRT) for locally‐advanced head and neck cancer (LAHNSCC) . Oral Oncol . 2014 ;50 :947 ‐955 .25132089 \n12 \n\nMagrini \nSM \n, \nBuglione \nM \n, \nCorvò \nR \n, et al. Cetuximab and radiotherapy versus cisplatin and radiotherapy for locally advanced head and neck cancer: a randomized phase II trial . J Clin Oncol . 2016 ;34 :427 ‐435 .26644536 \n13 \n\nOu \nD \n, \nLevy \nA \n, \nBlanchard \nP \n, et al. Concurrent chemoradiotherapy with cisplatin or cetuximab for locally advanced head and neck squamous cell carcinomas: does human papilloma virus play a role? \nOral Oncol . 2016 ;59 :50 ‐57 .27424182 \n14 \n\nHuang \nJ \n, \nBaschnagel \nAM \n, \nChen \nP \n, et al. A matched‐pair comparison of intensity‐modulated radiation therapy with cetuximab versus intensity‐modulated radiation therapy with platinum‐based chemotherapy for locally advanced head neck cancer . Int J Clin Oncol . 2014 ;19 :240 ‐246 .23479120 \n15 \n\nLefebvre \nJL \n, \nPointreau \nY \n, \nRolland \nF \n, et al. Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study . J Clin Oncol . 2013 ;31 :853 ‐859 .23341517 \n16 \n\nPetrelli \nF \n, \nCoinu \nA \n, \nRiboldi \nV \n, et al. Concomitant platinum‐based chemotherapy or cetuximab with radiotherapy for locally advanced head and neck cancer: a systematic review and meta‐analysis of published studies . Oral Oncol . 2014 ;50 :1041 ‐1048 .25176576 \n17 \n\nPadmanabhan \nTK \n, \nSamuel \nJ \n, \nPavithran \nK \n, \nIyer \nS \n, \nKuriakose \nMA \n, \nGeeta \nSN \n. Comparison of acute toxicities of two chemotherapy schedules for head and neck cancers . J Cancer Res Ther . 2006 ;2 :100 ‐104 .17998687 \n18 \n\nMitra \nD \n, \nChoudhury \nK \n, \nRashid \nMA \n. Concurrent chemotherapy in advanced head and neck carcinoma – a prospective randomized trial . Bangladesh J Otorhinolaryngol . 2011 ;17 .\n19 \n\nRawat \nS \n, \nSrivastava \nH \n, \nAhlawat \nP \n, et al. Weekly versus Three‐Weekly Cisplatin‐based Concurrent Chemoradiotherapy as definitive treatment in Head and Neck Cancer—where do we stand? \nGulf J Oncolog . 2016 ;1 :6 ‐11 .\n20 \n\nChang \nCL \n, \nYuan \nKS \n, \nWu \nSY \n. High‐dose or low‐dose cisplatin concurrent with radiotherapy in locally advanced head and neck squamous cell cancer . Head Neck . 2017 ;39 :1364 ‐1370 .28370614 \n21 \n\nNair \nLM \n, \nKumar \nRR \n, \nThomachan \nKC \n, et al. Phase IIb trial comparing two concurrent cisplatin schedules in locally advanced head and neck cancer . South Asian J Cancer . 2017 ;6 :64 ‐68 .28702409 \n22 \n\nSahoo \nTK \n, \nSamanta \nDR \n. \nSenapati \nSN \n, \nParida \nK \n\nA comparative study on weekly versus three weekly cisplatinum based chemoradiation in locally advanced head and. neck cancers . J Clin Diagn Res . 2017 ;11 :XC07‐XC11 .28274031 \n23 \n\nGarden \nAs \n, \nHarris \nJ \n, \nVokes \nEe \n, et al. Preliminary results of Radiation Therapy Oncology Group 97–03: a randomized phase ii trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of the head and neck . J Clin Oncol . 2004 ;22 :2856 ‐2864 .15254053 \n24 \n\nHaddad \nR \n, \nO'Neill \nA \n, \nRabinowits \nG \n, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial . Lancet Oncol . 2013 ;14 :257 ‐264 .23414589 \n25 \n\nSzturz \nP \n, \nWouters \nK \n, \nKiyota \nN \n, et al. Weekly low‐dose versus three‐weekly high‐dose cisplatin for concurrent chemoradiation in locoregionally advanced non‐nasopharyngeal head and neck cancer: a systematic review and meta‐analysis of aggregate data . Oncologist . 2017 ;22 :1056 ‐1066 .28533474 \n26 \n\nForastiere \nAA \n, \nZhang \nQ \n, \nWeber \nRS \n, et al. Long‐term results of RTOG 91–11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer . J Clin Oncol . 2013 ;31 :845 ‐852 .23182993 \n27 \n\nGuan \nJ \n, \nZhang \nY \n, \nLi \nQ \n, et al. A meta‐analysis of weekly cisplatin versus three weekly cisplatin chemotherapy plus concurrent radiotherapy (CRT) for advanced head and neck cancer (HNC) . Oncotarget . 2016 ;7 :70185 ‐70193 .27602493 \n28 \n\nNoronha \nV \n, \nJoshi \nA \n, \nPatil \nVM \n, et al. Once‐a‐week versus once‐every‐3‐weeks Cisplatin Chemoradiation for locally advanced head and neck cancer: a phase III randomized noninferiority trial . J Clin Oncol . 2018 ;36 :1064 ‐1072 .29220295 \n29 \n\nBonner \nJA \n, \nHarari \nPM \n, \nGiralt \nJ \n, et al. Radiotherapy plus cetuximab for squamous‐cell carcinoma of the head and neck . N Engl J Med . 2006 ;354 :567 ‐578 .16467544 \n30 \n\nKies \nMS \n, \nHaraf \nDJ \n, \nRosen \nF \n, et al. Concomitant infusional paclitaxel and fluorouracil, oral hydroxyurea, and hyperfractionated radiation for locally advanced squamous head and neck cancer . J Clin Oncol . 2001 ;19 :1961 ‐1969 .11283128 \n31 \n\nHaraf \nDJ \n, \nRosen \nFR \n, \nStenson \nK \n, et al. Induction chemotherapy followed by concomitant TFHX chemoradiotherapy with reduced dose radiation in advanced head and neck cancer . Clin Cancer Res . 2003 ;9 :5936 ‐5943 .14676118 \n32 \n\nVokes \nEE \n, \nStenson \nK \n, \nRosen \nFR \n, et al. Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: curative and organ‐preserving therapy for advanced head and neck cancer . J Clin Oncol . 2003 ;21 :320 ‐326 .12525525 \n33 \n\nAdelstein \nDJ \n, \nSaxton \nJP \n, \nRybicki \nLA \n, et al. Multiagent concurrent chemoradiotherapy for locoregionally advanced squamous cell head and neck cancer: mature results from a single institution . J Clin Oncol . 2006 ;24 :1064 ‐1071 .16505425 \n34 \n\nAguiar \nPN \n, \nTadokoro \nH \n, \nda Silva \nGF \n, et al. Definitive chemoradiotherapy for squamous head and neck cancer: cisplatin versus carboplatin? \nA meta‐analysis. Future Oncol . 2016 ;12 :2755 ‐2764 .27549331 \n35 \n\nPignon \nJp \n, \nBourhis \nJ \n, \nDomenge \nC \n, \nDesigné \nL \n. Chemotherapy added to locoregional treatment for head and neck squamous‐cell carcinoma: three meta‐analyses of updated individual data. MACH‐NC Collaborative Group. meta‐analysis of chemotherapy on head and neck cancer . Lancet . 2000 ;355 :949 ‐955 .10768432 \n36 \n\nSuntharalingam \nM \n, \nHaas \nML \n, \nConley \nBA \n, et al. The use of carboplatin and paclitaxel with daily radiotherapy in patients with locally advanced squamous cell carcinomas of the head and neck . Int J Radiat Oncol Biol Phys . 2000 ;47 :49 ‐56 .10758304 \n37 \n\nAgarwala \nS \n, \nCano \nE \n, \nHeron \nD \n, et al. Long‐term outcomes with concurrent carboplatin, paclitaxel and radiation therapy for locally advanced, inoperable head and neck cancer . Ann Oncol . 2007 ;18 :1224 ‐1229 .17675395 \n38 \n\nChougule \nPB \n, \nAkhtar \nMS \n, \nRathore \nR \n, et al. Concurrent chemoradiotherapy with weekly paclitaxel and carboplatin for locally advanced head and neck cancer: long‐term follow‐up of a Brown University Oncology Group Phase II Study (HN‐53) . Head Neck . 2008 ;30 :289 ‐296 .17657799 \n39 \n\nDobrosotskaya \nIY \n, \nBellile \nE \n, \nSpector \nME \n, et al. Weekly chemotherapy with radiation versus high‐dose cisplatin with radiation as organ preservation for patients with HPV‐positive and HPV‐negative locally advanced squamous cell carcinoma of the oropharynx . Head Neck . 2014 ;36 :617 ‐623 .23596055 \n40 \n\nNien \nHH \n, \nSturgis \nEM \n, \nKies \nMS \n, et al. Comparison of systemic therapies used concurrently with radiation for the treatment of human papillomavirus‐associated oropharyngeal cancer . Head Neck . 2016 ;38 (Suppl 1 ):E1554 ‐E1561 .26595157 \n41 \n\nRoskies \nM \n, \nKay‐Rivest \nE \n, \nMascarella \nMa \n, \nSultanem \nK \n, \nMlynarek \nA \n, \nHier \nM \n. Survival outcomes in patients with oropharyngeal cancer treated with carboplatin/paclitaxel and concurrent radiotherapy . J Otolaryngol Head Neck Surg . 2016 ;45 :50 .27724969\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-7634",
"issue": "8(6)",
"journal": "Cancer medicine",
"keywords": "Head and neck cancer; chemotherapy; radiation therapy",
"medline_ta": "Cancer Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D059248:Chemoradiotherapy; D002945:Cisplatin; D003131:Combined Modality Therapy; D015897:Comorbidity; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011838:Radiation-Sensitizing Agents; D000077195:Squamous Cell Carcinoma of Head and Neck",
"nlm_unique_id": "101595310",
"other_id": null,
"pages": "2730-2739",
"pmc": null,
"pmid": "30968604",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "23414589;28274031;29313949;23182993;23341517;23596055;17998687;27250881;15254053;21472715;19446902;11283128;28702409;20947269;12525525;28533474;27724969;26595157;30449625;14645636;10758304;27424182;25176576;28370614;27602493;26644536;27549331;24638267;12506176;16505425;30968604;23479120;30449623;17675395;17657799;25132089;29220295;15128894;14676118;10768432;16467544",
"title": "Comparing high-dose cisplatin with cisplatin-based combination chemotherapy in definitive concurrent chemoradiation setting for locally advanced head and neck squamous cell carcinoma (LAHNSCC).",
"title_normalized": "comparing high dose cisplatin with cisplatin based combination chemotherapy in definitive concurrent chemoradiation setting for locally advanced head and neck squamous cell carcinoma lahnscc"
} | [
{
"companynumb": "US-HQ SPECIALTY-US-2019INT000171",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,... |
{
"abstract": "We report the case of a 63-year-old female undergoing evaluation of symptomatic anemia, gastroesophageal reflux disease, and abdominal pain. After a thorough diagnostic workup, a large, ulcerated mass was identified in the patient's stomach, and surgical pathology in combination with molecular analysis yielded a diagnosis of primary extraskeletal Ewing sarcoma. In our report, we discuss the epidemiologic, clinicopathologic, and radiographic features of this rare disease and provide a review of the existing literature.",
"affiliations": "Department of Diagnostic Imaging, The Warren Alpert Medical School of Brown University, 593 Eddy Street, Providence, RI, 02903, USA. Electronic address: Aaron.Maxwell@lifespan.org.;Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School of Brown University, 593 Eddy Street, Providence, RI, 02903, USA.;Department of Diagnostic Imaging, The Warren Alpert Medical School of Brown University, 593 Eddy Street, Providence, RI, 02903, USA.",
"authors": "Maxwell|Aaron W P|AW|;Wood|Stephanie|S|;Dupuy|Damian E|DE|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0899-7071",
"issue": "40(5)",
"journal": "Clinical imaging",
"keywords": "Ewing sarcoma; Ewing sarcoma family tumors; Extraskeletal Ewing sarcoma; Gastric cancer",
"medline_ta": "Clin Imaging",
"mesh_terms": "D001706:Biopsy; D005260:Female; D006801:Humans; D008875:Middle Aged; D000072078:Positron Emission Tomography Computed Tomography; D035583:Rare Diseases; D012512:Sarcoma, Ewing; D013270:Stomach; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8911831",
"other_id": null,
"pages": "843-5",
"pmc": null,
"pmid": "27179157",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Primary extraskeletal Ewing sarcoma of the stomach: a rare disease in an uncommon location.",
"title_normalized": "primary extraskeletal ewing sarcoma of the stomach a rare disease in an uncommon location"
} | [
{
"companynumb": "US-PFIZER INC-2016306032",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Pancreatic cancer represents one of the most aggressive types of cancer, resulting in a late diagnosis and rapid death (poor overall survival). After adenocarcinoma (counting almost 80% of cases of pancreatic cancer), the second category, as frequency, is represented by the family of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Pancreatic cancer is characterized by genetic heterogeneity and may results in different evolution among metastases, which may acquire driver mutations with the ability to transform under the action of several cancer treatments. Here we report a case of a 64-year-old patient diagnosed with pancreatic tumor localized on the body and tail, invasive in the splenic and portal vein, pT3pN0M0 (adenocarcinoma pancreatic cancer), treated with a multimodal approach: surgery (splenectomy and distal pancreatectomy, with suture of the portal vein), chemotherapy, in 2010, that relapsed in 2015, with local recurrence that was resected and distant liver metastases. Immunohistochemistry of the recurrence tumor showed a neuroendocrine transformation of the tumor, with major implications in treatment and prognosis. Computed tomography examination, as well as histopathological and immunohistochemically testing, sustained positive and differential diagnosis.",
"affiliations": "Department of Medical Oncology, \"Prof. Dr. Alexandru Trestioreanu\" Institute of Oncology, Bucharest, Romania; dlstanculeanu@gmail.com.",
"authors": "Stănculeanu|Dana Lucia|DL|;Ardeleanu|Carmen Maria|CM|;Zob|Daniela LuminiŢa|DL|;Mihăilă|Raluca Ioana|RI|;Toma|Oana Cătălina|OC|;Simion|LaurenŢiu|L|;Stovicek|Puiu Olivian|PO|;Schenker|Michael|M|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1220-0522",
"issue": "58(3)",
"journal": "Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie",
"keywords": null,
"medline_ta": "Rom J Morphol Embryol",
"mesh_terms": "D000230:Adenocarcinoma; D018278:Carcinoma, Neuroendocrine; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "9112454",
"other_id": null,
"pages": "1091-1097",
"pmc": null,
"pmid": "29250695",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Adenocarcinoma versus pancreatic neuroendocrine tumor - case report.",
"title_normalized": "adenocarcinoma versus pancreatic neuroendocrine tumor case report"
} | [
{
"companynumb": "RO-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-166179",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"druga... |
{
"abstract": "Resistance to antimicrobial agents of pathogenic bacteria has become a major problem in routine medical practices. Carbapenem resistance has long been increasing. The production of carbapenem- hydrolysing β-lactamases (carbapenamases), which include NDM, KPC, OXA-48, IMP-1 and VIM is the most common mechanism.\n\n\n\nA 56 years old male presented with fever and mental changes with progressively decreasing sensorium for the last 3 days. He was admitted to Intensive care unit (ICU) with a diagnosis of meningoencephalitis. On day seven, he developed ventilator associated pneumonia due Klebsiella pnemoniae and Acinetobacter baumannii. He was on meropenem, but the isolates were susceptible to colistin, tigecyclin and amikacin solely. Hence, amikacin was started with addition of intravenous and nebulized colistin. Subsequently, vital signs improved with resolution of fever. However, on day 18, he developed fever once again with a drop in blood pressure. Inotropic support was maintained, and echinocandins and tigecycline were added to the regimen.Repeat blood and urine culture grew Providencia species, which were resistant to most of the drugs on phenotypic Kirby-Bauer disk diffusion method and are intrinsically resistant to colistin and tigecycline. Phenotypic detection of ESBL (combined disk method), MBL, KPCs, AmpC and co-producer were tested according to updated CLSI guideline and all were negative. But the Modified Hodges test was found to be positive. Consequenty, OXA-48 drug resistance pattern was brought into action by blank disc method according to A Tsakris et al., which revealed indentation of growth toward both EDTA and EDTA/PBA disk indicating production of OXA-48 carbapenamase. To confirm the resistance pattern we processed the isolated colonies for Xpert Carba-R (Cepheid) assay, which detected blaOXA-48 gene and confirmed the OXA-48 drug resistance pattern. Hence, the infecting organism was not susceptible to any of the antibiotics. The patient was kept under isolation and on 31th day of admission, he died of septic shock.\n\n\n\nCarbapenamase production along with intrinsic colistin resistance in infecting bacterial pathogens can cause fatal outcomes in the resource limited countries like Nepal where new antibiotic combinations ceftazidime+ Avibactam, or aztreonam +avibactam are not available. Drug resistance patterns including OXA 48 producer should be characterized in all cases by standard phenotypic methods or by Xpert Carba-R assay and larger studies are required to know the exact burden of OXA 48 producer in Nepal.",
"affiliations": "Department of Microbiology, Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal.;Department of Microbiology, Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal.;Department of Anesthesiology (ICU), Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal.;Department of Anesthesiology (ICU), Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal.;Department of Anesthesiology (ICU), Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal.;Department of Anesthesiology (ICU), Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal.;Department of Microbiology, Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal.;Department of Microbiology, Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal.;Department of Microbiology, Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal.;3Research Department, Institute of Medicine, Kathmandu, Nepal.;Department of Microbiology, Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal.;IDI-IRI, Ankara, Turkey.",
"authors": "Sah|Ranjit|R|0000-0002-2695-8714;Khadka|Shusila|S|;Shrestha|Gentle Sunder|GS|;Acharya|Subhash|S|;Aryal|Diptesh|D|;Shrestha|Pramesh|P|;Kattel|Hari Prasad|HP|;Shah|Niranjan Prasad|NP|;Pokhrel|Bharat Mani|BM|;Singh|Yogendra Prasad|YP|;Rijal|Basista|B|;Erdem|Hakan|H|",
"chemical_list": "D001618:beta-Lactamases",
"country": "England",
"delete": false,
"doi": "10.1186/s13756-019-0608-1",
"fulltext": "\n==== Front\nAntimicrob Resist Infect ControlAntimicrob Resist Infect ControlAntimicrobial Resistance and Infection Control2047-2994BioMed Central London 60810.1186/s13756-019-0608-1Case ReportDetection of Pan drug resistance OXA-48 producing Providencia in an ICU patient for the first time in Nepal http://orcid.org/0000-0002-2695-8714Sah Ranjit ranjitsah57@gmail.comranjitsah@iom.edu.np 1Khadka Shusila shushila.mbbs9@gmail.com 1Shrestha Gentle Sunder gentlesunder@hotmail.com 2Acharya Subhash drsuvash@gmail.com 2Aryal Diptesh diptesharyal@gmail.com 2Shrestha Pramesh drpramesh@outlook.com 2Kattel Hari Prasad kattelhari@hotmail.com 1Shah Niranjan Prasad niranjshah@yahoo.comnirpshah@gmail.com 1Pokhrel Bharat Mani bmp268@hotmail.com 1Singh Yogendra Prasad ypsingh2065@gmail.comyp_singh@hotmail.com 3Rijal Basista basistarijal@gmail.com 1Erdem Hakan erdemhakan@gmail.com 41 Department of Microbiology, Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal 2 Department of Anesthesiology (ICU), Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal 3 0000 0001 2114 6728grid.80817.36Research Department, Institute of Medicine, Kathmandu, Nepal 4 IDI-IRI, Ankara, Turkey 15 10 2019 15 10 2019 2019 8 15510 5 2019 21 9 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Abstracts\nBackground\nResistance to antimicrobial agents of pathogenic bacteria has become a major problem in routine medical practices. Carbapenem resistance has long been increasing. The production of carbapenem- hydrolysing β-lactamases (carbapenamases), which include NDM, KPC, OXA-48, IMP-1 and VIM is the most common mechanism.\n\nCase presentation\nA 56 years old male presented with fever and mental changes with progressively decreasing sensorium for the last 3 days. He was admitted to Intensive care unit (ICU) with a diagnosis of meningoencephalitis. On day seven, he developed ventilator associated pneumonia due Klebsiella pnemoniae and Acinetobacter baumannii. He was on meropenem, but the isolates were susceptible to colistin, tigecyclin and amikacin solely. Hence, amikacin was started with addition of intravenous and nebulized colistin. Subsequently, vital signs improved with resolution of fever. However, on day 18, he developed fever once again with a drop in blood pressure. Inotropic support was maintained, and echinocandins and tigecycline were added to the regimen.\n\nRepeat blood and urine culture grew Providencia species, which were resistant to most of the drugs on phenotypic Kirby-Bauer disk diffusion method and are intrinsically resistant to colistin and tigecycline. Phenotypic detection of ESBL (combined disk method), MBL, KPCs, AmpC and co-producer were tested according to updated CLSI guideline and all were negative. But the Modified Hodges test was found to be positive. Consequenty, OXA-48 drug resistance pattern was brought into action by blank disc method according to A Tsakris et al., which revealed indentation of growth toward both EDTA and EDTA/PBA disk indicating production of OXA-48 carbapenamase. To confirm the resistance pattern we processed the isolated colonies for Xpert Carba-R (Cepheid) assay, which detected blaOXA-48 gene and confirmed the OXA-48 drug resistance pattern. Hence, the infecting organism was not susceptible to any of the antibiotics. The patient was kept under isolation and on 31th day of admission, he died of septic shock.\n\nConclusions\nCarbapenamase production along with intrinsic colistin resistance in infecting bacterial pathogens can cause fatal outcomes in the resource limited countries like Nepal where new antibiotic combinations ceftazidime+ Avibactam, or aztreonam +avibactam are not available. Drug resistance patterns including OXA 48 producer should be characterized in all cases by standard phenotypic methods or by Xpert Carba-R assay and larger studies are required to know the exact burden of OXA 48 producer in Nepal.\n\nKeywords\nOXA-48Drug resistanceProvidencia speciesNepalissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nThe development of antibiotics remains one of the most significant advances in modern medicine. Antibiotics have saved countless lives and continue to be the mainstay of therapy for bacterial infections. The clinical success of the first β-lactam, penicillin G (benzylpenicillin), prompted the search for and development of additional derivatives. This quest gave rise to the β-lactam antibiotics in clinical use today (penicillins, narrow- and extended-spectrum cephalosporins, monobactams, and carbapenems) [1, 2]. Unfortunately, β-lactamase-mediated resistance to β-lactam antibiotics emerged as a significant clinical threat to these lifesaving drugs.\n\nThere are two globally accepted classification schemes for β-lactamases, the first one is based on amino-acid sequence classification and the second one is based on functionality. β-lactamases were divided into four classes (Class A–D) based on their sequence similarity by Ambler in 1980. Classes A, C and D function by the serine ester hydrolysis mechanism, whereas class B β-lactamases, also known as metallo β-lactamases, have a zinc ion participating in catalysis [3–5]. The classification scheme by functionality was purposed by Bush et al. in 1995 and was updated in 2009 by Bush-Jacoby group. It takes into account the substrate and inhibitor profiles in an attempt to group the enzymes in ways that can be correlated with their phenotypes in clinical isolates [6]. The updated system includes group 1 (class C) cephalosporinases; group 2 (classes A and D) broad-spectrum, inhibitor-resistant, and extended-spectrum β-lactamases and serine carbapenamases; and group 3 metallo-β-lactamases, each of which is also divided into several different subgroups [6]. Awareness is required to all infectious diseases (ID) and general physicians since penicillins, cephalosporins, and carbapenems are included in the preferred treatment regimens for many infectious diseases due to the fact that presence and characteristics of these enzymes play a critical role in the selection of appropriate therapy [6].\n\nResistance to antimicrobial agents of pathogenic bacteria has become a major problem in current medical practices. Over the last decades, carbapenems have been used as the last-resort drugs in the treatment of serious nosocomial infections caused by multidrug-resistant Gram-negative bacteria. However, carbapenem resistance has been increasing and the most common mechanism is the production of carbapenem-inactivating β-lactamases (carbapenamases) [7]. Here, we report an OXA-48 drug resistance pattern observed in blood and urinary isolates of Providencia species in a fatal meningoencephalitis case who subsequently developed ventilator associated pneumonia and urinary tract infection.\n\nCase presentation\nA 56 years old male from Parsa (district) in Nepal presented to emergency department with fever and altered conscious for the last 3 days. His sensorium was progressively worsening, and thus, he was admitted to intensive care unit (ICU) with a diagnosis of meningoencephalitis. The patient was intubated at ICU admission, on day seven he developed ventilator associated pneumonia. Klebsiella pneumoniae and Acinetobacter baumannii were isolated from the sputum sample. He was on meropenem, but the isolates were susceptible to colistin, tigecycline and amikacin solely (beta-lactam antibiotics, fluroquinolones, doxycycline, gentamicin and cotrimoxazole were resistant on phenotypic Kirby-Bauer disk diffusion method). Hence, amikacin was started with addition of intravenous and nebulized colistin. Subsequently, vital signs improved with resolution of fever. However, on day 18, he was febrile once again with drop in blood pressure. Inotropic support was maintained and both echinocandins and tigecycline were added to the regimen.\n\nAlthough blood and urine cultures grew Providencia species, sputum samples were sterile. Microscopic examination of urine revealed plenty of pus cells, few epithelial cells and no erythrocytes. Patient was at septic shock and he was diagnosed as meningoencephalitis with overlapping ventilator associated pneumonia and urinary tract infection.\n\nThe recovered Providencia isolates were resistant to most of the drugs including colistin (intrinsic resistance). Culture of blood and urine revealed gram negative bacilli with non-lactose fermenting colonies on MacConkey and CLED (Cystine Lactose Electrolyte Deficient) agar (Fig. 1) respectively. The organism fermented glucose, but could not utilize lactose and sucrose on sugar fermentation test. Sulphite indole motility test revealed motile indole positive organism. Citrate utilization and urea hydrolysis tests were positive. To confirm that the organism belongs to the tribe Proteeae of family Enterobacteriaceae, phenyl pyruvic acid test was performed which was found to be positive (Fig. 2). On the basis of aforementioned phenotypic tests, Providencia species were identified. Antibiotic susceptibility testing was done by Kirby Bauer method according to CLSI (Clinical & Laboratory Standards Institute) [8] which revealed pan-drug resistant isolate (resistance to almost all drugs available in the laboratory like amoxycillin/ampicillin, ciprofloxacin, levofloxacin, amikacin, gentamicin, meropenem, imipenem, erythromycin, clindamycin, ceftriaxone, ceftazidime, cefoperazone-sulbactam, ampicillin-sulbactum, chloramphenicol, tetracycline, doxycyclin and since Providencia species belongs to tribe Proteeae of family Enterobacteriaceae, they are intrinsically resistant to colistin and tigecycline and therefore drug susceptibility testing is not recommended for this group of organisms).\nFig. 1 non-lactose fermenting colonies of Providencia vermicola on CLED (Cystine Lactose Electrolyte Deficient) agar\n\n\nFig. 2 Biochemical tests showing the organism belonging to Providencia species\n\n\n\nTo characterize the drug resistance pattern, phenotypic detection of ESBL and Modified Hodge test were done according to CLSI guideline [8]. ESBLs were tested by combination disk method in which ceftazidime (CAZ) and ceftriaxone (CTX) alone and in combination with clavulanic acid (CA) (10 μg) were used. An increase in zone of inhibition of more than or equal to 5 mm for either antimicrobial agent in combination with CA versus its zone when tested alone were negative, but Modified Hodges test revealed carbapenamase producing bacteria (Figs. 3 and 4). Subsequently, phenotypic detection of MBL, KPCs, AmpC and co-producer were tested according to CLSI guideline and all were negative. On the background of positive Modified Hodge test and negative ESBL, MBL, KPCs, AmpC and co-producer, OXA-48 drug resistance pattern was brought into action. We used blank disc method for this purpose according to A Tsakris et al. [9] which revealed indentation of growth toward both EDTA and EDTA/PBA disc (Figs.5 and 6) indicating production of OXA-48 carbapenamase. The isolates were transported to India, where they were confirmed as Providencia vermicola by VITEK MS, which use matrix-assisted laser desorption/ionization time-of- flight (MALDI-TOF) technology. Added to that, the resistance pattern of the isolated colonies was processed by Xpert Carba-R (Cepheid) assay, which detect blaOXA-48 gene (Figs. 7 and 8) and OXA48 drug resistance pattern was confirmed. The patient was kept under isolation. On 31th day of admission he died of septic shock and lack of other antibiotic option (intrinsic resistance to colistin and unavailability of ceftazidime+ avibactam or aztreonam +avibactam combination in both Nepal and India for testing in laboratory or for systemic use in patient).\nFig. 3 Modified Hodge Test positive for test organism (Providencia)\n\n\nFig. 4 Modified Hodge Test positive for test organism (Providencia)\n\n\nFig. 5 Detection of OXA-48 by using antibiotic containing disk which is intrinsically resistant to Providencia instead of Blank Disk3. {E – EDTA-0.1 M 10 μl (292 μg of EDTA), P-Phenyl Boronic Acid- 10 μL (containing 600 μg of PBA)}3\n\n\nFig. 6 Detection of OXA-48 by using antibiotic containing disk which is intrinsically resistant to Providencia instead of Blank Disk3. {E – EDTA-0.1 M 10 μl (292 μg of EDTA), P-Phenyl Boronic Acid- 10 μL (containing 600 μg of PBA)}3\n\n\nFig. 7 Cepheid Xpert Carba-R Assay showing detection of blaOXA-48 gene sequences\n\n\nFig. 8 Cepheid Xpert Carba-R Assay showing detection of blaOXA-48 gene sequences\n\n\n\nDiscussion and conclusion\nAmong the carbapenamase-producing Enterobacteriaceae species, production of OXA-48 can be suspected when the Modified Hodge Test (MHT) is positive and the inhibitor-based combined disk tests for KPC and MBL production are negative. This phenotypic test (OXA-48 disk test) provided a straightforward, convenient, and accurate means of detection of OXA-48 carbapenamase in organisms exhibiting reduced susceptibility to carbapenems [9]. In developing countries where genetic confirmation of the isolates and detection of drug resistance gene is not available, phenotypic detection by standard methods and genetic confirmation by Xpert Carba-R assay is a proper alternative. Cepheid Xpert Carba-R assay is a qualitative, on-demand real-time PCR test for rapid detection and differentiation carbapenamase producing organism by detecting the blaKPC, blaNDM, blaVIM, blaIMP-1 and blaOXA-48 gene sequences from pure colonies encoding the KPC, NDM, VIM, IMP-1, and OXA-48 enzymes respectively and helps clinicians to optimize and direct therapeutic strategy (antibiotic therapy) for patient management [10]. In our case we have first performed phenotypic testing as described by Tsakris et al. [9] and subsequently confirmed OXA-48 enzyme by detecting the blaOXA-48 gene by Xpert Carba-R assay.\n\nThe first identification of OXA-48-producing Enterobacteriaceae was in an isolate in Turkey in 2001 [11, 12]. Shortly thereafter, there was an outbreak of OXA-48-producing Klebsiella pneumoniae isolates reported in Istanbul in 2006 [12, 13]. Since its recognition, there have been increasing numbers of reports of OXA-48-producing organisms worldwide. Avibactam in combination with either of ceftazidime, cefepime, aztreonam, imipenem, or meropenem can inhibit OXA-48-producing Enterobacteriaceae and are drug of choice [13]. Among them ceftazidime/avibactam has proven to be most successful combination [13]. International Network for Optimal Resistance Monitoring (INFORM) global surveillance study in 2012 to 2015 suggested that the in vitro activity of ceftazidime-avibactam was better against the subset of metallo-β-lactamase (MBL)-negative, OXA-48- and OXA-48-like-positive isolates (99.2 and 100% susceptible, respectively) [14]. Vasoo et al. also emphasized that ceftazidime-avibactam was active against all KPC-, IMI-, SME-, and most OXA-48 group-producing isolates (93%), but not to metallo-β-lactamase producers [15].\n\nSader et al. they analysed in vitro activity of aztreonam-avibactam against a large collection (2016) clinical Enterobacteriaceae isolates recovered from patients hospitalized in U.S. medical centers, as well as selected carbapenemase (NDM-like and OXA-48-like)-producing Enterobacteriaceae isolates recovered outside the United States. They found aztreonam-avibactam was very active against KPC, MBL and OXA-48-like producers. Among 57 OXA-48-producing isolates obtained from outside the US, two were sensitive with MIC ≤0.03 μg/ml, two were sensitive with a MIC of 0.06 μg/ml, and 17 were sensitive with MIC of 0.12 μg/ml, 32 were sensitive with MIC 0.25 μg/ml and four were sensitive with MIC of 0.5 μg/ml. All OXA-48-like producers (100%) were sensitive at MIC 0.5 μg/ml. They also tested against the 63 strain of MDR Providencia species and eight XDR Providencia species and found sensitivity to aztreonam-avibactam at MIC 0.5 μg/ml. They concluded that aztreonam-avibactam may represent a valuable option for treating infections caused by CRE, MDR and XDR Enterobacteriaceae, including OXA-48 and MBL-producing strains [16]. Chew et al. observed that aztreonam-avibactam combination can also be used in dual-carbapenemase-producing Enterobacteriaceae to inhibit MβLs (NDM, IMP, or VIM MβLs) with coexistent KPC or OXA-48-like carbapenemases [17].\n\nHackel et al. tested 1521 isolates of Enterobacteriaceae intrinsically resistant to colistin and found 100% sensitive to ceftazidime-avibactam [18]. Jayol et al. tested 63 colistin resistant Klebsiella pneumonia isolates, among which 32 were OXA-48 producers and suggested ceftazidime-avibactam is an effective therapeutic option for treating infections caused by colistin resistant and KPC or OXA-48 Klebsiella pneumoniae. In addition to that they also recommend ceftazidime-avibactam and aztreonam combination against colistin resistant and NDM-producing K. pneumoniae [19]. Petrosillo et al. described the use of ceftazidime-avibactam and fosfomycin for colistin resistant K. pneumoniae. They also emphasized on soon-to-be commercially available plazomicin and cefiderocol, as novel antimicrobial options and advised to consider the future use of innovative therapeutic strategies in development, including bacteriophages therapy and monoclonal antibodies [20]. OXA 48 producer, which is a global threat has now been detected in Nepal as well. Ceftazidime- avibactam combination or aztreonam -avibactam combination is the drug of choice which is not available in Nepal. Thus, knowledge on the occurrence of the OXA-48 producers may also encourage the pharmaceutical companies and The Ministry of Health to facilitate provision of drug of choice like ceftazidime-avibactam in Nepal.\n\nSince OXA-48 enzyme leads to carbapenem resistance, we are obliged to use colistin and tigecycline due to unavailability of drug of choice in our country. However, some organisms belonging to tribe Proteeae of family Enterobacteriaceae (Proteus, Providencia and Morganella) are intrinsically resistant to colistin and tigecycline. Therefore, organisms which are OXA-48 producers and intrinsically resistant to colistin when infect patients causes high mortality. Use of colistin for colistin susceptible organisms but OXA- producer can help treat the infection, although it may result in adverse effects like renal toxicity. OXA-48 carbapenamase producers are a rising threat to the whole world so that their routine detection is a must. The potential benefits identifying the resistance pattern like OXA producer include initiation of early appropriate therapy in carbapenemase producing isolates.\n\nThrough this paper we alarm the official and governmental agencies to focus on the drug resistance mechanisms and to make arrangements for the provision of drugs like ceftazidime+ avibactam or aztreonam + avibactam in Nepal because carbapenamase producing pathogens with intrinsic colistin resistance can be fatal in the resource limited countries where new avibactam-based antibiotic combinations are not available. Protocols should be generated to make this drug available just for the prescription of ID physicians. In addition, developing infectious diseases expert academic programs in the medical institutes of Nepal is needed.\n\nIn conclusion, carbapenamase producing bacteria such as MBL, KPC, AmpC and co-producers are frequently detected in our laboratory and in the country. Unfortunately, phenotypic detection of OXA-48 is not routinely practiced. Since, we have detected OXA-48, which results in resistance to almost all antibiotics, drug resistance patterns should be characterized in each case by standard phenotypic method or by Xpert Carba-R assay for appropriate antibiotic selection and better patient care. Also larger studies are required to know the exact burden of OXA 48 producer in Nepal.\n\nAbbreviations\nAmpCclass C cephalosporinase\n\nCLSIClinical and Laboratory Standards Institute\n\nEDTAEthylene diamine tetraacetic acid\n\nESBLExtended spectrum beta-lactamase\n\nKPCKlebsiella pneumoniae Carbapenamase\n\nMBLMetallo-beta-lactamase MHT\n\nModified Hodge Test\n\nNDMNew Delhi metallo-beta-lactamase\n\nOXA-48Oxacillinase-48\n\nPBAPhenyl Boronic Acid\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe would like to thanks Dr. Mahesh Adhikari, Dr. Neha Shrestha, Prof. Jeevan Bahadur Sherchand, Prof. Keshab Parajuli, Assistant Professor Dr. Sangita Sharma, Dr. Rupendra Thapa, Dr. Samikshya Neupane, Dr. Sanjit Sah, Dr. Shyam Sah and Dr. Ranjana Sah for their constant support and guidance.\n\nAuthors’ contributions\nRS made the diagnosis, RS, SK, GSS, SA, DA, PS, HPK, NPS, BMP, YPS and BR designed the manuscript, reviewed the literature and prepared the article for submission. GSS, SA, DA, PS, HPK, NPS, BMP, YPS and BR helped for literature review, gave concept of research paper and critically reviewed the manuscript. HE helps to review the literature, revise the article and improved the content of the article. All authors read and approved for the final manuscript. The manuscript has not been previously published nor is not being considered for publication elsewhere.\n\nFunding\n“No funding was received”.\n\nAvailability of data and materials\nData generated or analyzed during this study are included in this published article and remaining are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThere is no need for ethical approval for a case report according to the local ethical guidelines.\n\nConsent for publication\nWritten informed consent was taken from the patient’s wife for publication of this Case Report and any accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Drawz SM Robert A Bonomo Three Decades of b-Lactamase Inhibitors Clin Microbiol Rev 2010 23 1 160 10.1128/CMR.00037-09 20065329 \n2. Shaikh S Fatima J Shakil S Rizvi SM Kamal MA Antibiotic resistance and extended spectrum beta-lactamases: types, epidemiology and treatment Saudi J Biol Sci 2015 22 1 90 101 10.1016/j.sjbs.2014.08.002 25561890 \n3. Dever LA Dermody TS Mechanisms of bacterial resistance to antibiotics Arch Intern Med 1991 151 5 886 895 10.1001/archinte.1991.00400050040010 2025137 \n4. Munita JM Arias CA Mechanisms of Antibiotic Resistance Microbiol Spectr 2016 4 2 10.1128/microbiolspec.VMBF-0016-2015 \n5. Peterson E Kaur P Antibiotic resistance mechanisms in Bacteria: relationships between resistance determinants of antibiotic producers, environmental Bacteria, and clinical pathogens Front Microbiol 2018 9 1 21 10.3389/fmicb.2018.02928 29403456 \n6. Bush K Jacoby GA Updated functional classification of beta-lactamases Antimicrob Agents Chemother 2010 54 3 969 976 10.1128/AAC.01009-09 19995920 \n7. Studentova V Detection of OXA-48-type carbapenamase-producing Enterobacteriaceae in diagnostic laboratories can be enhanced by addition of bicarbonates to cultivation media or reaction buffers PMC 2015 60 2 119 129 \n8. Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Sixth Informational Supplement. Wayne, Pennsylvania, USA: CLSI; 2016.\n9. Tsakris A Evaluation of a New Phenotypic OXA-48 Disk Test for Differentiation of OXA-48 Carbapenamase-Producing Enterobacteriaceae Clinical Isolates JCM 2015 53 4 10.1128/JCM.03318-14 \n10. Tato M Ruiz-Garbajosa P Traczewski M Dodgson A McEwan A Humphries R Multisite evaluation of Cepheid Xpert Carba-R assay for detection of Carbapenamase-producing organisms in rectal swabs J Clin Microbiol 2016 54 7 1814 1819 10.1128/JCM.00341-16 27122379 \n11. Poirel L Héritier C Tolün V Nordmann P Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae Antimicrob Agents Chemother 2004 48 1 15 22 10.1128/aac.48.1.15-22.2004 14693513 \n12. Carrër A Poirel L Eraksoy H Cagatay AA Badur S Nordmann P Spread of OXA-48-positive carbapenem-resistant Klebsiella pneumoniae isolates in Istanbul, Turkey Antimicrob Agents Chemother 2008 52 8 2950 2954 10.1128/AAC.01672-07 18519712 \n13. Stewart A Harris P Henderson A Paterson D Treatment of Infections by OXA-48-Producing Enterobacteriaceae Antimicrob Agents Chemother 2018 62 11 10.1128/AAC.01195-18 \n14. Kazmierczak KM, Bradford PA, Stone GG, de Jonge BLM, Sahm DF. In Vitro Activity of Ceftazidime-Avibactam and Aztreonam-Avibactam against OXA-48-Carrying Enterobacteriaceae Isolated as Part of the International Network for Optimal Resistance Monitoring (INFORM) Global Surveillance Program from 2012 to 2015. Antimicrob agents Chemother. 2018;62(12):e00592–e00518 Published 2018 Nov 26. doi:10.1128/AAC.00592-18.\n15. Vasoo S Cunningham SA Cole NC In vitro activities of Ceftazidime-Avibactam, Aztreonam-Avibactam, and a panel of older and contemporary antimicrobial agents against Carbapenemase-producing gram-negative bacilli Antimicrob Agents Chemother 2015 59 12 7842 7846 10.1128/AAC.02019-15 26392487 \n16. Sader HS, Mendes RE, Pfaller MA, Shortridge D, Flamm RK, Castanheira M. Antimicrobial Activities of Aztreonam-Avibactam and Comparator Agents against Contemporary (2016) Clinical Enterobacteriaceae Isolates. Antimicrob Agents Chemother 2017;62(1):e01856–17 Published 2017 Dec 21. doi:10.1128/AAC.01856-17.\n17. Chew KL, Tay MKL, Cheng B, Lin RTP, Octavia S, Teo JWP. Aztreonam-Avibactam Combination Restores Susceptibility of Aztreonam in Dual-Carbapenemase-Producing Enterobacteriaceae. Antimicrob Agents Chemother. 2018;62(8):e00414–e00418. Published 2018 Jul 27. doi:10.1128/AAC.00414-18\n18. M. Hackel, S. Bouchillon, R. Badal, W.W. Nichols. Activity of Ceftazidime-Avibactam and Comparators against Colistin Non-Susceptible Enterobacteriaceae and Pseudomonas aeruginosa Isolated in 2012: The International Network For Optimal Resistance Monitoring (INFORM) Study. 24th ECCMID Congress, Barcelona, Spain, 10–13 May 2014, eP437.\n19. Jayol A Nordmann P Poirel L Dubois V Ceftazidime/avibactam alone or in combination with aztreonam against colistin-resistant and carbapenemase-producing Klebsiella pneumoniae J Antimicrob Chemother. 2018 73 2 542 544 10.1093/jac/dkx393 29165563 \n20. Petrosillo N Taglietti F Granata G Treatment Options for Colistin Resistant Klebsiella pneumoniae : Present and Future J Clin Med 2019 8 7 10.3390/jcm8070934\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2047-2994",
"issue": "8()",
"journal": "Antimicrobial resistance and infection control",
"keywords": "Drug resistance; Nepal; OXA-48; Providencia species",
"medline_ta": "Antimicrob Resist Infect Control",
"mesh_terms": "D052978:Disk Diffusion Antimicrobial Tests; D024901:Drug Resistance, Multiple, Bacterial; D017809:Fatal Outcome; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008590:Meningoencephalitis; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009390:Nepal; D011532:Providencia; D012772:Shock, Septic; D001618:beta-Lactamases",
"nlm_unique_id": "101585411",
"other_id": null,
"pages": "155",
"pmc": null,
"pmid": "31636898",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Detection of Pan drug resistance OXA-48 producing Providencia in an ICU patient for the first time in Nepal.",
"title_normalized": "detection of pan drug resistance oxa 48 producing providencia in an icu patient for the first time in nepal"
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{
"abstract": "BACKGROUND\nErtapenem, cefepime, imipenem, ofloxacin, ceftazidime, clarithromycin, cefaclor, levofloxacin, linezolid, moxifloxacin, azithromycin, piperacillin-tazobactam, trimethoprim-sulfamethoxazole, metronidazole, ciprofloxacin, and cefuroxime are known to be associated with delirium. Other antibiotics may also lead to delirium, but no study has systemically compared delirium associations for many available antibiotics.\n\n\nOBJECTIVE\nThe objective of this study was to evaluate the association between delirium and antibiotics using the FDA Adverse Event Reporting System (FAERS).\n\n\nMETHODS\nFAERS reports from January 1, 2004 to December 31, 2018 were included in the study. Reporting odds ratios (RORs) and corresponding 95% confidence intervals (95% CI) for the association between antibiotics and delirium were calculated. An association was considered to be statistically significant when the lower limit of the 95% CI was greater than 1.0.\n\n\nRESULTS\nA total of 10,015,622 reports (including 16,982 delirium reports) were considered, after inclusion criteria were applied. Statistically significant delirium RORs (95% CI) for antibiotics were: ertapenem 21.07 (16.38-27.10), cefepime 9.8 (6.37-15.09), imipenem 9.68 (6.75-13.89), ofloxacin 7.73 (4.00-14.92), ceftazidime 6.09 (2.73-13.62), clarithromycin 5.34 (4.37-6.53), cefaclor 5.32 (1.71-16.58), ampicillin-sulbactam 4.49 (2.13-9.45), levofloxacin 4.47 (3.88-5.16), linezolid 4.33 (3.28-5.72), moxifloxacin 3.51 (2.81-4.38), azithromycin 2.76 (2.09-3.64), piperacillin-tazobactam 2.41 (1.47-3.93), trimethoprim-sulfamethoxazole 2.36 (1.61-3.47), metronidazole 1.85 (1.31-2.60), ciprofloxacin 1.83 (1.44-2.33), and cefuroxime 1.81 (1.03-3.20).\n\n\nCONCLUSIONS\nThis study found statistically significant increased risk of reporting delirium with ertapenem, cefepime, imipenem, ofloxacin, ceftazidime, clarithromycin, cefaclor, ampicillin-sulbactam, levofloxacin, linezolid, moxifloxacin, azithromycin, piperacillin-tazobactam, trimethoprim-sulfamethoxazole, metronidazole, ciprofloxacin, and cefuroxime.",
"affiliations": "Department of Clinical Pharmacy and Outcomes Sciences, College of Pharmacy, The University of South Carolina, 715 Sumter Street, Columbia, SC, 29208, USA. TENGC@mailbox.sc.edu.;Pharmacotherapy Division, College of Pharmacy, The University of Texas at Austin, San Antonio, TX, USA.",
"authors": "Teng|Chengwen|C|http://orcid.org/0000-0001-9239-2125;Frei|Christopher R|CR|http://orcid.org/0000-0002-0692-4787",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s40801-021-00268-1",
"fulltext": "\n==== Front\nDrugs Real World Outcomes\nDrugs Real World Outcomes\nDrugs - Real World Outcomes\n2199-1154\n2198-9788\nSpringer International Publishing Cham\n\n34275113\n268\n10.1007/s40801-021-00268-1\nOriginal Research Article\nDelirium Associations with Antibiotics: A Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS)\nhttp://orcid.org/0000-0001-9239-2125\nTeng Chengwen TENGC@mailbox.sc.edu\n\n1\nhttp://orcid.org/0000-0002-0692-4787\nFrei Christopher R. 2345\n1 grid.411021.7 0000 0004 4658 9818 Department of Clinical Pharmacy and Outcomes Sciences, College of Pharmacy, The University of South Carolina, 715 Sumter Street, Columbia, SC 29208 USA\n2 grid.89336.37 0000 0004 1936 9924 Pharmacotherapy Division, College of Pharmacy, The University of Texas at Austin, San Antonio, TX USA\n3 grid.267309.9 0000 0001 0629 5880 Pharmacotherapy Education and Research Center, Long School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX USA\n4 grid.280682.6 0000 0004 0420 5695 South Texas Veterans Health Care System, San Antonio, TX USA\n5 grid.412489.2 0000 0004 0608 2801 University Health System, San Antonio, TX USA\n17 7 2021\n17 7 2021\n3 2022\n9 1 2329\n22 6 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial 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-nc/4.0/.\nBackground\n\nErtapenem, cefepime, imipenem, ofloxacin, ceftazidime, clarithromycin, cefaclor, levofloxacin, linezolid, moxifloxacin, azithromycin, piperacillin–tazobactam, trimethoprim–sulfamethoxazole, metronidazole, ciprofloxacin, and cefuroxime are known to be associated with delirium. Other antibiotics may also lead to delirium, but no study has systemically compared delirium associations for many available antibiotics.\n\nObjective\n\nThe objective of this study was to evaluate the association between delirium and antibiotics using the FDA Adverse Event Reporting System (FAERS).\n\nMethods\n\nFAERS reports from January 1, 2004 to December 31, 2018 were included in the study. Reporting odds ratios (RORs) and corresponding 95% confidence intervals (95% CI) for the association between antibiotics and delirium were calculated. An association was considered to be statistically significant when the lower limit of the 95% CI was greater than 1.0.\n\nResults\n\nA total of 10,015,622 reports (including 16,982 delirium reports) were considered, after inclusion criteria were applied. Statistically significant delirium RORs (95% CI) for antibiotics were: ertapenem 21.07 (16.38–27.10), cefepime 9.8 (6.37–15.09), imipenem 9.68 (6.75–13.89), ofloxacin 7.73 (4.00–14.92), ceftazidime 6.09 (2.73–13.62), clarithromycin 5.34 (4.37–6.53), cefaclor 5.32 (1.71–16.58), ampicillin–sulbactam 4.49 (2.13–9.45), levofloxacin 4.47 (3.88–5.16), linezolid 4.33 (3.28–5.72), moxifloxacin 3.51 (2.81–4.38), azithromycin 2.76 (2.09–3.64), piperacillin–tazobactam 2.41 (1.47–3.93), trimethoprim–sulfamethoxazole 2.36 (1.61–3.47), metronidazole 1.85 (1.31–2.60), ciprofloxacin 1.83 (1.44–2.33), and cefuroxime 1.81 (1.03–3.20).\n\nConclusion\n\nThis study found statistically significant increased risk of reporting delirium with ertapenem, cefepime, imipenem, ofloxacin, ceftazidime, clarithromycin, cefaclor, ampicillin–sulbactam, levofloxacin, linezolid, moxifloxacin, azithromycin, piperacillin–tazobactam, trimethoprim–sulfamethoxazole, metronidazole, ciprofloxacin, and cefuroxime.\n\nhttp://dx.doi.org/10.13039/100006108 National Center for Advancing Translational Sciences UL1 TR001120 UL1 TR002645 Frei Christopher R. issue-copyright-statement© The Author(s) 2022\n==== Body\npmcKey Points\n\nThis study identifies previously unknown delirium reporting association with ampicillin–sulbactam.\t\nErtapenem had the highest delirium reporting association among antibiotics evaluated in the study.\t\nOlder patients had a higher delirium Reporting Odds Ratio than younger patients among most of the antibiotic classes analyzed.\t\n\nIntroduction\n\nDelirium is diagnosed in the presence of a disturbance in attention and awareness that develops over a short period of time, represents a change from baseline, tends to fluctuate, has an additional cognitive disturbance (e.g., memory deficit, disorientation, language, visuospatial ability, or perception), all of which are not better explained by other diagnoses (e.g., coma) [1]. Delirium is associated with higher mortality rates, affects up to 50% of hospitalized elderly patients, and costs more than $164 billion per year in the United States [2]. Delirium may be nothing more than a marker of severity of illness likened to a cough for pneumonia. Treatment of pneumonia resolves the cough like treatment of sepsis may resolve delirium. This point was proven in multiple trials of critically ill patients including BRAIN-ICU, which showed ICU delirium is associated with long-term cognitive impairment, and MIND-USA, which showed delirium treatment in those with hypoactive delirium does not improve outcome [3, 4].\n\nMany antibiotics are known to be associated with delirium. Overall quality of evidence for many reports is very low. Multiple case reports have reported on ertapenem-induced delirium [5–7]. A case of hypoactive delirium and another case of encephalopthy as adverse effects of imipenem were reported [8, 9]. A case report demonstrated a case of delirium with hallucinations likely caused by a combination of diphenhydramine and linezolid [10]. Delirium was also reported to be induced by clarithromycin monotherapy or a combination of clarithromycin and fluoxetine [11–13]. Delirium was associated with azithromycin in two geriatric patients treated for lower respiratory tract infection [14]. There are at least 6 published case reports of delirium associated with the use of azithromycin, including one pediatric patient, and 12 published case reports of delirium associated with the use of clarithromycin [15]. Four fluoroquinolone antibiotics, which were ofloxacin, levofloxacin, moxifloxacin, and ciprofloxacin, were all reported to be associated with delirium [16–19]. Cefepime use was associated with increased likelihood and duration of acute encephalopathy (presence of delirium or depressed level of consciousness in the absence of deep sedation) in critically ill patients in a retrospective case–control study [20]. A nested cohort study concluded that first, second, and third-generation cephalosporins doubled the odds of delirium [21]. A case report reported higher-level gait disorder and nocturnal delirium likely induced by trimethoprim–sulfamethoxazole [22]. In another case report, metronidazole and levofloxacin induced delirium in a chronic kidney disease patient [23]. Delirium was also reported to be induced by piperacillin–tazobactam in a peritoneal dialysis patient [24].\n\nFew studies have looked at antibiotics and compared their associations with delirium. The objective of this study was to evaluate the association between delirium and antibiotics using FDA Adverse Event Reporting System (FAERS).\n\nMethods\n\nData Source\n\nFAERS is a publicly available database composed of adverse event reports that were submitted to United States Food and Drug Administration (FDA) [25]. FAERS data contain drug information (drug name, active ingredient, route of administration, the drug’s reported role in the event) and reaction information. Healthcare professionals, consumers or manufacturers may submit reports. The types of data found in FAERS include reason for administration, specific reaction, seriousness, outcome, gender, event data, patient age, who sent the report, reporter type, country, whether or not it was reported to the manufacturer and whether or not it was published. Quarterly Data Files were used to obtain FAERS data. The Institutional Review Board (IRB) of The University of South Carolina determined that this study is not human subjects research (IRB number: Pro00101342).\n\nStudy Design\n\nFAERS data from January 1, 2004 to December 31, 2018 were included in the study. Some adverse event reports were submitted multiple times with updated information. Therefore, duplicate reports were removed by case number, with the most recent submission included in the study.\n\nDrug Exposure Definition\n\nEach antibiotic was identified in FAERS by generic and brand names listed in the Drugs@FDA Database [26]. Antibiotics with less than three delirium Adverse Drug Reaction (ADR) reports were excluded from this data analysis [27]. All reports were included, regardless of route of administration and the drug’s reported role in the event. Antibiotics included in the study were ertapenem, imipenem, meropenem, linezolid, clarithromycin, azithromycin, erythromycin, ofloxacin, levofloxacin, moxifloxacin, ciprofloxacin, cefepime, ceftazidime, cefaclor, cefuroxime, cephalexin, ceftriaxone, trimethoprim–sulfamethoxazole, metronidazole, ampicillin-sulbactam, piperacillin–tazobactam, amoxicillin–clavulanate, amoxicillin, nitrofurantoin, daptomycin, vancomycin, minocycline, and clindamycin. Antibiotic classes included in the study were carbapenems, macrolides, fluoroquinolones, cephalosporins, and penicillin combinations.\n\nAdverse Drug Reaction Definition\n\nFAERS defines ADRs using Preferred Terms (PT) from the Medical Dictionary for Regulatory Activities (MedDRA) [28]. Preferred Term “Delirium” was used to identify delirium cases.\n\nStatistical Analysis\n\nA disproportionality analysis was conducted by computing Reporting Odds Ratios (ROR) and corresponding 95% confidence intervals (95%CI) for the association between delirium and each antibiotic class or individual antibiotic [29]. ROR was calculated as the ratio of the odds of reporting delirium versus all other ADRs for a given drug, compared with this reporting odds for all other drugs present in FAERS [29]. An association was considered to be statistically significant if the lower limit of 95% CI was above 1.0 [29]. A subgroup analysis was performed on patients who were 65 years or older and patients less than 65 years old. Data analysis was performed using Microsoft Excel 2016 (Microsoft Corporation, Redmond, WA) and SAS 9.4 (SAS Institute, Cary, NC).\n\nResults\n\nA total of 10,015,622 reports (including 16,982 delirium reports) were considered, after inclusion criteria were applied (Fig. 1). The number of cases for each drug and drug class is listed in Fig. 2. Statistically significant delirium RORs (95% CI) for antibiotic classes were: carbapenems 10.49 (8.59–12.80), macrolides 3.65 (3.11–4.28), fluoroquinolones 3.40 (3.05-3.78), cephalosporins 2.54 (1.99–3.23), and penicillin combinations 1.62 (1.20–2.18).Fig. 1 Flow diagram for inclusion and exclusion of the FAERS reports\n\nFig. 2 Reporting odds ratios (ROR) for delirium with antibiotics\n\nStatistically significant delirium RORs (95% CI) for antibiotics were: ertapenem 21.07 (16.38–27.10), cefepime 9.8 (6.37–15.09), imipenem 9.68 (6.75–13.89), ofloxacin 7.73 (4.00–14.92), ceftazidime 6.09 (2.73–13.62), clarithromycin 5.34 (4.37–6.53), cefaclor 5.32 (1.71–16.58), ampicillin–sulbactam 4.49 (2.13–9.45), levofloxacin 4.47 (3.88–5.16), linezolid 4.33 (3.28–5.72), moxifloxacin 3.51 (2.81–4.38), azithromycin 2.76 (2.09–3.64), piperacillin–tazobactam 2.41 (1.47–3.93), trimethoprim–sulfamethoxazole 2.36 (1.61–3.47), metronidazole 1.85 (1.31–2.60), ciprofloxacin 1.83 (1.44–2.33), and cefuroxime 1.81 (1.03–3.20) (Fig. 2).\n\nAmong patients who took carbapenems, linezolid, macrolides, fluoroquinolones, cephalosporins, trimethoprim–sulfamethoxazole, metronidazole, penicillin combinations, and clindamycin, patients who were 65 years or older had a higher delirium ROR than those less than 65 years old (Fig. 3). Among patients who took amoxicillin and vancomycin, patients who were 65 years or older had a lower delirium ROR than those less than 65 years old (RORs were not statistically significant considering that the lower limit of 95% CI was below 1.0).Fig. 3 Reporting odds ratios (RORs) for delirium with antibiotics stratified by age\n\nDiscussion\n\nOur results indicated significant delirium reporting associations (from strongest to weakest) with the following antibiotic classes: carbapenems, macrolides, fluoroquinolones, cephalosporins, and penicillin combinations (Fig. 2).\n\nOur results demonstrated significant delirium reporting associations (from strongest to weakest) with the following antibiotics: ertapenem, cefepime, imipenem, ofloxacin, ceftazidime, clarithromycin, cefaclor, ampicillin–sulbactam, levofloxacin, linezolid, moxifloxacin, azithromycin, piperacillin–tazobactam, trimethoprim–sulfamethoxazole, metronidazole, ciprofloxacin, and cefuroxime (Fig. 2). Our results were in agreement with previously known delirium associations with ertapenem, cefepime, imipenem, ofloxacin, ceftazidime, clarithromycin, cefaclor, levofloxacin, linezolid, moxifloxacin, azithromycin, piperacillin–tazobactam, trimethoprim–sulfamethoxazole, metronidazole, ciprofloxacin, and cefuroxime [5–24]. Ampicillin–sulbactam was found to be associated with delirium in FAERS, which was not reported in the literature.\n\nCefepime is known to be able to induce neurotoxicity due to its ability to cross the blood–brain barrier and to exhibit concentration-dependent competitive gamma-aminobutyric acid (GABA) antagonism [30–32]. The signs and symptoms of cefepime-induced neurotoxicity included altered mental status, reduced consciousness, confusion, myoclonus, aphasia, agitation, and seizures [32]. Many of the signs and symptoms of cefepime-induced neurotoxicity correlated well with signs and symptoms of delirium [1]. Therefore, it is not surprising to find the significant association between cefepime and delirium in FAERS.\n\nCarbapenem antibiotics may have a higher neurotoxic potential than that of penicillins and cephalosporins [33]. Indeed, in our study, carbapenem antibiotic class had the highest delirium ROR among all antibiotic classes included in the study (Fig. 1). This may not be a class-wide effect and certain carbapenems may be more offensive (e.g., imipenem) than others (e.g., meropenem). Prior studies have suggested that cefepime may have a tenfold greater risk for neurotoxicity than meropenem [34, 35]. Neurotoxicity of carbapenems was also thought to be caused by an interaction with GABA receptors [33]. The association between imipenem and delirium found in FAERS may be due to this mechanism.\n\nAlthough ampicillin–sulbactam-induced delirium was not reported in the literature, ampicillin–sulbactam is a beta-lactam, which has the potential to induce neurotoxicity via interactions with GABA receptors [31]. The association between ampicillin–sulbactam and delirium found in FAERS may be explained by this mechanism. It is interesting that ampicillin–sulbactam was associated with delirium given its minimal penetration across the blood–brain-barrier. Prior reports have stated its penetrance is 1% of the plasma concentration and only increases in the setting of inflamed meninges [36].\n\nAlthough a case of meropenem-associated delirium was reported in the literature, our study did not find statistically significant ROR for meropenem and delirium. The low number of meropenem delirium reports in FAERS may be the reason of statistical insignificance (Fig. 2).\n\nIn the subgroup analysis, the delirium ROR rank order in both subgroups (< 65 years old and ≥ 65 years old) were similar to that in all patients. Our results showed that older patients had a higher delirium ROR than younger patients among most of the antibiotic classes analyzed (Fig. 3). Carbapenems, macrolides, fluoroquinolones, cephalosporins, and trimethoprim–sulfamethoxazole had significantly greater associations with delirium in older patients than those in younger patients. It is known that delirium risk is higher in older patients [1]. To note, ciprofloxacin and trimethoprim–sulfamethoxazole were also included in the American Geriatrics Society Beers Criteria for potentially inappropriate medication use in older adults [37]. Ciprofloxacin was in the Beers Criteria for tendon rupture and hyperkalemia, but not for delirium.\n\nLimitations\n\nA causal relationship between a drug and an ADR cannot be determined by FAERS. Significant bias may occur because of the spontaneous and voluntary reporting of ADRs. Media attention and recent publication of an ADR in the literature might affect the reporting behaviors. The association between a drug and an ADR is confounded by comorbidities and concomitant drugs. According to FDA, information submitted has not been verified by a medical professional. FAERS data may be submitted by healthcare professionals, consumers and manufacturers. Source of submission must be considered. Some information is missing or incomplete in FAERS. There have been cases in which age was not reported or drug names were misspelled. FDA does not receive reports for every adverse event or medication error that occurs with a product. In addition, ROR only investigates an increased risk of ADR reporting and not risk of ADR occurrence in absolute terms [38]. Some of the confidence intervals are quite wide such as cefaclor 5.32 (1.71–16.58) because of the low number of cefaclor ROR reports for delirium. An additional limitation of this study is the reliance on “delirium” as the search term in the FAERS database. Terms such as delirium, encephalopathy, acute confusional state, acute brain dysfunction and acute brain failure are often used synonymously and inappropriately in the literature [39]. Without the ability to determine how delirium was diagnosed, it is possible that numerous cases were misclassified and could have altered the findings. Despite the limitations, FAERS has a large sample size and is suitable for discovering a signal of new and rare drug-ADR associations.\n\nConclusion\n\nThis study found statistically significant increased risk of reporting delirium with ertapenem, cefepime, imipenem, ofloxacin, ceftazidime, clarithromycin, cefaclor, ampicillin–sulbactam, levofloxacin, linezolid, moxifloxacin, azithromycin, piperacillin–tazobactam, trimethoprim–sulfamethoxazole, metronidazole, ciprofloxacin, and cefuroxime. Results obtained from FAERS should be interpreted with caution in the context of data limitations. Antibiotic stewardship is needed to prevent delirium and to improve health outcomes.\n\nAcknowledgements\n\nNo funding was sought for this research study. Dr. Frei was supported, in part, by a NIH Clinical and Translational Science Award (National Center for Advancing Translational Sciences, UL1 TR001120 and UL1 TR002645) while the study was being conducted. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs, the National Institutes of Health, or the authors’ affiliated institutions.\n\nDeclarations\n\nFunding\n\nNo funding was sought for this research study. Dr. Frei was supported, in part, by a NIH Clinical and Translational Science Award (National Center for Advancing Translational Sciences, UL1 TR001120 and UL1 TR002645) while the study was being conducted. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.\n\nConflict of interest\n\nDr. Frei’s institution has received grants for research from AstraZeneca Pharmaceuticals in the last 36 months.\n\nEthics approval\n\nThe Institutional Review Board (IRB) of The University of South Carolina determined that this study is not human subjects research (IRB number: Pro00101342).\n\nConsent to participate\n\nNot applicable.\n\nConsent for publication\n\nNot applicable.\n\nAvailability of data and material\n\nThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nCode availability\n\nCodes used during the current study are available from the corresponding author on reasonable request.\n\nAuthor contributions\n\nStudy concept and design: all authors. 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Grahl JJ Stollings JL Rakhit S Person AK Wang L Thompson JL Antimicrobial exposure and the risk of delirium in critically ill patients Crit Care 2018 22 1 337 10.1186/s13054-018-2262-z 30541600\n22. Dakin LE Probable trimethoprim/sulfamethoxazole-induced higher-level gait disorder and nocturnal delirium in an elderly man Ann Pharmacother 2009 43 1 129 133 10.1345/aph.1L295 19109207\n23. Velickovic-Radovanovic R Catic-Dordevic A Dinic K Radivojevic J Zikic O Cvetkovic T Metronidazole- and levofloxacin-induced psychotic disorders in chronic kidney patient Eur J Hosp Pharm 2019 26 6 347 349 10.1136/ejhpharm-2018-001677 31798860\n24. Tong MK Siu YP Yung CY Kwan TH Piperacillin/tazobactam-induced acute delirium in a peritoneal dialysis patient Nephrol Dial Transplant 2004 19 5 1341 10.1093/ndt/gfh048 15102992\n25. Food and Drug Administration. FDA Adverse Event Reporting System (FAERS). 2020. https://www.fda.gov/drugs/surveillance/questions-and-answers-fdas-adverse-event-reporting-system-faers. Accessed 1 Oct 2020.\n26. Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. 2020. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed 1 Oct 2020.\n27. Evans SJ Waller PC Davis S Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports Pharmacoepidemiol Drug Saf 2001 10 6 483 486 10.1002/pds.677 11828828\n28. MedDRA MSSO. Introductory Guide for Standardised MedDRA Queries (SMQs) Version 23.1. 2020. https://admin.new.meddra.org/sites/default/files/guidance/file/SMQ_intguide_23_1_English.pdf. Accessed 1 Oct 2020.\n29. Bate A Evans SJ Quantitative signal detection using spontaneous ADR reporting Pharmacoepidemiol Drug Saf 2009 18 6 427 436 10.1002/pds.1742 19358225\n30. Fugate JE Kalimullah EA Hocker SE Clark SL Wijdicks EF Rabinstein AA Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy Crit Care 2013 17 6 1 6 10.1186/cc13094\n31. Grill MF Maganti R Cephalosporin-induced neurotoxicity: clinical manifestations, potential pathogenic mechanisms, and the role of electroencephalographic monitoring Ann Pharmacother 2008 42 12 1843 1850 10.1345/aph.1L307 19033476\n32. Payne LE Gagnon DJ Riker RR Seder DB Glisic EK Morris JG Cefepime-induced neurotoxicity: a systematic review Crit Care 2017 21 1 276 10.1186/s13054-017-1856-1 29137682\n33. Norrby SR Neurotoxicity of carbapenem antibacterials Drug Saf 1996 15 2 87 90 10.2165/00002018-199615020-00001 8884160\n34. Tanaka A Takechi K Watanabe S Tanaka M Suemaru K Araki H Comparison of the prevalence of convulsions associated with the use of cefepime and meropenem Int J Clin Pharm 2013 35 5 683 687 10.1007/s11096-013-9799-3 23733559\n35. Chaïbi K Chaussard M Soussi S Lafaurie M Legrand M Not all β-lactams are equal regarding neurotoxicity Crit Care 2016 20 1 1 2 10.1186/s13054-016-1522-z 26728475\n36. Kearney BP Aweeka FT The penetration of anti-infectives into the central nervous system Neurol Clin 1999 17 4 883 900 10.1016/S0733-8619(05)70171-7 10517933\n37. BY the American Geriatrics Society Beers Criteria Update Expert Panel American Geriatrics Society 2019 Updated AGS Beers Criteria(R) for Potentially Inappropriate Medication Use in Older Adults J Am Geriatr Soc 2019 67 4 674 694 10.1111/jgs.15767 30693946\n38. Montastruc JL Sommet A Bagheri H Lapeyre-Mestre M Benefits and strengths of the disproportionality analysis for identification of adverse drug reactions in a pharmacovigilance database Br J Clin Pharmacol 2011 72 6 905 908 10.1111/j.1365-2125.2011.04037.x 21658092\n39. Slooter AJ Otte WM Devlin JW Arora RC Bleck TP Claassen J Duprey MS Ely EW Kaplan PW Latronico N Morandi A Updated nomenclature of delirium and acute encephalopathy: statement of ten Societies Intensive Care Med 2020 46 5 1020 1022 10.1007/s00134-019-05907-4 32055887\n\n",
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"title": "Delirium Associations with Antibiotics: A Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS).",
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"abstract": "Pegfilgrastim can be utilized to prevent neutropenia-associated complications in patients receiving myelosuppressive chemotherapy for breast cancer. A common adverse event associated with pegfilgrastim is bone pain. Clinicians may opt to reduce the dose of pegfilgrastim when administering it to patients with previous severe or refractory bone pain. There is limited and conflicting evidence with regard to the safety and efficacy of this practice. The purpose of this study was to investigate the impact of administering reduced doses of pegfilgrastim on neutropenia-associated outcomes in patients with breast cancer receiving myelosuppressive chemotherapy.\nA retrospective chart review was conducted at a large, multistate health system with several different medical oncology practice sites. The primary outcome was the incidence of febrile neutropenia. Secondary outcomes included the incidence and severity of neutropenia, hospitalization for febrile, use of intravenous antimicrobials for febrile, delays in chemotherapy or dose reductions in chemotherapy secondary to neutropenia or febrile, rationale for dose reduction of pegfilgrastim, and improvement in bone pain.\nA total of 80 patients received reduced dose pegfilgrastim. Most patients had their doses reduced secondary to bone pain (54%) or leukocytosis (14%). One (1.25%) patient experienced febrile neutropenia that did not require hospitalization or intravenous antimicrobials. Chemotherapy treatment delays and dose reductions secondary to neutropenia or febrile neutropenia occurred in 1 (1.25%) and 2 (2.5%) patients, respectively.\nReduced doses of pegfilgrastim in patients receiving myelosuppressive chemotherapy for breast cancer resulted in a low incidence of neutropenia-associated events, including febrile neutropenia and grade 3/4 neutropenia.",
"affiliations": "Department of Pharmacy, Atrium Health, Levine Cancer Institute, Charlotte, NC, USA.;Department of Pharmacy, Atrium Health, Levine Cancer Institute, Charlotte, NC, USA.;Department of Pharmacy, Atrium Health, Levine Cancer Institute, Charlotte, NC, USA.;Novant Health Cancer Specialists Matthews, Matthews, NC, USA.;Department of Pharmacy, Atrium Health, Levine Cancer Institute, Charlotte, NC, USA.;Department of Pharmacy, Atrium Health, Levine Cancer Institute, Charlotte, NC, USA.",
"authors": "Moore|Donald C|DC|;Gebru|Tsion|T|;Pellegrino|Annie|A|;Fasan|Adenike|A|;Patel|Jolly|J|;Ringley|J Tanner|JT|",
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"keywords": "breast cancer; neutropenia; oncology; pegfilgrastim; supportive care",
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"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D009503:Neutropenia; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012189:Retrospective Studies",
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"title": "Neutropenia-Associated Outcomes in Patients With Breast Cancer Receiving Myelosuppressive Chemotherapy With Reduced Doses of Pegfilgrastim.",
"title_normalized": "neutropenia associated outcomes in patients with breast cancer receiving myelosuppressive chemotherapy with reduced doses of pegfilgrastim"
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"abstract": "Paraneoplastic cerebellar ataxia is a rare immune-induced, non-metastatic neurologic syndrome, most frequently associated with gynecological cancers, which carries an abysmal prognosis. We report the case of a patient with advanced-stage uterine cancer, who developed severe pancerebellar ataxia, while in partial remission, after the completion of 3 cycles of neoadjuvant platinum-based chemotherapy. Swift initiation of immunosuppressive therapy with corticosteroids combined with plasmapheresis did not result in significant clinical benefit. Early recognition of this debilitating condition and standardization of its treatment strategy are prerequisites for both improved survival outcomes and quality of life in these patients. Further studies are warranted to clarify the immune-stimulating impact of effective cytotoxic chemotherapy and the occurence of autoimmune paraneoplastic neurological syndromes.",
"affiliations": "Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.;Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.;1st Department of Neurology, Medical School, National and Kapodistrian University of Athens, NKUA, Aeginition Hospital, Athens, Greece.;Division of Gynecologic Oncology, 1st Department of Obstetrics and Gynaecology, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece.;Department of Pathology, Alexandra Hospital, Athens, Greece.;Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.;Multiple Sclerosis & Demyelinating Diseases Unit and Immunogenetics Laboratory, 1st Department of Neurology, Medical School, National and Kapodistrian University of Athens, NKUA, Aeginition Hospital, Athens, Greece.;Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.",
"authors": "Liontos|Michalis|M|;Fiste|Oraianthi|O|;Drakopoulou|Danai|D|;Thomakos|Nikolaos|N|;Goula|Kalliroi|K|;Zagouri|Flora|F|;Anagnostouli|Maria|M|;Dimopoulos|Meletios-Athanasios|MA|",
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"doi": "10.1016/j.gore.2021.100826",
"fulltext": "\n==== Front\nGynecol Oncol Rep\nGynecol Oncol Rep\nGynecologic Oncology Reports\n2352-5789\nElsevier\n\nS2352-5789(21)00130-2\n10.1016/j.gore.2021.100826\n100826\nReview Article\nParaneoplastic cerebellar degeneration in platinum-responsive endometrial cancer: A case report and review of literature\nLiontos Michalis mliontos@gmail.com\na1⁎\nFiste Oraianthi ofiste@med.uoa.gr\na1\nDrakopoulou Danai b\nThomakos Nikolaos c\nGoula Kalliroi d\nZagouri Flora florazagouri@yahoo.co.uk\na\nAnagnostouli Maria mdimop@med.uoa.gr\ne\nDimopoulos Meletios-Athanasios a\na Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece\nb 1st Department of Neurology, Medical School, National and Kapodistrian University of Athens, NKUA, Aeginition Hospital, Athens, Greece\nc Division of Gynecologic Oncology, 1st Department of Obstetrics and Gynaecology, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece\nd Department of Pathology, Alexandra Hospital, Athens, Greece\ne Multiple Sclerosis & Demyelinating Diseases Unit and Immunogenetics Laboratory, 1st Department of Neurology, Medical School, National and Kapodistrian University of Athens, NKUA, Aeginition Hospital, Athens, Greece\n⁎ Corresponding author. mliontos@gmail.com\n1 These authors contributed equally to this work.\n\n29 6 2021\n8 2021\n29 6 2021\n37 10082629 4 2021\n22 6 2021\n27 6 2021\n© 2021 The Authors. Published by Elsevier Inc.\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/).\nHighlights\n\n• Paraneoplastic cerebellar ataxia (PCA) represents an uncommon autoimmnue neurological disorder.\n\n• It usually precedes the occurrence or relapse of gynecological cancer; especially ovarian cancer.\n\n• We present the case of platinum-responsive endometrial cancer who developed PCA.\n\nParaneoplastic cerebellar ataxia is a rare immune-induced, non-metastatic neurologic syndrome, most frequently associated with gynecological cancers, which carries an abysmal prognosis. We report the case of a patient with advanced-stage uterine cancer, who developed severe pancerebellar ataxia, while in partial remission, after the completion of 3 cycles of neoadjuvant platinum-based chemotherapy. Swift initiation of immunosuppressive therapy with corticosteroids combined with plasmapheresis did not result in significant clinical benefit. Early recognition of this debilitating condition and standardization of its treatment strategy are prerequisites for both improved survival outcomes and quality of life in these patients. Further studies are warranted to clarify the immune-stimulating impact of effective cytotoxic chemotherapy and the occurence of autoimmune paraneoplastic neurological syndromes.\n\nKeywords\n\nParaneoplastic cerebellar ataxia\nUterine cancer\nGynecological cancers\nAutoimmunity\n==== Body\n1 Introduction\n\nParaneoplastic neurological syndromes (PNS) affect less than 1% of oncological patients and represent neurological manifestations related to immune-mediated responses caused by the expression of onconeural antigens from the underlying solid tumor (Höftberger et al., 2015, Braik et al., 2010). PNS usually precede the diagnosis of neoplasia or its recurrence, whereas, treatment of the underlying malignancy is considered to be the pillar of their management (Hammack et al., 1990, Blaes et al., 1999). Paraneoplastic cerebellar ataxia (PCA), associated with Purkinje cell cytoplasmic antibody type 1 (PCA1) or Anti-Yo, is the most common among PNS (O’Brien et al., 1995), usually observed in gynecological cancers (Yan et al., 2018).\n\nHerein, we present a rare case of an elderly female who developed rapidly progressive PCA during the course of effective platinum-based chemotherapy for locally advanced uterine carcinoma of serous histology. Despite the early introduction of both high dose corticosteroids and plasmapheresis her neurological symptoms deteriorated and rendered her bedridden.\n\n2 Case presentation\n\nA 70-year-old, ex-smoker female, of Caucasian origin, with multiple comorbidities, presented with postmenopausal vaginal bleeding of 1-year duration. An endometrial biopsy was performed and pathology revealed uterine serous carcinoma showing immunohistochemical expression of p16, estrogen receptor (ER), and WT1, absence of human epidermal growth factor receptor 2 (HER2)/neu overexpression, and wild-type pattern of p53 expression. Immunohistochemical analysis was also indicative of extensive lymphocytic infiltration (Fig. 1). By that time no further molecular analysis of the neoplasm was performed and was classified as serous uterine carcinoma based on the histopathological analysis only.Fig. 1 Histopathological analysis of endometrial sampling tissue with 10× (A) and 20× (B) magnifications, respectively, indicative of extensive lymphocytic infiltration, immunohistochemical expression of p16, estrogen receptor (ER), and WT1, absence of human epidermal growth factor receptor 2 (HER2)/neu overexpression, and wild-type pattern of p53 expression.\n\nA subsequent abdominal magnetic resonance imaging (MRI) demonstrated the presence of a 6 × 4 cm bulky mass that distended the uterine cavity and enlarged iliac, femoral, and inguinal lymph nodes (Fig. 2A); thus, tumor was classified as FIGO stage IVB. The patient was not considered as candidate for surgical intervention and neoadjuvant chemotherapy with three-weekly regimen of carboplatin and paclitaxel was commenced.Fig. 2 Pre-treatment abdominal magnetic resonance imaging (MRI) (A) and post-treatment abdominal computed tomography (B), indicative of partial response.\n\nPost 1st cycle of chemotherapy patient presented with symmetrical numbness in the lower extremities resulting in gait abnormality, attributed to taxane-associated neuropathy. Due to this adverse event dose of paclitaxel was initially reduced and subsequently permanently discontinued. After the completion of 3 cycles of treatment, the patient developed a rapidly progressive cerebellar syndrome with blurry vision, horizontal nystagmus, truncal ataxia, and pronounced dysarthria. Nevertheless, computed tomography (CT) scan of the chest and abdomen revealed partial response of the disease (Fig. 2B).\n\nMRI of the brain excluded metastatic disease, structural abnormalities, ischemia, and hematomas (Fig. 3a), whereas cerebrospinal fluid (CSF) analysis showed mild lymphocytic pleocytosis (10 cells per mm3), mild elevation of protein and glucose levels, and negative results on both cytology and culture. The presence of a positive titer of anti-Yo antibodies both in serum and CSF confirmed the diagnosis of PCA.Fig. 3 Μagnetic resonance imaging (MRI) of the brain (A) at initial diagnosis of paraneoplastic cerebellar ataxia (T1-weighted) and (B) 3 months later (T2-weighted and flair sequences) revealing evolving cerebellar atrophy (black and white arrows).\n\nWithin 15 days after the onset of neurological symptoms, intravenous followed by oral dexamethasone (24 mg daily at first followed by slow tapering schedule) was commenced. She also underwent three sessions of plasmapheresis without any clinical improvement.\n\nDespite the early initiation of treatment, including intravenous corticosteroids and plasmapheresis, her neurological symptoms relentlessly progressed and no further therapeutic approaches had been attempted. Due to her disability, our patient relocated to her hometown whereas she received best supportive care. She eventually died 11 months after the diagnosis of her endometrial cancer and 8 months after the diagnosis of PCA, presumably due to liver metastatic disease after a brief hospitalization for abdominal pain.\n\n3 Discussion\n\nDirect invasion of the nervous system by malignancy, metastatic disease, cancer treatment-related toxicity, infections, metabolic and vascular disorders are among the common causes of neurological complications in cancer patients (Höftberger et al., 2015). PNS represent a rather rare, heterogeneous group of neurological syndromes characterized by cancer-stimulated immune responses, directed by specific antibodies, which cross-react with neural tissue, causing its damage (Braik et al., 2010). PCA, which accounts for 25% of PNS, is associated with breast, ovarian, and lung cancer, exhibits a strong preference for middle-aged female patients, and usually antedates tumor occurrence (Yan et al., 2018, Tanriverdi et al., 2013, Rojas et al., 2000). To the best of our knowledge, there have been published only 14 cases of PCA associated with endometrial cancer so far (Hammack et al., 1990, Peterson et al., 1992, Tsaukamoto et al., 1989, Brock et al., 2001, Lie et al., 2016, Karpathiou et al., 2016, Erez et al., 2007, Henry et al., 2005, Johns et al., 1999, Giometto et al., 1997, Petit et al., 1997, Rana et al., 2012), whilst our case is the first to be reported in a patient with chemotherapy-responsive uterine cancer.\n\nAlmost 50% of PCA cases correlate with Anti-Yo antibody, of IgG1 subtype (Amyes et al., 2001), which is synthesized in the central nervous system of the patients as an autoimmune response against an ectopically expressed neuronal antigen, the Yo antigen (Posner et al., 1989). This antigen is a cytoplasmic protein, called cerebellar degeneration-related protein 2 (CDR2), normally expressed in the Purkinje cells (PCs) of the cerebellum, but also in brain stem, spermatogonia, and ectopically in gynecological and breast tumors (Amyes et al., 2001, Aboul-Enein et al., 2008, Darnell et al., 2000).\n\nIt has been observed that CDR2 protein sequesters the transcription factor c-Myc, downregulating its activity, whereas the presence of anti-Yo antibodies disrupt this interaction, increasing c-Myc activity, thus leading to extensive PC apoptosis (Albert et al., 2000, Okano et al., 1999). It has also been postulated that the internalization of CDR2/CDR2-like (CDR2L) antibodies by Purkinje cells could lead to cells’ impaired calcium homeostasis, thus neuronal destruction and excessive cell death (Schubert et al., 2014). Recently, Small et al. demonstrated that each PCA patient with anti-Yo antibodies carried at least one genetic alteration in CDR2 gene, suggesting that these somatic mutations in tumor cells might be sufficient to elicit an autoimmune response (Small et al., 2018).\n\nΥet, the administration of anti-Yo antibodies in preclinical animal models may not always result in PCA (Verschuuren et al., 1996, Graus et al., 1991), whereas, both CDR2 and CDR2L antigens are widely expressed in ovarian cancers (Raspotnig et al., 2017, Darnell and Albert, 2000), hence seem to be inadequate to trigger autoimmunity. Accumulating evidence suggests that auto-reactive, cytotoxic, CDR2-specific CD8 T lymphocytes not only intensely infiltrate into gynecological tumors of anti-Yo positive patients with PCA (Vialatte de Pémille et al., 2018) but also appear to represent the final mediators of neuronal loss (Albert et al., 1998, Yshii et al., 2016). Indeed, the immunohistochemistry in our patient’s diagnostic biopsy revealed prominent tumor lymphocytic infiltration.\n\nAnti-Yo antibody was found to be present in some patients with paraneoplastic cerebellar degeneration (PCD), but it was very early documented that there is no evidence of its causal contribution in Purkinje cell loss (Tanaka and Tanaka, 1999). Instead, the interaction between peptide and Human Leucocyte Antigens (HLA) molecules had been demonstrated. Specifically, the HLA-class I restricted cytotoxic T cell (CTL) activity against autologous fibroblasts was shown, using a peptide of the Yo protein with the HLA A24-specific allele. It was the first evidence of the presence of CTL reacting with a peptide of Yo protein in the peripheral venous blood from a patient with PCD (Tanaka and Tanaka, 1999). Furthermore, in another research paper, a complex HLA association in paraneoplastic cerebellar ataxia with anti-Yo antibodies was found, with protective or risk effect, mainly of the Class II domain (Hillary et al., 2018). This targeted HLA-driven autoimmunity was also documented in another case of a patient having multiple autoimmune disorders and malignancies, including gynecological tumors (Anagnostouli et al., 2014).\n\nClinically, PCA is usually characterized by pancerebellar dysfunction (ataxia, diplopia, nystagmus, dysphagia, dysarthria) with subacute onset and rapid progression (Dalmau and Rosenfeld, 2008). Dedicated neuroimaging techniques of the cerebellum, including CT scan, MRI, and or functional MRI (fMRI), are usually normal, especially at the initial stages of the disease, thus of limited value. Yet, fluorodeoxyglucose positron emission tomography (FDG-PET) could reveal hypermetabolism due to the inflammatory responses at first, followed by abnormal decreased metabolism related to the undergoing neuronal cell degeneration (Dalmau and Rosenfeld, 2008).\n\nCSF analysis reveals nonspecific abnormalities (Dalmau and Rosenfeld, 2008, Hasadsri et al., 2013). Among the well-characterized paraneoplastic antibodies, which could be present in both patient’s CSF and/or sera and include the anti-Yo (PCA-1), anti-Tr, anti-Hu (ANNA-1), anti-Ri (ANNA-2), anti-CRMP5 (CV2), anti-Ma1, anti-Ma2 (Ta), anti-Recoverin, anti-Amphiphysin, and anti-SOX1, the first three are the main, highly specific antibodies related to PCA, with anti-Yo being the most common, strongly related to gynecological cancers (Tanriverdi et al., 2013, Graus et al., 2004). Nevertheless, it has been suggested to test the entire range of these 10 onconeural autoantibodies, despite that almost 40% of PNS cases have undetectable antibodies (Giometto et al, 2010). Histopathologic examination reveals cerebellar atrophy, inflammatory infiltrates especially at the early stages of PCA, and gliosis (Giometto et al., 1997, Small et al., 2018).\n\nGiven its rarity, there are not established evidence-based therapeutic protocols. Yet, PCA stabilization is primarily associated with the treatment of the underlying malignancy (Dalmau and Rosenfeld, 2008). Immunosuppressive therapy consisting of corticosteroids, cyclophosphamide, azathioprine, and rituximab, with intravenous immunoglobulin (IVIG) and/or plasma exchanges most often have poor results (Kannoth, 2012). Accurate and timely diagnosis is needed, considering that treatment initiation within 1 month seem to correlate with better outcomes; breast cancer and young age have also been described as prognostic factors (Rojas et al., 2000, Widdess-Walsh et al., 2003, Vedeler et al., 2006). Overall, disease progression is the leading cause of death in PCA patients, despite PCA itself deteriorates patients’ quality of life more than the underlying cancer (Hasadsri et al., 2013, Noorani et al., 2008).\n\nIn our uncommon case, the ataxic symptoms occurred while our patient’s uterine cancer was in partial response, after the initiation of platinum-based chemotherapy. As our knowledge of the immunomodulating effects of chemotherapy deepens in relation to the well-described immunological basis of PCA pathogenesis, the hypothesis of accelerated immune responses to tumor antigens, expressed by the rapidly apoptotic cancer cells, seems appealing.\n\nIndeed, cytotoxic chemotherapeutic agents have been the mainstay of treatment in cancer patients for over 70 years (Farber and Diamond, 1948). Despite their mechanism of action relies on impairment of mitosis (Opzoomer et al., 2019), however, accumulating evidence recognizes their potential immunomodulatory properties (Kroemer et al., 2013, Bracci et al., 2014, Pfirschke et al., 2016, Sakai et al., 2013, Pol et al., 2015). A few years ago, Kroemer et al. first characterized the immunogenic cell death (ICD), an immunostimulatory type of apoptosis, initiated by some chemotherapeutic agents (most commonly anthracyclines, alkylating agents, and platinum compounds), whereas the release of antigenic material expressed by dying tumor cells triggers an adaptive immune response, improving the overall antineoplastic efficacy (Dudek et al., 2013, Ghiringhelli et al., 2009, Schiavoni et al., 2011, McGranahan et al., 2016). Finally, it has also been described that apoptotic tumor cells yield a potent mean of antigen transfer to dendritic cells, which migrate to local draining lymph nodes and activate cytotoxic, CDR2-specific CD8 T lymphocytes, thus generating an antigen-specific immunity (Albert et al., 2000, Darnell, 2004).\n\nFurther studies are warranted to deepen the understanding of the exact pathogenetic mechanisms of PCA, and how the innate immune responses to immunomodulating effects of chemotherapy may precipitate autoimmune neurologic disease in particular.\n\n4 Conclusion\n\nPCA is a rare, devastating neurological disorder induced by paraneoplastic autoimmunity against the cerebellum, posing both a diagnostic and therapeutic challenge. The precise pathogenetic pathways promoting the breakdown of immune tolerance in PCA awaits to be fully deciphered, in order to provide the biological rationale for advancing its treatment in the near future.\n\nCRediT authorship contribution statement\n\nMichalis Liontos: Conceptualization, Data curation, Writing - review & editing, Project administration. Oraianthi Fiste: Data curation, Writing - original draft, Writing - review & editing. Danai Drakopoulou: Data curation, Writing - review & editing. Nikolaos Thomakos: Data curation, Writing - review & editing. Kalliroi Goula: Data curation, Writing - review & editing. Flora Zagouri: Writing - review & editing, Supervision, Project administration. Maria Anagnostouli: Conceptualization, Data curation, Writing - review & editing, Project administration. Meletios-Athanasios Dimopoulos: Writing - review & editing, Supervision, Project administration.\n\nDeclaration of Competing Interest\n\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n\nAcknowledgements\n\nNone.\n\nEthics\n\nNo ethical approval was required for this manuscript.\n\nFunding\n\nThis review article received no external funding.\n\nPatient consent for publication\n\nWritten informed consent has been obtained from the patient to publish this paper.\n==== Refs\nReferences\n\nAboul-Enein F. Hoftberger R. Buxhofer-Ausch V. Neocortical neurones may be targeted by immune attack in anti-Yo paraneoplastic syndrome Neuropathol. Appl. Neurobiol. 34 2008 248 252 17995920\nAlbert M.L. Austin L.M. Darnell R.B. Detection and treatment of activated T cells in the cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration Ann. Neurol. 47 1 2000 9 17 10632096\nAlbert M.L. Darnell J.C. Bender A. Tumor-specific killer cells in paraneoplastic cerebellar degeneration Nat. Med. 4 1998 1321 1324 9809559\nAmyes E. Curnow J. Stark Z. Restricted IgG1 subclass of anti-Yo antibodies in paraneoplastic cerebellar degeneration J. Neuroimmunol. 114 1–2 2001 259 264 11240040\nAnagnostouli M. Anagnostoulis G. Katsavos S. HLA-DRB1 15:01 and Epstein-Barr virus in a multiple sclerosis patient with psoriasis, nasopharyngeal and breast cancers. Lessons for possible hidden links for autoimmunity and cancer J. Neurol. Sci. 339 1–2 2014 26 31 24576802\nBlaes F. Strittmatter M. Merkelbach S. Intravenous immunoglobulin in the therapy of paraneoplastic neurological disorders J. Neurol. 246 1999 299 303 10367699\nBracci L. Schiavoni G. Sistigu A. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer Cell Death Differ. 21 2014 15 25 23787994\nBraik T. Evans A.T. Telfer M. Paraneoplastic neurological syndromes: Unusual presentations of cancer. A practical review Am. J. Med. Sci. 340 2010 301 308 20460982\nBrock S. Ellison D. Frankel J. Anti-Yo antibody-positive cerebellar degeneration associated with endometrial carcinoma: case report and review of the literature Clin. Oncol. (R Coll Radiol). 13 6 2001 476 479 11824891\nDalmau J. Rosenfeld M.R. Paraneoplastic syndromes of the CNS Lancet Neurol. 7 4 2008 327 340 18339348\nDarnell J.C. Albert M.L. Darnell R.B. Cdr2, a target antigen of naturally occuring human tumor immunity, is widely expressed in gynecological tumors Cancer Res. 60 2000 2136 2139 10786675\nDarnell R.B. Paraneoplastic neurologic disorders: windows into neuronal function and tumor immunity Arch. Neurol. 61 1 2004 30 32 14732616\nDarnell R.B. Albert M.L. Cdr2-specific CTLs are detected in the blood of all patients with paraneoplastic cerebellar degeneration analyzed Ann. Neurol. 48 2000 270 271 10939585\nDudek A.M. Garg A.D. Krysko D.V. Inducers of immunogenic cancer cell death Cytokine Growth Factor Rev. 24 2013 319 333 23391812\nErez Y. Rojansky N. Shveiky D. Endometrial carcinoma first presenting as paraneoplastic cerebellar degeneration Gynecol. Oncol. 105 3 2007 826 827 17428523\nFarber S. Diamond L.K. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid N. Engl. J. Med. 238 1948 787 793 18860765\nGhiringhelli F. Apetoh L. Tesniere A. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1betadependent adaptive immunity against tumors Nat. Med. 15 2009 1170 1178 19767732\nGiometto B. Grisold W. Vitaliani R. Paraneoplastic neurologic syndrome in the PNS Euronetwork database: a European study from 20 centers Arch. Neurol. 67 2010 330 335 20212230\nGiometto B. Marchiori G.C. Nicolao P. Sub-acute cerebellar degeneration with anti-Yo autoantibodies: immunohistochemical analysis of the immune reaction in the central nervous system Neuropathol. Appl. Neurobiol. 23 6 1997 468 474 9460712\nGraus F. Delattre J.Y. Antoine J.C. Recommended diagnostic criteria for paraneoplastic neurological syndromes J. Neurol. Neurosurg. Psychiatr. 75 2004 1135 1140\nGraus F. Illa I. Ugusti M. Effect of intravenous injection of anti-Purkinje cell antibody (anti-Yo) in a guinea pig model J. Neurol. Sci. 106 1991 82 87 1779243\nHammack J.E. Kimmel D.W. O’Neill B.P. Paraneoplastic cerebellar degeneration: a clinical comparison of patients with and without Purkinje cell cytoplasmic antibodies Mayo Clin. Proc. 65 1990 1423 1431 2232897\nHasadsri L. Lee J. Wang B.H. Anti-Yo associated paraneoplastic cerebellar degeneration in a man with large cell cancer of the lung Case Rep. Neurol. Med. 2013 2013 725936\nHenry R.J. Harries-Jones R. Balakrishnan V.K. Gynaecology meets neurology: paraneoplastic cerebellar degeneration Aust. N. Z. J. Obstet. Gynaecol. 45 4 2005 342 16029316\nHillary R.P. Ollila H.M. Lin L. Complex HLA association in paraneoplastic cerebellar ataxia with anti-Yo antibodies J. Neuroimmunol. 315 2018 28 32 29306402\nHöftberger R. Rosenfeld M.R. Dalmau J. Update on neurological paraneoplastic syndromes Curr. Opin. Oncol. 27 2015 489 495 26335665\nJohns J.B. Odunsi K.O. Fleischman S. Serous adenocarcinoma of the uterus presenting as paraneoplastic cerebellar degeneration Gynecol. Oncol. 73 2 1999 326 330 10329056\nKannoth Sudheerna Paraneoplastic neurologic syndrome: A practical approach Ann Indian Acad Neurol 15 1 2012 6 12 10.4103/0972-2327.93267 22412264\nKarpathiou G. Da Cruz V. Casteillo F. Paraneoplastic cerebellar degeneration and endometrial cancer: a rare occurrence Pathology. 48 3 2016 275 278 27020505\nKroemer G. Galluzzi L. Kepp O. Immunogenic cell death in cancer therapy Annu. Rev. Immunol. 31 2013 51 72 23157435\nLie, G., Morley, T., Chowdhury, M., 2016. Paraneoplastic cerebellar degeneration as a marker of endometrial cancer recurrence. BMJ Case Rep. 18, 2016:bcr2016215286.\nMcGranahan N. Furness A.J. Rosenthal R. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade Science 351 2016 1463 1469 26940869\nNoorani A. Sadiq Z. Minakaran N. Paraneoplastic cerebellar degeneration as a presentation of breast cancer—a case report and review of the literature Int. Semin. Surg Oncol. 5 2008 8 18426566\nO’Brien T.J. Pasaliaris B. D’Apice A. Byrne, E. Anti-Yo positive paraneoplastic cerebellar degeneration: a report of three cases and review of the literature J. Clin. Neurosci. 2 1995 316 320 18638835\nOkano H.J. Park W.Y. Corradi J.P. The cytoplasmic Purkinje onconeural antigen cdr2 down-regulates c-Myc function: implications for neuronal and tumor cell survival Genes Dev. 13 16 1999 2087 2097 10465786\nOpzoomer J.W. Sosnowska D. Anstee J.E. Cytotoxic chemotherapy as an immune stimulus: A molecular perspective on turning up the immunological heat on cancer Front. Immunol. 10 2019 1654 31379850\nPeterson K. Rosenblum M.K. Kotanides H. Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients Neurology. 42 1992 1931 1937 1407575\nPetit T. Janser J.C. Achour N.R. Paraneoplastic temporal lobe epilepsy and anti-Yo autoantibody Ann. Oncol. 8 9 1997 919\nPfirschke C. Engblom C. Rickelt S. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy Immunity 44 2016 343 354 26872698\nPol J. Vacchelli E. Aranda F. Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy Oncoimmunology. 4 4 2015 e1008866\nPosner, J.B., Furneaux, H.M., Rosa, E., 1989. Central nervous system synthesis of autoantibodies in paraneoplastic syndromes. Neurology. 39: Suppl 1: 244. Abstract.\nRana A.Q. Rana A.N. Adlul A. Acute ataxia due to anti-Yo antibody paraneoplastic cerebellar degeneration 4 months prior to diagnosis of uterine carcinoma Acta Neurol. Belg. 112 3 2012 303 304 22426676\nRaspotnig M. Haugen M. Thorsteinsdottir M. Cerebellar degeneration-related proteins 2 and 2-like are present in ovarian cancer in patients with and without Yo antibodies Cancer Immunol. Immunother. 66 2017 1463 1471 28710511\nRojas I. Graus F. Keime-Guibert F. Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies Neurology. 55 2000 713 715 10980743\nSakai H. Kokura S. Ishikawa T. Effects of anticancer agents on cell viability, proliferative activity and cytokine production of peripheral blood mononuclear cells J. Clin. Biochem. Nutr. 52 1 2013 64 71 23341700\nSchiavoni G. Sistigu A. Valentini M. Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis Cancer Res. 71 2011 768 778 21156650\nSchubert M. Panja D. Haugen M. Paraneoplastic CDR2 and CDR2L antibodies affect Purkinje cell calcium homeostasis Acta Neuropathol. 128 2014 835 852 25341622\nSmall M. Treilleux I. Couillault C. Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration Acta Neuropathol. 135 2018 565 579\nTanaka M. Tanaka K. A candidate peptide reacting with cytotoxic T cells in paraneoplastic cerebellar degeneration with anti-Yo antibody Rinsho Shinkeigaku. 39 6 1999 603 605 10502981\nTanriverdi O. Meydan N. Barutca S. Anti-Yo antibody-mediated paraneoplastic cerebellar degeneration in a female patient with pleural malignant mesothelioma Jpn. J. Clin. Oncol. 43 2013 563 568 23475537\nTsaukamoto T. Yamamoto H. Iwasaki Y. Antineural autoantibodies in patients with paraneoplastic cerebellar degeneration Arch. Neurol. 46 1989 1225 1229 2818258\nVedeler C.A. Antoine J.C. Giometto B. Management of paraneoplastic neurological syndromes: report of an EFNS task force Eur. J. Neurol. 13 2006 682 690 16834698\nVerschuuren J. Chuang L. Rosenblum F. Inflammatory infiltrates and complete absence of Purkinje cells in anti-Yo-associated paraneoplastic cerebellar degeneration Acta Neuropathol. 91 1996 519 525 8740233\nVialatte de Pémille C. Berzero G. Small M. Transcriptomic immune profiling of ovarian cancers in paraneoplastic cerebellar degeneration associated with anti-Yo antibodies Br. J. Cancer 119 1 2018 105 113 29899393\nWiddess-Walsh P. Tavee J.O. Schuele S. Response to intravenous immunoglobulin in anti-Yo associated paraneoplastic cerebellar degeneration: case report and review of the literature J. Neurooncol. 63 2003 187 190 12825823\nYan L. Dong X. Xu H. Paraneoplastic cerebellar degeneration associated with breast cancer: A case report and review of the literature Mol. Clin. Oncol. 9 2 2018 163 167 30101014\nYshii L.M. Gebauer C.M. Pignolet B. CTLA4 blockade elicits paraneoplastic neurological disease in a mouse model Brain. 139 2016 2923 2934 27604307\n\n",
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"issue": "37()",
"journal": "Gynecologic oncology reports",
"keywords": "Autoimmunity; Gynecological cancers; Paraneoplastic cerebellar ataxia; Uterine cancer",
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"title": "Paraneoplastic cerebellar degeneration in platinum-responsive endometrial cancer: A case report and review of literature.",
"title_normalized": "paraneoplastic cerebellar degeneration in platinum responsive endometrial cancer a case report and review of literature"
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"abstract": "A 66-year-old woman was diagnosed with a brain abscess. The abscess was drained by sterotactic catheter insertion. She was administered metronidazole at a dose of 2 g/day. On the 30th day of treatment, she had nausea that gradually progressed. On the 45th day, she developed a disturbance of consciousness and was admitted to our department. She was in stuporous state, and had slight vestibular and cerebellar dysfunctions. Diffusion-weighted and FLAIR brain MR images showed bilateral symmetrical high signals in the splenium of the corpus callosum (SCC), cerebellar dentate nucleus, and inferior colliculus. The apparent diffusion coefficient (ADC) map was reduced in the SCC, but not in the other locations. The peak of lactate on MR spectroscopy was increased in the SCC. The clinical presentation and image changes of the patient were thought to be most consistent with metronidazole toxicity. Metronidazole was discontinued, and her condition improved rapidly. She was discharged 14 days later. The lesions in her cerebellar dentate nucleus and inferior colliculus, suspected to be vasogenic edema, had disappeared 5 to 10 days later, whereas the lesion in the SCC, which gradually diminishing, could still be faintly detected 40 days later, which corresponded to our suspicion of cytotoxic edema.",
"affiliations": "Department of Neurology, Brain Attack Center Ota Memorial Hospital.",
"authors": "Neshige|Shuichiro|S|;Kanaya|Yuhei|Y|;Takeshima|Shinichi|S|;Yoshimoto|Takeshi|T|;Tanaka|Akio|A|;Kuriyama|Masaru|M|",
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"mesh_terms": "D000368:Aged; D000890:Anti-Infective Agents; D001922:Brain Abscess; D001929:Brain Edema; D002529:Cerebellar Nuclei; D003337:Corpus Callosum; D038524:Diffusion Magnetic Resonance Imaging; D004322:Drainage; D005260:Female; D006801:Humans; D007245:Inferior Colliculi; D009682:Magnetic Resonance Spectroscopy; D008795:Metronidazole; D016896:Treatment Outcome; D028761:Withholding Treatment",
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"abstract": "BACKGROUND\nThromboembolic events are a known complication of Inflammatory Bowel Disease (IBD) especially during disease relapse, more commonly in deep veins of extremities and lung, and rarely as Cerebral Sinovenous Thrombosis (CSVT).\n\n\nMETHODS\nWe describe an 11 year, old male patient with 3 months history of Ulcerative Colitis (UC) who presented as pseudotumor cerebri due to superior sagittal sinus thrombosis during an acute exacerbation of his colitis, that was successfully treated with heparin and then warfarin.\n\n\nCONCLUSIONS\nIn any known cases of UC presenting as acute severe headache, consider CSVT and request brain MRI and MRV to facilitate the diagnosis and early treatment.",
"affiliations": "Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran ; Growth & Development Research Center, Tehran University of Medical Sciences, Tehran, Iran ; Children's Medical Center, Pediatrics Center of Excellence, Tehran, Iran.",
"authors": "Mahmoud Reza|Ashrafi|A|;Firozeh|Hosseini|H|;Houman|Alizadeh|A|;Mehri|Najafi Sani|NS|",
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"fulltext": "\n==== Front\nIran J PediatrIran J PediatrIJPDIranian Journal of Pediatrics2008-21422008-2150Tehran University of Medical Sciences 23549165IJPD-23-109Case ReportPseudotumor Cerebri in a Case of Ulcerative Colitis with Sagittal Sinus Thrombosis Ashrafi Mahmoud Reza MD123Hosseini Firozeh MD3*Alizadeh Houman MD3Najafi Sani Mehri MD131 Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran2 Growth & Development Research Center, Tehran University of Medical Sciences, Tehran, Iran3 Children's Medical Center, Pediatrics Center of Excellence, Tehran, Iran* Corresponding Author:Address: Division of Neurology, Children's medical Center, No 62, Dr Gharib St., Tehran, Iran. E-mail:firozeh_hosseini@yahoo.com2 2013 23 1 109 112 24 12 2011 22 6 2012 © 2013 Iranian Journal of Pediatrics & Tehran University of Medical Sciences2013This is an open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0), which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.Background\nThromboembolic events are a known complication of Inflammatory Bowel Disease (IBD) especially during disease relapse, more commonly in deep veins of extremities and lung, and rarely as Cerebral Sinovenous Thrombosis (CSVT).\n\nCase Presentation\nWe describe an 11 year, old male patient with 3 months history of Ulcerative Colitis (UC) who presented as pseudotumor cerebri due to superior sagittal sinus thrombosis during an acute exacerbation of his colitis, that was successfully treated with heparin and then warfarin.\n\nConclusion\nIn any known cases of UC presenting as acute severe headache, consider CSVT and request brain MRI and MRV to facilitate the diagnosis and early treatment.\n\nInflammatory Bowel DiseasePseudotumor CerebriUlcerative ColitisCerebral Thrombosis\n==== Body\nIntroduction\nCerebral Sinovenous Thrombosis (CSVT) is a significant cause of pseudotumor cerebri or secondary intracranial hypertension, that is being increasingly detected due to practice of newer neuroimaging techniques including Magnetic Resonance Imaging (MRI) and Magnetic Resonance Venography (MRV). The incidence of CSVT is at least 0.67 per 100,000 children per year[1]. The risk of thromboembolism in Inflammatory Bowel Disease (IBD) is 3-4 fold more than general population[2]. CSVT is a rare and often under, diagnosed complication of IBD, more common in UC than in Crohn's Disease (CD). Pseudotumor cerebri is a rare presentation of sinovenousus thrombosis. We report a newly diagnosed case of ulcerative colitis (UC) that was admitted because of pseudotumor cerebri due to Superior Sagittal Sinus Thrombosis during the flare up of his colitis.\n\nCase Presentation\nAn 11, year, old boy was admitted due to severe pulsatile bilateral frontal and occipital headache since 2 days ago. Headache was associated with orbital pain, photophobia, somnolence, transient blurred vision and recurrent vomiting for two days. Blood Pressure 130/80 mmHg, respiratory rate 30 per minute; temperature normal. The patient was a known case of UC that has been treated with prednisolone, Asacol since 3 months ago. Because of flare up of colitis from one week ago the dose of prednisolone was increased up to 40 mg. In past medical history neonatal jaundice and operated hypospadiasis was reported. The mother had migraine since 15 years ago. Neurologic examination was normal except for bilateral papilledema and exaggerated (+++) bilateral deep tendon reflexes. In complete blood count (CBC) white blood cells (WBC) was 26430 (PMN73%, L17.8%, M8.8%), hemoglobin (Hgb) 11 and hematocrit (Hct) 34 and platelets (Plt) was 436000. Other laboratory findings include erythrocyte sedimentation rate (ESR) was 6 and Anti-nuclear antibodies was negative. In second CBC, WBC, Hgb and Plt were 10180 and 9.5, 344000 respectively. Urynalysis and renal function tests were normal. Lumbar puncture (LP) findings were WBC: 0.2, Pro: 6.5, RBC: 700, Glu: 65 and lactate: 15.\n\nBrain Computerized Tomography (CT) scan showed right parasagittal low attenuated lesion in subcortical area above the central sulcus. First brain MRI showed some narrowing of superior sagittal sinus without strong evidences of thrombosis in T1 and T2 weighted imaging sequences (Fig. 1). LP showed normal cerebro-spinal fluid (CSF) analysis with increased (32.5 cm H2O) CSF opening pressure. With the diagnosis of pseudotumor cerebri, we continued corticosteroid administration and started acetazolamide. The second LP showed normal (14 cm H2O) CSF pressure. The patient was readmitted one week after the discharge because of severe headache, photophobia, drowsiness and painful eye movements. LP showed increased CSF opening pressure (60 cm H2O). In order to reduce the cerebrospinal pressure 30 ml of CSF was withdrawn. Although the second brain MRI seemed almost normal (Fig. 1), brain MRV was performed with phase contrast sequence after Gd injection that showed clearly superior sagittal sinus filling defects and irregularities due to thrombosis (Fig. 2). During the second admission an episode of transient gross hematuria was seen but abdominal sonography was normal. Serum homocysteine and B12 level were within normal limits. Visual evoked potential and visual field evaluation were also normal.\n\nFig. 1 Axial T2 WI looks almost normal. Note signal void superior sagittal sinus against evidence of thrombosis\n\nFig. 2 MRV with Gd injection revealed nonvisualization of superior sagittal sinus due to complete thrombosis\n\nTreatment with intravenous heparin infusion was initiated for 7 days and then continued with warfarin for 6 months. Control brain MRV revealed remarkable improvement in venous flow, with some residual thrombosis after three months and normal MRV after 6 months. During 6 months follow up, the patient had 2 flare-ups of ulcerative colitis without neurologic complication.\n\nDiscussion\nIBD and its thrombotic complications were first noticed by Bargen and Barker in 1936[3]. Thromboembolic events are a known complication of IBD occurring in 1.3% to 7/5% of these patients[4–6]. Thromboembolic complications are three fold more likely in IBD patients than in controls and the relative risk exceeds 15 during disease flares[7].\n\nDeep venous thrombosis and pulmonary emboli are the most common thrombotic complications of IBD, but CSVT is rare and more critical event. The most frequently involved vessels are transverse sinus (86%), superior sagittal sinus (62%), straight sinus (18%), cortical veins (17%), vein of Galen and internal cerebral veins (11%)[7, 8]. In our case the superior sagittal sinus is involved; this is reported in 0.8% of UC patients[9]. The clinical presentations of CSVT are various including headache, encephalopathy, focal deficit and intracranial hypertension. The clinical manifestations of CSVT are nonspecific; therefore its diagnosis is difficult and requires improved attention and more suspicion. In older children headache is a common presentation of CSVT[10]. Pseudotumor cerebri is a well documented[11] but rare presentation of CSVT in IBD. The reported patient is a known case of UC, in whom thromboembolic complications presented as pseudotumor cerebri.\n\nCauses of hypercoagulable state in IBD are complex, including increased procoagulants, decreased anticoagulants, depressed fibrinolysis, platelet abnormalities, endothelial dysfunction and immunological abnormalities[12]. Other risk factors that may play a role for thrombotic complications are corticosteroid therapy, dehydration, immobilization, iron deficiency, increased homocysteine, B12 deficiency and infections[2]. Our reported case had normal serum homocysteine and B12 level but increment of corticosteroid dosage and relapse of his colitis were the known risk factors of the CSVT.\n\nModern neuroimaging techniques such as brain MRI and MRV are the most important investigating tools for the diagnosis of CSVT. Although linear densities and the empty delta sign in an unenhanced brain CT may suggest the diagnosis of CSVT[1], even enhanced CT may miss the diagnosis in up to 40% of patients[8, 13]. In this patient brain CT did not suggest the diagnosis and surprisingly brain MRI was normal while MRV confirmed the diagnosis of sagittal sinus thrombosis. Cooperation between the clinician and radiologist can be helpful for appropriate imaging and establishing a faster and more accurate diagnosis. Antithrombotic therapy with standard or low molecular weight heparin for 7-10 days followed by oral anticoagulants for 3-6 months has been proved to be effective and safe[14]. In this case we started intravenous heparin infusion and then continued antithrombotic therapy with warfarin.\n\nPrognosis of CSVT is poor and 50% of these patients had neurologic sequelae or died[9]. In one study 38% of the patients had neurologic deficits and 8% died[6]. Eight months follow-up of this case showed him in a good clinical condition and last MRV was normal.\n\nConclusion\nWe recommend considering the occurrence of CSVT in any case of UC that complains of acute severe headache and performing brain MRI and MRV to confirm the diagnosis and then faster initiation of antithrombotic therapy.\n==== Refs\nReferences\n1 De Veber G Monagle P Chan A Prothrombotic disorders in infants and children with cerebral thromboembolism Arch Neurol 1998 55 12 1539 43 9865798 \n2 Twig G Zandman-Goddard G Szyper-Kravitz M Systemic thromboembolism in inflammatory bowel disease: mechanisms and clinical applications Ann N Y Acad Sci 2005 1051 166 173 16126956 \n3 Bargen JA Barker NW Extensive arterial and venous thrombosis complicating chronic ulcerative colitis Arch Intern Med 1936 58 1 17 31 \n4 Murata S Ishikawa N Oshikawa S Cerebral sinus thrombosis associated with severe active ulcerative colitis Intern Med 2004 43 5 400 3 15206553 \n5 Shigemori Y Koshinaga M Suma T Superior sagittal sinus thrombosis suffered as a complication of ulcerative colitis: case report No Shinkei Geka 2006 34 9 939 42 16984029 \n6 Kawanishi M Yoshida Y Sakaguchi I Cerebral venous sinus thrombosis in a patient with ulcerative colitis J Stroke Cerebrovasc Dis 2003 12 6 271 5 17903939 \n7 Zitomersky NL Verhave M Trenor CC Thrombosis and inflammatory bowel disease: A call for improved awareness and prevention Inflamm Bowel Dis 2001 17 1 458 70 20848518 \n8 De Veber G Maureen A Adams C Cerebral sinovenous thrombosis in children N Engl JMed 2001 345 6 417 22 11496852 \n9 Ozdil S Akyüz F Pinarbasi B Ulcerative colitis: analyses of 116 cases (do extraintestinal manifestations effect the time to catch remission?) Hepatogastroenterology 2004 51 57 768 70 15143912 \n10 Nudelman RJ Rosen DG Rouah E Verstovsek G Cerebral sinus thrombosis: a fatal neurological complication of ulcerative colitis Patholog Res Int 2010 2010 132754 21152173 \n11 Carvalho KS Bodensteiner JB Connolly PJ Garg BP Cerebral venous thrombosis in children J Child Neurol 2000 16 8 574 80 11510928 \n12 Biousse V Ameri A Bousser MG Isolated intracranial hypertension the only sign of cerebral venous thrombosis Neurology 1999 53 7 1537 42 10534264 \n13 Barron TF Gusnard DA Zimmerman RA Cerebral venous thrombosis in neonate and children Pediatr Neurol 1992 8 2 112 6 1580953 \n14 Sebire G Tabarki D Saunders E Cerebral venus sinus thrombosis in children: risk factors, presentation, diagnosis and outcome Brain 2005 128 pt 3 477 89 15699061\n\n",
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"issn_linking": "2008-2142",
"issue": "23(1)",
"journal": "Iranian journal of pediatrics",
"keywords": "Cerebral Thrombosis; Inflammatory Bowel Disease; Pseudotumor Cerebri; Ulcerative Colitis",
"medline_ta": "Iran J Pediatr",
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"title": "Pseudotumor cerebri in a case of ulcerative colitis with sagittal sinus thrombosis.",
"title_normalized": "pseudotumor cerebri in a case of ulcerative colitis with sagittal sinus thrombosis"
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{
"abstract": "OBJECTIVE\nWe described the use of adjunctive ketamine to terminate seizure activity and decrease the dose and duration of pentobarbital coma in 2 patients with refractory status epilepticus (SE).\n\n\nMETHODS\nA 56-year-old woman (patient 1) developed SE after cardiac arrest, which was refractory to antiepileptic agents and escalating doses of continuous midazolam. Midazolam was replaced with pentobarbital infusion with no significant change in electroencephalography. A continuous ketamine infusion was initiated as an adjunct to pentobarbital. After initiation of ketamine, seizure frequency decreased and sustained burst suppression was achieved. After 48 hours of induced burst suppression, pentobarbital was discontinued followed by ketamine and the patient remained seizure on oral anticonvulsants alone. Meanwhile, a 57-year-old woman (patient 2) with autoimmune encephalitis developed SE, which was refractory to first-line medications. Pentobarbital infusion was initiated with attainment of burst suppression on electroencephalography. Multiple attempts at weaning pentobarbital failed because of recurrence of seizures. To minimize the dose of pentobarbital needed, a continuous ketamine infusion was initiated as an adjunct to pentobarbital with maintenance of burst suppression at much lower doses of pentobarbital than before. Ketamine was continued for 19 days with titration of other antiepileptic therapy, without return of SE.\n\n\nCONCLUSIONS\nThese cases demonstrate that ketamine may show promise as an adjunct to induced pentobarbital coma for refractory SE. Adjunctive use of ketamine may reduce the dose and duration of pentobarbital required, hence preventing complications associated with barbiturate therapy. Future studies are needed to define the optimal dose, timing, and role of ketamine infusions in the management of refractory SE.",
"affiliations": "*Department of Pharmacy Practice, Auburn University, Harrison School of Pharmacy, Auburn; †Department of Surgery, University of South Alabama Medical Center, Mobile, AL; and ‡Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, NC.",
"authors": "McGinn|Kaitlin Ann|KA|;Bishop|Laura|L|;Sarwal|Aarti|A|",
"chemical_list": "D006993:Hypnotics and Sedatives; D007649:Ketamine; D010424:Pentobarbital; D008874:Midazolam",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000128",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "39(1)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D003128:Coma; D004569:Electroencephalography; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D007649:Ketamine; D008874:Midazolam; D008875:Middle Aged; D010424:Pentobarbital; D013226:Status Epilepticus",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "62-5",
"pmc": null,
"pmid": "26757317",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of Ketamine in Barbiturate Coma for Status Epilepticus.",
"title_normalized": "use of ketamine in barbiturate coma for status epilepticus"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2017US-145298",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MIDAZOLAM"
},
"druga... |
{
"abstract": "BACKGROUND\nThe prevalence of diabetes mellitus continues to inexorably rise in the United States and throughout the world. Lower limb amputations are a devastating comorbid complication of diabetes mellitus. Osteomyelitis increases the risk of amputation fourfold and commonly presages death. Antimicrobial therapy for diabetic foot osteomyelitis (DFO) varies greatly, indicating that high quality data are needed to inform clinical decision making. Several small trials have indicated that the addition of rifampin to backbone antimicrobial regimens for osteomyelitis outside the setting of the diabetic foot results in 28 to 42% higher cure rates.\n\n\nMETHODS\nThis is a prospective, randomized, double-blind investigation of the addition of 6 weeks of rifampin, 600 mg daily, vs. matched placebo (riboflavin) to standard-of-care, backbone antimicrobial therapy for DFO. The study population are patients enrolled in Veteran Health Administration (VHA), ages ≥18 and ≤ 89 years with diabetes mellitus and definite or probable osteomyelitis of the foot for whom an extended course of oral or intravenous antibiotics is planned. The primary endpoint is amputation-free survival. The primary hypothesis is that using rifampin as adjunctive therapy will lower the hazard rate compared with the group that does not use rifampin as adjunctive therapy. The primary hypothesis will be tested by means of a two-sided log-rank test with a 5% significance level. The test has 90% power to detect a hazard ratio of 0.67 or lower with a total of 880 study participants followed on average for 1.8 years.\n\n\nCONCLUSIONS\nVA INTREPID will test if a rifampin-adjunctive antibiotic regimen increases amputation-free survival in patients seeking care in the VHA with DFO. A positive finding and its adoption by clinicians would reduce lower extremity amputations and their associated physical and emotional impact and reduce mortality for Veterans and for the general population with diabetic foot osteomyelitis. Given that rifampin-adjunctive regimens are currently employed for therapy for the majority of DFO cases in Europe, and only in a small minority of cases in the United States, the trial results will impact therapeutic decisions, even if the null hypothesis is not rejected.\n\n\nBACKGROUND\nRegistered January 6, 2017 at ClinicalTrials.gov, NCT03012529.",
"affiliations": "Department of Veterans Affairs Eastern Colorado Healthcare System, Denver, CO, USA.;Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, MA, USA.;Department of Veterans Affairs, Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Office of Research and Development, Albuquerque, NM, USA.;Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, MA, USA.;Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, MA, USA.;Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, USA.;Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, MA, USA.;Department of Veterans Affairs, Cooperative Studies Program Central Office, Washington, DC, USA.;James J. Peters VA Medical Center, New York, NY, USA. Sheldon.Brown@va.gov.",
"authors": "Bessesen|Mary T|MT|;Doros|Gheorghe|G|;Henrie|Adam M|AM|;Harrington|Kelly M|KM|;Hermos|John A|JA|;Bonomo|Robert A|RA|;Ferguson|Ryan E|RE|;Huang|Grant D|GD|;Brown|Sheldon T|ST|http://orcid.org/0000-0002-4563-4854",
"chemical_list": "D000900:Anti-Bacterial Agents; D010919:Placebos; D012293:Rifampin",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-019-4751-3",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 475110.1186/s12879-019-4751-3Study ProtocolA multicenter randomized placebo controlled trial of rifampin to reduce pedal amputations for osteomyelitis in veterans with diabetes (VA INTREPID) Bessesen Mary T. 12Doros Gheorghe 34Henrie Adam M. 5Harrington Kelly M. 36Hermos John A. 37Bonomo Robert A. 89Ferguson Ryan E. 310Huang Grant D. 11http://orcid.org/0000-0002-4563-4854Brown Sheldon T. Sheldon.Brown@va.gov 12131 Department of Veterans Affairs Eastern Colorado Healthcare System, Denver, CO USA 2 0000 0001 0703 675Xgrid.430503.1Division of Infectious Diseases, Department of Medicine, University of Colorado – Denver, Aurora, CO USA 3 0000 0004 4657 1992grid.410370.1Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, MA USA 4 0000 0004 1936 7558grid.189504.1Department of Biostatistics, Boston University, Boston, MA USA 5 Department of Veterans Affairs, Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Office of Research and Development, Albuquerque, NM USA 6 0000 0004 0367 5222grid.475010.7Department of Psychiatry, Boston University School of Medicine, Boston, MA USA 7 0000 0004 0367 5222grid.475010.7Department of Medicine, Boston University School of Medicine, Boston, MA USA 8 0000 0004 0420 190Xgrid.410349.bCleveland Department of Veterans Affairs Medical Center, Cleveland, OH USA 9 0000 0001 2164 3847grid.67105.35Case Western Reserve University, Cleveland, OH USA 10 0000 0004 1936 7558grid.189504.1Department of Epidemiology, Boston University School of Public Health, Boston, MA USA 11 0000 0004 0478 7015grid.418356.dDepartment of Veterans Affairs, Cooperative Studies Program Central Office, Washington, DC USA 12 0000 0004 0420 1184grid.274295.fJames J. Peters VA Medical Center, New York, NY USA 13 0000 0001 0670 2351grid.59734.3cDepartment of Medicine, Icahn School of Medicine at Mt. Sinai, New York, NY USA 8 1 2020 8 1 2020 2020 20 231 11 2019 30 12 2019 © The Author(s). 2020Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe prevalence of diabetes mellitus continues to inexorably rise in the United States and throughout the world. Lower limb amputations are a devastating comorbid complication of diabetes mellitus. Osteomyelitis increases the risk of amputation fourfold and commonly presages death.\n\nAntimicrobial therapy for diabetic foot osteomyelitis (DFO) varies greatly, indicating that high quality data are needed to inform clinical decision making. Several small trials have indicated that the addition of rifampin to backbone antimicrobial regimens for osteomyelitis outside the setting of the diabetic foot results in 28 to 42% higher cure rates.\n\nMethods/design\nThis is a prospective, randomized, double-blind investigation of the addition of 6 weeks of rifampin, 600 mg daily, vs. matched placebo (riboflavin) to standard-of-care, backbone antimicrobial therapy for DFO. The study population are patients enrolled in Veteran Health Administration (VHA), ages ≥18 and ≤ 89 years with diabetes mellitus and definite or probable osteomyelitis of the foot for whom an extended course of oral or intravenous antibiotics is planned. The primary endpoint is amputation-free survival. The primary hypothesis is that using rifampin as adjunctive therapy will lower the hazard rate compared with the group that does not use rifampin as adjunctive therapy. The primary hypothesis will be tested by means of a two-sided log-rank test with a 5% significance level. The test has 90% power to detect a hazard ratio of 0.67 or lower with a total of 880 study participants followed on average for 1.8 years.\n\nDiscussion\nVA INTREPID will test if a rifampin-adjunctive antibiotic regimen increases amputation-free survival in patients seeking care in the VHA with DFO. A positive finding and its adoption by clinicians would reduce lower extremity amputations and their associated physical and emotional impact and reduce mortality for Veterans and for the general population with diabetic foot osteomyelitis. Given that rifampin-adjunctive regimens are currently employed for therapy for the majority of DFO cases in Europe, and only in a small minority of cases in the United States, the trial results will impact therapeutic decisions, even if the null hypothesis is not rejected.\n\nTrial registration\nRegistered January 6, 2017 at ClinicalTrials.gov, NCT03012529.\n\nKeywords\nRifampinOsteomyelitisDiabetic footAmputationSurvivalLower extremityDiabetes mellitusDouble-blindClinical trialVeteranshttp://dx.doi.org/10.13039/100000738U.S. Department of Veterans Affairs0000000issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nDiabetes mellitus prevalence is rising inexorably in the Unites States and globally. The 2011–2012 National Health and Nutritional Examination Survey (NHANES) data indicate that 14.3% of Americans have diabetes mellitus, and 38% have prediabetes [1]. Strategies for management of hyperglycemia have improved, but severe complications continue to impact survival and quality of life among diabetics. Lower extremity ulcerations with soft tissue and bone infections are common complications of diabetes mellitus with potentially devastating consequences. Osteomyelitis is found underlying 20% of all infected diabetic foot ulcers, and 60% of severe infections [2]. In a recent study, the risk of amputation was 14% in patients with infection limited to the soft tissue of the foot, and 60% in patients with osteomyelitis [3]. Therefore, control of bone infection is an important target in efforts to improve limb salvage in diabetics.\n\nThere is considerable variability in therapy prescribed for diabetic foot osteomyelitis (DFO) and there are few high-quality controlled trials of DFO to guide selection of antibiotic treatment regimens [4]. Adjunctive rifampin therapy is commonly employed in Europe, where 56 to 100% of practitioners select oral antimicrobial therapy with adjunctive rifampin for osteomyelitis [5] including DFO [6–9]. Use of rifampin for DFO in the United States is uncommon. The frequency of direct toxicity is similar for rifampin and other antibacterial agents used for bone infections [10]. The lack of randomized controlled data supporting rifampin therapy in DFO may contribute to U.S. physicians’ choice to omit rifampin therapy for DFO. A large controlled trial of adjunctive therapy for DFO has significant potential to impact practice if clinical benefit is confirmed and would also supply a wealth of data on DFO diagnostics, management and outcomes.\n\nRifampin has unique properties that make it an attractive adjunctive agent for DFO. It penetrates osteoblasts and retains antimicrobial activity within these cells [11]. Rifampin also penetrates biofilms and retains activity within them [12]. Adjunctive rifampin therapy has improved outcomes in several studies of osteomyelitis outside the setting of the diabetic foot [13, 14]. There are limited comparative data available on the impact of rifampin therapy of osteomyelitis in the setting of the diabetic foot. Effect sizes in randomized trials of rifampin for osteomyelitis not limited to the diabetic foot range from 28 to 42%.\n\nRifampin has broad spectrum activity against gram-positive organisms, which are the most common pathogens in DFO. S. aureus is the most common bacteria recovered from bone cultures in DFO. Other gram-positive organisms, including coagulase negative staphylococci and streptococci are recovered from 30 to 70% of cases [15]. Gram-negative organisms are found in a minority of cases of DFO. Clinical activity of rifampin against gram-negative pathogens has been observed in combination therapy of serious gram-negative infections that had failed other therapies [16, 17]. Antimicrobial activity from rifampin may consequently be seen in most cases of DFO.\n\nIn summary, rifampin’s broad antimicrobial spectrum, potent bactericidal activity, tissue penetration, and activity within biofilms, along with accumulating evidence from clinical trials in non-diabetic osteomyelitis and uncontrolled clinical experience in DFO make it attractive for formal study as an adjunctive therapy in DFO. A large pragmatic trial, enrolling patients with DFO without regard to culture results, will be feasible and will provide results that are generalizable to the broad population of DFO patients.\n\nMethods/study design\nVA-INTREPID is a prospective, randomized, double-blind, placebo-controlled, investigation of a six-week course of adjunctive rifampin vs. adjunctive matched placebo (containing riboflavin) added to backbone antibacterial therapy for the treatment of definite or probable DFO, as defined by the International Working Group on the Diabetic Foot, summarized in Table 1 [18]. Backbone antibacterial therapy will be selected by the clinical treatment team and can be administered either intravenously or orally. The primary outcome measure is amputation-free survival. Amputation events include both below- and above-ankle amputations. Primary outcomes will be determined by systematic medical record review and through confirmatory research visits, phone calls and, as needed, information from non-VA providers. The secondary outcomes of complete wound epithelialization and remission of osteomyelitis will be determined by direct examination by the site investigators. Participants will have in person visits at baseline, 2, 4, and 6 weeks, 3 months, 6 months, and 12 months. The medical record will be reviewed up to 24 months to ascertain endpoints. Key secondary objectives are 1) to determine the differential effect of adding rifampin versus placebo to backbone antibiotic treatment on the time to each component of the primary endpoint, 2) to assess the heterogeneity of response to adjunctive rifampin treatment by specific subgroups, a) route of administration of backbone antibiotic therapy (IV vs. oral) b) baseline microbiological culture results (staphylococcal infections vs. non-staphylococcal infections vs. no culture) and c) baseline measures of vascular perfusion (toe pressure, TCpO2). Figure 1 describes the visit schedule and key procedures used throughout the study.\nTable 1 Diagnostic criteria for DFO (adapted from Berendt et al., 2008 with permission)\n\nCategory\tPost-test probability of osteomyelitis\tManagement advice\tCriteria\t\nDefinite\t> 90%\tTreat for osteomyelitis\tBone sample with positive culture AND\n\npositive histology OR\n\nPurulence in bone found at surgery OR\n\nAtraumatically detached bone fragment removed from ulcer by podiatrist/surgeon OR\n\nIntraosseous abscess on MRI OR\n\nAny two probable criteria OR one probable and two possible criteria OR any four possible criteria below\n\n\t\nProbable\t51–90%\tConsider treating\tVisible cancellous bone in ulcer OR\n\nMRI showing bone edema with other signs of osteomyelitis OR\n\nBone sample with positive culture but negative or absent histology OR\n\nBone sample with positive histology but negative or absent culture OR\n\nAny two possible criteria below\n\n\t\nPossible\t10–50%\tTreatment may be justified, but further investigation usually advised\tPlain X-rays show cortical destruction OR\n\nMRI shows bone edema or cloaca OR\n\nProbe to bone positive or visible cortical bone OR\n\nESR > 70 mm/hr. with no other plausible explanation OR\n\nNon-healing wound despite adequate offloading and perfusion for >6 weeks or ulcer of >2 weeks duration with clinical evidence of infection\n\n\t\nUnlikely\t< 10%\tUsually no need for further investigation or treatment\tNo signs or symptoms of inflammation AND normal X-rays AND ulcer present for <2 weeks or absent AND any ulcer present is superficial OR\n\nNormal MRI OR Normal bone scan\n\n\t\n\nFig. 1 Schedule of Study Procedures\n\n\n\nStudy setting\nVA-INTREPID is sponsored and conducted by the Department of Veterans Affairs (VA) Cooperative Studies Program (CSP), a research infrastructure that is dedicated to improving the healthcare of veterans through the conduct of clinical trials [19]. The Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC) serves as the study’s CSP coordinating center (CSPCC), providing project management and statistical support, and the CSP Clinical Research Pharmacy Coordinating Center (CSPCRPCC) serves as the study’s drug distribution center, providing clinical trial materials and safety monitoring.\n\nStudy sites were selected based on caseload and investigator resources and are listed in Table 2. Patients between the ages of 18 and 90 years will be recruited from Podiatry, Primary Care, Surgery, Infectious Diseases and Endocrine clinics and from inpatient services at 28 Department of Veterans Affairs Medical Centers across the United States. Potential participants will also be identified from Radiology, Pathology and Surgery logs.\nTable 2 Participating sites\n\nStudy Sites\tLocation\t\nStudy Chairs’ Offices\t\n James J. Peters VA Medical Center\tBronx, NY\t\n VA Eastern Colorado Healthcare System\tDenver, CO\t\nEnrollment sites\t\n Atlanta VA Medical Center\tAtlanta, GA\t\n Bay Pines VA Healthcare System\tBay Pines, FL\t\n Cincinnati VA Medical Center\tCincinnati, OH\t\n Dayton VA Medical Center\tDayton, OH\t\n James A. Haley Veterans Hospital\tTampa, FL\t\n James J. Peters VA Medical Center\tBronx, NY\t\n Louis Stokes Cleveland VA Medical Center\tCleveland, OH\t\n Malcom Randall VA Medical Center\tGainesville, FL\t\n Miami VA Healthcare System\tMiami, FL\t\n Michael E. DeBakey VA Medical Center\tHouston, TX\t\n Minneapolis VA Medical Center\tMinneapolis, MN\t\n Phoenix VA Healthcare System\tPhoenix, AZ\t\n Portland VA Medical Center\tPortland, OR\t\n Salem VA Medical Center\tSalem, VA\t\n South Texas Veterans Healthcare System\tSan Antonio, TX\t\n VA Ann Arbor Healthcare System\tAnn Arbor, MI\t\n VA Eastern Colorado Healthcare System\tDenver, CO\t\n VA Greater Los Angeles Healthcare System, West LA\tLos Angeles, CA\t\n VA Loma Linda Healthcare System\tLoma Linda, CA\t\n VA Long Beach Healthcare System\tLong Beach, CA\t\n VA North Texas Health Care System: Dallas VA Medical Center\tDallas, TX\t\n VA Northern California Healthcare System, Sacramento\tMather, CA\t\n VA Palo Alto Healthcare System\tPalo Alto, CA\t\n VA Salt Lake City Healthcare System\tSalt Lake City, UT\t\n VA St. Louis Healthcare System, John Cochran Division\tSt. Louis, MO\t\n W.G. (Bill) Hefner VA Medical Center\tSalisbury, NC\t\n Washington DC VA Medical Center\tWashington, DC\t\n William S. Middleton Memorial Veterans Hospital\tMadison, WI\t\nCSP centers\t\n Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC) CSP Coordinating Center\tBoston, MA\t\n CSP Clinical Research Pharmacy Coordinating Center (CSPCRPCC)\tAlbuquerque, NM\t\n\n\nParticipants\nVA-INTREPID will enroll and randomize a total of 880 study participants. The key inclusion criterion is a diagnosis of osteomyelitis in the diabetic foot, as defined by the International Working Group on the Diabetic Foot [18]. The key exclusion criteria are therapy with drugs that have critical interactions with rifampin, that either require empiric dose adjustment, or are considered absolutely contraindicated in combination with rifampin. The identity of the infecting organism(s) is not an inclusion or exclusion criterion. Full inclusion and exclusion criteria are listed in Table 3. Permission to approach patients who screen as eligible for the study will be obtained from clinical providers. Prior to enrollment, study personnel will explain all aspects of the study to potential participants and obtain informed consent in keeping with guidelines for human research subjects protection. Participants will be followed actively through the end of the second year after randomization or until death occurs, with the exceptions of those who withdraw consent early or who enroll in the last year of study recruitment. Participants will be encouraged at each study visit to complete the trial. If consent is withdrawn, study personnel will confirm with the participant whether they can continue reviewing the participant’s medical record until the end of the expected study participation. If a participant is lost to follow-up, regular review the medical record will continue until the end of the expected study participation. On average, study participants will be followed for 1.8 years through systematic review of medical records, and by study visits and phone calls. For participants who reach a primary endpoint of amputation, study drug, if still being administered, will be discontinued and continuing medical care will be determined by the treating providers. In such cases, participants will continue to be followed actively according to the study visit schedule. Participants who discontinue study drug treatment early due to an adverse event will also continue to be followed actively according to the study visit schedule.\nTable 3 Study population\n\nInclusion Criteria:\t\n● Men and Women age ≥ 18 and ≤ 89 years\t\n● Diabetes Mellitus\t\n○ Defined either by: 1) use of oral hypoglycemic agents or insulin at the time of enrollment; or 2) a hemoglobin A1c (HgA1c) level within the past 90 days >6.5\t\n● Definite or probable osteomyelitis of the foot (DFO)\t\n○ Defined by the International Working Group on the Diabetic Foot (Table 1)\t\n● All planned debridement has been completed prior to randomization\t\n● A definitive course of backbone antibiotic treatment has been selected\t\nExclusion Criteria:\t\n● Patient is unable to receive enteral medication\t\n● Patient is allergic to or intolerant of rifampin\t\n● Patient is taking a drug that has interactions with rifampin that would require either stoppage, substitution or an empiric dose modification that may place the patient at medical risk\t\n● Within 30 days of enrollment, patient is taking immunosuppressive medications to prevent rejection of an organ transplant or is receiving chemotherapy or molecularly targeted therapies for cancer\t\n● Patient is receiving antiretroviral therapy for HIV or antiviral medication for Hepatitis B or C\t\n● Enrollment in another trial of a therapeutic agent with a documented or suspected interaction with rifampin\t\n● Patient has an ALT >3 times the upper limit of normal for the site laboratory, or total bilirubin >2.5 times the upper limit of normal for the site laboratory; patient has Child-Pugh Class C Cirrhosis.\t\n● Patient has a baseline white blood cell count (WBC) <2000 cells/mm3 OR platelet count <50,000 cells/mm3 OR hemoglobin <8.0 g/dL.\t\n● Women of child-bearing potential (those with menses within the last year) with a positive serum pregnancy test.\t\n● Patient is believed unlikely to be able to complete the trial due to medical conditions such as metastatic cancer or end-stage organ failure\t\n● Patient is believed unlikely to complete the trial due to neurologic and psycho-behavioral disorders such as active substance abuse or dependence, disabling dementias or psychoses\t\n● Patient refuses or is clinically unable to undergo the recommended level of debridement\t\n● Patient’s prescribed backbone antibiotic therapy does not meet standard of care for either empirical treatment or culture-directed therapy\t\n● Indwelling hardware present in the foot, at the site of the index osteomyelitis\t\n● Treatment with antibacterial agents for infection at another site, where the duration of treatment is anticipated to be greater than 14 days\t\n\n\nManagement of Potential Drug-drug Interactions\nThe research team will screen study candidates for potentially contraindicated or interacting medications when taken with blinded study drug (rifampin or placebo) that would preclude enrollment. Patients will be excluded from the trial if they are 1) taking a medication that is considered contraindicated when combined with rifampin, or 2) taking a medication which would require a priori dose adjustment if rifampin was utilized, because blinding would preclude such dose adjustments. Table 4 contains a list of all excluded medications. After consent and immediately prior to randomization, the study team will again review the patients continued eligibility including any new contraindicated medications that, and confirm the patients continued willingness to participate. Finally, the research team will review concomitant medications while participants receive treatment with study drug to determine if a concomitant medication which would have precluded enrollment has been started and would require early discontinuation of study medication. The study participants and local research teams will be blinded to treatment assignment throughout the trial’s conduct. In instances where knowledge of the study treatment assignment would influence emergency medical treatment, unblinding may occur after consultation with a Study Chair and by obtaining information regarding treatment assignment from the CSPCRPCC.\nTable 4 Excluded Concomitant Medications\n\nContraindicated\t\n Artemether\t\n Atazanavir\t\n Bocepravir\t\n Cobicistat\t\n Daclatasvir\t\n Darunavir\t\n Dasabuvir\t\n Delamanid\t\n Elbasvir\t\n Elvitegravir\t\n Fosamprenavir\t\n Grazoprevir\t\n Isovuconazonium\t\n Lopinavir\t\n Lurasidone\t\n Maraviroc\t\n Nelfinavir\t\n Ombitasvir\t\n Pariteprevir\t\n Praziquantel\t\n Ranolazine\t\n Rilpivirine\t\n Ritonavir\t\n Saquinavir\t\n Telaprevir\t\n Tipranivir\t\n Voriconazole\t\nRequire Empiric Dose Adjustment\t\n Abiraterone\t\n Afatinib\t\n Amiodarone\t\n Aripiprazole\t\n Apixaban\t\n Cabozanitib\t\n Canaglifozin\t\n Clozapine\t\n Hormonal contraceptives\t\n Cyclosporine\t\n Dabigatran etexilate mesylate\t\n Desferasirox\t\n Digoxin\t\n Disopyramide\t\n Dolutegravir\t\n Dronedarone\t\n Edoxaban\t\n Efavirez\t\n Erlotinib\t\n Everolimus\t\n Exemestane\t\n Fosphenytoin\t\n Gefitinib\t\n Guanfacine\t\n Ibrutinib\t\n Imatinib\t\n Ixabepilone\t\n Mexilitene\t\n Lamotrigine\t\n Lapatinib\t\n Long acting opioids\t\n Phenytoin\t\n Propafenone\t\n Quetiapine\t\n Quinidine\t\n Raltegravir\t\n Rivaroxaban\t\n Temsirolimus\t\n Ticragrelor\t\n Vilazodone\t\n Vortioxetine\t\n Warfarin\t\n\n\nStudy intervention\nSubjects will be randomly assigned to adjunctive rifampin or similar-appearing riboflavin placebo orally once daily for a six-week period. Each capsule of matching placebo will contain 12.5 mg of riboflavin for purposes of mimicking urine discoloration produced by rifampin.\n\nThe rifampin dose will be 600 mg orally daily, taken as two capsules of rifampin 300 mg once daily. If a subject experiences gastrointestinal intolerance on once daily dosing, the study drug may be administered as one capsule of rifampin 300 mg or placebo taken twice daily. Subjects will be informed that the study drug (either rifampin or the riboflavin placebo) may or may not cause a discoloration of their urine and other bodily fluids ranging from bright yellow to orange to orange-red.\n\nStudy drug therapy will be started immediately after randomization and will be prescribed for a treatment course totaling 84 capsules over a period of six calendar-weeks (42 days). Study drug administration will be discontinued: 1) at the time that a primary endpoint is reached; 2) at completion of protocol-defined therapy on Day 42; 3) if the participant experiences an adverse event that is considered to be at least possibly related to rifampin and that reaches grade 3 or 4 severity (Table 5); 4) if the LSI determines that continued study drug administration jeopardizes patient safety; 5) if the participant withdraws consent for the study; 6) if backbone antibiotic therapy is discontinued for clinical reasons earlier than initially planned, 7) if the participant requires a new concomitant medication that is listed as an exclusion criterion for study enrollment and requires this medication for a total course lasting more than 72 h.\nTable 5 Toxicity Criteria [20]\n\n\tMild (Grade 1)\tModerate (Grade 2)\tSevere or Medically Significant but Not Immediately Life-Threatening (Grade 3)\tLife-Threatening Consequences (Grade 4)\t\nLiver Enzymes –either ALT, AST increase by factor\t>ULN-3.0 x ULN\t>3.0–5.0 x ULN\t>5.0–20 x ULN\t> 20 x ULN\t\nBilirubin\t>ULN-1.5 x ULN\t>1.5–3.0 x ULN\t>3.0–10.0 x ULN\t>10 x ULN\t\nCreatinine – mg/dL\n\nNormal baseline\n\n\t1.5 x ULN\t>1.5–3.0 x ULN\t>3.0–6.0 x ULN\t> 6.0 x ULN\t\nCreatinine – mg/dL\n\nElevated baseline\n\n\t1.5 x baseline\t>1.5–3.0 x baseline\t>3.0–6.0 x baseline\t> 6.0 x baseline\t\nHemoglobin gm/dL\t< LLN-10.0\t< 10.0 to 8.0\t< 8.0\tLife-threatening, urgent intervention indicated\t\nWBC Decrease - cell/mm3\tLLN- 3000\t2000 – 3000\t1000 – 2000\t< 1000\t\nPlatelets Decreased - cell/mm3\tLLN - 75,000\t50,000 - < 75,000\t< 50,000–25,000\t< 25,000\t\n\n\nCommercially-available rifampin 300 mg capsules will be acquired by the CSPCRPCC and re-bottled into blinded packaging in accordance with current good manufacturing practices (cGMP). The CSPCRPCC will also manufacture matching placebo capsules containing 12.5 mg of riboflavin under cGMP conditions. The matching placebo will be similar in exterior appearance to the acquired rifampin 300 mg capsules and will be bottled into matching blinded packaging. Bottles of study medication will be labeled with unique bottle numbers to facilitate blinded administration.\n\nBackbone antibiotic therapy\nBackbone antibiotic therapy will be selected by the local treatment team. The oral or intravenous backbone therapy selected by the treating physician will be communicated to the CSP coordinating center when the subject is enrolled to support stratification by route of administration of backbone therapy. Backbone therapy may be discontinued and replaced by alternative agents by the local treatment team in the event of drug intolerance, toxicity, hypersensitivity reaction, change in route of administration (e.g. switch from oxacillin to levofloxacin for MSSA), or recovery of microorganisms that are resistant to the selected agents or more effectively treated by a different agent.\n\nSurgical and podiatric management\nSites will be expected to follow the recommendations described in the Delphi consensus statement on surgical management of diabetic foot osteomyelitis [21]. Sites will be expected to utilize the most effective offloading method available [22]. Subjects will not be excluded for failure to comply with the recommended method of off-loading.\n\nOutcome measures\nPrimary outcome\nThe primary endpoint is amputation-free survival, ending with amputation or death from any cause. Amputation is defined as surgical treatment of osteomyelitis by removal or debridement of necrotic bone (all or part of a bone) from a lower extremity limb or digit on the ipsilateral side of the protocol-treated osteomyelitis. Debridement prior to randomization may include removal of bone. Because this debridement occurs early, prior to exposure to study drug or placebo, removal of bone at that time is not a study endpoint.\n\nThe amputation component of the primary endpoint for procedures at the site will be determined and documented by the Site Investigator’s review of all written operative notes and reports and surgical pathology reports within VA or outside medical facilities. The survival component of the primary endpoint will be determined by review of the medical record, review of death records, and telephone call to the phone number of record. All primary endpoints will be confirmed by the Site Investigator, and if requested, by final consultation with and confirmation by the Study Chair’s Office. The primary efficacy analysis will be on the intention-to-treat (ITT) population. The analysis will include all randomized subjects according to treatment assignment.\n\nSecondary outcomes\nSecondary outcomes include: 1) time from randomization to the occurrence of each component of the primary outcome 2) new courses of antibacterial therapy for ipsilateral foot infection during the first year after randomization, 3) quality of life measured by the 36-Item Short Form Health Survey (SF-36), 4) ambulatory status, 5) incidence of falls, 6) incidence of adverse events due either to direct drug toxicity or to drug-drug interactions, 7) remission of osteomyelitis at 12 months (defined as epithelialization of any overlying soft tissue defect and the absence of local signs and symptoms of inflammation), and 8) time to complete epithelialization of the wound.\n\nAdverse events\nParticipants will be assessed for potential rifampin toxicity every 2 weeks during the treatment course with study medication, as outlined in Fig. 1. Toxicity to study medication detected from the select laboratory studies will be graded according to Table 5. All serious adverse events and certain non-serious adverse events that occur after treatment initiation and before 6 weeks post-completion of study medication will be collected. For adverse events that do not result in a serious outcome, they will only be collected if the local site investigator considers the event to be at least possibly related to study medication. Additionally, reports of bodily fluid discoloration (unless it has caused the participant to seek medical care) and mild to moderate toxicities will not be collected as adverse events.\n\nData collection and management\nThe MAVERIC CSPCC will manage clinical data and study documents using an Electronic Data Capture (EDC) and clinical trial management system (CTMS). The EDC system captures clinical data using electronic case report forms (CRFs), which are then stored at a central server location. Use of the EDC system allows site personnel to conduct data entry, review edit checks, and make updates to resolve discrepancies.\n\nEthical considerations\nThe protocol and Informed Consent Form have been reviewed and approved by the Coordinating Center’s Human Rights Committee and by VA’s Central Institutional Review Board. Written informed consent will be obtained from all study participants consistent with the requirements of the Common Rule. An independent data monitoring committee (DMC) will meet semiannually to provide treatment effects monitoring during the trial’s conduct supplemented by real-time monitoring of safety events at the CSPCRPCC. The CSP Site Monitoring and Auditing Resource Team (SMART) will perform site and remote monitoring and auditing throughout the trial, with assistance from the Boston CSP Coordinating Center and the CSPCRPCC. Onsite monitoring visits will be conducted by SMART and will focus on assuring that study site personnel understand and follow the protocol and employ a risk-based approach to source document verification and source document review of original records. Each site will receive one onsite visit followed by additional onsite visits as needed based on any identified issues. Remote data review of critical data will also be routinely conducted by SMART throughout the trial. Finally, staff at the Boston CSP Coordinating Center will review Informed Consent Forms and regulatory documentation as well as generate reports from site data in order to asses site performance. The Food and Drug Administration has determined that VA-INTREPID is exempt from investigational new drug requirements.\n\nBiostatistical considerations\nSample size and statistical power considerations for the primary hypotheses\nBased on data obtained from the Veterans Health Administration Corporate Data Warehouse, and published studies we hypothesized a relative reduction of 25% in the 2-year event rate with the use of rifampin as an adjunctive therapy compared with the use of adjunctive placebo. Data on the primary outcome measure will be analyzed by means of the two-sided log-rank test at a two-sided 5% significance level. The test has 90% power to detect a hazard ratio of 0.67 or lower with a total of 880 study participants, 440 per study arm. This allows for an interim analysis using O’Brian-Fleming [23] approach after half of the events in the trial have been observed and assumes that at most 6% of the study participants are lost to follow-up over the course of their participation into the study and before a study event is observed.\n\nRandomization\nAfter confirming eligibility, participants will be randomized in a 1:1 fashion to adjunctive rifampin or placebo by the research team using a centrally-administered interactive web response system (IWRS). The IWRS will also be used to facilitate blinded administration of study medication by providing the research team with a unique bottle number that contains study medication located on-site that corresponds to the participant’s assignment. To control for potential imbalance in randomization, both stratification and blocking will be employed. The randomization scheme, which will be generated by the study biostatistician and utilized by the IWRS when randomizing participants, will be stratified by participating site in addition to predominant route (oral or intravenous) of the clinician-prescribed backbone antibiotic regimen. Participants will be randomized to adjunctive therapy of rifampin or placebo within permuted random blocks.\n\nStatistical methods\nThe primary analysis will be performed according to the intention-to-treat (ITT) principle. Sensitivity analyses will be performed based on adherence to study drug during the six-week treatment phase by conducting the proposed analyses on the per-protocol (PP) set. The PP set will include participants adherent to the study medication. in the arm they were randomized to. A patient will be considered adherent if pill counts indicate that he/she took two-thirds or more of the dispensed 84 pills (i.e. 56 pills or more) of treatment medication during the 6 weeks after dispensation of the study medication. An additional sensitivity analysis will be carried out on a modified per-protocol (mPP) set that will account for participants who were so briefly on-study drug that the treatment was not likely to have had an effect. The mPP set will include in addition to patients in the PP set the patients who had their study medication withdrawn because of an outcome event and have taken their study medication for at least two-thirds of the indicated study drug prior to the outcome event. Adherence with study drug (rifampin or placebo) will be primarily assessed by pill count during the study visit at 6 weeks. The assessment of study drug adherence at the 6-week research visit will be used for the PP analysis. These sensitivity analyses will be considered as supplemental to the ITT analysis of the primary and secondary efficacy endpoints. Secondary outcomes will be analyzed using a Cox regression model, logistic regression analysis, or log rank testing, as appropriate.\n\nData analysis of the primary endpoint\nThe primary analysis will be a time-to-event analysis with the use of the log-rank test based on intention-to-treat principles. Analytic reports will provide the hazard ratios and the 95% confidence interval about the hazard ratio. Kaplan-Meier curves will be used to represent estimates of the amputation-free survival distribution in the two intervention groups. Reports will also include estimates of event rates in the two treatment groups at 6 months, 1-year and 2-years of follow-up. Primary analyses will be followed by exploratory analyses, using Cox proportional hazards regression modeling, to account for the effects of baseline covariates on the primary outcome measure.\n\nInterim analysis\nAn interim analysis, considering stops for both superiority and futility, will be performed after approximately 50% of the planned total number of events has occurred (155 events of the anticipated 310 events). An O’Brien–Fleming stopping boundary for efficacy and futility will be used. Our calculations indicate that this will be achieved around month 28 into the study or after 685 subjects are enrolled. Based on the O’Brien Fleming boundary, at the interim analysis, it is recommended to stop for superiority if the two-sided p-value is < 0.0052 and the estimated Hazard Ratio comparing the risk of amputation or death between the rifampin and placebo is < 1, and we will reject for futility if the 2 sided p-value is < 0.0052 and the estimated Hazard Ratio comparing the risk of amputation or death between the rifampin and placebo is > 1. Additionally, we will confer with the Data Monitoring Committee (DMC) members and the program leadership for potential stopping guidelines based on findings from the interim analysis.\n\nHarms\nGiven the comorbidity expected in the study population, it is anticipated that a large number of adverse events (AEs) will be observed, most of which will not be related to the study intervention. For this reason, the study will only collect reports of all severe adverse events and those non-serious AEs that, in a site investigator’s clinical judgment, are at least possibly attributed to a study intervention and cannot be attributed to non-study intervention causes.\n\nDiscussion\nAdjunctive rifampin therapy is commonly employed in management of osteomyelitis in Europe, especially when S. aureus is identified [5, 6]. In contrast, data from the VA Corporate Data Warehouse showed that only 2% of cases of DFO were treated with rifampin. Physicians in North America may be dissuaded by the lack of an FDA indication for rifampin in osteomyelitis, or by concern for direct drug toxicity or drug interactions [24]. If the null hypothesis is rejected, including adjunctive rifampin with treatment of DFO in North America will be strongly supported, which should lead to a decrease in amputations and improved survival among patients with DFO. If the study shows no difference in outcomes with the addition of rifampin to backbone therapy, reconsideration of current management of DFO in Europe would be warranted. As newer agents with activity against bacteria in biofilms are developed [25], the demonstration of effectiveness of rifampin therapy will set the stage for new combination therapy approaches. The trial will provide safety data for rifampin in patients in an older age group with a high burden of comorbidity. The rich database provided by VA INTREPID will inform numerous aspects of DFO management including the impact of route of administration of backbone antimicrobial therapy, microbial etiology, role of vascular perfusion, glycemic control, effect of offloading modalities on outcomes, and the role of serum inflammatory markers in predicting outcomes.\n\nPreliminary data obtained from the VHA Corporate Data Warehouse showed improved outcomes in patients with DFO treated with adjunctive rifampin, regardless of bone culture results. We therefore designed this study as a large, simple trial, including patients with DFO without regard to the identity of the infecting pathogen(s). Previous studies of rifampin adjunctive therapy for osteomyelitis focus on patients with staphylococcal infections and are therefore not generalizable to treatment of DFO as a whole [13]. Outcome data will be analyzed to determine whether use of rifampin should be broadly recommended or limited to a restricted range of organisms.\n\nThe diagnosis of DFO is most certain when bone biopsy shows positive cultures and histopathology, but these data are not available in up to 50% of cases of subsequently confirmed osteomyelitis [18]. Rather than limiting the study recruitment and the generalizability of the results to patients with definite DFO, we adopted the entry criteria for definite or probable DFO, according to the criteria of the International Working Group on the Diabetic Foot [18].\n\nStudies of DFO commonly use wound healing as the primary outcome [26]. Given the high mortality observed in published studies of diabetic foot infections [27], and in our preliminary data, we chose to also include mortality in the primary outcome. Amputation free survival is an objective outcome, leaving little room for interpretation, which is appropriate for a large, simple trial. While most amputations will result from failure of treatment of the index infection, some amputations will occur due to biomechanical issues, or new infection that is not adjacent to the index osteomyelitis. These will be included in the primary outcome. A secondary outcome, ipsilateral amputation for the treatment of osteomyelitis related to the index osteomyelitis, will allow us to gather data that are more specific to the efficacy of the study intervention in treatment of infection. Wound healing at 1 year is an important, patient centered outcome, which we will also analyze as a secondary outcome.\n\nMaintaining the integrity of the blind for rifampin posed unique challenges arising from the distinct physical appearance of rifampin, which appears as a red-brown crystalline powder, and arising from rifampin’s ability to discolor bodily fluids [28]. To mitigate the risk of unblinding and bias arising from knowledge of the treatment assignment by either patients or study personnel, the matching placebo will be manufactured such that it will be similar in exterior appearance to the rifampin product used in this trial. Riboflavin, which can also discolor urine, will be added to the matching placebo so that patients and the site research teams can be informed that both study medications discolor bodily fluids. The risk of information bias adversely affecting the trial’s internal validity will be further mitigated by employing a composite primary outcome with components that are readily detectable and ascertainable in the medical record and objectively evaluated.\n\nPharmacokinetic interactions between rifampin and other drugs are very common, limiting the number of patients who may be treated. Retrospective data suggest that 18% of Veterans with DFO had an active prescription for one of the common contraindicated medications. While many interactions can be managed by dose adjustment, some are considered contraindications to the use of rifampin. This trial will further elucidate the frequency of use of interacting drugs in this population, and the clinical impact of combination of rifampin with drugs that are considered to have a mild to moderate interaction.\n\nVA-INTREPID is a large, simple trial of a readily available, inexpensive medication that is commonly employed in Europe. Our preliminary data suggest that rifampin may improve amputation free survival in patients with DFO. A limitation of the design is the inability to identify a masking agent that perfectly mimics the effect of rifampin on body fluids. The choice of riboflavin was driven by its safety, as compared to other possibilities, e.g. pyridium. Inclusion of patients who have pathogens with less sensitivity to rifampin than S. aureus may increase the risk of a Type 2 error. However, our preliminary data suggested that patients with and without cultures positive for S. aureus had similar benefit from rifampin. Furthermore, secondary analyses of the impact of bacteriology on the primary outcome could help to detect an effect. The strengths of the design include the use of a consensus case definition for DFO, objectively evaluated primary outcomes, stringent power analysis, and a multicenter design.\n\nAbbreviations\nAEAdverse Event\n\nALTAlanine Aminotransferase\n\nASTAspartate Aminotransferase\n\ncGMPCurrent Good Manufacturing Practices\n\nCRFCase Report Form\n\nCRPCCClinical Research Pharmacy Coordinating Center\n\nCSPCooperative Studies Program\n\nCSPCCCooperative Studies Program Coordinating Center\n\nCTMSClinical Trial Management System\n\nDFODiabetic Foot Osteomyelitis\n\nDMCData Monitoring Committee\n\nEDCElectronic Data Capture\n\nFDAFood and Drug Administration\n\nGCPGood Clinical Practice\n\nHgA1cHemoglobin A1c\n\nHIVHuman Immunodeficiency Virus\n\nICMJEInternational Committee of Medical Journal Editors\n\nINTREPIDInvestigation of Rifampin to Reduce Pedal Amputations for Osteomyelitis in Diabetics\n\nITTIntention to Treat\n\nIWRSInteractive Web Response System\n\nLLNLower Limit of Normal\n\nMAVERICMassachusetts Veterans Epidemiology Research and Information Center\n\nmPPModified Per-Protocol\n\nMRIMagnetic Resonance Imaging\n\nNHANESNational Health and Nutritional Examination Survey\n\nPPPer-Protocol\n\nSF-36Short Form-36\n\nSMARTSite Monitoring, Auditing, and Resource Team\n\nTCpO2Transcutaneous Oxygen Pressure\n\nULNUpper Limit of Normal\n\nVAVeterans Affairs\n\nVHAVeterans Health Administration\n\nWBCWhite Blood Cell count\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nRoles and Responsibilities: Key design input was provided by the Planning Committee members: Robert Bonomo, Brad Spellberg, Jeffrey M. Robbins, Neal Barshes, Angelike Liappis, Gheorghe Doros, Sheldon Brown, Mary Bessesen, Kelly Harrington, John Hermos, and Ryan Ferguson. Support for protocol development was provided by Yara Dwivedi, Jacqueline DiBella, Tiaira Winn, Jason Koury, Sharon Jenkins, Caterina Brown and Georgette Nichols.\n\nTrial oversight is provided by the Executive Committee, whose membership includes Neal Barshes, Mary Bessesen, Robert Bonomo, Sheldon Brown, Gheorghe Doros, Robert Frykberg, Kelly Harrington, Adam Henrie, John Hermos, Carol Kauffman, Benjamin Lipsky, and Brad Spellberg.\n\nLocal Site Investigators: lead investigator at each VA medical facility; responsible for recruitment, data collection, and completion of case report forms; follow study participants; ensure adherence to study protocol and investigators brochure.\n\nMAVERIC (Boston) CSP Coordinating Center: Coordinate design and conduct of CSP#2001; preparation of protocol and revisions; preparation of investigators brochure and case report forms; organizing investigator meetings; data collection and management; data verification; lead site performance review; statistical analyses; interpretation of data; regulatory compliance; study publication and dissemination.\n\nCSP Clinical Research Pharmacy Coordinating Center: Study planning and monitoring; liaising with the US FDA; reviewing and distributing reports of adverse events during the study; centrally controlling and distributing study drugs.\n\nPlanning Committee: multidisciplinary group responsible for preparing the final study proposal submitted for peer review; study design and planning; determine clinical impact, design and feasibility of proposed study.\n\nExecutive Committee: acts as the management group and decision-making body for the scientific execution of the study; includes two local site investigators from the field; reviews and makes decisions for all proposed changes to the study protocol and use of study data; reviews proposals for publication of study results; recommends actions for sites with unsatisfactory performance.\n\nData Monitoring Committee: evaluates study progress; reviews aggregate safety data reports; recommends continuation or discontinuation of study.\n\nSite Monitoring, Auditing, and Resource Team (SMART): provides monitoring and other good clinical practice (GCP) support; monitoring and auditing both centrally and through local site visits.\n\nProtocol amendments\nImportant protocol amendments will be communicated to the VA Central IRB with request for approval, to investigators via electronic mail and at monthly conference calls, and to participants by local site investigators.\n\nThe opinions expressed in this article are those of the authors and do not necessarily represent those of the U.S. Department of Veterans Affairs.\n\nAuthors’ contributions\nMTB, RAB, and STB conceptualized the study. MTB, JAH, KMH, AMH, GD, STB designed the study and drafted the protocol. REF and GDH provided valuable advice and expertise in trial design. MTB drafted the manuscript. All authors contributed to the manuscript and read and approved the final version.\n\nFunding\nThis trial is fully funded by the U.S. Department of Veterans Affairs Cooperative Studies Program. CSP is a complete clinical research program which is responsible for the planning, conduct and funding support of multicenter clinical and epidemiologic research studies. CSP staff were involved in the design of this study and will have a role during study implementation, data collection and management, statistical analyses, interpretation of data, regulatory compliance, and study publication and dissemination. CSP also provided the general principles, policies and quality standards for how its studies should be conducted within the VA healthcare system.\n\nAuthorship policy: All presentations and publications from this study will be done in accordance with current CSP Investigator Guidelines, including the Authorship Policy. CSP subscribes to the criteria for determining who qualifies for authorship based on the “Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals,” developed by the International Committee of Medical Journal Editors (ICMJE).\n\nAvailability of data and materials\nDigital data underlying primary scientific publications from this study will be held as part of a data sharing resource maintained by the Cooperative Studies Program (CSP). Study data held for this purpose may include data, data content, format, and organization. The data may contain but are not limited to individually identifiable information, other protected health information, and study codes. The data may be available to the public and other VA and non-VA researchers under certain conditions and consistent with the informed consent and CSP policy which prioritize protecting subjects’ privacy and confidentiality to the fullest extent possible. It is the policy of the CSP that outcome data will not be revealed to the participating investigators until the study is completed. This policy safeguards against possible biases affecting the data collection. The presentation or publication of any or all data collected by participating investigators on patients entered into the VA Cooperative Study is under the direct control of the study’s Executive Committee. No individual participating investigator has any inherent right to perform analyses or interpretations or to make public presentations or seek publication of any or all of the data other than under the auspices and approval of the Executive Committee.\n\nEthics approval and consent to participate\nVA-INTREPID was approved by the Department of Veterans Affairs Central Institutional Review Board on July 7, 2017. All subjects participate in a thorough informed consent process supervised by the local site investigator, and document that by signature on an IRB approved informed consent form.\n\nAncillary and post-trial care: The clinical care team at each participating site will provide needed medical care to participants. If a participant is injured as a result of taking part in this study, the VA will provide necessary medical treatment at no cost to the participant unless the injury was due to not following study procedures.\n\nConfidentiality: Personal identifiable information will be maintained in the secure electronic medical record. All study data will be collected on case report forms with a subject code, and maintained in DataLabs, a secure research database.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Menke A Casagrande S Geiss L Cowie CC Prevalence of and trends in diabetes among adults in the United States, 1988-2012 Jama 2015 314 10 1021 1029 10.1001/jama.2015.10029 26348752 \n2. 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Li HK Rombach I Zambellas R Walker AS McNally MA Atkins BL Oral versus intravenous antibiotics for bone and joint infection N Engl J Med 2019 380 5 425 436 10.1056/NEJMoa1710926 30699315 \n10. Valour F Karsenty J Bouaziz A Ader F Tod M Lustig S Antimicrobial-related severe adverse events during treatment of bone and joint infection due to methicillin-susceptible Staphylococcus aureus Antimicrob Agents Chemother 2014 58 2 746 755 10.1128/AAC.02032-13 24247130 \n11. Valour F Trouillet-Assant S Riffard N Tasse J Flammier S Rasigade JP Antimicrobial activity against intraosteoblastic Staphylococcus aureus Antimicrob Agents Chemother 2015 59 4 2029 2036 10.1128/AAC.04359-14 25605365 \n12. Saginur R Stdenis M Ferris W Aaron SD Chan F Lee C Multiple combination bactericidal testing of staphylococcal biofilms from implant-associated infections Antimicrob Agents Chemother 2006 50 1 55 61 10.1128/AAC.50.1.55-61.2006 16377667 \n13. Norden CW Bryant R Palmer D Montgomerie JZ Wheat J Chronic osteomyelitis caused by Staphylococcus aureus: controlled clinical trial of nafcillin therapy and nafcillin-rifampin therapy South Med J 1986 79 8 947 951 10.1097/00007611-198608000-00008 3526570 \n14. Sanchez C Matamala A Salavert M Cuchi E Pons M Angles F Cotrimoxazole plus rifampicin in the treatment of staphylococcal osteoarticular infection Enferm Infecc Microbiol Clin 1997 15 1 10 13 9147500 \n15. Spellberg B Lipsky BA Systemic antibiotic therapy for chronic osteomyelitis in adults Clin Infect Dis 2012 54 3 393 407 10.1093/cid/cir842 22157324 \n16. Majewski P Wieczorek P Ojdana D Sacha PT Wieczorek A Tryniszewska EA In vitro activity of rifampicin alone and in combination with imipenem against multidrug-resistant Acinetobacter baumannii harboring the blaOXA-72 resistance gene Scand J Infect Dis 2014 46 4 260 264 10.3109/00365548.2013.865141 24447252 \n17. Acar JF Goldstein FW Duval J Use of rifampin for the treatment of serious staphylococcal and gram-negative bacillary infections Rev Infect Dis 1983 5 Suppl 3 S502 S506 10.1093/clinids/5.Supplement_3.S502 6635440 \n18. Berendt AR Peters EJ Bakker K Embil JM Eneroth M Hinchliffe RJ Diabetic foot osteomyelitis: a progress report on diagnosis and a systematic review of treatment Diabetes Metab Res Rev 2008 24 Suppl 1 S145 S161 10.1002/dmrr.836 18442163 \n19. Huang GD Ferguson RE Peduzzi PN O’Leary TJ Scientific and organizational collaboration in comparative effectiveness research: the VA cooperative studies program model Am J Med 2010 123 12 e24 e31 10.1016/j.amjmed.2010.10.005 21184863 \n20. Services DoHaH Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 2010 \n21. Allahabadi S Haroun KB Musher DM Lipsky BA Barshes NR Consensus on surgical aspects of managing osteomyelitis in the diabetic foot Diabet Foot Ankle 2016 7 30079 10.3402/dfa.v7.30079 27414481 \n22. Piaggesi A Macchiarini S Rizzo L Palumbo F Tedeschi A Nobili LA An off-the-shelf instant contact casting device for the management of diabetic foot ulcers: a randomized prospective trial versus traditional fiberglass cast Diabetes Care 2007 30 3 586 590 10.2337/dc06-1750 17327325 \n23. Jennison Christopher Turnbull Bruce Group Sequential Methods 1999 \n24. Riedel DJ Weekes E Forrest GN Addition of rifampin to standard therapy for treatment of native valve infective endocarditis caused by Staphylococcus aureus Antimicrob Agents Chemother 2008 52 7 2463 2467 10.1128/AAC.00300-08 18474578 \n25. Conlon BP Nakayasu ES Fleck LE LaFleur MD Isabella VM Coleman K Activated ClpP kills persisters and eradicates a chronic biofilm infection Nature 2013 503 7476 365 370 10.1038/nature12790 24226776 \n26. Lazaro-Martinez JL Aragon-Sanchez J Garcia-Morales E Antibiotics versus conservative surgery for treating diabetic foot osteomyelitis: a randomized comparative trial Diabetes Care 2014 37 3 789 795 10.2337/dc13-1526 24130347 \n27. Ricci L Scatena A Tacconi D Ventoruzzo G Liistro F Bolognese L All-cause and cardiovascular mortality in a consecutive series of patients with diabetic foot osteomyelitis Diabetes Res Clin Pract 2017 131 12 17 10.1016/j.diabres.2017.06.006 28668718 \n28. VersaPharm Rifampin Package Insert 2014\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "20(1)",
"journal": "BMC infectious diseases",
"keywords": "Amputation; Clinical trial; Diabetes mellitus; Diabetic foot; Double-blind; Lower extremity; Osteomyelitis; Rifampin; Survival; Veterans",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000671:Amputation; D000900:Anti-Bacterial Agents; D019072:Antibiotic Prophylaxis; D017719:Diabetic Foot; D004311:Double-Blind Method; D005260:Female; D005528:Foot; D006801:Humans; D008297:Male; D008875:Middle Aged; D010019:Osteomyelitis; D010919:Placebos; D011446:Prospective Studies; D012293:Rifampin; D055502:Secondary Prevention; D014728:Veterans; D055815:Young Adult",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "23",
"pmc": null,
"pmid": "31914940",
"pubdate": "2020-01-08",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "25468170;24130347;3526570;24247130;18474578;28668718;6635440;17327325;24226776;24447252;22619242;26348752;27414481;18184898;21184863;23496344;9147500;11733482;22157324;30699315;23384323;18442163;10764999;25605365;16377667",
"title": "A multicenter randomized placebo controlled trial of rifampin to reduce pedal amputations for osteomyelitis in veterans with diabetes (VA INTREPID).",
"title_normalized": "a multicenter randomized placebo controlled trial of rifampin to reduce pedal amputations for osteomyelitis in veterans with diabetes va intrepid"
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"abstract": "BACKGROUND Posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy, is a neurotoxic state with multiple etiologies characterized by altered mental state, headaches, visual abnormalities, and seizures. This clinico-radiological syndrome is rare, and a high index of suspicion is needed to diagnose, provide adequate treatment, and prevent irreversible neurological sequelae. CASE REPORT We present a case of a woman with end-stage renal disease (ESRD) who presented with acute confusion and non-convulsive seizures and was later diagnosed with PRES. In this case, altered mental status was initially thought to be secondary to uremic encephalopathy. A diagnosis of PRES was subsequently made after she had several sessions of HD without significant improvement in her mental state, prompting magnetic resonant imaging (MRI) for further evaluation. Specific risk factors for PRES, including blood pressure fluctuations, were targeted and she made significant clinical recovery but had residual functional impairment. CONCLUSIONS This case underscores the need for a high index of suspicion, especially in cases with atypical presentation, as delayed diagnosis can lead to suboptimal outcomes.",
"affiliations": "Department of Internal Medicine, New York Medical College, Metropolitan Hospital Center, New York City, NY, USA.;Department of Internal Medicine, New York Medical College, Metropolitan Hospital Center, New York City, NY, USA.;Department of Internal Medicine, New York Medical College, Metropolitan Hospital Center, New York City, NY, USA.;Department of Internal Medicine, New York Medical College, Metropolitan Hospital Center, New York City, NY, USA.;Department of Internal Medicine, New York Medical College, Metropolitan Hospital Center, New York City, NY, USA.",
"authors": "Adetiloye|Adebola Oluwabusayo|AO|;Valencia Manrique|Julio|J|0000-0002-9826-0585;Victoria|Ana|A|;Haider|Haider|H|;Al-Juboori|Mohammed T|MT|",
"chemical_list": null,
"country": "United States",
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"doi": "10.12659/AJCR.933667",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n34737256\n10.12659/AJCR.933667\n933667\nArticles\nPosterior Reversible Encephalopathy Syndrome Presenting Atypically as a Non-Convulsive Seizure\nAdetiloye Adebola Oluwabusayo E F\nManrique Julio Valencia F https://orcid.org/0000-0002-9826-0585\n\nVictoria Ana F\nHaider Haider F\nAl-Juboori Mohammed T. E F\nDepartment of Internal Medicine, New York Medical College, Metropolitan Hospital Center, New York City, NY, USA\nCorresponding Author: Adebola Oluwabusayo Adetiloye, e-mail: adetiloa@nychhc.org, docbola@gmail.com\nAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nFinancial support: None declared\n\nConflict of interest: None declared\n\n2021\n05 11 2021\n22 e933667-1e933667-8\n20 6 2021\n25 9 2021\n07 10 2021\n© Am J Case Rep, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Female, 59-year-old\n\nFinal Diagnosis: Posterior reversible encephalopathy syndrome (PRES)\n\nSymptoms: Altered mental status\n\nMedication:—\n\nClinical Procedure: —\n\nSpecialty: Cardiology • Critical Care Medicine • General and Internal Medicine • Nephrology • Neurology\n\nObjective:\n\nUnusual clinical course\n\nBackground:\n\nPosterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy, is a neurotoxic state with multiple etiologies characterized by altered mental state, headaches, visual abnormalities, and seizures. This clinico-radiological syndrome is rare, and a high index of suspicion is needed to diagnose, provide adequate treatment, and prevent irreversible neurological sequelae.\n\nCase Report:\n\nWe present a case of a woman with end-stage renal disease (ESRD) who presented with acute confusion and non-convulsive seizures and was later diagnosed with PRES. In this case, altered mental status was initially thought to be secondary to uremic encephalopathy. A diagnosis of PRES was subsequently made after she had several sessions of HD without significant improvement in her mental state, prompting magnetic resonant imaging (MRI) for further evaluation. Specific risk factors for PRES, including blood pressure fluctuations, were targeted and she made significant clinical recovery but had residual functional impairment.\n\nConclusions:\n\nThis case underscores the need for a high index of suspicion, especially in cases with atypical presentation, as delayed diagnosis can lead to suboptimal outcomes.\n\nKeywords:\n\nHypertension\nPosterior Leukoencephalopathy Syndrome\nSeizures\n==== Body\npmcBackground\n\nPosterior reversible encephalopathy syndrome (PRES) was first described in 1966 in a group of 15 patients with renal insufficiency, hypertension. and immunosuppression [1]. In these patients, a constellation of symptoms, including headache, decreased level of consciousness, visual changes, and seizures, associated with characteristic neuroimaging findings of posterior cerebral white-matter edema, was observed [1]. PRES has since been described in a number of clinical conditions with different pathophysiology. The exact cause and incidence of PRES is unknown, but an altered blood-brain barrier as a result of elevated blood pressure (BP) and/or endothelial injury seems to be a common denominator [2]. The clinical presentation of PRES is nonspecific and there is no well-defined diagnostic criteria, making for broad differentials; therefore, clinical suspicion needs to be high to ensure proper diagnosis and adequate management [3]. Although generalized tonic clonic seizure is the most commonly reported seizure type, a few cases, as well as the index case, had non-convulsive status epilepticus as a presenting symptom, which can manifest as confusion or psychotic symptoms [4,5].\n\nCase Report\n\nA 59-year-old African American woman with a known history of hypertension, hyperlipidemia, type 2 diabetes mellitus, and end-stage renal disease secondary to diabetes mellitus nephropathy was admitted to our hospital for altered mental status of 8-h duration prior to her presentation in the Emergency Department. Her daughter reported bizarre behavior, which included slow irrational speech with delusions and abnormal movements. She also stated that her mother was more somnolent than usual and had been experiencing headaches and worsening dyspnea for a few days prior to admission. She was scheduled for dialysis at an outside facility on the day of presentation, but the procedure was put on hold due to her altered mental status, agitation, and automatisms in the form of hand, head, and orofacial movements. Her home medications included amlodipine, carvedilol, lisinopril, hydralazine, isosorbide dinitrite, insulin, and methadone, but the daughter could not ascertain if she was complaint with her medications.\n\nAt presentation, she was hypertensive (BP 160/63 mmHg). No other abnormalities were noted in the vital signs. On neurological examination, she appeared restless, with stereotypical movement of head turning from side to side, eyes closed, with episodes of staring and nonsensical involuntary movements. She was oriented to person infrequently but not to time or place. She could not follow commands and responded to questions inappropriately, mostly with incomprehensible sounds. Her Glasgow Coma Scale (GCS) was 8/15: eye opening (E) 2, verbal response (V) 2, motor response (M) 4. She had no focal weakness, facial droop, or signs of meningeal irritation. A chest examination revealed bibasilar rales. The initial assessment was altered mental status secondary to metabolic verses toxic encephalopathy. A computed tomography (CT) scan of the head was unremarkable (Figure 1). A chest X-ray showed cardiomegaly and bilateral infiltrates suspicious for pulmonary edema. The toxicology screen from urine did not reveal any evidence of illicit drug use, and her blood ethanol level was <10 mg/dl. A comprehensive metabolic panel revealed sodium 145 mEq/L (136–145 mEq/L), potassium 5.1 mEq/L (3.5–5.1 mEq/L), chloride 102 mEq/L (98–107 mEq/L), bicarbonate 21 mmol/l (22–29 mmol/L), glucose 197 mg/dl (74–109 mg/dl), alkaline phosphatase 102 U/L (35–104 U/L), alanine aminotransferase 76 U/L (0–31 U/L), aspartate aminotransferase 43 mg/dl (0–32 U/L), calcium 9.8 mg/dl (8.6–10 mg/dl), and magnesium 2.3 mg/dl (1.4–2.6 mg/dl). Serum blood urea nitrogen (BUN) and creatinine levels were elevated at 45 mg/dl (6–20 mg/dl) and 8.2 mg/dl (0.7–0.9mg/dl), respectively. A complete blood count revealed white counts of 7800 cell/mcl (4300–11 000 cells/mcl), hemoglobin 12.7 g/dl (12–16 g/dl), platelets 123 000 cells/mcl (150 000–450 000 cells/mcl). Acute-phase reactants were elevated with C-reactive protein 4.99 mg/dl (0–0.4 mg/dl), and ferritin 1581 ng/ml (15–150 ng/ml) but antinuclear antibody (ANA) and other markers of autoimmune disease such as anti-double stranded DNA, antineutrophil cytoplasmic antibody (ANCA), and rheumatoid factor (RF) were unremarkable. Troponin and pro-brain natriuretic peptide were mildly elevated, while electrocardiography showed normal sinus rhythm with occasional premature ventricular complexes.\n\nOn the second day of admission, the patient was still confused, not obeying commands, and had no purposeful movements, GCS 7/15 15 with eye opening (E) 1, verbal response (V) 2, and motor response (M) 4, and BP ranged from 190–210 to 70–100 mmHg. She also had episodes of severe agitation. Serum BUN and creatinine trended up to 70 mg/dl and 11.0 mg/dl, respectively. A nasogastric tube (NGT) was placed for feeding and medications. She was started on hydralazine and labetalol via NGT and labetalol intravenously as needed to lower the BP to below 150/90 mmHg. The Nephrology Unit was consulted, and she had a session of hemodialysis on day 2 of admission. From day 3 to 10, she received 3 sessions of hemodialysis, but she continued to be in a fluctuating altered mental state. BUN during this period ranged from 17 mg/dl to 63 mg/dL (Table 1). Cardiology was consulted and recommended adding clonidine via NGT to the current antihypertensive regimen; however, BP ranged from 160–210 to 65–120 mmHg, with episodes of hypotension, necessitating withholding antihypertensive medications. A repeat CT scan of the brain on day 7 was unremarkable (Figure 2). Cerebral spinal fluid (CSF) studies showed mildly elevated white counts, mildly elevated protein, and negative oligoclonal band (Table 2). Electroencephalography (EEG) on day 10 showed severe diffuse cerebral dysfunction with frequent to continuous medium-to-high-voltage sharp and slow wave epileptiform discharges, synchronous and asynchronous, with amplitude predominance mainly in the frontal, central parietal, and occipital regions, consistent with epileptic encephalopathy (Figure 3). Based on EEG findings, we commenced intravenous levetiracetam 1 g loading dose, followed by 250 mg twice daily and 250 mg after each section of hemodialysis for maintenance. On day 11, the patient became more alert and oriented, she started following verbal commands, and her GCS improved from 8/15 to 13/15.\n\nHowever, on day 13, she became lethargic and febrile without an apparent source of infection. Vitals revealed BP of 188/110 mmHg. She had with elevated white counts of 25 000 cells/mcL and neutrophilia. A repeat chest X-ray showed atelectatic changes, but repeat CSF cell count, protein, and glucose contents were not unremarkably different from the prior study (Table 2). Blood, urine, and CSF cultures, CSF viral panel polymerase chain reaction (PCR), and CSF encephalopathy markers were obtained (Table 2). She was transferred to the Intensive Care Unit due to her deteriorating mental status. Intravenous meropenem 1 g every 24 h and acyclovir 220 mg daily (doses adjusted for renal impairment) were commenced pending culture reports. A repeat EEG showed diffuse encephalopathy. At this time, which was day 15 of admission, magnetic resonance imaging (MRI) of the brain was performed, revealing findings in keeping with PRES (Figure 4A ,4B). Over the next few days, she was on continuous cardiopulmonary monitoring and received labetalol by continuous infusion titrated to achieve better BP control with a goal of BP less than 150/90 mmHg and to avoid fluctuations in BP (Figure 5). A repeat CSF viral panel PCR and autoimmune encephalopathy markers came back negative (Table 2); therefore, acyclovir was discontinued but i.v. meropenem was continued for 7 days to treat sepsis. Cultures (CSF, blood, urine) also came back negative, with resolution of leukocytosis in the next 3 days. By day 20, the patient was completely alert and oriented, obeying commands, with GCS of 15/15 and steady blood pressure readings below 150/80. She continued to have regular hemo-dialysis sessions and was started on an outpatient antihypertensive regimen. She was also counseled on the importance of adherence to antihypertensive medications and hemodialysis. A repeat MRI on day 20 of admission showed increased late subacute hemorrhage associated with PRES and areas of developing encephalomalacia (Figure 6). She was subsequently discharged to a subacute rehabilitation facility with a modified Rankin scale of 4. She was followed up by a neurologist 2 months after discharge, with a repeat MRI revealing residual brain abnormalities. As result of persistent neuroimaging abnormalities, patient was maintained on long-term oral levetiracetam to prevent recurrent seizures.\n\nDiscussion\n\nThe precise incidence of PRES is unknown, but with increasing awareness of its possibility as a differential in various clinical scenarios coupled with more widespread use of MRI, more cases are being reported. In our patient, we hypothesized that elevated blood pressure as well as blood pressure fluctuation in the setting of kidney disease was the major factor predis-posing to the development of PRES. The pathophysiology of PRES is not well understood, but appears to be related to loss of cerebral autoregulation and endothelial dysfunction [1,6].\n\nHypertension with autoregulatory failure is believed to play a pivotal role in PRES. Normal autoregulation maintains constant cerebral blood flow over a range of systemic BP by means of arteriolar constriction and dilatation, as needed. Loss of auto-regulation occurs at MAP of >150–160 mmHg. In chronic hypertension, it occurs at relatively higher pressures, leading to breakdown of the blood-brain barrier and extravasation of fluid and blood products to brain parenchyma, causing vasogenic edema [7,8]. In addition, the speed of rise of blood pressure or random fluctuations in blood pressure suggests a higher risk of PRES compared to elevated blood pressure itself [6].\n\nEndothelial dysfunction also plays a crucial role in PRES patho-physiology, which could explain the occurrence of PRES in normotensive individuals. Diseases associated with activation of immune system or production of vasotoxic products can lead to abnormal endothelial activation, which in turn leads to production of molecules that triggers cytotoxic edema [9,10].\n\nPRES has been described in series of patients with acute and chronic kidney disease, as well as in those with ESRD. This suggests that abnormal kidney function is an important cause of PRES [11,12]. The association of kidney disease with PRES could be attributed to elevated blood pressure with kidney dysfunction, as well as endothelial dysfunction [9]. Autoimmune disorders such as systemic lupus erythematosus, granulomatosis with polyangiitis, rheumatoid arthritis, and Sjögren syndrome are also present in up to half of patients with PRES [1,8,13]. Some of these diseases have kidney dysfunction as a comorbidity. In addition, some of the medications used in the treatment of autoimmune diseases with kidney involvement, such as cyclosporin and tacrolimus, have been known to induce PRES [14]. Fluid overload in the setting of kidney dysfunction can also contribute to the development of PRES [3].\n\nThere are no validated diagnostic criteria for PRES, and its clinical presentation is not unique to the disease, making early diagnosis challenging, especially in patients with atypical presentation. The diagnosis of PRES should always be considered among the differentials in patients with risk factors such as ESRD or hypertension in the setting of acute neurological symptoms with typical neuroimaging findings, especially when unexplained by common etiologies. In our patient, we entertained possible diagnoses of metabolic encephalopathy, toxic encephalopathy, meningoencephalitis, and severe sepsis. However, CSF analysis results were not indicative of central nervous system infection or autoimmune limbic encephalitis. In addition, the toxicology screen was negative, and our patient did not have remarkable electrolyte derangement like hypomagnesemia, which is a documented risk factor for PRES. She continued regular sessions of hemodialysis, ruling out uremic encephalopathy as a cause of her altered mental status. Although our patient developed fever and leukocytosis during the course of hospitalization, raising the suspicion for sepsis, cultures came back negative. However, she was treated for sepsis with unclear etiology with resolution of fever and normalization of white blood cell counts. Moreover, reports have suggested that septic encephalopathy requires the absence of CNS infection, absence of other potential cause of encephalopathy, and nonspecific findings on neuroimaging [15]. Sepsis also a potential cause of PRES, which could have contributed to the severity of PRES in the index case [16].\n\nIn most reports, generalized tonic clonic seizure is the most common seizure type in patients with PRES. Nonetheless, the prevalence and clinical significance of non-convulsive seizures is unknown in these patients. Such an atypical presentation can delay the diagnosis of PRES, as seen in our case, leading to poorer outcomes. A high prevalence of non-convulsive seizures was found in critically ill patients with PRES, and an association was found between restricted diffusion on MRI and worse outcome [17]. Moreover, psychosis as a presentation of PRES, as in our patient, is rare and only a few cases of such unusual presentation have been reported in the literature [18].\n\nIt is important to note that the syndrome is not always reversible, and it is often not confined to either the white matter or the posterior regions of the brain. Vasogenic edema mostly occurs in the parieto-occipital region, but lesions affecting ‘atypical’ regions such as the frontal lobe, cerebellum, or basal ganglia have also been reported [19]. In the index case, lesions were present in the fronto-parietal regions of the brain in addition to the parieto-occipital regions. A study of 76 patient with PRES reported frontal lobe involvement in almost 80% of patents [20]. Management instituted early has been shown to prevent unfavorable outcomes.\n\nTreatment often involves use of antihypertensive medications to maintain BP in the autoregulatory range and withdrawal or treatment of other precipitating factors [1]. In a report of 15 patient with PRES, 100% of the patients had resolution of neurologic deficits within 2 weeks after timely institution of appropriate management [1]. However, in severe PRES, increased morbidity and mortality has been associated with delayed treatment, preexisting diabetes mellitus, and patients requiring dialysis. Complications include acute hemorrhage, extensive edema, and persistence of MRI abnormalities [6,21,22]. A study of 188 patients with PRES suggested that CSF pleocytosis was associated with cerebral hemorrhage, while elevated CSF protein was corrected with radiographic severity, similar to what was observed in the index case [23]. In our patient, the atypical PRES presentation contributed to delayed diagnosis; however, once PRES was diagnosed, we optimized blood pressure management and treated possible concurrent risk factors such as sepsis and fluid overload, with resolution of fluctuating levels of consciousness.\n\nConclusions\n\nPRES is an uncommon non-inflammatory vasculopathy, which is not always as reversible as its name suggests. As there is no specific treatment of PRES, the management goal is to control the precipitating factors. Our case underscores the need for a high index of suspicion, timely diagnosis, and management of risk factors to avoid permanent neurological sequelae.\n\nFigure 1. Computed tomography (CT) scan of the head done on the day of admission, showing age-related diffuse cerebral and cerebral volume loss.\n\nFigure 2. Repeat computed tomography (CT) scan of the head 7 days later, showing no interval changes.\n\nFigure 3. EEG showing epileptiform discharges, synchronous and asynchronous, with amplitude predominance mainly in the frontal, central parietal, and occipital regions.\n\nFigure 4. MRI Brain on day 15 of admission showing abnormal FLAIR (A) and T2-weighted (B) signals of the parieto-occipital and high bilateral fronto-parietal lobes, predominantly in the white matter. The signal abnormality is largely bilateral and symmetrical. Findings are suggestive of posterior reversible encephalopathy syndrome (PRES).\n\nFigure 5. Fluctuating blood pressure measurements in the first few days of admission.\n\nFigure 6. Repeat MRI Brain on day 20 of admission, showing increased late subacute and chronic hemorrhage associated with PRES and areas of developing encephalomalacia.\n\nTable 1. Blood urea nitrogen, creatinine, and electrolyte values before and after hemodialysis sessions.\n\n\tBlood urea nitrogen\tCreatinine\tPotassium\tSodium\tBicarbonate\t\nBefore HD 1st session\t70.0 mg/dL\t11.0 mg/dL\t4.5 mmol/L\t148 mmol/L\t22.0 mmol/L\t\nAfter HD 1st session\t49.0 mg/dL\t7.9 mg/dL\t4.7 mmol/L\t144 mmol/L\t20.0 mmol/L\t\nBefore HD 2nd session\t52.0 mg/dL\t8.1 mg/dL\t4.7 mmol/L\t140 mmol/L\t20.0 mmol/L\t\nAfter HD 2nd session\t17.0 mg/dL\t3.2 mg/dL\t3.7 mmol/L\t138 mmol/L\t22.0 mmol/L\t\nBefore HD 3rd session\t40.0 mg/dL\t7.3 mg/dL\t5.6 mmol/L\t133 mmol/L\t23.0 mmol/L\t\nAfter HD 3rd session\t25.0 mg/dL\t5.5 mg/dL\t4.9 mmol/L\t139 mmol/L\t26.0 mmol/L\t\nBefore HD 4th session\t45.0 mg/dL\t6.1 mg/dL\t3.8 mmol/L\t128 mmol/L\t26.0 mmol/L\t\nAfter HD 4th session\t23.0 mg/dL\t4.0 mg/dL\t3.4 mmol/L\t134 mmol/L\t32.0 mmol/L\t\nBefore HD 5th session\t63.0 mg/dL\t7.7 mg/dL\t4.1 mmol/L\t136 mmol/L\t24.0 mmol/L\t\nAfter HD 5th session\t19.0 mg/dL\t3.1 mg/dL\t2.9 mmol/L\t139 mmol/L\t26.0 mmol/L\t\nHD – hemodialysis.\n\nTable 2. Cerebrospinal fluid analysis.\n\nCSF characteristics\tDay 7\tDay 13\t\n\t\nAppearance\tClear\tClear\t\n\t\nWBC count (<5 cells/mcl)\t100 cells/mcL\t100 cells/mcL\t\n\t\nProtein (14–45 mg/dl)\t32.2 mg/dL\t65.4 mg/dL\t\n\t\nGlucose (40–80 mg/dl)\t100 mg/dL\t78 mg/dL\t\n\t\nAcid-fast stain\tNo acid-fast bacilli isolated after 6 weeks\tNo acid-fast bacilli isolated after 6 weeks\t\n\t\nCulture\tNo growth\tNo growth\t\n\t\nFungus CSF/India Ink\tNo fungus isolated after 4 weeks\tNo fungus isolated after 4 weeks\t\n\t\nBioFire meningitis encephalitis panel (CSF PCR): Neisseria meningitidis, Streptococcal pneumoniae, Streptococcal agalactiae, Hemophilus influenzae, Listeria monocytogens, HSV-1, HSV-2, VZV, HHV6, Parechovirus, Enterovirus, CMV, Escherichia coli, Cryptococcus\tNot detected\tNot detected\t\n\t\nWest Nile virus PCR\t\tNot detected\t\n\t\nEncephalopathy evaluation\t\t\t\nAMPA-R Antibody CBA\t\tNegative\t\nAnti-Glial Nuclear Antibody, Type 1\t\tNegative\t\nAnti-Neuronal Nuclear Antibody, Type 1, 2,3\t\tNegative\t\nCASPR2-IgG\t\tNegative\t\nCRMP-5-IgG\t\tNegative\t\nAmphiphysin Ab\t\tNegative\t\nDPPX Antibody IFA\t\tNegative\t\nGABA-B-R Antibody CBA\t\tNegative\t\nGAD 65\t\tNegative\t\nLeucine-Rich Glioma Inactivated Protein-1 IgG\t\tNegative\t\nmGluR1\t\tNegative\t\nNMDA-R Antibody CBA\t\tNegative\t\nPurkinje Cell Cytoplasmic Antibody, Type 1,2\t\tNegative\t\nPurkinje Cell cytoplasmic Antibody, Type Tr\t\tNegative\t\nGFAP IFA\t\tNegative\t\nCSF – cerebrospinal fluid; PCR – polymerase chain reaction; IFA – immunofluorescent assay; IgG – immunoglobulin G; HSV – herpes simplex virus; VZV – Varicella zoster virus; HHV – human herpes virus; AMPA-R – α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CBA – cell binding assay; CASPR2 – contactin-associated protein-like 2; CRMP – collapsin response-mediator protein-5 neuronal; DPPX – dipeptidyl peptidase-like protein; NMDA-R – N-methyl-D-aspartate receptor; GABA-B-R – gamma-amino butyric acid receptor, type B; GAD – glutamic acid decarboxylase; GFAP – glial fibrillary acidic protein; mGluR1 – metabotropic glutamate receptor 1.\n\nDepartment and Institution Where Work Was Done\n\nDepartment of Medicine, Metropolitan Hospital Center, New York City, NY, USA.\n\nDeclaration of Figures’ Authenticity\n\nAll figures submitted have been created by the authors who confirm that the images are original with no duplication and have not been previously published in whole or in part.\n==== Refs\nReferences:\n\n1. Hinchey J Chaves C Appignani B A reversible posterior leukoencephalopathy syndrome N Engl J Med 1996 334 494 500 8559202\n2. Bartynski WS Posterior reversible encephalopathy syndrome, Part 2: Controversies surrounding pathophysiology of vasogenic edema Am J Neuroradiol 2008 29 1043 49 18403560\n3. Sudulagunta SR Sodalagunta MB Kumbhat M Nataraju AS Posterior reversible encephalopathy syndrome (PRES) Oxford Med Case Reports 2017 2017 43 46\n4. Kozak OS Wijdicks EFM Manno EM Status epilepticus as initial manifestation of posterior reversible encephalopathy syndrome Neurology 2007 69 894 97 17724292\n5. Díaz-Ramírez GS Salgado-Cifuentes CA Zúñiga-Escobar G Morales-Plaza CD Posterior reversible leukoencephalopathy syndrome associated with psychosis: An unusual presentation Neurol (Engl Ed) 2019 34 549 51\n6. Fugate JE Rabinstein AA Posterior reversible encephalopathy syndrome: Clinical and radiological manifestations, pathophysiology, and outstanding questions Lancet Neurol 2015 14 914 25 26184985\n7. Ruland S Aiyagari V Cerebral autoregulation and blood pressure lowering Hypertension 2007 49 977 78 17353508\n8. Fischer M Schmutzhard E Posterior reversible encephalopathy syndrome J Neurol 2017 264 1608 16 28054130\n9. Marra A Vargas M Striano P Posterior reversible encephalopathy syndrome: The endothelial hypotheses Med Hypotheses 2014 82 619 22 24613735\n10. Chen Z Shen GQ Lerner A Gao B Immune system activation in the pathogenesis of posterior reversible encephalopathy syndrome Brain Res Bull 2017 131 93 99 28373149\n11. Gavrilovici C Miron I Voroneanu L Bădărau S Stârcea M Posterior reversible encephalopathy syndrome in children with kidney disease Int Urol Nephrol 2017 49 1793 800 28836059\n12. Fugate JE Rabinstein AA Posterior reversible encephalopathy syndrome: Clinical and radiological manifestations, pathophysiology, and outstanding questions Lancet Neurol 2015 14 914 25 26184985\n13. Gatla N Annapureddy N Sequeira W Jolly M Posterior reversible encephalopathy syndrome in systemic lupus erythematosus J Clin Rheumatol 2013 19 334 40 23965484\n14. Tam CS Galanos J Seymour JF Reversible posterior leukoencephalopathy syndrome complicating cytotoxic chemotherapy for hematologic malignancies Am J Hematol 2004 77 72 76 15307110\n15. Gofton TE Young GB Sepsis-associated encephalopathy Nat Rev Neurol 2012 8 557 66 22986430\n16. Garner O Ramirez A Lardino A A case of posterior reversible encephalopathy syndrome associated with sepsis BMJ Case Rep 2018 2018 bcr2018225128\n17. Bastide L Legros B Rampal N Clinical correlates of periodic discharges and nonconvulsive seizures in posterior reversible encephalopathy syndrome (PRES) Neurocrit Care 2018 29 481 90 29949000\n18. Herlimus FT Wardani IAK Widyadharma IPE Unspecified severe mental and behavior disorder associated with puerperium (postpartum psychosis) in posterior reversible encephalopathy syndrome: A case report Int J Res Med Sci 2021 9 607\n19. Raman R Devaramane R Jagadish GM Chowdaiah S Various imaging manifestations of posterior reversible encephalopathy syndrome (PRES) on magnetic resonance imaging (MRI) Pol J Radiol 2017 82 64 70 28243339\n20. McKinney AM Short J Truwit CL Posterior reversible encephalopathy syndrome: Incidence of atypical regions of involvement and imaging findings Am J Roentgenol 2007 189 904 12 17885064\n21. Hinduja A Habetz K Raina S Predictors of poor outcome in patients with posterior reversible encephalopathy syndrome Int J Neurosci 2017 127 135 44 26892843\n22. Hinduja A Posterior reversible encephalopathy syndrome: Clinical features and outcome Front Neurol 2020 11 71 32117030\n23. Ellis CA McClelland AC Mohan S Cerebrospinal fluid in posterior reversible encephalopathy syndrome: Implications of elevated protein and pleocytosis Neurohospitalist 2019 9 58 64 30915182\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "22()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D003952:Diagnostic Imaging; D005260:Female; D006261:Headache; D006801:Humans; D008279:Magnetic Resonance Imaging; D054038:Posterior Leukoencephalopathy Syndrome; D012307:Risk Factors; D012640:Seizures",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "e933667",
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"pmid": "34737256",
"pubdate": "2021-11-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28243339;28473920;24613735;26892843;17885064;28373149;32117030;18403560;29991547;17724292;29949000;28222932;30915182;26184985;15307110;23965484;28054130;28836059;17353508;22986430;8559202",
"title": "Posterior Reversible Encephalopathy Syndrome Presenting Atypically as a Non-Convulsive Seizure.",
"title_normalized": "posterior reversible encephalopathy syndrome presenting atypically as a non convulsive seizure"
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"abstract": "The relationship between freezing of gait (FOG) and levodopa response is complex. Some patients respond, some have no response and in some patients levodopa causes FOG. We present 2 cases demonstrating a diphasic worsening of FOG after levodopa dosing.\nTwo PD patients with FOG were examined during the practically defined off state, the transition from off to on (15 and 22 minutes postdose), and in the full on state (45 and 60 minutes postdose). FOG was measured using Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III, item 11: freezing of gait. Both patients experienced worsening of FOG during the transition followed by improvement during the on state. Case 1 had serum levodopa levels measured. Videos are provided.\nTo our knowledge, this diphasic pattern of worsening of FOG has not been previously reported. The cause of this phenomenon is unknown but may relate to an inhibitory action of subthreshold levels of levodopa.",
"affiliations": "Jean & Paul Amos PD & Movement Disorders Program Department of Neurology Emory University Atlanta Georgia USA.;Wallace H. Coulter Department of Biomedical Engineering Georgia Tech and Emory University Atlanta Georgia USA.;Jean & Paul Amos PD & Movement Disorders Program Department of Neurology Emory University Atlanta Georgia USA.",
"authors": "Perez Parra|Sahyli|S|;McKay|J Lucas|JL|https://orcid.org/0000-0002-8361-8943;Factor|Stewart A|SA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/mdc3.12918",
"fulltext": null,
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"issn_linking": "2330-1619",
"issue": "7(3)",
"journal": "Movement disorders clinical practice",
"keywords": "Parkinson's disease; diphasic; freezing of gait; levodopa",
"medline_ta": "Mov Disord Clin Pract",
"mesh_terms": null,
"nlm_unique_id": "101630279",
"other_id": null,
"pages": "325-328",
"pmc": null,
"pmid": "32258233",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports",
"references": "30357892;30982582;15300651;2405297;25899545;22744752;25446341;3419597;31799377;22262741",
"title": "Diphasic Worsening of Freezing of Gait in Parkinson's Disease.",
"title_normalized": "diphasic worsening of freezing of gait in parkinson s disease"
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"companynumb": "US-ORION CORPORATION ORION PHARMA-ENT 2020-0020",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstancename": "AMANTADINE HYDROCHLORIDE"
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{
"abstract": "People in different age groups are susceptible to SARS-CoV-2 infection as a newly emerging virus. However, the clinical course, symptoms and disease outcome vary from case to case. Although COVID-19 is usually milder in children than adults, some studies reported nonspecific symptoms. Here, we report eight pediatric cases of COVID-19 admitted in the Taleghani Children Hospital in Gorgan city, north of Iran, with complicated symptoms. The current case series poses several challenges to the pediatricians regarding the pediatric cases of COVID-19. As most literature relating to adults are not always transferable to children, clinicians should be warned about such presentations among children with COVID-19.",
"affiliations": "Department of Pediatrics, School of Medicine, Taleghani Children's Hospital, Golestan University of Medical Sciences, Gorgan, Iran.;Department of Pediatrics, School of Medicine, Taleghani Children's Hospital, Golestan University of Medical Sciences, Gorgan, Iran.;Department of Radiology, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.;Department of Pediatrics, School of Medicine, Taleghani Children's Hospital, Golestan University of Medical Sciences, Gorgan, Iran.;Department of Pediatrics, School of Medicine, Taleghani Children's Hospital, Golestan University of Medical Sciences, Gorgan, Iran.;Department of Microbiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.;Department of Pediatrics, School of Medicine, Taleghani Children's Hospital, Golestan University of Medical Sciences, Gorgan, Iran.;Infectious Diseases Research Centre, Golestan University of Medical Sciences, Gorgan, Iran.;Infectious Diseases Research Centre, Golestan University of Medical Sciences, Gorgan, Iran.",
"authors": "Cheraghali|Fatemeh|F|;Barati|Leila|L|;Amanian|Dayan|D|;Shahkar|Lobat|L|;Najafinejad|Maryam|M|;Naziri|Hamed|H|;Shahabi|Somayeh|S|;Tabarraei|Alijan|A|;Tahamtan|Alireza|A|https://orcid.org/0000-0001-7680-5698",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.2217/fvl-2021-0091",
"fulltext": "\n==== Front\nFuture Virol\nFuture Virol\nFVL\nFuture Virology\n1746-0794\n1746-0808\nFuture Medicine Ltd London, UK\n\n10.2217/fvl-2021-0091\nCase Series\nA case series of pediatric COVID-19 with complicated symptoms in Iran\nCheraghali Fatemeh 1\nBarati Leila 1\nAmanian Dayan 2\nShahkar Lobat 1\nNajafinejad Maryam 1\nNaziri Hamed 3\nShahabi Somayeh 1\nTabarraei Alijan 4 5\nhttps://orcid.org/0000-0001-7680-5698\nTahamtan Alireza * 4 5\n1 1Department of Pediatrics, School of Medicine, Taleghani Children’s Hospital, Golestan University of Medical Sciences, Gorgan, Iran\n2 2Department of Radiology, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran\n3 3Department of Microbiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran\n4 4Infectious Diseases Research Centre, Golestan University of Medical Sciences, Gorgan, Iran\n5 5Department of Microbiology, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran\n* Author for correspondence: Alireza.tmn@gmail.com\n08 10 2021\n9 2021\n08 10 2021\n10.2217/fvl-2021-009116 4 2021\n15 9 2021\n08 10 2021\n© 2021 Future Medicine Ltd\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 License\n\nPeople in different age groups are susceptible to SARS-CoV-2 infection as a newly emerging virus. However, the clinical course, symptoms and disease outcome vary from case to case. Although COVID-19 is usually milder in children than adults, some studies reported nonspecific symptoms. Here, we report eight pediatric cases of COVID-19 admitted in the Taleghani Children Hospital in Gorgan city, north of Iran, with complicated symptoms. The current case series poses several challenges to the pediatricians regarding the pediatric cases of COVID-19. As most literature relating to adults are not always transferable to children, clinicians should be warned about such presentations among children with COVID-19.\n\nKeywords: \n\ncase series\nCOVID-19\nIran\npediatrics\nSARS-CoV-2\n==== Body\npmcToday, COVID-19 has spread worldwide, caused by SARS-CoV-2. While all people in different age groups are susceptible to the newly emerging virus infection, the clinical course and disease outcome vary from case to case [1–3]. Due to weakened immune responses, older patients with underlying diseases are more affected by COVID-19 and associated with much higher case-fatality rates [4,5]. Preliminary evidence suggests that children are less prone to severe disease and death, possibly because of their immune system status with relatively low levels of inflammatory cytokines and having more pulmonary stem cells that can repair the damaged cells [6–8]. Despite this, there is not enough data to determine the exact behavior of SARS-CoV-2 infection in pediatrics. Although the disease is usually milder in children than in adults, some studies reported nonspecific symptoms. As the COVID-19 situation appears to be changing, clinicians should be warned of pediatrics infection. Here, we report eight pediatric cases of COVID-19 admitted in the Taleghani Children Hospital in Gorgan city, north of Iran, with complicated symptoms.\n\nCases description\n\nCase 1\n\nA 34-month-old male was admitted with a history of fever, recurrent seizure and low-level consciousness. Fever began 4 days before the seizure. Clinical and laboratory findings of all cases are shown in Table 1. In lumbar puncture (LP), the cerebrospinal fluid (CSF) appeared clear with normal protein and glucose level, normal white and red blood cell count (WBC and RBC), and negative for bacterial growth. The brain MRI proposed viral encephalitis with possible parenchymal hemorrhagic components. The molecular tests for HSV-1 and 2 were negative. Although CSF analysis did not reveal any evidence of CNS infection, SARS-CoV-2 RNA was detected in the nasopharyngeal swab and CSF with the same cycle threshold. After that, patchy consolidation in the superior segment of the left-lower lobe was observed in the spiral chest computed-tomography (CT) scan (Figure 1). At admission, treatment was started with dexamethasone and wide-spectrum antibiotics, but after SARS-CoV-2 detection, it changed to hydroxychloroquine, azithromycin, intravenous immunoglobulin (IVIG), lopinavir, ritonavir and caltra. His situation has not improved, and he got cerebral palsy. More details of this case have been published in our earlier work as a case report article [9].\n\nTable 1. Clinical and laboratory findings of all cases at admission.\n\n \tCase 1\tCase 2\tCase 3\tCase 4\tCase 5\tCase 6\tCase 7\tCase 8\t\nAge (months)\t34\t12\t33\t8\t54\t7\t2\t72\t\nGender\tMale\tMale\tMale\tMale\tMale\tFemale\tMale\tMale\t\nClinical findings\t\nMain symptoms\tSeizures, loss of consciousness\tFever, seizure, abdominal protrusion\tRespiratory distress, fever\tRespiratory distress, cyanosis\tFever, severe weakness, lethargy, anorexia, stomach ache, edema\tRespiratory distress, fever\tRespiratory distress, and no weight gain\tRespiratory distress, fever\t\nUnderlying diseases\t–\tFTT\tALL, FTT\tImmunodeficiency FTT\t–\tSevere FTT\tCongenital heart disease\tAsthma\t\nOutcome\tSevere neurologic morbidity\tComplete improvement\tDeath\tDeath\tComplete improvement\tDeath\tPartial improvement\tComplete improvement\t\nLaboratory findings\t\nWBC (cells/μl)\t23,300\t30,000\t31,300\t11,800\t17,700\t7700\t12,100\t10,400\t\nRBC (mil/mm3)\t5.41\t3.56\t3.66\t2.79\t3.87\t4.39\t3.37\t4.51\t\nHb (g/dl)\t12.3\t7.1\t8.9\t7.7\t10.6\t12.4\t9.8\t12.6\t\nHct (%)\t36.7\t22.7\t27.8\t22.8\t31.7\t36.1\t29.9\t35.9\t\nMCV (fl)\t67.84\t63.76\t73.16\t81.72\t81.91\t82.23\t88.72\t79.6\t\nMCH (pg)\t22.74\t19.94\t23.42\t27.6\t27.39\t28.25\t29.08\t27.9\t\nMCHC (g/dl)\t23.51\t31.28\t32.01\t33.77\t33.44\t34.35\t32.78\t35.1\t\nPLT\t727,000\t173,000\t107,000\t76,000\t29,000\t540,000\t454,000\t812,000\t\nPMN\t67%\t22%\t25%\t68%\t90%\t43%\t35%\t55%\t\nLymph\t20%\t74%\t75%\t32%\t10%\t57%\t65%\t40%\t\nBUN (mg/dl)\t7\t7\t12\t12\t17\t13\t12\t11\t\nCreatinine (mg/dl)\t0.5\t0.5\t0.6\t0.6\t0.6\t0.6\t0.6\t0.6\t\nNa (mg/dl)\t142\t138\t140\t140\t140\t138\t137\t139\t\nK (mg/dl)\t4.8\t5\t4.5\t4.9\t4\t4.2\t6.5\t4.4\t\nCRP\t+1\t+1\t1+\t+3\t+1\tNegative\tNegative\t3+\t\nESR (mm/h)\t35\t85\t17\t10\t18\t6\t7\t101\t\nLDH\t2826\t651\t1503\t1366\t651\t867\t712\t483\t\nAST\t154\t171\t49\t55\t36\t31\t27\t21\t\nALT\t111\t65\t20\t26\t35\t52\t22\t8\t\nCSF analysis\t\nGlucose\t65\t55\t \t \t \t \t \t \t\nProtein\t39\t39\t \t \t \t \t \t \t\nWBC\t2\t95\t \t \t \t \t \t \t\nPoly\t \t10%\t \t \t \t \t \t \t\nLymph\t \t90%\t \t \t \t \t \t \t\nCulture\tNegative\tNegative\t \t \t \t \t \t \t\nRT-PCR result\t\n1st test\tPositive\tNegative\tNegative\tPositive\tPositive\tNegative\tNegative\tPositive\t\n2nd test\t \tNegative\tSuspicious\t \t \tPositive\tPositive\t \t\n3rd test\t \tPositive\tPositive\t \t \t \t \t \t\nALL: Acute lymphoblastic leukemia; ALT: Alanine transaminase; AST: Aspartate transaminase; BUN: Blood urea nitrogen; CRP: C-reactive protein; CSF: Cerebrospinal fluid; ESR: Erythrocyte sedimentation rate; FTT: Failure to thrive; Hb: Hemoglobin; Hct: Hematocrit; LDH: Lactate dehydrogenase; MCH: Mean corpuscular hemoglobin; MCHC: Mean corpuscular hemoglobin concentration; MCV: Mean corpuscular volume; PLT: Platelet; PMN: Polymorphonuclear leukocytes; RBC: Red blood cell; RT-PCR: Real-time reverse transcription PCR; WBC: White blood cell.\n\nFigure 1. Computed tomography scan obtained from cases.\n\nCase 1: Patchy consolidation in the superior segment of the left-lower lobe and mild mosaic attenuation in both lungs. Case 2: Peripherally located patchy consolidations and ground-glass opacities in the basal segments of right-lower lobe (RLL) and inferior aspects of right-middle lobe and lingula. Case 3: Peripherally located patchy consolidation in the RLL and centrilobular ground-glass opacities in both lungs. Case 4: Collapse-consolidations in the posterior aspects of both lungs and patchy ground-glass opacity in the right-upper lobe. Case 5: Peripherally located patchy consolidations along with interlobular septal thickening. Case 6: Ground-glass opacities created regions of differing pulmonary attenuation (mosaic attenuation pattern) along with mild peribronchial wall thickening. Case 7: Collapse consolidations in posteromedial aspects of both lower lobes and mosaic attenuation in lungs. Case 8: Diffuse centrilobular ground-glass opacities and mild peribronchial wall thickening in both lungs.\n\nCase 2\n\nA 12-month-old male was referred because of fever, seizure and anemia while suffering from fever and diarrhea for 3 days. The seizure was upward gaze with generalized tonic–clonic movement in a few seconds. In the initial examination, abdominal distention and hepatosplenomegaly were observed. At admission, laboratory findings showed leukocytosis with lymphocytosis and decreased hemoglobin. The main findings of LP were pleocytosis with 90% lymph and negative for bacterial growth. The molecular test for SARS-CoV-2 and HSV-1 and 2 in CSF was negative. With suspicion of meningoencephalitis, wide-spectrum antibiotics were used. CT scan showed peripherally located patchy consolidations and ground-glass opacities in the basal segments of the right-lower lobe and inferior aspects of the right-middle lobe and lingula (Figure 1). SARS-CoV-2 and TB tests in respiratory samples were negative. Because of the reverse in CD4/CD8 ratio, an HIV test was ordered and reported as negative. The molecular test for SARS-CoV-2 again was negative. Abdominal sonography and CT scan showed hepatosplenomegaly and lymphadenopathy in the para-aorta and celiac trunk. Although his brain CT scan and MRI findings were normal, bone marrow aspiration revealed mild erythroid hyperplasia. Nasopharyngeal swab became positive for SARS-CoV-2 on day 18. Treatment was started with hydroxychloroquine, and the patient became well and was discharged.\n\nCase 3\n\nA 33-month-old male was admitted due to unilateral massive pleural effusion, respiratory distress and fever. Both a microbial examination in pleural fluid and the SARS-CoV-2 test in nasopharyngeal swab were negative. The main laboratory finding was leukocytosis with polymorphonuclear dominance. Pleural biopsy and bone marrow aspiration revealed acute lymphoblastic leukemia T cells. The patient was referred to the oncology department, and chemotherapy was performed for 3 weeks. One week later with sustained fever, lethargy and cough, the SARS-CoV-2 test was done, and the result was suspicious. His CT scan revealed peripherally located patchy consolidation in the right-lower lobe and centrilobular ground-glass opacities in both lungs (Figure 1). Treatment was started with cotrimoxazole, meropenem, vancomycin, nystatin, hydroxychloroquine, dexamethasone, pantoprazole and albumin. Four days later, the SARS-CoV-2 test became positive. Before receiving the RT-PCR result, the patient was transferred to the pediatric intensive care unit (PICU) because of respiratory distress and decreased O2 saturation, and he expired due to severe illness and anemia.\n\nCase 4\n\nAn 8-month-old male was referred to the pediatric emergency department with fever, productive cough, tachypnea, vomiting and diarrhea. At admission, bilateral whizzing and respiratory distress were heard with a stethoscope. He was born preterm and had normal delivery and development. The patient had a history of 33 days of hospitalization at birth and two-times due to pneumonia at 5 and 7 months. On arrival, the child had a respiratory rate of 61 per minute, a heart rate of 150 and O2 saturation of 75%. The level of total IgM and IgG was lower, which indicated humoral immune deficiency. Collapse consolidations in the posterior aspects of both lungs and patchy ground-glass opacity in the right-upper lobe were observed in the CT scan (Figure 1). TB and influenza tests were negative. The patient was transferred to the PICU, and treatment started with meropenem, vancomycin and cotrimoxazole. Nasopharyngeal swab became positive for SARS-CoV-2 RNA on day 4. He received IVIG and linezolid during the hospitalization, and hydroxychloroquine and ciprofloxacin were also added to the treatment. On day 20, the patient had a bilateral pneumothorax, and a chest tube was implanted, but the patient expired 2 days later.\n\nCase 5\n\nA 4.5-year-old male was hospitalized because of fever, severe weakness, lethargy, anorexia and abdominal pain. In the initial examination, the patient had a little edematous and tachypnea. At admission, the main laboratory findings were severe thrombocytopenia, anemia with hemoglobin of 7, leukocytosis with 90% polymorphonuclear and albumin of 2.2. His lung CT scan revealed peripherally located patchy consolidations along with interlobular septal thickening (Figure 1). With suspicion of COVID-19, the physician ordered the SARS-CoV-2 RT-PCR test. Due to the patient’s condition, albumin and caltra drugs were prescribed. Later day, the nasopharyngeal swab became positive for SARS-CoV-2 RNA. With the start of treatment, his condition improved, and he was discharged 6 days later in good condition.\n\nCase 6\n\nA 7-month-old female was admitted due to whizzing, fever and food intolerance. She weighed 1.5 kg at birth and 3 kg at the time of admission, but the development was normal. In previous hospitalizations, there was no found reason for her failure to thrive. Initial physical examination showed a little tachypnea with normal O2 saturation. At admission, laboratory findings were normal. In CT scan, ground-glass opacities created regions of differing pulmonary attenuation (mosaic attenuation pattern) along with mild peribronchial wall thickening were observed (Figure 1). Thus, COVID-19 was proposed by the attended physician, but the primary SARS-CoV-2 RT-PCR test was negative. Cefotaxime was used for the first 3 days of hospitalization, and the respiratory condition relatively improved. On the fourth day of hospitalization, she suddenly developed apnea, was transferred to the PICU and was intubated. Treatment was started with hydroxychloroquine, IVIG, meropenem and vancomycin. Later day, the nasopharyngeal swab became positive for SARS-CoV-2 RNA. Unfortunately, the patient expired 3 days later.\n\nCase 7\n\nA 2-month-old male was hospitalized with symptoms such as tachypnea, heart murmur, crying, lethargy, poor feeding and no weight gain. His mother reported that she had been wheezing and restless for about a month. The main finding of initial laboratory findings was anemia. The patient chest x-ray proposed bronchopneumonia, so antibiotic therapy started. There was no COVID-19 history in his family, and his primary COVID-19 test was negative. The CT scan showed subsegmental collapse consolidation in posteromedial aspects of both lower lobes and mosaic attenuation in lungs (Figure 1). According to the CT report, the COVID-19 test was repeated, and the nasopharyngeal swab became positive for SARS-CoV-2 RNA. After 10 days of antibiotic therapy, the patient was discharged in relatively good condition.\n\nCase 8\n\nA 6-year-old male was referred with symptoms and signs such as fever, cough and respiratory distress that started about 10 days prior. The patient was asthmatic and under treatment with salbutamol spray and corticosteroids. He had a history of hospitalization due to pneumonia last year. His body temperature reached over 40°C, O2 saturation was under 91%, and he had respiratory distress even while resting. The patient had no history of travel or contact with COVID-19 cases. The main laboratory findings were thrombocytosis and erythrocyte sedimentation rate of 101. The CT scan showed diffuse centrilobular ground-glass opacities and mild peribronchial wall thickening in both lungs (Figure 1). The patient was reported to be positive in the SARS-CoV-2 RT-PCR test. Treatment started with ceftriaxone, hydroxychloroquine and oxygen therapy. Finally, he was discharged in relatively good condition.\n\nDiscussion\n\nThe notifiable COVID-19 cases mainly were among adults, and pediatric patients were rarely reported. Importantly, preliminary clinical findings showed that children usually presented with mild or asymptomatic infections [10]. In theory, children are also susceptible to SARS-CoV-2 infection, and lower likelihood to get severe disease and death may be related to the children staying at home during the pandemic and having less contact with the source of infection. Other factors may include their still-developing immune system and having more pulmonary stem cells that can repair the injured cells. While the COVID-19 situation appears to be changing in pediatrics, its clinical profile in this population is less known [11]. This is a case series report on COVID-19 in children from Iran. These cases were in 2 months to 7 years, indicating no age group is safe from infection with SARS-CoV-2. Although with a small number of cases, we found that male children are more affected than females. This may be because of anatomical, genetic, hormonal and immunological differences. Notably, the expression level of ACE2 is found to be more in males than females [8].\n\nThe most important finding to come from the present analysis is the complicated pediatrics symptoms for COVID-19. Of the eight cases, five had respiratory symptoms, two had fever, seizures, low-level consciousness and one had edema, abdominal pain and severe weakness. Cases 1 and 2 were admitted with neurological manifestations, and this was different in that cases. While CSF analysis of case 1 was normal, the virus was detected in CSF. While the main LP findings in case 2 were pleocytosis with 90% lymph, CSF was negative for SARS-CoV-2. Neurological manifestations have been suggested as a presenting symptom or complication of COVID-19 [12], but only a few studies detected SARS-CoV-2 in the CSF [9,13]. Our case 1 represents the presence of SARS-CoV-2 in both the respiratory tract and CSF and highlights the importance of consideration of neurological complications as unknown signs of COVID-19. More studies are needed to guide the pediatricians further and confirm the CNS infection of SARS-CoV-2, neurologic manifestations and how the virus enters the CNS.\n\nIn these cases, inconsistent with the Liu et al.’s study [14], severe leukocytosis was observed in four patients, two of whom recovered and two died. The former two had polymorphonuclear, while the latter two had lymph dominance. No lymphopenia or leukopenia was seen that is inconsistent with other adult studies, indicating a different manifestation of the COVID-19 in pediatrics. The RT-PCR test was reported positive at admission only in four positive and in two cases were positive in the third test. Although the RT-PCR test confirmed all subjects as the ‘criterion-referenced’ for COVID-19 detection [15], we cannot rule out the potential of nosocomial infection or false-negative results, especially in cases that the test was negative for the first or second time. It is hard to determine common clinical characteristics in children with COVID-19, and it is unclear whether there is a common biomarker due to the small number of cases. Although the overall symptoms are relatively mild in children, the CT scan profiles are similar to adults.’\n\nConclusion\n\nThe current case series poses several challenges to the pediatricians regarding the pediatrics COVID-19. As most literature relating to adults are not always transferable to children, clinicians should be warned for such presentations among pediatrics with COVID-19. It is recommended that children with unusual clinical symptoms be screened for SARS-CoV-2 infection. Further research and reports are crucial to help us understand the clinical characteristics and natural history of COVID-19 in children.\n\nSummary points\n\nAs an emerging virus, all people in different age groups are susceptible to SARS-CoV-2 infection.\n\nAlthough COVID-19 is usually milder in children than in adults, some studies reported nonspecific symptoms.\n\nThe current case series poses several challenges to the pediatricians regarding the pediatrics COVID-19.\n\nOf the eight cases, five had respiratory symptoms, two had a fever, seizures and low-level consciousness, and one had edema, abdominal pain and severe weakness.\n\nCases 1 and 2 highlight the importance of consideration of neurological complications as unknown signs of COVID-19.\n\nAs most literature relating to adults are not always transferable to children, clinicians should be warned for such presentations among pediatrics with COVID-19.\n\nAuthor contributions\n\nA Tahamtan and F Cheraghali conceptualized and designed the study. F Cheraghali, L Barati, D Amanian, L Shahkar, M Najafinejad, S Shahabi and A Tabarraei collected data. A Tahamtan, H Naziri and F Cheraghali drafted the manuscript. All the authors evaluated and edited the manuscript and have read and approved the final manuscript.\n\nAcknowledgments\n\nThe authors thank Golestan University of Medical Sciences and the SARS-CoV-2 laboratory and nursing team fighting against the illness.\n\nFinancial & competing interests disclosure\n\nThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.\n\nNo writing assistance was utilized in the production of this manuscript.\n\nEthical conduct of research\n\nThis study was approved by the Ethics Committee of the Golestan University of Medical Sciences (IR.GOUMS.REC.1400.156). Informed consent has been obtained from the participants.\n==== Refs\nReferences\n\n1. Kay FU, Abbara S. The many faces of COVID-19: spectrum of imaging manifestations. Radiol: Cardiothorac. Imaging. 2 (1 ), e200037 (2020).33779634\n2. Xu X-W, Wu X-X, Jiang X-G Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-CoV-2) outside of Wuhan, China: retrospective case series. BMJ 368 , m606 (2020).32075786\n3. Teymoori-Rad M, Samadizadeh S, Tabarraei A Ten challenging questions about SARS-CoV-2 and COVID-19. Expert Rev. Respir. Med. 14 (9 ), 881–888 (2020).32536226\n4. Chen N, Zhou M, Dong X Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 395 (10223 ), 507–513 (2020).32007143\n5. Wang D, Hu B, Hu C Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 323 (11 ), 1061–1069 (2020).32031570\n6. Sinha IP, Harwood R, Semple MG COVID-19 infection in children. Lancet. Res. Med. 8 (5 ), 446–447 (2020).\n7. Kelvin AA, Halperin S. COVID-19 in children: the link in the transmission chain. Lancet. Infect. Dis. 20 (6 ), 633–634 (2020).32220651\n8. Samadizadeh S, Masoudi M, Rastegar M COVID-19: why does disease severity vary among individuals? Respir. Med. 180 , 106356 (2021).33713961\n9. Cheraghali F, Tahamtan A, Hosseini SA Case Report: detection of SARS-CoV-2 from cerebrospinal fluid in a 34-month-old child with encephalitis. Front. Pediatric. 9 , 194 (2021).\n10. Zheng F, Liao C, Fan Q-H Clinical characteristics of children with coronavirus disease 2019 in Hubei, China. Curr. Med. Sci. 40 (2 ), 275–280 (2020).32207032\n11. Tahamtan A, Tavakoli-Yaraki M, Salimi V. Opioids/cannabinoids as a potential therapeutic approach in COVID-19 patients. Expert Rev. Respir. Med. 14 (10 ), 965–967 (2020).32576053\n12. Filatov A, Sharma P, Hindi F Neurological complications of coronavirus disease (COVID-19): encephalopathy. Cureus 12 (3 ), e7352 (2020).32328364\n13. Moriguchi T, Harii N, Goto J A first case of meningitis/encephalitis associated with SARS-coronavirus-2. IJID 94 , 55–58 (2020).32251791\n14. Liu W, Zhang Q, Chen J Detection of Covid-19 in children in early January 2020 in Wuhan, China. N. Engl. J. Med. 382 (14 ), 1370–1371 (2020).32163697\n15. Tahamtan A, Ardebili A. Real-time RT-PCR in COVID-19 detection: issues affecting the results. Expert Rev. Mol. Diagn. 20 (5 ), 453–454 (2020).32297805\n\n",
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"issue": null,
"journal": "Future virology",
"keywords": "COVID-19; Iran; SARS-CoV-2; case series; pediatrics",
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"pubdate": "2021-09",
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"title": "A case series of pediatric COVID-19 with complicated symptoms in Iran.",
"title_normalized": "a case series of pediatric covid 19 with complicated symptoms in iran"
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"abstract": "BACKGROUND Salivary duct carcinoma (SDC) is a rare, aggressive head and neck cancer with frequent metastases. Current treatment options for recurrent or metastatic SDC include targeted anti-androgen therapy, HER2-targeted therapy, or systemic chemotherapy. We report the first use of a combination chemohormonal strategy. CASE REPORT A 68-year-old male who had never smoked with a past medical history of two-vessel coronary artery disease and systolic heart failure presented with a parotid mass and underwent surgical resection. Biopsy of the mass revealed high-grade, androgen receptor-positive and Erb-B2 receptor tyrosine kinase-2 (ERBB2)-amplified positive SDC. He subsequently received adjuvant radiation therapy. Four months after completion of adjuvant radiation therapy, recurrence with symptomatic pleural effusion and nodes, hepatic metastases, and boney metastases occurred. Due to significant symptomatic tumor, a rapid treatment response was desired. Combination chemohormonal therapy (CHT) was initiated with carboplatin area under the curve 4 and paclitaxel, 200 mg/m² in 21-day cycles along with combined androgen blockade using leuprolide, 45 mg subcutaneously every 6 months and bicalutamide, 50 mg daily. The treatment was well tolerated with fatigue as the main adverse event. Positron emission tomography-computed tomography at 3 and 6 months after treatment initiation showed good partial response. The patient experienced uveal progression after 8 months and alternate treatment was started. CONCLUSIONS Combination CHT with carboplatin, paclitaxel, and combined androgen deprivation may be a good treatment option in androgen receptor-positive recurrent or metastatic SDC if rapid treatment response is desired. Combination chemotherapy with androgen deprivation for validation through clinical trials.",
"affiliations": "School of Medicine, Loma Linda University, Loma Linda, CA, USA.;Division of Hematology and Oncology, Department of Internal Medicine, Loma Linda University Medical Center, Loma Linda, CA, USA.;Department of Pathology, Veterans Affairs Loma Linda Healthcare System, Loma Linda, CA, USA.;Department of Hematology and Oncology, Veterans Affairs Loma Linda Healthcare System, Loma Linda, CA, USA.",
"authors": "Jeong|Il Seok Daniel|ISD|;Moyers|Justin|J|;Thung|Irene|I|;Thinn|Mie Mie|MM|",
"chemical_list": "D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D009570:Nitriles; D014105:Tosyl Compounds; C053541:bicalutamide; D016190:Carboplatin; D016729:Leuprolide; D017239:Paclitaxel",
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"doi": "10.12659/AJCR.925181",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n32601266\n10.12659/AJCR.925181\n925181\nArticles\nCombination Chemohormonal Therapy in Metastatic Salivary Duct Carcinoma\nJeong Il Seok Daniel ABDEF1 Moyers Justin ABDEF2 Thung Irene DE3 Thinn Mie Mie ABDEF4 \n1 School of Medicine, Loma Linda University, Loma Linda, CA, U.S.A.\n\n2 Division of Hematology and Oncology, Department of Internal Medicine, Loma Linda University Medical Center, Loma Linda, CA, U.S.A.\n\n3 Department of Pathology, Veterans Affairs Loma Linda Healthcare System, Loma Linda, CA, U.S.A.\n\n4 Department of Hematology and Oncology, Veterans Affairs Loma Linda Healthcare System, Loma Linda, CA, U.S.A.\nCorresponding Author: Justin Moyers, e-mail: justintmoyers@gmail.comAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n30 6 2020 \n21 e925181-1 e925181-4\n15 4 2020 08 5 2020 29 5 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 68-year-old\n\nFinal Diagnosis: Salivary duct carcinoma\n\nSymptoms: Bone pain • dyspnea\n\nMedication:—\n\nClinical Procedure: Chemotherapy\n\nSpecialty: Oncology\n\nObjective:\nRare disease\n\nBackground:\nSalivary duct carcinoma (SDC) is a rare, aggressive head and neck cancer with frequent metastases. Current treatment options for recurrent or metastatic SDC include targeted anti-androgen therapy, HER2-targeted therapy, or systemic chemotherapy. We report the first use of a combination chemohormonal strategy.\n\nCase Report:\nA 68-year-old male who had never smoked with a past medical history of two-vessel coronary artery disease and systolic heart failure presented with a parotid mass and underwent surgical resection. Biopsy of the mass revealed high-grade, androgen receptor-positive and Erb-B2 receptor tyrosine kinase-2 (ERBB2)-amplified positive SDC. He subsequently received adjuvant radiation therapy. Four months after completion of adjuvant radiation therapy, recurrence with symptomatic pleural effusion and nodes, hepatic metastases, and boney metastases occurred. Due to significant symptomatic tumor, a rapid treatment response was desired. Combination chemohormonal therapy (CHT) was initiated with carboplatin area under the curve 4 and paclitaxel, 200 mg/m2 in 21-day cycles along with combined androgen blockade using leuprolide, 45 mg subcutaneously every 6 months and bicalutamide, 50 mg daily. The treatment was well tolerated with fatigue as the main adverse event. Positron emission tomography-computed tomography at 3 and 6 months after treatment initiation showed good partial response. The patient experienced uveal progression after 8 months and alternate treatment was started.\n\nConclusions:\nCombination CHT with carboplatin, paclitaxel, and combined androgen deprivation may be a good treatment option in androgen receptor-positive recurrent or metastatic SDC if rapid treatment response is desired. Combination chemotherapy with androgen deprivation for validation through clinical trials.\n\nMeSH Keywords:\nAndrogensAntineoplastic Combined Chemotherapy ProtocolsCarboplatinLeuprolidePaclitaxelSalivary Ducts\n==== Body\nBackground\nSalivary duct carcinoma (SDC) is a rare, aggressive histologic subtype of salivary gland carcinoma (SGC) with a predilection to present as locally advanced disease and to undergo early metastasis [1]. Prognosis of metastatic disease is poor with median overall survival of only 15 months [1]. It has histologic resemblance to invasive ductal carcinoma of the breast and commonly expresses androgen receptor (AR) in up to 79% of cases and human epidermal growth factor receptor 2 (HER2) overexpression or ErB receptor tyrosine kinase-2 (ErB-B2) amplification in 25% of tumors [2]. Although there is no standard treatment for SDC, current treatment options for recurrent or metastatic SDC utilize chemotherapy, anti-HER2-targeted therapy, or antiandrogen therapy. Common systemic therapy options have included anthracycline or platinum-based combination or single-agent chemotherapy with response rates between 20% and 60% [3,4]. Similarly, antiandrogen hormonal therapies have been used for AR- positive tumors with response rates between 20% and 65% [5]. Herein, we present the first reported case of metastatic SDC treated with combination chemohormonal therapy (CHT).\n\nCase Report\nA 68-year-old male who had never smoked with normal performance status and a history of two-vessel coronary artery disease and systolic heart failure presented with a left parotid mass. Surgical resection with cervical lymph node dissection showed 3.5-cm high-grade SDC with multiple positive margins and 12/29 nodes positive for metastasis with extracapsular extension to the stratified muscle (pT4aN3b). The patient subsequently underwent 66 Gray of adjuvant radiation over 33 fractions. Four months after completing adjuvant therapy, a surveillance computed tomography (CT) scan revealed multiple lung nodules, large pleural effusion, cervical adenopathy, and diffuse bony metastases of the axial and appendicular skeleton. Biopsy of a cervical node and pleural fluid revealed recurrent metastatic AR-positive SDC (Figure 1). Next-generation sequencing revealed ErB-B2 amplification. A thoracic drainage catheter was placed for symptomatic control.\n\nGiven the symptomatic large burden of disease and desire for rapid response, combination therapy was initiated with carboplatin AUC 4 and paclitaxel, 200 mg/m2 in 21-day cycles along with leuprolide, 45 mg subcutaneous every 6 months and bicalutamide, 50 mg daily. During Cycle 1 of therapy, the patient developed diplopia and headache. Brain magnetic resonance imaging (MRI) revealed multiple cerebral and cerebellar metastases. He underwent 30 Gray of whole brain radiation over 10 fractions. After three cycles of therapy, a positron emission tomography (PET)/CT scan of the chest revealed partial response with decreased fluorodeoxyglucose activity of bony metastases and reduced thoracic catheter drainage. During Cycle 5, the patient was hospitalized for acute heart failure and non-ST-elevation myocardial infarction thought to be secondary to his pre-existing cardiovascular disease (CVD). He was subsequently maintained on androgen deprivation therapy (ADT) alone with continued partial response. Six months after beginning CHT, PET-CT showed further improvement of tumor burden in axial and appendicular skeletons and lungs (Figure 2). However, blurred vision after 8 months of therapy showed new uveal metastases on orbital MRI and the patient began alternate treatment for disease progression.\n\nDiscussion\nOur patient experienced a rapid partial and sustained response to combination CHT with amelioration of his symptomatic pleural effusion, liver metastases, and bony metastasis. We developed this treatment regimen due to his tumor characteristics and desire for quick response.\n\nStandard single-agent or combination chemotherapy regimens have low response rates with significant hematologic, cardiac, and neurologic toxicities. For those eligible, the response rates of nearly 40% have been seen with combination regimens including cyclophosphamide, doxorubicin, and cisplatin (CAP); carboplatin and paclitaxel; and carboplatin and docetaxel [5–8]. In contrast, single-agent cytotoxic chemotherapy has limited activity with response rates varying between 10% and 40% with cisplatin, doxorubicin, mitoxantrone, or vinorelbine [3,5]. Recently, targeted therapies have come to the forefront of salivary gland carcinomas for those with AR-positive, HER2-expressing, or NTRK gene fusion-positive tumors.\n\nAnti-HER2 therapy has become the preferred therapy for those with HER2 overexpression or amplification of the ErB-B2 gene [9]. The combination of anti-HER2 trastuzumab with docetaxel was found to be promising in a single-center phase II study of 57 patients that achieved an overall response rate of 70.2% with an overall survival of 39.7 months [10]. The treatment was noted to have manageable toxicity with hemato-logic adverse events as the most common Grade 3–4 reactions (anemia, neutropenia, and febrile neutropenia). Moreover, the MYPATHWAY Phase IIa basket trial to assess the efficacy of dual anti-HER2 therapy with trastuzumab and pertuzumab on ErB-B2-amplified tumors included five patients with advanced or metastatic SGC. Four of 5 patients with SGC achieved a partial response on therapy [11]. The antibody-drug conjugate ado-trastuzumab ematansine (TDM-1), has been used in the NCI-MATCH basket trial in three patients with SGC as well as a case series of seven patients with SGC by Swed et al. in which response was seen in all 10 patients between cohorts [12,13]. Unfortunately, heart failure is a potential side effect of all anti-HER2 therapies, which are contraindicated in patients with significant preexisting heart failure and could not be used for our patient due to preexisting ischemic cardiomyopathy [14].\n\nA recent single-arm, single-institution, prospective phase II trial using combined ADT for recurrent or metastatic AR-positive SDC showed less toxicity and an overall response rate of 41.7%, similar to historical response rates with conventional chemotherapy without dose-limiting toxicity [15]. The largest retrospective cohort study of 58 recurrent or metastatic AR-positive patients found median overall survival to be 25 months in both the first-line androgen therapy and first-line chemotherapy groups while the overall response rate favored first-line ADT in 45% versus 12% [16]. Because response to androgen blockade was reported to take months, we were concerned about whether treatment could produce improvement quickly enough, given significant respiratory decline.\n\nWhile combination CHT has not been employed in SDC, it is standard of care for advanced and metastatic hormone-sensitive prostate cancer. Two large phase III randomized controlled trials, CHAARTED and STAMPEDE, in advanced or metastatic prostate cancer trial showed superior safety and efficacy of combination docetaxel with androgen deprivation compared to standard-of-care androgen deprivation alone [17,18]. Androgen blockade with chemotherapy was well tolerated in prostate cancer with predominant AEs including hematologic and peripheral neuropathy. This provided evidence of safety for combining androgen blockade with cytotoxic chemotherapy.\n\nThis treatment regimen was well tolerated by our patient. His primary complaint was Grade II fatigue that he experienced after four cycles of chemotherapy. Furthermore, he was hospitalized for heart failure exacerbation during the course of treatment.\n\nAlthough paclitaxel has cardiotoxicity primarily through arrhythmia or heart failure [19,20], we did not attribute it to the combination therapy in this novel regimen to due to this patient’s unstable cardiac disease which predated initiation of his therapy.\n\nWe cannot determine if the combination of chemotherapy and hormonal therapy led to improved response compared to single-modality treatment. It is also possible that one therapy was driving the effect more than the other. While a combination chemohormonal strategy has been successful in prostate cancer, it has not yielded substantial survival benefits in breast cancer, where single-modality chemotherapy or hormonal treatments in sequence are standard of care [21,22].\n\nConclusions\nCombination CHT may be an efficacious treatment option in AR-positive recurrent or metastatic SDC requiring rapid treatment response or when anti-HER2 therapy is contraindicated. This combination strategy should be considered for validation in prospective trials.\n\nFigure 1. (A) Hematoxylin and eosin staining (20×) of salivary duct carcinoma showing ducts with cribriform pattern in a background of fibrosis. The tumor cells are markedly pleomorphic with ample eosinophilic cytoplasm. (B) Androgen receptor immunohistochemical staining with red chromogen (20×) of salivary duct carcinoma showing immunoreactivity.\n\nFigure 2. (A) Pretreatment PET/CT and brain MRI showing pleural effusion, mediastinal adenopathy, and bony, liver, and cerebellar metastases. (B) PET/CT after 6 months of treatment showing good partial response to treatment with near resolution of pleural effusion, chest adenopathy, and bony metastases with shrinking of cerebellar metastasis.\n==== Refs\nReferences:\n1. Jayaprakash V Merzianu M Warren GW Survival rates and prognostic factors for infiltrating salivary duct carcinoma: Analysis of 228 cases from the Surveillance, Epidemiology, and End Results database Head Neck 2014 36 5 694 701 23606370 \n2. Williams MD Roberts D Blumenschein GR Jr Differential expression of hormonal and growth factor receptors in salivary duct carcinomas: biologic significance and potential role in therapeutic stratification of patients Am J Surg Pathol 2007 31 11 1645 52 18059220 \n3. Laurie SA Licitra L Systemic therapy in the palliative management of advanced salivary gland cancers J Clin Oncol 2006 24 17 2673 78 16763282 \n4. Ruzich JC Ciesla MC Clark JI Response to paclitaxel and carboplatin in metastatic salivary gland cancer: A case report Head Neck 2002 24 4 406 10 11933184 \n5. Chintakuntlawar AV Okuno SH Price KA Systemic therapy for recurrent or metastatic salivary gland malignancies Cancers Head Neck 2016 1 11 31093341 \n6. Dreyfuss AI Clark JR Fallon BG Cyclophosphamide, doxorubicin, and cisplatin combination chemotherapy for advanced carcinomas of salivary gland origin Cancer 1987 60 12 2869 72 2824016 \n7. Okada T Saotome T Nagao T Carboplatin and docetaxel in patients with salivary gland carcinoma: A retrospective study In vivo (Athens, Greece) 2019 33 3 843 53 \n8. Nakano K Sato Y Sasaki T Combination chemotherapy of carboplatin and paclitaxel for advanced/metastatic salivary gland carcinoma patients: Differences in responses by different pathological diagnoses Acta Otolaryngol 2016 136 9 948 51 27094013 \n9. Schvartsman G Pinto NA Bell D Ferrarotto R Salivary gland tumors: Molecular characterization and therapeutic advances for metastatic disease Head Neck 2019 41 1 239 47 30552848 \n10. Takahashi H Tada Y Saotome T Phase II Trial of trastuzumab and docetaxel in patients with human epidermal growth factor receptor 2-positive salivary duct carcinoma J Clin Oncol 2019 37 2 125 34 30452336 \n11. Hainsworth JD Meric-Bernstam F Swanton C Targeted therapy for advanced solid tumors on the basis of molecular profiles: Results from MyPathway, an open-label, phase IIa multiple basket study J Clin Oncol 2018 36 6 536 42 29320312 \n12. Jhaveri KL Wang XV Makker V Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: Results from the NCI–MATCH trial (EAY131) subprotocol Q Ann Oncol 2019 30 11 1821 30 31504139 \n13. Swed BL Cohen RB Aggarwal C Targeting HER2/neu oncogene overexpression with ado-trastuzumab emtansine in the treatment of metastatic salivary gland neoplasms: A single-institution experience JCO Precis Oncol 2019 3 10.1200/PO.1800351 \n14. Ponde NF Lambertini M de Azambuja E Twenty years of anti-HER2 therapy-associated cardiotoxicity ESMO Open 2016 1 4 e000073 27843627 \n15. Fushimi C Tada Y Takahashi H A prospective phase ii study of combined androgen blockade in patients with androgen receptor-positive meta-static or locally advanced unresectable salivary gland carcinoma Ann Oncol 2018 29 4 979 84 29211833 \n16. Viscuse PV Price KA Garcia JJ First line androgen deprivation therapy vs . chemotherapy for patients with androgen receptor positive recurrent or metastatic salivary gland carcinoma – a retrospective study Front Oncol 2019 9 701 31428578 \n17. Sweeney CJ Chen YH Carducci M Chemohormonal Therapy in metastatic hormone-sensitive prostate cancer N Engl J Med 2015 373 8 737 46 26244877 \n18. James ND Sydes MR Clarke NW Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive, multiarm, multistage, platform randomised controlled trial Lancet 2016 387 10024 1163 77 26719232 \n19. Schlitt A Jordan K Vordermark D Cardiotoxicity and oncological treatments Dtsch Arztebl Int 2014 111 10 161 68 24666651 \n20. Osman M Elkady M A prospective study to evaluate the effect of paclitaxel on cardiac ejection fraction Breast Care 2017 12 4 255 59 29070990 \n21. Sledge GW Jr Hu P Falkson G Comparison of chemotherapy with chemohormonal therapy as first-line therapy for metastatic, hormone-sensitive breast cancer: An Eastern Cooperative Oncology Group study J Clin Oncol 2000 18 2 262 66 10637238 \n22. Bedognetti D Sertoli MR Pronzato P Concurrent vs . sequential adjuvant chemotherapy and hormone therapy in breast cancer: A multicenter randomized phase III trial J Natl Cancer Inst 2011 103 20 1529 39 21921285\n\n",
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"medline_ta": "Am J Case Rep",
"mesh_terms": "D000368:Aged; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002277:Carcinoma; D006801:Humans; D016729:Leuprolide; D008297:Male; D009570:Nitriles; D017239:Paclitaxel; D018987:Salivary Ducts; D012468:Salivary Gland Neoplasms; D014105:Tosyl Compounds",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "e925181",
"pmc": null,
"pmid": "32601266",
"pubdate": "2020-06-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "31028207;11933184;31428578;27094013;21921285;26719232;18059220;16763282;31093341;31504139;30552848;23606370;29211833;29320312;10637238;30452336;26244877;27843627;2824016;29070990;30906914;24666651",
"title": "Combination Chemohormonal Therapy in Metastatic Salivary Duct Carcinoma.",
"title_normalized": "combination chemohormonal therapy in metastatic salivary duct carcinoma"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-258573",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drug... |
{
"abstract": "OBJECTIVE\nAmiodarone, a commonly used class III antiarrhythmic agent notable for a relatively long half-life of up to 6 months and its pronounced adverse effect profile, is used for both acute and chronic management of cardiac arrhythmias. Chronic use of amiodarone has been associated with asymptomatic hepatotoxicity; however, acute toxicity is thought to be uncommon. There are only six reported cases of acute liver failure (ALF) secondary to amiodarone. In all these cases the outcome of death during the same hospitalization resulted. We aimed to report the only case of acute liver failure secondary to amiodarone infusion in the existing literature where the patient survived.\n\n\nMETHODS\nA 79-year-old woman admitted with atrial flutter was being treated with intravenous (IV) amiodarone when she abruptly developed coagulopathy, altered mental status and liver enzyme derangement. She was diagnosed with acute liver failure (ALF) secondary to an amiodarone adverse drug reaction, with a calculated score of seven on the Naranjo adverse drug reaction probability scale. Amiodarone was immediately withheld, and N-acetylcysteine (NAC) was initiated. Clinical improvement was seen within 48 hours of holding the drug and within 24 hours of initiating NAC. On post-hospital follow-up visit she was reported to have complete recovery.\n\n\nCONCLUSIONS\nThis report emphasizes the importance of monitoring liver enzymes and mental status while a patient is being administered IV amiodarone. N-acetylcysteine administration may have possibly contributed to the early and successful recovery from ALF in our patient. To date, she is the only patient in the existing literature who has been reported to survive ALF secondary to amiodarone administration.",
"affiliations": "Department of Internal Medicine, John H. Stroger, Jr. Hospital of Cook County, Chicago, IL, USA.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, John H. Stroger, Jr. Hospital of Cook County, Chicago, IL, USA.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, John H. Stroger, Jr. Hospital of Cook County, Chicago, IL, USA.;Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.;Department of Internal Medicine, Forest Hills Hospital, Forest Hills, NY, USA.;Department of Internal Medicine, John H. Stroger, Jr. Hospital of Cook County, Chicago, IL, USA.;Department of Pharmacy, John H. Stroger, Jr. Hospital of Cook County, Chicago, IL, USA.;Department of Internal Medicine, Mercy Catholic Medical Center, Darby, PA, USA.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, John H. Stroger, Jr. Hospital of Cook County, Chicago, IL, USA.",
"authors": "Jaiswal|P|P|http://orcid.org/0000-0001-7775-1708;Attar|B M|BM|;Yap|J E|JE|;Devani|K|K|;Jaiswal|R|R|;Wang|Y|Y|;Szynkarek|R|R|;Patel|D|D|;Demetria|M|M|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D000638:Amiodarone",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12594",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "43(1)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "N-acetylcysteine; acute hepatic failure; acute liver failure; amiodarone; systematic review; treatment",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000368:Aged; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D005260:Female; D006760:Hospitalization; D006801:Humans; D007262:Infusions, Intravenous; D017114:Liver Failure, Acute",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "129-133",
"pmc": null,
"pmid": "28714083",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Acute liver failure with amiodarone infusion: A case report and systematic review.",
"title_normalized": "acute liver failure with amiodarone infusion a case report and systematic review"
} | [
{
"companynumb": "US-MYLANLABS-2018M1017052",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nHydralazine is an effective antihypertensive drug which acts by vasodilatation. It is well known to cause drug-induced lupus erythematosus. Nevertheless, the overall safety profile is good and cutaneous adverse effects are uncommon. To the best of our knowledge, hydralazine has never been reported to cause Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).\n\n\nMETHODS\nWe herein report the first case of hydralazine-induced TEN in a patient with end-staged renal failure. Despite meticulous wound management and intensive medical care, the patient died of a sudden cardiac arrest on day 10 of admission.\n\n\nCONCLUSIONS\nWe speculate that patients with renal failure may be predisposed to a higher risk of allergy to drug entities that are rarely associated. Physicians should be aware that hydralazine can be a potential cause for severe allergic reaction such as SJS or TEN, particularly in the setting of poor renal excretory function. Patient education and cautious monitoring by physicians are essential for early diagnosis and hence successful management of the life-threatening condition.",
"affiliations": "Division of Dermatology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.",
"authors": "Chan|J C|JC|;Yap|D Y|DY|;Yeung|C K|CK|",
"chemical_list": "D006830:Hydralazine",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12141",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "39(3)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "Stevens-Johnson syndrome; hydralazine; renal failure; toxic epidermal necrolysis",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D006830:Hydralazine; D007676:Kidney Failure, Chronic; D010531:Peritoneal Dialysis, Continuous Ambulatory; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "322-4",
"pmc": null,
"pmid": "24588409",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hydralazine-induced toxic epidermal necrolysis in a patient on continuous ambulatory peritoneal dialysis.",
"title_normalized": "hydralazine induced toxic epidermal necrolysis in a patient on continuous ambulatory peritoneal dialysis"
} | [
{
"companynumb": "HK-WATSON-2015-00791",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FERROUS SULFATE ANHYDROUS"
},
"drugadditional": nu... |
{
"abstract": "Experiences with new multikinase inhibitors are limited, especially in children. In this report we summarize our experience with 2 patients with relapsed acute myeloblastic leukemia (AML), one with FMS-like tyrosine kinase-3-internal tandem duplication mutation and the other with a single base mutation (D835Y). Both patients received sorafenib, one for 19 days and the other for 42 days, with clofarabine-including chemotherapy. One additionally received sunitinib for a total of 20 days. Both patients developed severe pancytopenia, hypertension, life-threatening bleedings from the gastrointestinal system, and, finally, intrapulmonary hemorrhage. Although both reached severe aplasia of the bone marrow without blastic infiltration, death occurred with neutropenic sepsis.",
"affiliations": "Ege University Faculty of Medicine, Department of Pediatric Hematology, İzmir, Turkey Phone: +90 232 390 11 13 E-mail: dyilmazk@yahoo.com.",
"authors": "Yılmaz Karapınar|Deniz|D|;Karadaş|Nihal|N|;Önder Siviş|Zühal|Z|;Balkan|Can|C|;Kavaklı|Kaan|K|;Aydınok|Yeşim|Y|",
"chemical_list": "D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D007211:Indoles; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D011480:Protease Inhibitors; D011758:Pyrroles; D003561:Cytarabine; D009536:Niacinamide; D000077866:Clofarabine; D000077157:Sorafenib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D000077210:Sunitinib",
"country": "Turkey",
"delete": false,
"doi": "10.4274/tjh.2014.0250",
"fulltext": "\n==== Front\nTurk J HaematolTurk J HaematolTJHTurkish Journal of Hematology1300-77771308-5263Galenos Publishing 2591228310.4274/tjh.2014.02501511Case ReportHypertension and Life-Threatening Bleeding in Children with Relapsed Acute Myeloblastic Leukemia Treated with FLT3 Inhibitors FLT3 İnhibitörleri ile Tedavi Edilen Nüks Akut Miyeloblastik Lösemili Çocuklarda Hipertansiyon ve Hayatı Tehdit Eden Kanama Karapınar Deniz Yılmaz 1*Karadaş Nihal 1Önder Siviş Zühal 1Balkan Can 1Kavaklı Kaan 1Aydınok Yeşim 11 \nEge University Faculty of Medicine, Department of Pediatric Hematology, İzmir, Turkey\n* Address for Correspondence: Ege University Faculty of Medicine, Department of Pediatric Hematology, İzmir, Turkey Phone: +90 232 390 11 13 E-mail: dyilmazk@yahoo.com9 2015 1 8 2015 32 3 263 266 19 6 2014 14 8 2014 © Turkish Journal of Hematology, Published by Galenos Publishing.\n\n2015This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Multikinaz inhibitörleri ile deneyim, özellikle çocuklarda çok sınırlıdır. Burada, biri FMS-like tirozin kinaz 3-ITD ve diğeri tek baz mutasyonu (D835Y) taşıyan nüks akut miyeloblastik lösemi (AML) tanılı iki hastadan edindiğimiz deneyimi sunmak istedik. Her iki hasta sorafenib (biri 19, diğeri 42 gün olmak üzere) tedavisini klofarabin içeren yoğun kemoterapi protokolü ile birlikte aldı. D835Y mutasyonu bulunan hasta daha sonra 20 gün sunitinib ile tedaviye devam etti. Her iki hastada da ağır pansitopeni, hipertansiyon, yaşamı tehdit eden gastrointestinal sistem kanaması ve pulmoner kanama gelişti. Her iki hastanın kemik iliğinde ağır bir aplazi sağlanmış olsa da blastik infiltrasyon görülmeden nötropenik sepsisle hastalar kaybedildi.\n\nAcute myeloblastic leukemiaFLT3SorafenibSunitinibchildrenD835Y mutation\n==== Body\nABSTRACT\nExperiences with new multikinase inhibitors are limited, especially in children. In this report we summarize our experience with 2 patients with relapsed acute myeloblastic leukemia (AML), one with FMS-like tyrosine kinase-3-internal tandem duplication mutation and the other with a single base mutation (D835Y). Both patients received sorafenib, one for 19 days and the other for 42 days, with clofarabine-including chemotherapy. One additionally received sunitinib for a total of 20 days. Both patients developed severe pancytopenia, hypertension, life-threatening bleedings from the gastrointestinal system, and, finally, intrapulmonary hemorrhage. Although both reached severe aplasia of the bone marrow without blastic infiltration, death occurred with neutropenic sepsis.\n\nINTRODUCTION\nThe FMS-like tyrosine kinase-3 (FLT3) gene is mutated in approximately 30% of acute myeloblastic leukemia (AML) cases in adults and 10%-15% in children, especially those with normal karyotypes [1,2]. The most common mutation is internal tandem duplication (ITD). Single base mutations may also be seen, most commonly resulting in a substitution of aspartic acid with tyrosine or less commonly a histidine at residue 835 in the tyrosine kinase domain (D835). These mutations result in constitutive activation of the FLT3 receptor, hence downstream of some pathways [1,3,4]. They cause enhanced proliferation and reduced apoptosis of the myeloblasts, which contributes to leukemogenesis. Generally they are associated with leukocytosis, normal cytogenetics, lower remission and higher relapse rate, and worse survival [1,2,3,5,6]. Tyrosine kinase inhibitors (TKIs) work as competitive inhibitors of ATP, binding to its pocket in the kinase domain, and are used for targeted therapy to control tumor growth and angiogenesis [3,5,6]. Experiences with TKIs in children are restricted, showing some benefits with acceptable toxicities [7,8,9,10]. Here we report 2 pediatric relapsed AML patients treated with TKIs.\n\nCASE PRESENTATION\nPatient 1 was a 2-year-old girl diagnosed with AML after presenting with hyperleukocytosis and normal cytogenetics. She received chemotherapy according to the AML-BFM 2004 protocol and reached remission after the first course of induction therapy. No donor was available for stem cell transplantation and she developed relapse 5 months after remission was achieved. Combined chemotherapy including idarubicin (12 mg/m2/day for 3 days), fludarabine (30 mg/m2/day for 4 days), and cytarabine (2 g/m2/day for 4 days) was administered. Bone marrow aspiration (BMA) on day 28 showed 90% blastic cell infiltration. In retrospective analyses of bone marrow samples, FLT3-D835Y was found to be positive at initial diagnosis. Although it disappeared after the first course of induction chemotherapy, it was found to be positive again at relapse and 28 days after IDA-FLA treatment. After getting permission from the Turkish Republic Ministry of Health and from the patient’s family, sorafenib (200 mg/m2/day) was started as a salvage therapy. To prevent hand-foot-skin toxicities, protective measures were taken, such as prophylactic extensive moisturizing by local emollients to the whole body, and the patient was advised to wear soft, thin, cotton gloves and socks on her hands and feet. Five days later combined chemotherapy including clofarabine (40 mg/m2/day for 5 days) and cytarabine (1 g/m2/day for 5 days) was added to the sorafenib. One week later she had complaints of stomachache and developed hypertension. Although she had very severe pancytopenia, BMA at 28 days of chemotherapy did not show any decrease in the percentage of blastic cells. Therefore, at 32 days, sorafenib was switched to sunitinib (15 mg/m2/day). Three days after sunitinib treatment was started the hypertension increased and abdominal discomfort became prominent; several X-ray and ultrasonographic evaluations were performed and no obvious cause was identified. Electrolyte imbalance was seen (hypocalcaemia and hypokalemia; both required high amounts of intravenous replacement). She had gastrointestinal system (GIS) hemorrhage with normal prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen levels at day 7 of sunitinib treatment. It was managed with intensive support and the dose of sunitinib was lowered to 7.5 mg/m2/day. However, symptoms did not resolve and severe pancytopenia persisted with a white blood cell count below 100/mm3 and transfusion dependency. Severe hypertension was under control only after triple antihypertensive agents were added to the treatment. Very severe aplasia without blastic infiltration was seen in BMA at day 18 of sunitinib treatment. She again developed a severe upper GIS hemorrhage on day 19. Therefore, sunitinib was stopped at the 20th day. In spite of aggressive and prompt support with fresh frozen plasma and platelet and erythrocyte transfusions, she had a massive pulmonary hemorrhage, requiring intubation and mechanical ventilation. She expired with neutropenic sepsis 2 days after sunitinib was stopped. Informed consent was obtained.\n\nPatient 2 was a 12-year-old boy diagnosed with AML after presenting with hyperleukocytosis and normal cytogenetics. He received chemotherapy according to the AML-BFM 2004 protocol and achieved remission after the second course of induction therapy. He developed relapsed AML 4 months after first remission was achieved. IDA-FLA was administered. His BMA at day 28 showed 75% blastic cell infiltration. In retrospective analyses of bone marrow samples, FLT3-ITD was found to be positive at initial diagnosis. Although it disappeared after the second course of induction chemotherapy, it was found to be positive again at relapse. No hematological or molecular remission was seen after IDA-FLA treatment. On day 15, BMA showed severe aplasia. After the same formal permission procedure was followed and prophylactic measures were taken to prevent severe skin toxicities, sorafenib was started at a dose of 2x200 mg/m2/day on day 21 as salvage treatment. However, on day 28, repeated BMA showed 40% blastic cells. On day 29, 8 days after sorafenib was started, he developed hypertension and required antihypertensive therapy. Second-line relapse treatment with clofarabine (40 mg/m2/day for 5 days) and cytarabine (1 g/m2/day for 5 days) was started. He complained about severe muscle and bone pain and stomachache. Very severe pancytopenia occurred. BMA 15 days after second-line treatment was negative for FLT3-ITD mutation; he had then been receiving sorafenib for 42 days. After a total of 45 days of treatment with sorafenib he developed severe hypertension, abnormal renal function (urea: 176 mg/dL, creatinine: 5.9 mg/dL), severe metabolic acidosis, and intraocular and severe mouth bleeding. He was still in deep pancytopenia (WBC: 0.016x109/L, Hb: 49 g/L, Hct: 13% PLT: 17.7x109/L). Fibrinogen levels and PT and APTT were in the normal ranges. Sorafenib was ceased and intensive support with aggressive blood product supplementation was given. Because renal functions progressively worsened, renal replacement therapy with hemodialysis was started. He developed pulmonary hemorrhage; intensive support including platelet suspension, fresh frozen plasma, and recombinant factor VIIa was given. He developed neutropenic sepsis and died 12 days after cessation of sorafenib.\n\nDISCUSSION AND REVIEW OF THE LITERATURE\nFLT3-mutated AML patients respond poorly to conventional chemotherapy and have worse prognosis. Current studies put them into high-risk groups and they are candidates for hematopoietic stem cell transplantation. Sunitinib and sorafenib are multikinase inhibitors and were approved for treatment of renal cell and hepatocellular carcinoma. Some small case series and trials with sunitinib and especially with sorafenib alone or in combination with chemotherapy for treatment of refractory or relapsed AML for salvage therapy have been published [4,7,8,9,10,11,12,13,14]. Some of them showed that hematological remission may be achieved with acceptable toxicity profiles [4,9,10].\n\nIn this report we summarize our experience in 2 patients with relapsed AML, one with FLT3-ITD mutation and the other with D835Y. Both patients received idarubicin, fludarabine, and cytarabine combination therapy after hematological relapse occurred. Hematological remission could not be achieved. They were given TKIs with combined chemotherapy and reached severe aplasia with clearance of blastic cells. It was shown that sorafenib inhibits FLT3-ITD more potently than FLT3-D835Y, while sunitinib is equally effective against both mutant forms of FLT3 [13]. The patient with D835Y mutation thus received sunitinib since no response was seen after sorafenib.\n\nThe most common toxicities of TKIs are reported as reversible skin rash, hand-foot-skin reaction, diarrhea, abdominal pain, mild myelosuppression, and electrolyte abnormalities [5,7,9,10]. Children with leukemia who received sorafenib in combination with other agents experienced grade 2 or 3 hand-foot-skin reactions very frequently, at rates of up to 100% [5,7,9,10]. In adults, one-third of patients required dose reductions due to skin toxicity or diarrhea. Hypertension was infrequently reported in children, despite being very common in adults [7,9,10,11,12]. In these presented cases, most probably the prophylactic measures prevented skin toxicities, but the patients had very severe hypertension, which possibly contributed to the life-threatening bleedings.\n\nThe effects of TKIs are related to active N-oxide metabolites [9]. These metabolites might also be responsible for the toxic effects. A much higher rate of conversion of TKIs to active metabolites was shown in children than in adults by pharmacokinetic studies [9,10]. Thus, higher exposure to the metabolites may contribute to increased toxicity among children.\n\nIn our patients, persistent very severe pancytopenia did not allow us to assess remission status. Both of the patients were transfusion-dependent and intensively supported. Both patients died with neutropenic sepsis after major pulmonary hemorrhage.\n\nThe complications observed in our patients suggest that efficacy of TKIs may be limited by their toxicities. In particular, myelosuppression, severe hypertension, and bleeding problems had very significant effects on the continuation of therapy and resulted in death.\n\nExperiences with new multikinase inhibitors such as sorafenib or sunitinib are limited, especially in childhood AML. The requirement for prospective randomized studies to determine the safety and efficacy of these drugs is clear.\n\nConflict of Interest Statement\n\nThe authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included.\n==== Refs\nReferences\n1 Nakao M Yokota S Iwai T Kaneko H Horiike S Kashima K Sonoda Y Fujimoto T Misawa S Internal tandem duplication of the flt3 gene found in acute myeloid leukemia Leukemia 1996 10 1911 1918 8946930 \n2 Creutzig U Gibson B Dworzak MN Adachi S Bont E de Harbott J Hasle H Johnston D Kinoshita A Lehrnbecher T Leverger G Mejstrikova E Meshinchi S Pession A Raimondi SC Sung L Stary J Zwaan CM Kaspers GJ Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel Blood 2012 120 3187 3205 22879540 \n3 Hatzimichael E Georgiou G Benetatos L Briasoulis E Gene mutations and molecularly targeted therapies in acute myeloid leukemia Am J Blood Res 2013 3 29 51 23358589 \n4 Fiedler W Serve H Döhner H Schwittay M Ottmann OG O’Farrell AM Bello CL Allred R Manning WC Cherrington JM Louie SG Hong W Brega NM Massimini G Scigalla P Berdel WE Hossfeld DK A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease Blood 2005 105 986 993 15459012 \n5 Moore AS Kearns PR Knapper S Pearson AD Zwaan CM Novel therapies for children with acute myeloid leukemia Leukemia 2013 27 1451 1460 23563239 \n6 Fathi AT Chen YB Treatment of FLT3-ITD acute myeloid leukemia Am J Blood Res 2011 1 175 189 22432079 \n7 Watt TC Cooper T Sorafenib as treatment for relapsed or refractory pediatric acute myelogenous leukemia Pediatr Blood Cancer 2012 59 756 757 22052552 \n8 Baker SD Zimmerman EI Wang YD Orwick S Zatechka DS Buaboonnam J Neale GA Olsen SR Enemark EJ Shurtleff S Rubnitz JE Mullighan CG Inaba H Emergence of polyclonal FLT3 tyrosine kinase domain mutations during sequential therapy with sorafenib and sunitinib in FLT3-ITD-positive acute myeloid leukemia Clin Cancer Res 2013 19 5758 5768 23969938 \n9 Inaba H Rubnitz JE Coustan-Smith E Li L Furmanski BD Mascara GP Heym KM Christensen R Onciu M Shurtleff SA Pounds SB Pui CH Ribeiro RC Campana D Baker SD Phase I pharmacokinetic and pharmacodynamic study of the multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in pediatric relapsed/refractory leukemia J Clin Oncol 2011 29 3293 3300 21768474 \n10 Widemann BC Kim A Fox E Baruchel S Adamson PC Ingle AM Glade Bender J Burke M Weigel B Stempak D Balis FM Blaney SM A phase I trial and pharmacokinetic study of sorafenib in children with refractory solid tumors or leukemias: a Children’s Oncology Group Phase I consortium report Clin Cancer 2012 18 6011 6022 \n11 Metzelder SK Schroeder T Finck A Scholl S Fey M Götze K Linn YC Kröger M Reiter A Salih HR Heinicke T Stuhlmann R Müller L Giagounidis A Meyer RG Brugger W Vöhringer M Dreger P Mori M Basara N Schäfer-Eckart K Schultheis B Baldus C Neubauer A Burchert A High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses Leukemia 2012 26 2353 2359 22504140 \n12 Sharma M Ravandi F Bayraktar UD Chiattone A Bashir Q Giralt S Chen J Qazilbash M Kebriaei P Konopleva M Andreeff M Cortes J McCue D Kantarjian H Champlin RE Lima M de Treatment of FLT3-ITD-positive acute myeloid leukemia relapsing after allogeneic stem cell transplantation with sorafenib Biol Blood Marrow Transplant 2011 11 1874 1877 21767516 \n13 Kancha RK Grundler R Peschel C Duyster J Sensitivity toward sorafenib and sunitinib varies between different activating and drug-resistant FLT3-ITD mutations Exp Hematol 2007 35 1522 1526 17889720 \n14 Man CH Fung TK Ho C Han HH Chow HC Ma AC Choi WW Lok S Cheung AM Eaves C Kwong YL Leung AY Sorafenib treatment of FLT3-ITD+ acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation Blood 2012 119 5133 5143 22368270\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1300-7777",
"issue": "32(3)",
"journal": "Turkish journal of haematology : official journal of Turkish Society of Haematology",
"keywords": null,
"medline_ta": "Turk J Haematol",
"mesh_terms": "D000138:Acidosis; D058186:Acute Kidney Injury; D000227:Adenine Nucleotides; D000971:Antineoplastic Combined Chemotherapy Protocols; D001087:Arabinonucleosides; D002648:Child; D002675:Child, Preschool; D000077866:Clofarabine; D003561:Cytarabine; D017809:Fatal Outcome; D005260:Female; D006470:Hemorrhage; D006801:Humans; D006973:Hypertension; D007211:Indoles; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009363:Neoplasm Proteins; D009536:Niacinamide; D010146:Pain; D010198:Pancytopenia; D010671:Phenylurea Compounds; D011480:Protease Inhibitors; D011758:Pyrroles; D016879:Salvage Therapy; D018805:Sepsis; D000077157:Sorafenib; D000077210:Sunitinib; D051941:fms-Like Tyrosine Kinase 3",
"nlm_unique_id": "9606065",
"other_id": null,
"pages": "263-6",
"pmc": null,
"pmid": "25912283",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "21768474;21767516;23563239;23358589;17889720;22052552;23969938;22962440;8946930;15459012;22432079;22368270;22504140;22879540",
"title": "Hypertension and Life-Threatening Bleeding in Children with Relapsed Acute Myeloblastic Leukemia Treated with FLT3 Inhibitors.",
"title_normalized": "hypertension and life threatening bleeding in children with relapsed acute myeloblastic leukemia treated with flt3 inhibitors"
} | [
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"companynumb": "TR-PFIZER INC-2015269367",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYTARABINE"
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... |
{
"abstract": "BACKGROUND\nPituitary metastasis of lung cancer is rare; however, it often causes diabetes insipidus. Although the majority of such patients are treated with radiation therapy, it remains unclear whether diabetes insipidus can be controlled by radiation therapy.\n\n\nMETHODS\nA 72-year-old man was admitted to our hospital for hemosputum, headache, and polyuria. A chest CT scan showed a 3.0 cm mass in the left upper lobe of his lung. Bronchofiberscopy results confirmed the pathological diagnosis of lung adenocarcinoma. Based on the findings from PET-CT, head MRI, and endocrine tests, the diagnosis of lung adenocarcinoma( cT1bN0M1b, stage IV)accompanied with central diabetes insipidus caused by pituitary metastasis was made. Oral administration of desmopressin reduced urine volumes; however, chemotherapy for achieving stable disease in the primary tumor was ineffective in controlling the symptoms of diabetes insipidus. Chemotherapy was discontinued after 4 months because of severe hematological toxicity. During 2 months after the cessation of chemotherapy, polyuria worsened and, therefore, radiation therapy for pituitary metastasis was started. Following the radiation therapy, an apparent reduction in urine volume was observed.\n\n\nCONCLUSIONS\nOur experience of this case suggests that radiation therapy for pituitary metastasis should be considered at the time when diabetes insipidus becomes clinically overt.",
"affiliations": "Dept. of Respiratory Internal Medicine, Hiroshima University Hospital.",
"authors": "Izumi|Yusuke|Y|;Masuda|Takeshi|T|;Nabeshima|Shinji|S|;Horimasu|Yasushi|Y|;Nakashima|Taku|T|;Miyamoto|Shintaro|S|;Iwamoto|Hiroshi|H|;Fujitaka|Kazunori|K|;Murakami|Yuji|Y|;Hamada|Hironobu|H|;Nagata|Yasushi|Y|;Hattori|Noboru|N|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "44(6)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000368:Aged; D020790:Diabetes Insipidus, Neurogenic; D006801:Humans; D008175:Lung Neoplasms; D008279:Magnetic Resonance Imaging; D008297:Male; D010911:Pituitary Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "513-516",
"pmc": null,
"pmid": "28698444",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A Case of Central Diabetes Insipidus That Was Caused by Pituitary Metastasis of Lung Adenocarcinoma and Was Controlled by Radiation Therapy.",
"title_normalized": "a case of central diabetes insipidus that was caused by pituitary metastasis of lung adenocarcinoma and was controlled by radiation therapy"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2017RR-154864",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"dru... |
{
"abstract": "BACKGROUND\nTracheobronchial foreign body aspiration is a significant cause of childhood morbidity and mortality. We analyzed our experience in management of aspirated foreign bodies, including methods of anesthesia used, over a 4-year period.\n\n\nMETHODS\nWe retrospectively reviewed the records of tracheobronchial foreign body removal by rigid bronchoscopy with spontaneous ventilation in 435 children. All patients had received initial anesthesia with inhaled sevoflurane. One hundred and ninety-seven patients (Group PropRemi) then received intravenous propofol and remifentanyl for maintenance of anesthesia; the remaining 238 patients (Group PropSevo) received propofol and sevoflurane.\n\n\nRESULTS\nTracheobronchial foreign body was found in 405 children (93.1%) and successfully removed from 402 (99.3%) children. Among three patients who failed bronchoscopy, one child suffered cardiac arrest and died during the bronchoscopy, and two required subsequent tracheotomy for foreign body removal. Adverse effects (intraoperative coughing, breath holding, body movement, bronchospasm, and laryngospasm) were significantly more frequent in Group PropRemi than in Group PropSevo. No complications such as bleeding, pneumothorax, pneumomediastinum, or the need for thoracotomy were encountered.\n\n\nCONCLUSIONS\nSevoflurane induction followed by a combination of sevoflurane and continuous infusion of propofol resulted in fewer adverse events than sevoflurane induction followed by TIVA with propofol and remifentanyl during rigid bronchoscopy for airway foreign body removal in children with spontaneous ventilation.",
"affiliations": "Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China.",
"authors": "Chai|Jun|J|;Wu|Xiu-Ying|XY|;Han|Ning|N|;Wang|Li-Yin|LY|;Chen|Wei-Min|WM|",
"chemical_list": "D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D008738:Methyl Ethers; D000077149:Sevoflurane; D015742:Propofol",
"country": "France",
"delete": false,
"doi": "10.1111/pan.12509",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1155-5645",
"issue": "24(10)",
"journal": "Paediatric anaesthesia",
"keywords": "foreign body; propofol; remifentanyl; rigid bronchoscopy; sevoflurane; spontaneous ventilation",
"medline_ta": "Paediatr Anaesth",
"mesh_terms": "D000402:Airway Obstruction; D000758:Anesthesia; D000768:Anesthesia, General; D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D001999:Bronchoscopy; D002675:Child, Preschool; D005260:Female; D005547:Foreign Bodies; D006801:Humans; D007223:Infant; D008297:Male; D008738:Methyl Ethers; D011183:Postoperative Complications; D015742:Propofol; D015656:Respiratory Mechanics; D012189:Retrospective Studies; D000077149:Sevoflurane",
"nlm_unique_id": "9206575",
"other_id": null,
"pages": "1031-6",
"pmc": null,
"pmid": "25145573",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A retrospective study of anesthesia during rigid bronchoscopy for airway foreign body removal in children: propofol and sevoflurane with spontaneous ventilation.",
"title_normalized": "a retrospective study of anesthesia during rigid bronchoscopy for airway foreign body removal in children propofol and sevoflurane with spontaneous ventilation"
} | [
{
"companynumb": "CN-BAXTER-2014BAX067882",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugadditional": null,
... |
{
"abstract": "Linezolid has been used in the treatment of multidrug-resistant/extensively drug-resistant tuberculosis in adults with encouraging results, however experience in children is scarce. We describe our experience with the use of linezolid as part of a multidrug regimen in the treatment of 4 patients who had persistent positive cultures, despite prolonged combined therapy.",
"affiliations": "Department of Paediatrics, Infectious Diseases, Hospital Dona Estefânia, Lisbon, Portugal. kjollerstrom@sapo.pt",
"authors": "Kjöllerström|Paula|P|;Brito|Maria João|MJ|;Gouveia|Catarina|C|;Ferreira|Gonçalo|G|;Varandas|Luís|L|",
"chemical_list": "D000081:Acetamides; D000995:Antitubercular Agents; D023303:Oxazolidinones; D000069349:Linezolid",
"country": "England",
"delete": false,
"doi": "10.3109/00365548.2011.564649",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0036-5548",
"issue": "43(6-7)",
"journal": "Scandinavian journal of infectious diseases",
"keywords": null,
"medline_ta": "Scand J Infect Dis",
"mesh_terms": "D000081:Acetamides; D000293:Adolescent; D000995:Antitubercular Agents; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D054908:Extensively Drug-Resistant Tuberculosis; D005260:Female; D006801:Humans; D000069349:Linezolid; D008297:Male; D023303:Oxazolidinones; D016896:Treatment Outcome",
"nlm_unique_id": "0215333",
"other_id": null,
"pages": "556-9",
"pmc": null,
"pmid": "21391771",
"pubdate": "2011-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Linezolid in the treatment of multidrug-resistant/extensively drug-resistant tuberculosis in paediatric patients: experience of a paediatric infectious diseases unit.",
"title_normalized": "linezolid in the treatment of multidrug resistant extensively drug resistant tuberculosis in paediatric patients experience of a paediatric infectious diseases unit"
} | [
{
"companynumb": "ZA-ALKEM LABORATORIES LIMITED-ZA-ALKEM-2018-03717",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugad... |
{
"abstract": "Endometriosis involving the bladder is rare, but generally has a severe presentation with prominent lower urinary tract symptoms and can progress to renal failure. As endometriosis has a significant effect on quality of life and fertility, treatment plans must be centered on the patient's symptoms, expectations, and priorities. We present a case of a 37-year-old African American female with advanced bladder endometriosis and consequent renal failure, who desired to avoid extensive surgery and maintain her fertility. This case highlights the importance of shared decision making in balancing disease management with patient autonomy.",
"affiliations": "Vanderbilt University School of Medicine, Nashville, TN, United States.;Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, United States.;Department of Urology, Vanderbilt University Medical Center, Nashville, TN, United States.",
"authors": "Xu|Mark C|MC|;Yunker|Amanda C|AC|;Kaufman|Melissa R|MR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.eucr.2020.101263",
"fulltext": "\n==== Front\nUrol Case Rep\nUrol Case Rep\nUrology Case Reports\n2214-4420 Elsevier \n\nS2214-4420(20)30151-0\n10.1016/j.eucr.2020.101263\n101263\nFunctional Medicine\nConservative management of bladder endometriosis with acute renal failure\nXu Mark C. mark.c.xu@vanderbilt.edua∗1 Yunker Amanda C. b Kaufman Melissa R. c a Vanderbilt University School of Medicine, Nashville, TN, United States\nb Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, United States\nc Department of Urology, Vanderbilt University Medical Center, Nashville, TN, United States\n∗ Corresponding author. mark.c.xu@vanderbilt.edu1 Permanent Address: 1510 Edgehill Ave. Apartment A, Nashville, TN. 37212.\n\n\n19 5 2020 \n11 2020 \n19 5 2020 \n33 1012635 5 2020 14 5 2020 18 5 2020 © 2020 The Authors. Published by Elsevier Inc.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Endometriosis involving the bladder is rare, but generally has a severe presentation with prominent lower urinary tract symptoms and can progress to renal failure. As endometriosis has a significant effect on quality of life and fertility, treatment plans must be centered on the patient's symptoms, expectations, and priorities. We present a case of a 37-year-old African American female with advanced bladder endometriosis and consequent renal failure, who desired to avoid extensive surgery and maintain her fertility. This case highlights the importance of shared decision making in balancing disease management with patient autonomy.\n\nKeywords\nBladder endometriosisShared decision makingRenal FailureBladder hypo-compliance\n==== Body\nIntroduction\nEndometriosis affects 10–20% of reproductive-age women and involves ectopic implantation of endometrial glands and stroma outside the uterine cavity.1 Endometriosis affecting the urinary tract is comparatively rare, accounting for only 1–2% of all cases.1 Such cases are associated with more complex deeply-infiltrative disease and predominantly involve the bladder, presenting with lower urinary tract symptoms of dysuria, hematuria, frequency, and suprapubic pain.2 Obstructive uropathy is uncommon, but morbid, and can result in renal loss.3 Herein we present a case of bladder endometriosis leading to acute kidney injury successfully managed with medical therapy.\n\nCase report\nA 37-year-old African American female presented with worsening hypertension (185/109), elevated creatinine of 6.49, and deep venous thrombosis. Past medical history was significant for long-standing endometriosis and a year of lower urinary tract symptoms treated with oxybutynin that included dysuria, urgency incontinence, frequency and sensation of incomplete emptying. She denied gross hematuria or urinary tract infections. She underwent previous laparoscopic myomectomy for menorrhagia, but otherwise had no remarkable surgical history.\n\nRenal ultrasound revealed bilateral hydronephrosis with thinning of the right renal parenchyma. A 3.7cm heterogenous mass was identified on the right bladder wall. She underwent an operative cystoscopy revealing a >5cm infiltrative bladder mass distorting the trigone (Fig. 1), with substantial trabeculations throughout. Retrograde pyelograms demonstrated hydroureteronephrosis and tortuosity (Fig. 2a and 2b). A 6 x 28 double-J ureteral stent was passed into the left renal pelvis, but right stent placement was aborted due to exceptional difficulty navigating the tortuous ureter. Bladder biopsy revealed pathology consistent with intestinal metaplasia. Non-contrast CT scan showed severe cortical thinning of her right kidney, along with medial deviation and tortuous dilation of the ureters. Following left stent insertion, her creatinine trended downward to 3.85.Fig. 1 Infiltrative bladder mass distorting the trigone.\n\nFig. 1Fig. 2 Retrograde Pyelograms demonstrating hydroureteronephrosis and extreme tortuosity of ureters\n\n2a. Right Kidney and Ureter\n\n2b. Left Kidney and Ureter.\n\nFig. 2\n\nShe subsequently presented for repeat bladder resection and right stent placement, which was successful with a 7 × 30 cm stent. Resection revealed extensive hematogenous debris and vascularity. Pathologic analysis revealed positive staining with estrogen receptor (Fig. 3), leading to a diagnosis of deep infiltrating endometriosis. The patient opted for hormonal treatment, which she deferred until 1 month following surgical resection when she was discovered to have rising creatinine at 5.66. She reported that she recently discontinued oxybutynin due to symptoms of weak stream. Bladder drainage was optimized with catheter placement and following fluid resuscitation, her creatinine returned to baseline.Fig. 3 Endometrial cells staining positive for estrogen receptor.\n\nFig. 3\n\nShe subsequently began hormonal treatment of endometriosis with 11.25mg of IM depot Leuprolide. Unfortunately, she was again found to have an elevated creatinine of 6.74 and was again admitted. A CT scan of the abdomen and pelvis revealed both stents in appropriate position, with no significant change to the hydronephrosis. A percutaneous nephrostomy tube was placed on the left and her creatinine subsequently improved. On follow-up, the patient underwent stent removal and subsequent videourodynamics demonstrating decreased detrusor compliance with pressures greater than 60 cm H2O, a postvoid residual of 200mL, and vesicoureteral reflux. However, her endometriosis was visually improved on cystoscopy. She elected to begin treatment of her poorly compliant bladder with Botox and underwent first injection of 200 units shortly thereafter.\n\nAt her next follow up, repeat urodynamic screening showed improved compliance and bladder capacity. Her creatinine was at a baseline of 2.15, and her nephrostomy was eventually removed. She continued to be stable on depot Leuprolide and Botox and declined definitive treatment with a hysterectomy and salpingo-oophorectomy due to desire to maintain fertility. She was lost follow up until she presented for 2 years after her last depot Leuprolide injection. Notably, her creatinine remained stable at 1.82, but she developed increasing pain and heavy menses indicative of endometriosis relapse. She received depot Leuprolide and was scheduled for an MRI which is pending.\n\nDiscussion\nBladder endometriosis implies endometrial glands and stroma in the detrusor muscle, with the base and dome most commonly affected.4 It is associated with the deep infiltrating subtype of endometriosis, which is regarded as the most severe subtype.2 Bladder endometriosis is classified as primary or secondary, with primary endometriosis occurring spontaneously and secondary to iatrogenic implantation in pelvic surgery.4 Although iatrogenic implantation of endometrial tissue remains controversial, there is an increased incidence of bladder endometriosis in patients with a history of pelvic surgery, particularly cesarean sections.4 This patient developed lower urinary tract symptoms consistent with bladder endometriosis after myomectomy.\n\nBladder endometriosis often presents with nonspecific lower urinary tract symptoms, and there is a broad differential diagnosis to consider. Diagnosis of bladder endometriosis rests on appropriate imaging with ultrasound or MRIs.4 Cystoscopy may also be valuable, but endometrial lesions present a visible mass in only half of cases.4\n\nObstructive uropathy is closely linked to reduced bladder compliance and renal damage, as increased storage pressure results in structural and functional changes and vesicoureteral reflux.5 Anti-muscarinic drugs are the first line management, with therapeutic failure leading to progression to Botox.5 Although our patient's poorly compliant bladder was likely a long-standing issue given her history, Botox treatment led to a marked improvement in her urinary symptoms and renal function. This recovery was sustained over a year following Botox therapy.\n\nTreatment of bladder endometriosis involves both medical and surgical approaches. Medical management with hormonal treatments with combined contraceptives and progestogens results in relief of symptoms but are generally not curative.2 GnRH agonists have specifically been shown to be superior to combined oral contraceptives for inducing regression.4 Long term hormonal control is generally achieved through bilateral oophorectomy or menopause. With surgical treatment, the efficacy of transurethral resection is generally limited with high recurrence of disease.4 Partial cystectomy, however, demonstrates excellent long-term results in terms of symptom relief and recurrence.2 Surgical treatment is generally preferred after failure of medical management or with upper tract obstruction. For this patient, a conservative treatment approach was preferred based on patient preference and surgical risk due to trigonal location.\n\nThis case highlights the importance of shared decision making in managing advanced bladder endometriosis. with focus placed on managing patient symptoms versus disease eradication. For this patient, we were able to maintain symptom control and stabilize renal function without compromising fertility.\n\nSources of funding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nDeclaration of competing interest\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n1 Comiter C.V. Endometriosis of the urinary tract Urol Clin North Am 29 3 2002 625 635 12476526 \n2 Nezhat C. Falik R. McKinney S. King L.P. Pathophysiology and management of urinary tract endometriosis Nat Rev Urol 14 6 2017 359 372 28467398 \n3 Kane C. Drouin P. Obstructive uropathy associated with endometriosis Am J Obstet Gynecol 151 2 1985 207 211 3970087 \n4 Leone Roberti Maggiore U. Ferrero S. Candiani M. Somigliana E. Vigano P. Vercellini P. Bladder endometriosis: a systematic review of pathogenesis, diagnosis, treatment, impact on fertility, and risk of malignant transformation Eur Urol 71 5 2017 790 807 28040358 \n5 Prakash N.S. Lopategui D.M. Gomez C. Changes in management of poorly compliant bladder in botulinum toxin A era Curr Urol Rep 18 8 2017 64 28689244\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-4420",
"issue": "33()",
"journal": "Urology case reports",
"keywords": "Bladder endometriosis; Bladder hypo-compliance; Renal Failure; Shared decision making",
"medline_ta": "Urol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101626357",
"other_id": null,
"pages": "101263",
"pmc": null,
"pmid": "32489896",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports",
"references": "12476526;28689244;28467398;3970087;28040358",
"title": "Conservative management of bladder endometriosis with acute renal failure.",
"title_normalized": "conservative management of bladder endometriosis with acute renal failure"
} | [
{
"companynumb": "US-TOLMAR, INC.-20US021721",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "LEUPROLIDE ACETATE"
},
"drugadditional": nul... |
{
"abstract": "Placental chorioangioma is the most common type of a benign placental tumour that occurs in 1% of pregnancies. A large chorioangioma is associated with adverse pregnancy outcomes. We present a case of placental abruption necessitating preterm delivery after multiple amnioreductions for polyhydramnios caused by a large chorioangioma. If antenatal diagnosis of a significant chorioangioma is made as the cause of polyhydramnios, caution should be taken when performing rapid amnioreductions.",
"affiliations": "Department of Obstetrics and Gynecology, Harbor UCLA Medical Center, Torrance, California, USA.;Department of Obstetrics and Gynecology, Harbor UCLA Medical Center, Torrance, California, USA.;Department of Obstetrics and Gynecology, Harbor UCLA Medical Center, Torrance, California, USA.",
"authors": "Kim|Angela|A|;Economidis|Megan A|MA|;Stohl|Hindi E|HE|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-222399",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "materno-fetal medicine; pregnancy",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000037:Abruptio Placentae; D000328:Adult; D000653:Amniotic Fluid; D002585:Cesarean Section; D005260:Female; D005865:Gestational Age; D006391:Hemangioma; D006801:Humans; D007231:Infant, Newborn; D007752:Obstetric Labor, Premature; D010920:Placenta; D006831:Polyhydramnios; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011256:Pregnancy Outcome; D016216:Ultrasonography, Prenatal",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29507014",
"pubdate": "2018-03-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17012465;19760166;21745690;14770396;25751210;5454580;26948899;27200315;25429242;14672481;952800",
"title": "Placental abruption after amnioreduction for polyhydramnios caused by chorioangioma.",
"title_normalized": "placental abruption after amnioreduction for polyhydramnios caused by chorioangioma"
} | [
{
"companynumb": "PHHY2018US068658",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BETAMETHASONE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Oral papillary squamous cell carcinoma (PSCC) is an unusual variant of squamous cell carcinoma with a better prognosis. The most common location of PSCC in the oral cavity is the gingiva and buccal mucosa, and it is exceedingly rare in the tongue. Herein, we present a case of PSCC in an 85-year-old male with a history of heart transplant and long-term use of immunosuppression medication. A verrucous pedunculated mass measuring 3.5 cm in the greatest dimension was present on the tip of tongue and a partial glossectomy was performed. Histological diagnosis was well differentiated PSCC with focal and minimal stalk invasion. No vascular nor perineural invasion was identified. Based on the current WHO and AJCC oral cancer staging system, the tumor stage was T2N0M0. The tumor cells were focally positive for p16, but in situ hybridization was negative for low-risk HPV (types 6 and 11) and high-risk HPV (types 16, 18, 31, 33 and 51). To the best of our knowledge, this is the first documented case of PSCC present on the tip of tongue in patients with long-term immune suppression. The pathogenesis, stage and prognosis of this entity are discussed. More case studies with long-term follow up are needed to achieve an accurate tumor stage and definite prognosis.",
"affiliations": "Department of Oral and Maxillofacial Pathology, University of Florida College of Dentistry, Gainesville, FL, U.S.A.;Division of Cardiac Surgery, Department of Surgery, Second Xiangya Hospital, Central South University, Changsha, P.R. China.;Department of Otolaryngology-Head and Neck Surgery, University of Florida College of Medicine, Gainesville, FL, U.S.A.;Department of Pathology, Immunology, and Laboratory Medicine, Washington University in Saint Louis, St. Louis, MO, U.S.A.;Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China jinpinglai@ufl.edu zhaoyulinmail@163.com.;Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, U.S.A. jinpinglai@ufl.edu zhaoyulinmail@163.com.",
"authors": "Alotaiby|Faraj|F|;Song|Fenglin|F|;Boyce|Brian J|BJ|;Cao|Dengfeng|D|;Zhao|Yulin|Y|;Lai|Jinping|J|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.12715",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "38(7)",
"journal": "Anticancer research",
"keywords": "HPV in situ hybridization; Tip of tongue; heart transplant; p16 immunohistochemistry; papillary squamous cell carcinoma",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000369:Aged, 80 and over; D002291:Carcinoma, Papillary; D002294:Carcinoma, Squamous Cell; D016027:Heart Transplantation; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D014062:Tongue Neoplasms",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "4203-4206",
"pmc": null,
"pmid": "29970551",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unusual Papillary Squamous Cell Carcinoma of the Tip of Tongue Presenting in a Patient Status Post Heart Transplant.",
"title_normalized": "unusual papillary squamous cell carcinoma of the tip of tongue presenting in a patient status post heart transplant"
} | [
{
"companynumb": "US-TEVA-2018-US-943507",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
... |
{
"abstract": "Prolonged therapy with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is highly effective in newly diagnosed acute promyelocytic leukemia (APL) but there is limited data on the efficacy of this regimen in the relapse setting. We report here on 22 APL patients treated with prolonged ATRA-ATO therapy at the time of disease relapse. Twenty patients obtained molecular complete remission (CRm) after 2 cycles (90%). Of these, two patients underwent hematopoietic stem cell transplant (HSCT) while the remaining proceeded to receive additional cycles (up to a total of 5) of ATRA-ATO. With a median follow-up of 58 months from the time of relapse (range: 21-128 months), the 4-year OS probability was 0.85 (95% CI 0.61-0.94), DFS was 0.74 (95% CI 0.49-0.88), and EFS 0.68 (95% CI 0.45-0.83). Two patients were resistant to ATRA-ATO salvage and five relapsed at a median of 19 months. Of these, four died due to progressive disease while three relapsed achieved a new CRm after further salvage therapy. This experience confirms the potentially curative effect of prolonged ATRA-ATO therapy in relapsed APL, especially in patients with long first complete remission.",
"affiliations": "Department of Biomedicine and Prevention, University Tor Vergata, via Montpellier,1, 00133, Rome, Italy. cicconi.laura@yahoo.it.;Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.;Department of Biomedicine and Prevention, University Tor Vergata, via Montpellier,1, 00133, Rome, Italy.;Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.;Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.;Policlinico Tor Vergata, Rome, Italy.;Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.;Policlinico Tor Vergata, Rome, Italy.;Department of Biomedicine and Prevention, University Tor Vergata, via Montpellier,1, 00133, Rome, Italy.;Department of Biomedicine and Prevention, University Tor Vergata, via Montpellier,1, 00133, Rome, Italy.;Department of Biomedicine and Prevention, University Tor Vergata, via Montpellier,1, 00133, Rome, Italy.;Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.;Department of Biomedicine and Prevention, University Tor Vergata, via Montpellier,1, 00133, Rome, Italy.;Department of Biomedicine and Prevention, University Tor Vergata, via Montpellier,1, 00133, Rome, Italy.",
"authors": "Cicconi|Laura|L|http://orcid.org/0000-0001-5642-3051;Breccia|Massimo|M|;Franceschini|Luca|L|;Latagliata|Roberto|R|;Molica|Matteo|M|;Divona|Mariadomenica|M|;Diverio|Daniela|D|;Rizzo|Manuela|M|;Ottone|Tiziana|T|;Iaccarino|Licia|L|;Alfonso|Valentina|V|;Foa|Robin|R|;Voso|Maria Teresa|MT|;Lo-Coco|Francesco|F|",
"chemical_list": "D001152:Arsenicals; D010087:Oxides; D014212:Tretinoin; D000077237:Arsenic Trioxide",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-018-3400-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "97(10)",
"journal": "Annals of hematology",
"keywords": "ATO; ATRA; Acute promyelocytic leukemia; Molecular relapse; Stem cell transplant",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000077237:Arsenic Trioxide; D001152:Arsenicals; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D053208:Kaplan-Meier Estimate; D015473:Leukemia, Promyelocytic, Acute; D008297:Male; D008875:Middle Aged; D010087:Oxides; D016016:Proportional Hazards Models; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies; D016879:Salvage Therapy; D016896:Treatment Outcome; D014212:Tretinoin; D055815:Young Adult",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1797-1802",
"pmc": null,
"pmid": "29951912",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Prolonged treatment with arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) for relapsed acute promyelocytic leukemia previously treated with ATRA and chemotherapy.",
"title_normalized": "prolonged treatment with arsenic trioxide ato and all trans retinoic acid atra for relapsed acute promyelocytic leukemia previously treated with atra and chemotherapy"
} | [
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"companynumb": "IT-MYLANLABS-2019M1005240",
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"occurcountry": "IT",
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"actiondrug": "5",
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"activesubstancename": "TRETINOIN"
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"abstract": "In light of the massive growth of the scientific literature, text mining is increasingly used to extract biological pathways. Though multiple tools explore individual connections between genes, diseases and drugs, few extensively synthesize pathways for specific diseases and drugs.\n\n\n\nThrough community detection of a literature network, we extracted 3444 functional gene groups that represented biological pathways for specific diseases and drugs. The network linked Medical Subject Headings (MeSH) terms of genes, diseases and drugs that co-occurred in publications. The resulting communities detected highly associated genes, diseases and drugs. These significantly matched current knowledge of biological pathways and predicted future ones in time-stamped experiments. Likewise, disease- and drug-specific communities also recapitulated known pathways for those given diseases and drugs. Moreover, diseases sharing communities had high comorbidity with each other and drugs sharing communities had many common side effects, consistent with related mechanisms. Indeed, the communities robustly recovered mutual targets for drugs [area under Receiver Operating Characteristic curve (AUROC)=0.75] and shared pathogenic genes for diseases (AUROC=0.82). These data show that literature communities inform not only just known biological processes but also suggest novel disease- and drug-specific mechanisms that may guide disease gene discovery and drug repurposing.\n\n\n\nApplication tools are available at http://meteor.lichtargelab.org.\n\n\n\nSupplementary data are available at Bioinformatics online.",
"affiliations": "Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.;Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.;Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.;Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.;Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.",
"authors": "Pham|Minh|M|;Wilson|Stephen|S|;Govindarajan|Harikumar|H|;Lin|Chih-Hsu|CH|;Lichtarge|Olivier|O|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/bioinformatics/btz857",
"fulltext": "\n==== Front\nBioinformatics\nBioinformatics\nbioinformatics\nBioinformatics\n1367-4803 1367-4811 Oxford University Press \n\n31738408\n10.1093/bioinformatics/btz857\nbtz857\nOriginal Papers\nData and Text Mining\nDiscovery of disease- and drug-specific pathways through community structures of a literature network\nhttp://orcid.org/0000-0003-2363-0788Pham Minh Wilson Stephen Govindarajan Harikumar Lin Chih-Hsu Lichtarge Olivier Wren Jonathan Associate Editor \nDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA\nlichtarge@bcm.edu\n15 3 2020 \n18 11 2019 \n18 11 2019 \n36 6 1881 1888\n02 7 2019 29 10 2019 15 11 2019 © The Author(s) 2019. Published by Oxford University Press.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\nMotivation\nIn light of the massive growth of the scientific literature, text mining is increasingly used to extract biological pathways. Though multiple tools explore individual connections between genes, diseases and drugs, few extensively synthesize pathways for specific diseases and drugs.\n\nResults\nThrough community detection of a literature network, we extracted 3444 functional gene groups that represented biological pathways for specific diseases and drugs. The network linked Medical Subject Headings (MeSH) terms of genes, diseases and drugs that co-occurred in publications. The resulting communities detected highly associated genes, diseases and drugs. These significantly matched current knowledge of biological pathways and predicted future ones in time-stamped experiments. Likewise, disease- and drug-specific communities also recapitulated known pathways for those given diseases and drugs. Moreover, diseases sharing communities had high comorbidity with each other and drugs sharing communities had many common side effects, consistent with related mechanisms. Indeed, the communities robustly recovered mutual targets for drugs [area under Receiver Operating Characteristic curve (AUROC)=0.75] and shared pathogenic genes for diseases (AUROC=0.82). These data show that literature communities inform not only just known biological processes but also suggest novel disease- and drug-specific mechanisms that may guide disease gene discovery and drug repurposing.\n\nAvailability and implementation\nApplication tools are available at http://meteor.lichtargelab.org.\n\nSupplementary information\n\nSupplementary data are available at Bioinformatics online.\n\nNational Institutes of Health10.13039/100000002GM079656GM066099AG061105\n==== Body\n1 Introduction\nEven though pathway information is routinely used to explore hidden biological processes in large omics data, current pathway information is incomplete. Not only knowledgebases do not cover interactions of all human protein-encoding genome (Fabregat et al., 2018), they also focus on mainly general pathways, with few of them related to specific diseases and drugs. Manual curation to complete pathway information is the gold standard but hard-pressed to keep up with a biomedical literature of more than 29 million papers, with 900 000 added each year (Citations Added to MEDLINE® by Fiscal Year: https://www.nlm.nih.gov/bsd/stats/cit_added.html). Professional curators could review only a minuscule portion of the literature body: about 42 000 articles in 6 years (Davis et al., 2013, 2019). The difficulty of curating pathway information from the literature slows knowledge discovery. \n\nText mining can automate extracting information from the literature, supporting pathway curation (Krallinger et al., 2005). Multiple tools explore biological associations between genes, diseases and drugs from text. First, relevant biological entities have to be identified, through pre-defined rules and dictionaries (Narayanaswamy et al., 2003) or by learned text data features of machine learning (ML) (Habibi et al., 2017). These approaches often yield high precision but low recall due to limited training data. These tools are also not generalized enough to apply to other corpora and are computationally intensive. Medical Subject Headings (MeSH) offers a solution. MeSH terms reliably capture key entities of all articles in MEDLINE because they are manually curated by biocurators to index these articles. MeSH terms include over 28 000 MeSH main heading descriptors and 240 000 Supplementary Concept Records (SCRs) (Fact Sheet Medical Subject Headings: https://www.nlm.nih.gov/pubs/factsheets/mesh.html), which are updated daily to annotate new chemicals and rare diseases that are not covered by MeSH descriptors yet. MeSH terms can also be mapped to IDs in other databases, supporting integration of literature-mined information to knowledgebases and experimental networks.\n\nBiological associations for recognized bio-entities can be extracted from text through co-occurrence and natural language processing (NLP). Co-occurrence approaches assume that co-mentioned bio-entities in text are biologically related (Alako et al., 2005). The confidence for biological relatedness is based on the number of articles with co-mentions. NLP methods rely on prior knowledge or apply ML to learn how biological events are mentioned in text (Li et al., 2017). NLP approaches are often more accurate than co-occurrence methods and can reveal nature of the extracted associations. However, NLP methods are restricted to pre-defined/learned relationships and computationally intensive. Co-occurrence methods are more robust to detect novel biological associations and can be easily scaled up. Co-occurrence associations also cover various biological aspects, such as disease candidate genes (Hristovski et al., 2005), PPI (Tsuruoka et al., 2008) and chemical–gene associations (Rebholz-Schuhmann et al., 2007). Therefore, co-occurrence associations can efficiently supplement pathway information.\n\nTo construct pathways, individual text-mined associations can be manually integrated, which is a tedious task due to a great number of associations. Efforts to automate this process have been done, most notably through BioNLP 2013 Pathway Curation task (Pyysalo et al., 2015), which aimed to aggregate relevant entities and their genetic/molecular interactions together to curate pathways. Participating methods applied ML and achieved competitive performance, yet they were restricted by training data and had trouble scaling up. This urges a new approach to efficiently assemble relevant bio-entities and their associations in order to synthesize pathways.\n\nGraph theory can model the vast number of co-occurrence associations of bio-entities, facilitating pathway synthesis. Co-occurrence links can be constructed into networks, in which nodes are biological entities and edges are their co-occurrence relations. MeSH co-occurrence networks robustly recapitulate pathway information in knowledgebases and discover new associative patterns (Wilson et al., 2018). These networks also exhibit small world properties with dense local clusters: entities within clusters are highly interconnected while links among clusters are sparser (Kastrin et al., 2014). When entities have similar neighbors in the networks, they are more likely to link together or be involved in similar processes. In experimental PPI networks, small-world properties help pinpoint most relevant associations for certain biological processes and pathways (Chen et al., 2015; Voevodski et al., 2009). Therefore, we hypothesized that clusters in MeSH co-occurrence networks may also represent functional biological pathways.\n\nNetwork clusters or communities can be constructed through community detection algorithms using topological properties of the networks. Since crosstalk between biological pathways is observed, we are particularly interested in methods that detect overlapping and hierarchically nested communities, reflecting the intricated nature of biology. Previously, Clauset–Newman–Moore (Clauset et al., 2004), Louvain (Blondel et al., 2008), BIGCLAM (Yang and Leskovec, 2013), and Recursive Louvain (RL) (Wilson et al., 2017) methods detected meaningful clusters that represented functional pathways and disease processes in STRING 9.1 experimental PPI network (Franceschini et al., 2012). These tools performed well and fast on the massive network. They searched for densely overlapping and hierarchically nested communities as well as non-overlapped clusters to resemble actual biological pathways. RL, which iteratively breaks down further Louvain-detected communities into smaller groups, detected the similar number of communities with the most similar size distribution to those of annotated pathways than the aforementioned clustering tools. Genes in RL communities were significantly overlapped with control reference pathways, biased to pathogenic genes and co-expressed in breast cancer (Wilson et al., 2017). These data show that RL detected biologically functional gene groups in the PPI network.\n\nBecause community structure of the PPI network revealed functional pathways, we proposed generating communities in a co-occurrence network of both MeSH main heading descriptors and SCRs in order to efficiently synthesize pathways from literature-mined associations. Specifically, we now hypothesized that the detected communities, which were groups of highly associated genes, diseases and drugs/chemicals in the network, captured biological pathways and mechanisms of diseases and drugs. Our data validated the biological relevance of these literature communities, which were enriched for curated biological pathways. We further demonstrated that the communities captured curated pathogenic gene sets for diseases and chemical-perturbed gene expression profiles. Clinical relationships between disease–disease and between chemical–chemical in same communities were also validated. Finally, we showed that community structures in the MeSH network helped propose novel disease and drug mechanisms. Overall, the detected literature communities complement pathway curation from text by automating pathway synthesis, and support disease gene discovery and drug repurposing through novel predictions of disease- and drug-specific mechanisms.\n\n2 Materials and methods\n2.1 Detecting literature communities\nWe extracted functional gene sets for specific diseases and chemicals by applying community detection RL algorithm (Wilson et al., 2017) to Mesh Term Objective Reasoning (MeTeOR) network (Wilson et al., 2018) (Fig. 1A). MeTeOR was selected because it robustly captures biological knowledge by comprehensively aggregating co-occurrences of both MeSH main heading descriptors and SCRs, from 22 million MEDLINE publications up to year 2017 (Wilson et al., 2018). MeTeOR also extracts more high-quality associations from the literature than other text-mining methods (Wilson et al., 2018), i.e. STRING Literature (Szklarczyk et al., 2015), STITCH Literature (Szklarczyk et al., 2016), EVEX (Van Landeghem et al., 2013) and BeFree (Bravo et al., 2015). The network consists of 1.07 ×105 nodes of genes (12%), chemicals (83%) and diseases (5%). Human genes are mapped to EntrezID using NCBI’s annotations and chemicals to PubchemCID, facilitating our validation against curated databases (mapping details are described in Wilson et al., 2018). The network data were downloaded from http://meteor.lichtargelab.org. RL is the selected community detection algorithm due to its usability in detecting biologically meaningful clusters in a PPI network (Wilson et al., 2017). After running Louvain algorithm, RL makes a subgraph of communities with more than 10 nodes and reruns Louvain detection. The process is done iteratively until all communities are broken down to communities with at most 10 nodes or a node is detected in more than 3 communities. Finally, communities that were highly overlapped, i.e. Jaccard similarity score >0.9, were collapsed, reducing clustering redundancy.\n (1) Jaccard Similarity, JCi,Cj=|Ci∩Cj||Ci∪Cj| where a set of communities Ci,j ∈C.\n\nFig. 1. Overview of discovering biologically meaningful groups of genes, diseases and chemicals. (A) Communities of genes, diseases and chemicals were detected in the MeTeOR network. Through enrichment analyses, we evaluated whether the communities could capture biological pathways (B), disease pathogenic genes (C.i) and drug-perturbed gene expression (D.i). Clinical associations between disease pairs (C.ii) and drug pairs (D.ii) in same communities were also explored\n\nRL detected communities that contained genes, diseases and chemicals and were proposed to represent functional pathways. We excluded communities with fewer than three genes since they would not represent any reasonable pathways. In addition to communities constructed based on the whole literature that we have up to year 2017, we also retrieved communities based on past literature, i.e. up to year 2005 and up to year 2013, for retrospective studies.\n\n2.2 Evaluating the communities against curated pathways\nWe evaluated whether the literature communities captured knowledge from curated pathway databases (Fig. 1B). Selected databases include Molecular Signature Database (MSigDB) (Liberzon et al., 2011, 2015), Kyoto Encyclopedia of Genes and Genomes (KEGG) (Kanehisa and Goto, 2000), WikiPathways (Kelder et al., 2012), Reactome (Fabregat et al., 2018), Gene Ontology Annotation (GOA) for aspects of Cellular Component, Biological Process and Molecular Function (Huntley et al., 2015; The Gene Ontology Consortium, 2017). These databases have different year versions from year 2005 to year 2017. All gene sets of MSigDB were used and downloaded from http://software.broadinstitute.org/gsea/msigdb. The other references were downloaded from http://amp.pharm.mssm.edu/Enrichr/ (Kuleshov et al., 2016). We performed hypergeometric tests for each pair of a literature community and a curated gene set from a database. The hypergeometric P-value is calculated by the following equation:\n (2) \nwhere M is the number of genes in both the reference and MeTeOR network; Ci is the genes in a given community i; Ri is the genes in a given pathway in a referenced control.\n\nWe hypothesized that enrichment P-values of our communities for curated pathways were more significant than those of random sets, measured by Kolmogorov–Smirnov (KS) test. Random gene sets were constructed with similar sizes with the detected communities.\n\nIn addition, we compared the performance of MeTeOR communities with communities that were constructed from other text-mining networks. Specifically, we aggregated predictions of gene–gene (GG), gene–disease (GD) and gene–chemical (GC) associations from other literature-mining methods into a combined network. The other selected literature-mining methods are STRING Literature v10.5 (Szklarczyk et al., 2015), STITCH Literature v5.0 (Szklarczyk et al., 2016), EVEX (Van Landeghem et al., 2013) and DisGeNET’s BeFree v5.0 (Bravo et al., 2015) (network statistics summarized in Supplementary Table S1). To make the comparison fair, we also built communities from associations of GG, GD and GC from MeTeOR predictions. We hypothesized that the communities built from MeTeOR gene-specific edges only are more enriched for pathway information than communities built from other methods.\n\nWe also performed time-stamped experiments to validate our predictive power for future curated pathways. We conducted enrichment analyses of communities of past literature, i.e. up to year 2005 or 2013, against pathway databases dated in later years. False discovery rate (FDR) was applied and a community significantly captured a pathway when q-value ≤0.1. We evaluated whether a novel community, which did not capture any curated pathway at the year it was constructed, could later capture newly added pathways or be confirmed.\n\n2.3 Assessing disease knowledge of the communities\n2.3.1 Evaluating how well the communities captured curated disease pathways\nWe hypothesized that genes in communities that contained disease entities explained etiology of those specific diseases (Fig. 1C.i). We gathered curated disease pathways from Online Mendelian Inheritance in Man (OMIM: https://www.omim.org) (Hamosh, 2004), ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/) (Landrum et al., 2014) and CTD (http://ctdbase.org) (Davis et al., 2019). We also took union of pathways of all sources for each disease to form a ‘Total’ set. Disease pathways with fewer than three genes were excluded. For communities that contained any diseases with pathway data, we performed hypergeometric tests for disease pathways against the communities. We measured area under Receiver Operating Characteristic curve (AUROC) and area under Precision-Recall curve (AUPRC) to evaluate how well a disease-specific community captured genetic causes of that specific disease. The ranking was the inverse of enrichment P-values for each pair of a disease pathway and a community. The truth table indicated whether that disease was in that community.\n\n2.3.2 Evaluating clinical and genetic disease–disease relationships in the communities\nWe observed cases of multiple diseases in same communities, motivating us to understand their clinical relationships, i.e. shared pathology and comorbidity (Fig. 1C.ii). We obtained hierarchies of disease pathology classes from Disease Ontology (http://disease-ontology.org) (Schriml et al., 2012). We explored whether diseases in same communities fell under similar classes. We also retrieved odds ratio for diseases to occur in same patients from a study (Blair et al., 2013), which examined 8 clinical cohorts with more than 123 million unique patients. We explored whether diseases co-appearing in more communities have higher comorbidity. In both relationship types, we compared distributions of these values in disease pairs with 0, 1 and 2 (or more) communities. We performed KS and Fischer’s Exact tests to evaluate whether these distributions were significantly different from each other.\n\n2.4 Assessing drug information of the communities\n2.4.1 Evaluating how well the communities captured drug-specific gene expression\nWe assessed whether drug-related communities explained drug-perturbed gene expression profiles (Fig. 1D.i). We obtained LINCS L1000 Connectivity Map—mRNA expression profiles for cell lines following small molecule perturbation (Subramanian et al., 2017) from https://amp.pharm.mssm.edu/Enrichr. For each drug in LINCS that were mapped to the communities, we performed hypergeometric tests for the communities and drug-perturbed expressed gene sets. We used FDR q-value ≤0.1 as a cutoff for a significant pair of a community and gene expression set. We also performed similar enrichment analyses using 100 random gene sets with similar genes and drugs in the communities. We compared the number of drugs whose expression profiles were explained by the communities compared with random sets.\n\n2.4.2 Evaluating drug–drug relationships in communities\nWe investigated whether drugs in same communities shared side effects (Fig. 1D.ii). SIDER database v4.1 (http://sideeffects.embl.de) (Kuhn et al., 2016) curates side effects for drugs. We hypothesized that the more communities a pair of drugs share, the more similar side effects that they have. We compared the distribution of number of shared side effects of drug pairs in same communities with that of drug pairs in different communities through KS test.\n\n2.5 Predicting multi-relations for genes, diseases and drugs\nIn the communities, some of their genes, diseases and chemicals had no MeTeOR associations. We hypothesized that these entities were biologically connected, even though no paper had documented their associations through MeSH terms. We were particularly interested in predicting the following three-entity relations: mutual pathogenic genes for disease pairs, common diseases for gene pairs, shared gene targets for drug pairs and common drugs for gene pairs. In making predictions, we considered number of supporting papers for predicted associations (W), and number of shared communities of the three entities (Ncom), adjusting with sizes of shared communities (Sz). Figure 2 summarizes how we made the multi-relation predictions. For example, a prediction of mutual pathogenic gene (Entity 1) for a pair of diseases (Entities 2A and 2B) entailed W and Com-Sz, which is a combination of Ncom and Sz. If there is no edge linking Entity 1 to either Entity 2A or Entity 2B, W is 0 as it would be impossible to use only the number of supporting papers to predict the ‘mutual’ pathogenic gene Entity 1 because there was no paper linking that gene to either of the diseases.\n (3) W=WA+WBmaxWA+WB if WA≠0, WB≠0;else W=0 (4) Sz=1∑i=1NcomSi (5) Com-Sz=Ncom+SzmaxNcom+Sz where WA is the edge weight between Entity 1 and Entity 2A (i.e. the number of articles in which Entity 1 and Entity 2A co-occur); WB is the edge weight between Entities 1 and 2B; and Si is the number of entities in a community index i in a set of Ncom shared communities.\n\nFig. 2. Predicting multi-relations for genes, diseases and chemicals. For example, a prediction of a mutual pathogenic gene (Entity 1) for a disease pair (Entities 2A and 2B) entailed W and Com-Sz [calculated by Equations (3)–(5)]. The calculations took into account of edge weights among entities (WA and WB), number of the communities that these entities co-occur (Ncom) and sizes of those communities (Sz)\n\nEach multi-relation prediction was ranked by three measures: just W, just Com-Sz and their sum. Validation was made against curated gene-disease associations in databases OMIM, CTD and DisGeNET v5.0 (Piñero et al., 2017) and against gene-chemical associations in databases CTD and STITCH v5.0 (http://stitch.embl.de) (Szklarczyk et al., 2016). The AUROC was implemented to evaluate the performances of different measures. Note that since we were interested in pathway-relevant communities, we limited our communities to have equal and fewer than 100 genes in this analysis.\n\n3 Results\n3.1 Overview of literature communities\nWhen using the whole MeTeOR network information, the RL algorithm detected 3444 communities comprising a mix of gene, disease and chemical entities (Table 1; Fig. 3). All were defined to contain at least three genes in order to capture biological pathway context. A total of 958 communities consisted of all 3 entity types, potentially reflecting intricate relationships among the contained genes, diseases, and drugs. Of the rest, 201 communities contained just genes and diseases while 1330 communities had only genes and chemicals. This likely reflects that the number of chemical entities dominated the MeTeOR network. These communities should allow us to explore disease and drug processes.\n\nFig. 3. Distribution of the number of entities per communities\n\nTable 1. Summary for the detected communities in the MeTeOR network\n\nEntity type\tNo. entities\tNo. communities\t\nGene\t11 127\t3444\t\nDisease\t4773\t1159\t\nChemical\t67 385\t2288\t\n3.2 Communities captured current and predicted future biological pathways\nTo investigate whether the literature communities were biologically meaningful, a positive control first evaluated whether the communities captured knowledge from already curated pathways or functional gene sets. This was measured by the significance of any overlap between MSigDB pathways and the literature communities (Fig. 1B) compared with that with random genes. Figure 4A shows that the literature communities were systematically enriched for curated pathways (KS test: P < 0.0001). Specifically, nearly all of the overlap P-values of the communities were <0.01 unlike those of random genes centered above that threshold. Furthermore, MeTeOR communities, either with gene-specific edges only or all edges, captured MSigDB pathway information more than communities using other text-mining methods (Supplementary Fig. S1). These enrichment patterns were not special to MSigDB but held true against all the other databases we tested: Reactome, KEGG, WikiPathways, GO Biological Process, GO Cellular Component, GO Molecular Function (Supplementary Figs S1 and S2). Furthermore, the communities robustly captured the majority of gene sets in these databases, from 63.5 to 95.6% (Supplementary Table S2). These data go beyond prior tests (Wilson et al., 2018) to show that MeTeOR literature communities are enriched for high-quality meaningful, curated pathway associations.\n\nFig. 4. The communities captured knowledge from the curated pathways of MSigDB. (A) The community P-values for enrichment of MSigDB pathways were skewed to significance compared with random. (B) Novel communities in year 2005 predicted pathways added to MSigDB after year 2005. (C) RNase MRP complex gene set, which was curated in 2012, was majorly annotated in a community in year 2005 (Jaccard similarity=0.70)\n\nBased on the capture of known pathways, we hypothesized that MeTeOR communities could suggest new pathways as well. This was tested through time-stamped experiments. We constructed MeTeOR communities based on the literature up to a past date and then assessed their overlap against pathways added to the database after that date. This is possible because pathway databases, such as MSigDB, have sequential dated versions (from year 2005 and beyond), allowing us to keep track of newly added pathways. We showed that at a given time point, i.e. 2005, many ‘novel’ communities which were not enriched with any pathway then, eventually developed a significant overlap with the newly added pathways (Fig. 4B). For example, in 2012, MSigDB annotated the RNase MRP complex, 70% of which was already annotated as a MeTeOR community in 2005 (Fig. 4C). The information added to MSigDB fluctuates over time (Fig. 4B), with little in 2016–2017 so that few of the novel communities could be further validated. Over 12 years from 2005 to 2017, however, more than half of the communities were confirmed. These data show that literature communities can discover new pathways, and communities that are still not validated remain potential candidates for unknown biological processes and drug/disease pathways. In Sections 3.3 and 3.4, we specifically explored these novel communities for diseases and drugs, respectively.\n\nThere are two additional layers of complexity to this retrospective analysis. First, communities from 2005 could become enriched for pathways or stay novel depending on the reference used (Supplementary Fig. S3A). This is because each reference may hold a different type and source of data. We chose to focus on MSigDB because it is a high-quality dataset often used for pathway analysis, but our conclusions hold across many different sources (Supplementary Fig. S3). Second, the year 2005 is not unique in offering insights into pathways, and we demonstrated that communities created on 2013 data also predicted groups of genes about to be annotated (Supplementary Fig. S3B). Additionally, there were more communities obtained based on literature up to 2013 than 2005, suggesting that with more literature information, more groupings of biological entities can be generated that are of potential value. Interestingly, for similar reference versions, there were more communities in year 2013 validated than those constructed in year 2005, indicating that updating the literature information allowed more accurate recapitulation of biological pathways.\n\nIn conclusion, the communities built from modularity of the MeSH co-occurrence network summarized current pathway knowledge and predicted future pathway information worthy of experimental assessment.\n\n3.3 Communities captured disease-specific pathways\nMultiple communities contained diseases in addition to genes. We hypothesized that these communities suggested meaningful relationships among diseases and genes, such as disease pathogenic genes and disease comorbidity. We first investigated whether genes in same communities of diseases were causative for these diseases. We gathered curated disease pathways from OMIM, ClinVar and CTD, and used them to validate the gene sets for each disease-contained community. We proposed that when a community contained a specific disease, that community was highly enriched in pathogenic genes for the disease (Fig. 1C.i). Indeed, when predicting diseases that each community contained, we achieved an overall AUROC of 0.64 and up to 0.80 for OMIM (Table 2). AUPRC was worst for CTD even though AUROC for CTD was comparable with that for ClinVar, suggesting that predictions for CTD were less precise. Predictive performances for OMIM and ClinVar were better than that for CTD because CTD is more general in scope while OMIM and ClinVar are more clinically focused. This is best demonstrated at the level of annotation, where clinicians and physicians annotate OMIM and ClinVar while non-clinical specialists went through the literature to curate CTD to include a much greater number of general disease–gene associations (Supplementary Table S3). The majority of disease pathway information of the total or combined set was from CTD (Supplementary Table S3), leading to similar predictive performances between total and CTD. These data show that generally communities captured gene sets for diseases but represented clinically significant genes especially well.\n\nTable 2. Area under ROC curve (AUROC) and area under precision-recall (AUPRC) for community predictions of disease pathways\n\nReference\tAUROC\tAUPRC\t\nOMIM\t0.80\t0.71\t\nClinVar\t0.68\t0.44\t\nCTD\t0.64\t0.20\t\nTotal\t0.64\t0.20\t\nWe further unraveled clinical associations between disease–disease pairs within communities. Our hypothesis was that diseases in the same communities shared similar pathology (Fig. 1C.ii). We first looked at Disease Ontology, in which 2397 diseases were mapped to the MeTeOR communities. We investigated whether diseases detected in the same communities fell under similar disease classifications. We found that most diseases that shared communities were in the same classes, suggesting that they shared similar pathologies (Fischer’s Exact test: P < 0.0001, odds ratio = 6.3) (Supplementary Table S4). This finding highlights that communities depicted pathophysiological relationships for the diseases.\n\nAnother disease–disease relationship type that we explored in communities was comorbidity (Fig. 1C.ii). Previous studies show that there is a strong correlation between disease comorbidity and their genetic and molecular risk interactions (Blair et al., 2013; Lee et al., 2008). Likewise, we saw that the more communities a pair of diseases were detected together, the higher odds ratio that they co-occur in same patients (Fig. 5; Supplementary Table S5). This result further suggests that diseases in the same communities share pathophysiology. Combining with the previous finding that disease-specific communities recapitulated well curated information of disease driver genes, the data demonstrate that the common underlying mechanisms for diseases in same communities can be explained by genes in same communities.\n\nFig. 5. Diseases co-occurring in same communities had higher comorbidity, suggesting that they shared mechanisms. ****P ≤ 0.0001 (KS test)\n\n3.4 Communities captured drug-specific pathways\nWe explored whether genes in the communities reflected drug pathways (Fig. 1D). Specifically, we examined whether genes in drug-specific communities recapitulated drug-perturbed gene expression. We performed hypergeometric enrichment analyses for drug-containing communities and experimental gene expression profiles for specific drugs from LINCS database (Fig. 1D.i). We also compared the enrichment results with those when randomizing genes in the drug-specific communities. We observed that the number of drugs whose expression profiles were significantly captured by the communities was much higher than that by random sets (z-score = 15; Fig. 6A). This result demonstrates that genes in drug-specific communities were enriched for genes up/down-regulated by the corresponding drugs.\n\nFig. 6. The communities captured genetic and clinical information of drugs, and chemicals. (A) The communities significantly captured perturbed gene expression profiles for 50 drugs, much more than the number of drugs captured by random sets (N = 100) (gray bars) (z-score = 15). (B) Drugs in same communities shared great numbers of side effects, suggesting that they shared mechanisms. ****P ≤ 0.0001 (KS test)\n\nCommunities that contained a drug usually contained many drugs, motivating us to explore their clinical associations. We examined whether drugs in same communities shared side effects (Fig. 1D.ii). SIDER annotates side effects for 792 drugs mapped to the MeTeOR communities. Figure 6B illustrates that drugs co-occurring in more communities shared similar side effects, suggesting that they acted through similar mechanisms. We noted that multiple drug pairs shared up to 20 common side effects (e.g. itchy skin and headache), but drug pairs that co-occurred in 2 or more communities shared more side effects, up to 409. Two drugs that shared the highest number of side effects were Aripiprazole and Escitalopram, both treating depression (Nelson et al., 2008). The community that they co-occurred in was enriched for genes relating to neuroactive ligand–receptor interactions, explaining 409 side effects that they shared. Our findings demonstrate that drugs in the same communities often interacted or acted on genes in the same communities, inducing similar side effects.\n\n3.5 The literature communities proposed plausible disease and drug mechanisms\nSince the communities captured clinical and biological associations between genes, diseases and chemicals, we proposed that they could generate plausible disease and drug mechanisms. We were particularly interested in detecting the following multi-relations: mutual pathogenic genes for disease pairs, common diseases for gene pairs, shared gene targets for drug pairs and common drugs for gene pairs. Identifying mutual genes for disease pairs could explain the common underlying mechanisms for diseases with similar pathology and/or high comorbidity. Detecting common diseases for gene pairs shed light on disease pathways. Predicting shared gene targets for drug pairs and common drugs for gene pairs facilitates drug repurposing. The predictions could suggest new drugs for the same gene targets or repurposed drugs for other genes and diseases.\n\nWe started with detection of shared pathogenic genes for a pair of diseases (Fig. 2). Naively, we prioritized genes annotated on multiple papers together to indicate that these genes were linked to both diseases. For our literature network, the number of supporting papers for associations (W) is the sum of edge weights between genes and diseases. When compared against a combined gold standard of curated gene-disease associations, communities predicted shared genes for diseases well (AUROC = 0.79) (Table 3), suggesting that genes that are highly co-mentioned with diseases in publications may explain shared mechanisms of these diseases. Next, we explored whether the number of shared communities that a gene and a pair of diseases co-occur (Com-Sz) recovered underlying mechanisms for disease pairs. Com-Sz achieved a high AUROC of 0.75 (Table 3), indicating that community structure defined meaningful clusters of genes and diseases that explain common genetics of diseases.\n\nTable 3. Area under ROC for multi-relation predictions\n\nEntity 1 type\tEntity 2 type\t\nW\n\t\nCom-Sz\n\t\nW + Com-Sz\t\nGene\tDisease\t0.79\t0.75\t0.82\t\nDisease\tGene\t0.83\t0.79\t0.86\t\nGene\tChemical\t0.58\t0.77\t0.80\t\nChemical\tGene\t0.63\t0.70\t0.75\t\nThe edge weight (W) is more intuitive than the community measure (Com-Sz) because W prioritizes already known associations. However, Com-Sz unravels unannotated associations in the literature network that were grouped together due to connections with other entities in same communities. This goes back to our major hypothesis in which entities that share neighbors may be as well biologically related. Combining both edge weight and community structure can fully utilize their benefits. Indeed, summation of both measures improved detection of shared pathogenic genes for disease pairs (AUROC = 0.82) (Table 3).\n\nWe observed similar patterns when predicting common diseases for gene pairs, shared gene targets for drug pairs and common drugs for gene pairs (Table 3). In detection of shared diseases for gene pairs, W outperformed Com-Sz. In the case of identifying shared gene targets for drug pairs and common drugs for gene pairs, Com-Sz had higher predictive power than W. An explanation for this observation could be that the network information on relationships between genes and diseases was denser than relationships between genes and drugs. In all cases, combining both measures yielded the best performance, on average of 0.81 for AUROC (Table 3). These data show that community structure filled in the missing gap of annotating information and complemented with known knowledge.\n\nWe also searched for examples of drug repurposing through the use of the literature communities in a time-stamped experiment. Using the literature up to year 2013, we looked for disease–chemical pairs in communities that had no co-occurrence association. We proposed that the fact that these disease–chemical pairs co-occurred in multiple communities indicated that they had some clinical associations that would be validated later. Indeed, for disease–chemical pairs that co-occurred in multiple communities, even though many of them were not found associated together by MeSH co-occurrence in year 2013, several drugs were successfully repurposed for the corresponding diseases in later years (Table 4). For example, drug DC-2701 was found in seven communities with Neovascularization and its known treatments because DC-2701 and the treatments were highly connected together due to their similar mechanisms of action. Even though in year 2013, DC-2701 was not studied for the disease yet, the fact that they co-occurred in many communities suggests that DC-2701 may treat Neovascularization, which in fact, was confirmed in year 2015. These data suggest that the communities mimicked human hypothesis generation, efficiently grouped clinically relevant chemicals and diseases and thus, reliably synthesized plausible drug repurposing hypotheses.\n\nTable 4. Novel disease–chemical associations suggested by the top number of shared communities in 2013 (seven communities) were validated by publications in later year\n\nDisease\tChemical\tDrug function\tPMID (year)\t\nNeovascularization, pathologic\tDCC-2701\tTherapeutic\t26285778 (2015)\t\nVitreous detachment\tperfluorooctane\tUsed in surgery\t24800216 (2014)\t\nExfoliation syndrome\tAR-12286\tTherapeutic\t27552517 (2016)\t\nExfoliation syndrome\tK-115\tTherapeutic\t28349329 (2017)\t\nGastrointestinal neoplasms\tdotatate gallium ga-68\tDiagnostic\t29159606 (2018)\t\nAnhedonia\tfluvoxamine\tTherapeutic\t27987210 (2017)\t\nAdenomyosis\tgestrinone\tPalliative\t25510683 (2014)\t\nHeavy metal poisoning\tsodium arsenite\tCausative\t26091798 (2015)\t\n4 Discussion\nIndividual associations between bio-entities are extensively explored, yet it is challenging to integrate them into useful pathway information. Here, we proposed a new approach that utilized modularity of an MeSH co-occurrence network in order to efficiently mine new pathway information from the literature. Specifically, we generated functional groups or communities of genes, diseases and chemicals that reliably summarized knowledge from biological processes. Most communities captured significant portions of the curated pathways or included pathways as their subsets, thus highlighting core drivers of curated pathways and expanding current curated information. The communities that were not significantly overlapped with any curated pathway, on the other hand, proposed yet unknown functional processes or disease- and drug-specific mechanisms, which were not curated in the tested pathway databases. The proposed processes can be confirmed in the future (Fig. 4B) or may have already been experimentally validated but not curated yet. Overall, the communities provided meaningful biological information to supplement current pathway knowledgebases.\n\nFurthermore, the communities provided known and novel genetic and clinical information for diseases and drugs. The communities detected diseases and drugs with similar clinical manifestations (e.g. disease comorbidity) and captured disease- and drug-specific mechanisms of actions through the genes in the same communities. The communities also robustly recovered multi-relations among genes, diseases and drugs (e.g. mutual drug targets), many of which were not already curated. Finally, the communities proposed promising hypotheses for disease gene discovery and drug repurposing with many successful cases as shown in a retrospective study (Table 4).\n\nOverall, the literature communities automate integrating related associations to synthesize functional pathways and provide genetic and clinical contexts for genes, diseases and drugs of interest. Furthermore, the communities can imitate human hypothesis generation and reliably propose ideas for disease gene discovery and drug repurposing that are worthy of experimental assessment. Instead of scientists going through individual associations to formulate hypotheses, the communities efficiently aggregate relevant biological interactions to propose plausible mechanisms. Even if entities of novel associations are distant from each other in the network, the fact that they share multiple neighbors, as detected by the communities, strongly suggests that they are biologically relevant, and that their associations are valid. For predictions of novel associations, the communities also inform their functional and clinical nature in the context of other genes, diseases and drugs co-occurring in same communities and easily point out specific publications that were used to construct communities and thus, are relevant to novel associations.\n\nThere are aspects that we would like to improve with the communities. Currently, knowledge of the communities is limited to MeSH terms. MeSH terms were selected because they are reliably curated by biocurators and their IDs can be mapped easily to other databases, supporting knowledge integration. Yet, they do not cover all keywords, leading to insufficient information in the communities. We attempted to complete gene information of the communities by supplementing the MeTeOR network with more than 8000 additional human genes extracted by PubTator (Wei et al., 2019), a named entity recognition method for PubMed-indexed citations. The communities after supplementing with PubTator-mined genes were significantly less enriched with curated pathway information than the original MeTeOR communities. This suggests that the genes extracted by PubTator were not necessary key entities of articles, adding spurious information (Supplementary Fig. S4). Only when we restricted to use PubTator-mined genes that appeared more than 50 citation mentions in order to reduce the redundant information, the newly constructed communities improved their pathway information enrichments and was even comparable to the original communities for some pathway references (Supplementary Fig. S4). For a future study, we plan to combine other curated network data in order to improve completeness and quality of the community information.\n\nIn addition, even though the communities propose meaningful associations, they lack directionality, e.g. the communities could not differentiate whether chemicals treat or cause diseases (Table 4). Currently, the nature of novel associations can be inferred from the literature information of relevant associations in same communities. To automate this process, we plan to integrate the literature network with directional biological networks to deduce directionality of proposed associations. We can also apply NLP to specific publications relevant to the novel associations to validate and improve our annotations.\n\nTo support utilization of the communities, we provide data and tools on http://meteor.lichtargelab.org. Users can explore the detected literature communities for discovery of novel mechanisms of diseases and drugs. The website can also extract significantly overlapped communities for any given groups of genes, diseases and/or chemicals of interest. For example, the website can detect communities that are significantly enriched for users’ genes of interest and simultaneously highlight diseases and chemicals that co-occur in these communities and thus, are functionally related with the genes. This function is particularly helpful for users to identify novel diseases and drugs linked to genes of interest and to investigate unknown biological processes for omics data.\n\nFunding\nThis work has been supported by the National Institutes of Health [GM079656, GM066099, AG061105]. \n\n\nConflict of Interest: none declared.\n\nSupplementary Material\nbtz857-Supplementary_Data Click here for additional data file.\n==== Refs\nReferences\n\nAlako B.T. \net al (2005 ) \nCoPub Mapper: mining MEDLINE based on search term co-publication\n. BMC Bioinformatics , 6 , 51 .15760478 \n\nBlair D.R. \net al (2013 ) \nA nondegenerate code of deleterious variants in mendelian loci contributes to complex disease risk\n. 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"fulltext_license": "CC BY-NC",
"issn_linking": "1367-4803",
"issue": "36(6)",
"journal": "Bioinformatics (Oxford, England)",
"keywords": null,
"medline_ta": "Bioinformatics",
"mesh_terms": "D057225:Data Mining; D058492:Drug Repositioning; D046650:Medical Subject Headings; D011642:Publications",
"nlm_unique_id": "9808944",
"other_id": null,
"pages": "1881-1888",
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"pmid": "31738408",
"pubdate": "2020-03-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "22096230;25352553;25412639;23203871;30247620;12603047;17237098;27896987;25378336;28881963;19183784;28359255;18599447;26590256;22080554;26481350;24074861;21546393;25006672;15694635;15808823;15697438;29195078;27924018;24288140;15760478;15608251;26771021;18772154;25886734;27141961;26202570;23613707;31114887;29145629;24234437;10592173;27899567;19765306",
"title": "Discovery of disease- and drug-specific pathways through community structures of a literature network.",
"title_normalized": "discovery of disease and drug specific pathways through community structures of a literature network"
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"abstract": "We report a patient with Essential Thrombocythemia (ET), subsequently diagnosed with concurrent myeloid and lymphoid leukemia. Generally, the molecular mechanisms underlying leukemic transformation of Philadelphia-negative myeloproliferative neoplasms (Ph-MPN) are poorly understood. Risk of transformation to acute myelogenous leukemia (AML) is low; transformation to both AML and acute lymphoblastic leukemia (ALL) is extremely low. Genetic defects, including allele burden, order of mutation acquisition, clonal heterogeneity and epigenetic mechanisms are important contributors to disease acceleration.\n\n\n\nA 78-year-old Caucasian female originally treated for stable ET, underwent disease acceleration and transition to myeloid sarcoma and B-cell ALL. Genomic reconstruction based on targeted sequencing revealed the presence of a large del(5q) in all three malignancies and somatic driver mutations: TET2, TP53, SF3B1, and ASXL1 at high allele frequency. We propose that the combination of genetic and molecular abnormalities led to hematopoietic stem cell (HSC) injury and disease progression through sub-clone branching. We hypothesize that ancestral reconstruction of genomic data is a useful tool to uncover subclonal events leading to transformation.\n\n\n\nThe use of ancestral reconstruction of genomic data sheds light on the unique clinical scenario described in this case report. By determining the mutational profile of tumors at several timepoints and deducing the most parsimonious relationship between them, we propose a reconstruction of their origin. We propose that blast progression originated from subclonal events with malignant potential, which coexisted with but did not originate from JAK2 p.V617F-positive ET. We conclude that the application of genomic reconstruction enhances our understanding of leukemogenesis by identifying the timing of molecular events, potentially leading to better chemotherapy choices as well as the development of new targeted therapies.",
"affiliations": "Department of Statistics and Bioengineering, Rice University, 6100 Main Street, Houston, TX, USA.;Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, USA.;The Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, USA.;The Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, USA.;Department of Statistics and Bioengineering, Rice University, 6100 Main Street, Houston, TX, USA.;Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, USA.;The Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, USA. iberia.sosa@fccc.edu.",
"authors": "Chen|Yujie|Y|;Talukder|Rafee|R|;Merritt|Brian Y|BY|;King|Katherine Y|KY|;Kimmel|Marek|M|;Rivero|Gustavo|G|;Sosa|Romina|R|0000-0003-3947-9330",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12920-021-00986-z",
"fulltext": "\n==== Front\nBMC Med Genomics\nBMC Med Genomics\nBMC Medical Genomics\n1755-8794\nBioMed Central London\n\n986\n10.1186/s12920-021-00986-z\nCase Report\nGenomic trajectory in leukemogenesis of myeloproliferative neoplasms: a case report\nChen Yujie 1\nTalukder Rafee 2\nMerritt Brian Y. 356\nKing Katherine Y. 37\nKimmel Marek 1\nRivero Gustavo 284\nhttp://orcid.org/0000-0003-3947-9330\nSosa Romina iberia.sosa@fccc.edu\n\n483\n1 grid.21940.3e 0000 0004 1936 8278 Department of Statistics and Bioengineering, Rice University, 6100 Main Street, Houston, TX USA\n2 grid.39382.33 0000 0001 2160 926X Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX USA\n3 grid.39382.33 0000 0001 2160 926X The Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine, 1 Baylor Plaza, Houston, TX USA\n4 grid.249335.a Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111 USA\n5 grid.39382.33 0000 0001 2160 926X Department of Pathology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX USA\n6 grid.39382.33 0000 0001 2160 926X Department of Molecular and Human Genetics, Baylor Genetics and Baylor College of Medicine, 1 Baylor Plaza, Houston, TX USA\n7 grid.39382.33 0000 0001 2160 926X Department of Pediatrics, Section of Infectious Disease, Baylor College of Medicine, 1102 Bates St. Suite 1150, Houston, TX USA\n8 grid.39382.33 0000 0001 2160 926X Section of Hematology and Oncology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX USA\n22 5 2021\n22 5 2021\n2021\n14 1376 10 2020\n18 5 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open 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.\nBackground\n\nWe report a patient with Essential Thrombocythemia (ET), subsequently diagnosed with concurrent myeloid and lymphoid leukemia. Generally, the molecular mechanisms underlying leukemic transformation of Philadelphia-negative myeloproliferative neoplasms (Ph-MPN) are poorly understood. Risk of transformation to acute myelogenous leukemia (AML) is low; transformation to both AML and acute lymphoblastic leukemia (ALL) is extremely low. Genetic defects, including allele burden, order of mutation acquisition, clonal heterogeneity and epigenetic mechanisms are important contributors to disease acceleration.\n\nCase presentation\n\nA 78-year-old Caucasian female originally treated for stable ET, underwent disease acceleration and transition to myeloid sarcoma and B-cell ALL. Genomic reconstruction based on targeted sequencing revealed the presence of a large del(5q) in all three malignancies and somatic driver mutations: TET2, TP53, SF3B1, and ASXL1 at high allele frequency. We propose that the combination of genetic and molecular abnormalities led to hematopoietic stem cell (HSC) injury and disease progression through sub-clone branching. We hypothesize that ancestral reconstruction of genomic data is a useful tool to uncover subclonal events leading to transformation.\n\nConclusions\n\nThe use of ancestral reconstruction of genomic data sheds light on the unique clinical scenario described in this case report. By determining the mutational profile of tumors at several timepoints and deducing the most parsimonious relationship between them, we propose a reconstruction of their origin. We propose that blast progression originated from subclonal events with malignant potential, which coexisted with but did not originate from JAK2 p.V617F-positive ET. We conclude that the application of genomic reconstruction enhances our understanding of leukemogenesis by identifying the timing of molecular events, potentially leading to better chemotherapy choices as well as the development of new targeted therapies.\n\nKeywords\n\nEssential thrombocythemia\nLeukemia\nClonal evolution\nMyeloproliferative neoplasms\nCase report\nhttp://dx.doi.org/10.13039/100000002 National Institutes of Health R01HL136333 R01HL134880 King Katherine Y. issue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nThe molecular mechanisms underlying leukemic transformation of Philadelphia-negative myeloproliferative neoplasms (Ph-MPN) are poorly understood. Risk of transformation to acute myelogenous leukemia (AML) is approximately 10–20% for patients with primary myelofibrosis (PMF) and considerably lower for those with Polycythemia Vera (PV) and Essential Thrombocythemia (ET), 5–10% and 2–5% respectively [1, 2]. Transformation of MPN to acute lymphoblastic leukemia (ALL) is rare, with only seventeen cases reported in the literature [3]. Retrospective studies suggest that genetic defects, including allele burden, order of mutation acquisition, clonal heterogeneity and epigenetic mechanisms play an important role in the observed conversion rate, as well as the varied clinical-pathologic entities that evolve [4, 5].\n\nIn this report, we describe a series of clonal events in an elderly patient originally diagnosed with JAK2 V617F-positive ET who presented in accelerated phase, with subsequent progression to concurrent myeloid sarcoma (MS) and B-cell ALL. We hypothesize that reconstruction of genomic mutations to build an ancestral tree may be a useful tool to characterize leukemogenesis in patients with high-risk disease.\n\nCase presentation\n\nA 78-year-old Caucasian female was diagnosed with JAK2 V617F-positive ET in 2010 based on laboratory data and molecular profiling of peripheral blood. She was initiated on hydroxyurea (HU) and low-dose aspirin. The patient remained on anticoagulation with coumadin due to a prior history of atrial fibrillation. She demonstrated stable and adequate platelet response to 10 mg/kg of HU.\n\nIn 2016, despite compliance with therapy, she presented with platelet count of 1150 k/µl, hemoglobin of 8.2 g/dL, and WBC of 6.0 k/µl with absolute neutrophil count of 2820/µl without detectable peripheral blasts. She underwent a bone marrow biopsy, which revealed 80–90% cellularity with increased myeloblasts (12%), megakaryocyte hyperplasia, dysmegakaryopoiesis and grade 2/4 reticulin fibrosis (Fig. 1a). Cytogenetics revealed del(5)(q22-q33),del(17)(p11.2)[17]/46,XX[3], with wild-type CALR and MPL. Fluorescent in situ hybridization (FISH) reconfirmed 5q deletion. Next generation sequencing (NGS) revealed the following mutations: JAK2 p.V617F, SF3B1 p.R625C and TET2 p.C1271fs (Table 1). Due to patient preference for an oral agent, lenalidomide was initiated at 10 mg orally daily for 21 days in a 28-day cycle. This intervention resulted in partial remission based on International Working Group-Myeloproliferative Neoplasms Research and Treatment Response Criteria, with clinical improvement of anemia and thrombocytosis (hemoglobin of 12.1 g/dL and platelet count of 344 K/µL, respectively). After seven cycles of lenalidomide, a repeat bone marrow biopsy revealed persistent blasts at 8%, persistent dysmegakaryopoiesis, and stable JAK2 p.V617F mutation. Despite cytogenetic remission, (46 XX in 20 metaphases analyzed), her MDS FISH panel revealed a new 20q12 (PTPRT/MYBL2) loss.Fig. 1 Summary of stages of leukemogenesis in the same patient. Tissue and cell-block formalin-fixed paraffin embedded (FFPE) sections stained with hematoxylin and eosin (H&E) were visualized by conventional bright-field Kohler illumination light microscopy (Olympus BX40, Japan) with a 20 × Plan achromat objective (Olympus, Japan), 20 × camera mount lens and a DP71 camera (Olympus, Japan). Photomicrographs were obtained after white balancing using the CellSense software (Olympus, Japan). Minor contrast adjustments were performed to the entire image to accurately represent the cells observed in manual microscopy. a Bone marrow biopsy prior to lenalidomide in 2016 at time of accelerated ET, with abnormally increased numbers of megakaryocytes that are atypical with hyperlobation, nucleomegaly and nuclear hyperchromasia and nucleoli with surrounding myeloid and erythroid progenitors. H&E nominal field magnification 400X. b Biopsy of ileocecal mass at time of leukemic transformation in 2018 diagnostic for myeloid sarcoma with sheets of MPO-positive myeloblasts with scant eosinophilic cytoplasm, irregular nuclear contours and prominent nucleoli. H&E nominal field magnification 400x. c Pleural fluid aspirate cytology cell block at time of leukemic transformation in 2018 demonstrates numerous blasts with scant cytoplasm and indistinct nuclear chromatin and surrounding red blood cells. H&E nominal field magnification 400X. Scale bars 50 µm\n\nTable 1 Summary of Karyotype, FISH and molecular mutations\n\nDisease stage\tPeripheral blood 2010\tBone marrow 2016\tBone marrow 2017\tBone marrow 2018\tColonic mass 2018\tPleural effusion 2018\t\nEssential Thrombocytosis\tAccelerated Phase Essential Thrombocytosis\tAccelerated Phase Essential Thrombocytosis\tMyeloid Sarcoma\tB-cell ALL\t\nChr\tMutations\t\t\t\t\t\t\t\n1\tNRAS (NM_002524) c.34G > A (p.G12S)\t\t0.0\t\t\t73.3\t0.0\t\n2\tSF3B1 (NM_012433) c.1873C > T (p.R625C)\t\t34.7\t\t\t43.5\t47.6\t\n4\tTET2 (NM_001127208) c.3812dupG (p.C1271fs)\t\t33.8\t\t\t47.9\t48.4\t\n9\tJAK2 (NM_004972) c.1849G > T (p.V617F)\tPos\t35.2\tPos\t\t0.0\t0.0\t\n17\tTP53 (NM_000546) c.215C > G (p.P72R)\t\t45.5\t\t\t9.3\t3.4\t\n17\tTP53\n\n(NM_000546)\n\nc.734G > C\n\n(p.G245A)\n\n\t\t0.0\t\t\t83.7\t93.8\t\n1\tMPL ex. 10\t\tNeg\tNeg\t\tNeg\tNeg\t\n19\tCALR ex. 9\t\tNeg\tNeg\t\t\t\t\n\tKaryotypes\t\t\t\t\t\t\t\n\t5del (q22-q33)\t\t43.5\t\t0.5\t43.0\t98.5\t\n\t17p del\t\t85.0\t\t\t49.0\t\t\n\t20q del\t\t\t9.0\t28.5\t\t96.0\t\n\tMLL (KMT2A) amplification\t\t\t\t0.0\t74.0\t92.0\t\n\tMYC amplification\t\t\t\t\t\t21.5\t\nVariant allele frequencies are defined as fractions of variant versus total sequencing read count expressed as percentages. Frequencies of chromosomal abnormalities are estimated similarly\n\nFISH fluorescent in situ hybridization, ALL acute lymphoblastic leukemia\n\nIn January 2018, she presented with shortness of breath, abdominal pain, nausea and vomiting. Computed tomography (CT) scan of chest, abdomen and pelvis revealed a large 7.9 cm × 4.9 cm ileocecal mass inducing partial colonic obstruction and moderate left pleural effusion. Pathology of the excised cecal mass showed a cluster of medium-sized MPO-positive myeloblasts with eccentric nuclei and scant cytoplasm, positive for CD33 and CD117 based on flow cytometry and consistent with MS (Fig. 1b). Macroscopic examination of her pleural fluid revealed medium-sized cells with large nuclei and scant basophilic cytoplasm positive for CD19, TdT and CD20 consistent with B-cell ALL (Fig. 1c). NGS of both the colonic mass and pleural fluid revealed SF3B1, TP53 exon 6 and exon 3 and TET2 (Table 1). JAK2-V617F and MPL were negative in both the colonic MS and B-cell ALL (Fig. 2).Fig. 2 Inferred phylogenetic tree of mutational process contributing to the sequential appearance of MDS/ET, MS and B-cell ALL. Branch splits are consistent with NGS and FISH data reviewed in Table 1. Notation: Chromosomal aberrations are denoted by a square. Solid squares (filled square) denote presence of chromosome abnormality; open squares (open square) denote their disappearance. X marks denote presence of point mutations, while open circles (circle) denote loss of mutation. The order of mutations between branch splits cannot be inferred from the data and therefore they are listed lexicographically. The founder cell is proposed to be an HSC containing del (5q) as well as somatic driver mutations (ASXL1, JAK2, TET2, TP53, SF3B1). Prior to blast transformation, the pluripotent HSC capable of myeloid and lymphoid differentiation, acquired new KMT2A (MLL) amplification. Absence of MLL amplification in bone marrow suggests this clone seeded into the periphery thereby accounting for its presence in the extramedullary blast transformation but not in the bone marrow. Deletion 17p was present in 2016 accelerated phase ET and appears to have been conserved in the subclone that evolved into myeloid sarcoma. Deletion 20q was first seen in bone marrow after lenalidomide therapy and is present in subclone that evolved into B-cell ALL. Treatment with lenalidomide contributed to the suppression of del(5q) clones in bone marrow but had little effect in extramedullary leukemias\n\nAmplicon-based NGS of a panel of 48 genes commonly mutated in hematologic malignancies was performed on the Ion Torrent PGM platform from unfractionated bone marrow DNA.\n\nAn inferred phylogenetic tree was constructed from NGS and karyotype data from bone marrow samples obtained during the evolution from ET to MDS, as well as from colon and pleural effusion samples obtained during blast transformation. The corresponding time-scale data points were aligned to reflect the hypothetical evolution of hematopoietic stem cells (HSC) most parsimonious with the sequencing and FISH findings reflected in Table 1. Note that between any two splits of the tree, the order of mutations and chromosomal deletions cannot be determined, and mutations are depicted sequentially for visual convenience (Fig. 2).\n\nDiscussion and Conclusions\n\nIn this single case report, genomic reconstruction importantly revealed the presence of a large del(5q) in all three malignancies: ET, MS and B-cell ALL, suggesting a common cell of origin. In chronic phase MPN, this finding should inform physicians about the imminent likelihood for disease progression. Episomal reprogramming has identified del(5q) as an early cytogenetic lesion with the capacity to perturb genome stability and differentiation [6]. Larger del(5q) size has been correlated with higher mutation frequency [5], which in this case included the somatic driver mutations: TET2, TP53, SF3B1, and ASXL1 at high allele frequency (Table 1). We propose that this combination led to HSC injury and disease progression through sub-clone branching (Fig. 2). The shared presence of JAK2-V617F and TET2 mutations in ET suggests that “megakaryocytic branching” originated directly from the HSC as opposed to a more lineage-restricted progenitor [7]. The JAK2-V617F mutation confers a weak proliferative advantage to HSC and its absence in blast phases suggests MS and B-cell ALL did not emerge from this subclone.\n\nBefore blast conversion, the patient received lenalidomide, an immune modulator that yields cytogenetic remission by inhibiting growth of del(5q) progenitors without affecting other cells [4]. Clinically, lenalidomide improves survival and reduces transfusion requirements in patients with del(5q) MDS [4, 8]. Some reports suggest an association between lenalidomide therapy and transformation to more aggressive phenotypes, including a review documenting transformation of MPN to ALL [3]. Emerging data suggest that progression to AML in patients treated with lenalidomide is associated with karyotype complexity and clonal selection rather than a drug-mediated transformation [4,9]. Accordingly, in our case, bone marrow biopsies after lenalidomide therapy reveal absence of del(5q) clones, likely as a result of known suppression from drug. They also revealed a new 20q deletion (Table 1), which may portend the malignant potential of uninhibited clones, as evidenced later by its high expression in B-cell ALL.\n\nBased on the ancestral reconstruction of genomic data modeled in Fig. 2, we hypothesize a mechanism for disease acceleration, whereby subclonal events with potential for blast conversion coexisted with but did not originate from JAK2 p.V617F-positive ET. The presence of del(5q) and molecular abnormalities (TP53, KMT2A) in both MS and B-cell ALL (Fig. 2) suggest that “disease progression” originated from diversification of a pluripotent HSC capable of both myeloid and lymphoid differentiation [10, 11], thereby leading to two distinct leukemia initiating cells (LIC): one containing 17p deletion and the other 20q deletion. Interestingly, del(5q) was suppressed in bone marrow but not from extramedullary sites where the blast phase manifested, suggesting variable sensitivity of different clones to lenalidomide. The concurrent presence of TP53 mutation in extramedullary sites [12] is known to confer a negative impact on survival and drug response to patients with del(5q) MDS treated with lenalidomide [7, 13]. Recent studies suggest that patients with high-risk MDS, characterized by unfavorable-risk cytogenetic abnormalities and/or TP53 mutations, exhibit favorable clinical responses with robust mutation clearance when treated with hypomethylating agents (HMA) [14]. Unfortunately, HMA do not provide durable responses. A combination of azacytidine plus anti-CD47 monoclonal antibody is currently being investigated on TP53-AML with preliminary results showing an objective response in 71% of subjects and 48% complete remission [15].\n\nWe are limited in our ability to confirm the proposed order of pathogenic mutations. We lack banked bone marrow cells at all time points of disease evolution to demonstrate the proposed patterns of clonal progression. As this is a single case report, computer simulation of similar cases of accelerated phase ET would reaffirm our proposed model. However, collecting replicate cases is difficult given the rarity of the events described. Despite the limitations in our analysis, the ancestral tree in this case report highlights how the relative accessibility of NGS continues to improve our understanding of leukemogenesis, specifically, the predictive significance of large del(5q). It also has the capacity to inform therapeutic choices. Notwithstanding the presence of del (5q), recent studies support that HMA is a superior choice to lenalidomide under the clinical scenario described here. HMA combination regimens [15] currently being investigated may provide durable responses to patients with TP53 mutations.\n\nIn conclusion, the advances in NGS technology have made it possible to generate a deep snapshot of the genetic composition of rapidly evolving tumor cells. The development and application of computational algorithms to harness NGS data for ancestral reconstruction could have a dramatic impact in how we practice medicine. Large scale simulation of similar cases to that described in this report would enhance our ability to predict disease progression. It would inform how a specific collection of molecular mutations would favor one therapeutic approach versus another. We propose exploring the use of computational algorithms to resolve patterns of clonal progression to enhance our understanding of leukemogenesis and the contribution of molecular targets, thereby leading to the development of more specific, tumor-tailored therapeutic interventions.\n\nAbbreviations\n\nALL Acute lymphoblastic leukemia\n\nAML Acute myelogenous leukemia\n\nCT Computed tomography\n\nET Essential thrombocythemia\n\nFISH Fluorescent in situ hybridization\n\nHMA Hypomethylating agents\n\nHSC Hematopoietic stem cell\n\nLIC Leukemia initiating cell\n\nMDS Myelodysplasia\n\nMPO Myeloperoxidase\n\nMS Myeloid sarcoma\n\nNGS Next generation sequencing\n\nPh-MPN Philadelphia-negative myeloproliferative neoplasm\n\nPMF Primary myelofibrosis\n\nPV Polycythemia vera\n\nAcknowledgements\n\nThe authors thank Cliff Bleiden, MD for preparing photomicrographs representing the histopathology of the patient’s disease.\n\nAuthors' contributions\n\nIRS clinically followed the patient. IRS, RT and GR summarized the clinical data, reviewed the literature and wrote the manuscript. YC, KYK and MK developed the phylogenetic tree. BYM, IRS and GR contributed to interpretation of molecular data. All Authors (IRS, RT, YC, KYK, BYM, MK, and GR) were responsible for content and editorial decisions throughout the development of the manuscript and agreed to be accountable for all aspects of the work. All authors have read and approved the manuscript.\n\nFunding\n\nKYK, MK and YC were supported in part by National Institute of Health (NIH) grants R01HL136333 and R01HL134880.\n\nAvailability of data and materials\n\nThe datasets generated and analyzed during the current study are available in the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) repository, accession number PRJNA727835 (http://www.ncbi.nlm.nih.gov/bioproject/727835). Mutational analyses by targeted sequencing panels are provided in the data table.\n\nDeclarations\n\nEthics approval and consent to participate\n\nSubmitted case was approved by the institutional review board [Baylor College of Medicine] approval number H-43327 dated 20th, August 2018. This process is in accordance with the Helsinki declaration.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication. A copy of the written consent is available for review.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nYujie Chen, Rafee Talukder contributed equally to this work\n==== Refs\nReferences\n\n1. Rampal R Ahn J Abdel-Wahab O Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms Proc Natl Acad Sci U S A 2014 111 E5401 E5410 10.1073/pnas.1407792111 25516983\n2. Iurlo A, Cattaneo D, Gianelli U. Blast transformation in myeloproliferative neoplasms: risk factors, biological findings, and targeted therapeutic options. Int J Mol Sci 2019;20:10.3390/ijms20081839.\n3. Alhuraiji A Naqvi K Huh YO Ho C Verstovsek S Bose P Acute lymphoblastic leukemia secondary to myeloproliferative neoplasms or after lenalidomide exposure Clin Case Rep 2017 6 155 161 10.1002/ccr3.1264 29375856\n4. Giagounidis A Mufti GJ Fenaux P Germing U List A MacBeth KJ Lenalidomide as a disease-modifying agent in patients with del(5q) myelodysplastic syndromes: linking mechanism of action to clinical outcomes Ann Hematol 2014 93 1 11 10.1007/s00277-013-1863-5 24018623\n5. Stengel A Kern W Haferlach T Meggendorfer M Haferlach C The 5q deletion size in myeloid malignancies is correlated to additional chromosomal aberrations and to TP53 mutations Genes Chromosomes Cancer 2016 55 777 785 10.1002/gcc.22377 27218649\n6. Hsu J Reilly A Hayes BJ Reprogramming identifies functionally distinct stages of clonal evolution in myelodysplastic syndromes Blood 2019 134 186 198 10.1182/blood.2018884338 31010849\n7. Noetzli LJ French SL Machlus KR New Insights Into the Differentiation of Megakaryocytes From Hematopoietic Progenitors Arterioscler Thromb Vasc Biol 2019 39 1288 1300 10.1161/ATVBAHA.119.312129 31043076\n8. Lee JH List A Sallman DA Molecular pathogenesis of myelodysplastic syndromes with deletion 5q Eur J Haematol 2019 102 203 209 10.1111/ejh.13207 30578738\n9. Pellagatti A Jadersten M Forsblom AM Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients Proc Natl Acad Sci U S A 2007 104 11406 11411 10.1073/pnas.0610477104 17576924\n10. Xie W Chen Z Wang SA Lymphoblastic leukemia following myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms Leuk Lymphoma 2019 60 2993 3001 10.1080/10428194.2019.1605509 31017498\n11. Janssen JW Buschle M Layton M Clonal analysis of myelodysplastic syndromes: evidence of multipotent stem cell origin Blood 1989 73 248 254 10.1182/blood.V73.1.248.248 2562924\n12. Tang G DiNardo C Zhang L MLL gene amplification in acute myeloid leukemia and myelodysplastic syndromes is associated with characteristic clinicopathological findings and TP53 gene mutation Hum Pathol 2015 46 65 73 10.1016/j.humpath.2014.09.008 25387813\n13. Mossner M Jann JC Nowak D Prevalence, clonal dynamics and clinical impact of TP53 mutations in patients with myelodysplastic syndrome with isolated deletion (5q) treated with lenalidomide: results from a prospective multicenter study of the german MDS study group (GMDS) Leukemia 2016 30 1956 1959 10.1038/leu.2016.111 27133825\n14. Welch JS Petti AA Miller CA TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes N Engl J Med 2016 375 2023 2036 10.1056/NEJMoa1605949 27959731\n15. Sallman D, Asch A, Kambhampati S, et al. The first-in-class anti-CD47 antibody magrolimab combined with azacitadine is well-tolerated and effective in AML patients: Phase 1b results. In: 62nd American Society of Hematology Meeting 2020;Session 613:Abstract 330 (oral).\n\n",
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"title": "Genomic trajectory in leukemogenesis of myeloproliferative neoplasms: a case report.",
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"abstract": "Calcium channel blockers (CCBs) have a narrow therapeutic index, and their intake in excess is associated with a critical clinical presentation of sustained hypotension and non-cardiogenic pulmonary edema, which are difficult to treat. Unfortunately, the available treatments fail to resuscitate a significant number of patients poisoned by CCBs, rendering them the main cardiovascular drugs involved in death due to overdose. Importantly, in all cases reported until now in the literature, CCB intoxication was known at the time of patients' presentation and the medical challenge solely consisted of the therapeutic approach. In this case report, we describe our experience in treating a 72-year-old patient with recurrent episodes of sustained hypotension refractory to crystalloid and vasoconstrictor infusions. Prolonged pharmacologic support and intermittent sessions of hemofiltration induced stabilization and recovery. The results of an extensive diagnostic workup to elucidate the cause were unfruitful. The recurrent and paroxysmal nature of the clinical presentation along with its incidence after the patient left the protected setting of the hospital led the diagnostic approach to search for a possible external factor, which was shown to be, after toxicological investigation, unintentional amlodipine intoxication.",
"affiliations": "Department of Cardiology, Laiko General Hospital, Athens, Greece. Electronic address: chriskapel@hotmail.com.;First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.;First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.;First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.;First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.;Department of Forensic Medicine and Toxicology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.;First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.",
"authors": "Kapelios|Chris J|CJ|;Karamanakos|George|G|;Liatis|Stavros|S|;Sarafadi|Magda|M|;Polizois|Marios|M|;Papoutsis|Ioannis|I|;Kokkinos|Alexander D|AD|",
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"title": "Recurrent episodes of life-threatening vasodilatory shock following unintentional intoxication with amlodipine.",
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{
"abstract": "Pyoderma gangrenosum (PG) is an inflammatory, ulcerative condition that is characterized by painful ulcers that commonly present on the lower extremities. Up to half of PG cases are associated with underlying systemic disease, including inflammatory bowel disease, various autoimmune conditions, and malignancy. Another well-known association is the manifestation of PG with recreational cocaine use, especially cocaine contaminated with the adulterant agent levamisole. Once utilized for its immunomodulatory capabilities, levamisole was withdrawn from the market in 2002. It has since been repurposed to potentiate the amphetamine-like effects and duration of cocaine and has reduced preparation cost. We present a 52-year-old woman with chronic maxillary sinusitis and cocaine use disorder presenting with a two-week history of painful ulcers on bilateral lower extremities, each with a purulent base and undermined, violaceous borders. Urine toxicology was positive for cocaine and serologic studies were positive for cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) and lupus anticoagulant. Underlying conditions, especially that of granulomatosis with polyangiitis, were considered and ultimately ruled out. The patient's lesions exhibited a marked response with a short course of oral corticosteroids, typical of PG associated with levamisole. This case highlights the crucial role that drug abstinence plays in the prevention of recurrence.",
"affiliations": "Department of Dermatology, University of Rochester Medical Center, Rochester, NY. molly_plovanich@urmc.rochester.edu.",
"authors": "Gadarowski|Mary Beth|MB|;Agnihothri|Ritesh|R|;Scott|Glynis|G|;Plovanich|Molly|M|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D019268:Antibodies, Antineutrophil Cytoplasmic; D007978:Levamisole; C011175:betamethasone-17,21-dipropionate; D001623:Betamethasone; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "27(1)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D019268:Antibodies, Antineutrophil Cytoplasmic; D001623:Betamethasone; D002908:Chronic Disease; D019970:Cocaine-Related Disorders; D003937:Diagnosis, Differential; D004340:Drug Contamination; D005260:Female; D006801:Humans; D007978:Levamisole; D015523:Maxillary Sinusitis; D008875:Middle Aged; D011241:Prednisone; D017511:Pyoderma Gangrenosum",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33560793",
"pubdate": "2021-01-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pyoderma gangrenosum associated with levamisole-adulterated cocaine in a c-ANCA positive patient.",
"title_normalized": "pyoderma gangrenosum associated with levamisole adulterated cocaine in a c anca positive patient"
} | [
{
"companynumb": "US-ORGANON-O2112USA001990",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BETAMETHASONE DIPROPIONATE"
},
"drugadditiona... |
{
"abstract": "Certolizumab is a monoclonal antibody against tumour necrosis factor-alpha (TNF-α) commonly used in rheumatologic conditions such as rheumatoid arthritis. Skin rashes are an uncommon side effect with few cases of lichenoid drug eruption reported in the literature. We describe a patient with rheumatoid arthritis who presented 6 weeks after initiating certolizumab pegol. Physical examination showed pink-to-violaceous papules on her upper and lower extremities. Biopsy confirmed a lichenoid drug eruption. The medication was discontinued and she was treated with topical steroids and a calcineurin inhibitor, with resolution of her lesions. Clinicians should be cognizant of such adverse reactions to TNF-α inhibitors and keep drug-induced lichenoid eruptions on the differential. Lichenoid eruptions induced by certolizumab pegol may affect the skin and/or mucous membranes. While most cases occur within weeks to months of starting therapy, eruptions may occur years after treatment initiation, underscoring the importance of a thorough review of medications.",
"affiliations": "College of Medicine, University of Central Florida, Orlando, Florida, USA.;Dermatology, New York Medical College, Valhalla, New York, USA.;Dermatology, University of Central Florida, Orlando, Florida, USA nsderm@gmail.com.",
"authors": "Kunadia|Anuj|A|;Shulman|Kenneth|K|;Sami|Naveed|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-245875",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(12)",
"journal": "BMJ case reports",
"keywords": "dermatology; drug interactions; immunology; rheumatoid arthritis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34887290",
"pubdate": "2021-12-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Certolizumab-induced lichenoid eruption in a patient with rheumatoid arthritis.",
"title_normalized": "certolizumab induced lichenoid eruption in a patient with rheumatoid arthritis"
} | [
{
"companynumb": "US-UCBSA-2021059811",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CERTOLIZUMAB PEGOL"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nThere are an increasing number of reports of pregnancy following liver transplantation, but many questions remain regarding preconception counseling and management of the pregnancy. The aim of this study was to report pregnancy outcomes in women who had undergone liver transplants and to gain insight into these issues.\n\n\nMETHODS\nWe conducted a retrospective review of liver transplant recipients who had received prenatal care at Kyoto University Hospital between January 2001 and December 2015.\n\n\nRESULTS\nTwenty-six consecutive pregnancies in 17 liver transplant recipients were identified during the period. The most common indication for liver transplantation was biliary atresia (65%). The median age at transplantation was 19 years (range, 2-38). The median age at conception was 28 years (range, 20-41) with a median time between transplantation and conception of 8 years (range, 0-22). A tacrolimus-based immunosuppressive regimen (n = 21, 81%) was the most common at the time of conception. There were 13 live births (50%), four spontaneous miscarriages (15%), and nine induced abortions (35%). Median gestational age at delivery was 38 weeks (range, 32-42), and the median birthweight was 2858 g (range, 1815-3864 g). Pregnancy and maternal complications included preterm deliveries (23%), intrauterine growth restriction (23%), pre-eclampsia (8%), cesarean delivery (23%), bacterial infection (15%), and biopsy-proven acute cellular rejection (15%). Two infants had congenital anomalies (tetralogy of Fallot and hydronephrosis).\n\n\nCONCLUSIONS\nPregnancy after liver transplantation can achieve relatively favorable outcomes. Obstetricians should be involved in the contraceptive and fertility counseling of female transplant recipients to prevent unintended pregnancies.",
"affiliations": "Department of Gynaecology and Obstetrics, Kyoto University, Kyoto, Japan.;Department of Gynaecology and Obstetrics, Kyoto University, Kyoto, Japan. kondo@kuhp.kyoto-u.ac.jp.;Department of Gynaecology and Obstetrics, Kyoto University, Kyoto, Japan.;Department of Gynaecology and Obstetrics, Kyoto University, Kyoto, Japan.;Department of Gynaecology and Obstetrics, Kyoto University, Kyoto, Japan.;Department of Gynaecology and Obstetrics, Kyoto University, Kyoto, Japan.",
"authors": "Kanzaki|Yu|Y|;Kondoh|Eiji|E|;Kawasaki|Kaoru|K|;Mogami|Haruta|H|;Chigusa|Yoshitsugu|Y|;Konishi|Ikuo|I|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.13096",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "42(11)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "liver transplantation; preconception counseling; pregnancy; rejection; unintended pregnancy",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000028:Abortion, Induced; D000022:Abortion, Spontaneous; D000328:Adult; D001724:Birth Weight; D005260:Female; D005865:Gestational Age; D006801:Humans; D007564:Japan; D016031:Liver Transplantation; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "1476-1482",
"pmc": null,
"pmid": "27557727",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pregnancy outcomes in liver transplant recipients: A 15-year single-center experience.",
"title_normalized": "pregnancy outcomes in liver transplant recipients a 15 year single center experience"
} | [
{
"companynumb": "JP-MYLANLABS-2017M1000817",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "Cyanide toxicity is common after significant smoke inhalation. Two cases are presented that provide framework for the discussion of epidemiology, pathogenesis, presenting signs and symptoms, and treatment options of inhalational cyanide poisoning. An evidence-based algorithm is proposed that utilizes point-of-care testing to help physicians identify patients who benefit most from antidotal therapy.",
"affiliations": "University of Massachusetts, 55 Lake Ave North, Worcester, MA, 01605, USA. eike.blohm@umassmemorial.org.;Department of Emergency Medicine, University of Massachusetts, 55 Lake Ave North, Worcester, MA, 01605, USA.;Department of Emergency Medicine and Medical Toxicology, University of Colorado School of Medicine, Aurora, CO, USA.",
"authors": "Hamad|Eike|E|;Babu|Kavita|K|;Bebarta|Vikhyat S|VS|",
"chemical_list": "D000931:Antidotes; D015415:Biomarkers; D006856:Hydrogen Cyanide; D006879:Hydroxocobalamin",
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-016-0533-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9039",
"issue": "12(2)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": "Cyanide; Fire; Hydroxocobalamin; Smoke inhalation; Sodium thiosulfate",
"medline_ta": "J Med Toxicol",
"mesh_terms": "D000046:Academic Medical Centers; D000465:Algorithms; D000931:Antidotes; D015415:Biomarkers; D003131:Combined Modality Therapy; D003663:Decision Trees; D055416:Evidence-Based Emergency Medicine; D005257:Fellowships and Scholarships; D005260:Female; D005739:Gas Poisoning; D006801:Humans; D006856:Hydrogen Cyanide; D006879:Hydroxocobalamin; D008297:Male; D008404:Massachusetts; D000067716:Point-of-Care Testing; D015208:Smoke Inhalation Injury; D014116:Toxicology; D000078329:Workforce",
"nlm_unique_id": "101284598",
"other_id": null,
"pages": "192-8",
"pmc": null,
"pmid": "26831054",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "16771012;2868959;23689094;22828651;7662055;16395080;10589625;12352039;22882141;19401990;3726889;20185266;3147294;16860672;9141943;2746547;9470088;8555853;17481777;18282534;1944484;1853342;22336184;17098327;8363114;12856122;16175068;12854870;23917894;19944487;15976683;561541;16990192;15362233;17439922;23537683;15533025;11350258;170077;1442864",
"title": "Case Files of the University of Massachusetts Toxicology Fellowship: Does This Smoke Inhalation Victim Require Treatment with Cyanide Antidote?",
"title_normalized": "case files of the university of massachusetts toxicology fellowship does this smoke inhalation victim require treatment with cyanide antidote"
} | [
{
"companynumb": "US-SERB S.A.S.-1054955",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HYDROXOCOBALAMIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo present two cases of acute endophthalmitis after intravitreal dexamethasone implant injection and discuss the management of intravitreal implant-associated endophthalmitis.\n\n\nMETHODS\nTwo patients, who underwent intravitreal dexamethasone implant injection for macular edema secondary to diabetic retinopathy in one and branch retinal vein occlusion in the other, were admitted with decreased vision, pain, and redness in their treated eyes, 3 days and 5 days after the injection, respectively. The clinical findings of both patients were consistent with acute endophthalmitis.\n\n\nRESULTS\nAfter obtaining aqueous and vitreous samples, the patients were treated with intravitreal antibiotic injection and topical fortified antibiotics. Both patients revealed favorable clinical response and functional vision was recovered.\n\n\nCONCLUSIONS\nIntravitreal dexamethasone implant-associated endophthalmitis is an uncommon and a challenging situation. Intravitreal antibiotics may lead to favorable visual outcomes without the need for a pars plana vitrectomy and implant removal in selected cases.",
"affiliations": "Department of Ophthalmology, School of Medicine, Cukurova University, Adana, Turkey.",
"authors": "Esen|Ebru|E|;Sizmaz|Selcuk|S|;Demircan|Nihal|N|",
"chemical_list": "D004343:Drug Implants; D005938:Glucocorticoids; D003907:Dexamethasone",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000213",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "10(2)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D003907:Dexamethasone; D004343:Drug Implants; D009877:Endophthalmitis; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D058449:Intravitreal Injections; D008269:Macular Edema; D008875:Middle Aged; D012160:Retina; D014792:Visual Acuity",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "154-6",
"pmc": null,
"pmid": "26426482",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "TWO CASES OF ACUTE ENDOPHTHALMITIS AFTER INTRAVITREAL DEXAMETHASONE IMPLANT INJECTION.",
"title_normalized": "two cases of acute endophthalmitis after intravitreal dexamethasone implant injection"
} | [
{
"companynumb": "TR-BAUSCH-BL-2016-009779",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo evaluate whether the selection of first-line chemotherapy based on ERCC1 and RRM1 mRNA expression levels would improve clinical outcomes in advanced non-small cell lung cancer (NSCLC) patients.\n\n\nMETHODS\nEligible patients were randomly assigned 1:1 to the experimental and control arms; the experimental arm received gemcitabine/carboplatin (GC) if ERCC1 and RRM1 expression was low, gemcitabine/vinorelbine (GV) if ERCC1 was high and RRM1 was low, docetaxel/carboplatin (DC) if ERCC1 was low and RRM1 was high, and docetaxel/vinorelbine (DV) if both were high. In the control arm, patients received DC.\n\n\nRESULTS\nThis study was prematurely terminated after the futility analysis of 43 progression-free survival (PFS) events. A total of 55 patients (n = 26 in the experimental arm, n = 29 in the control arm) were evaluable for efficacy and toxicity. Nineteen (73.1%) patients were assigned to receive GC, 0 (0.0%) to GV, 4 (15.4%) to DC, and 3 (11.5%) to DV in the experimental arm. The overall response rates were 42.3 and 48.3% in the experimental and control arms, respectively, which were not statistically different (P = 0.657). The median PFS was 5.2 months in the experimental arm and 5.4 months in the control arm (P = 0.286). The median overall survival was 17.4 months in the experimental arm and 12.6 months in the control arm (P = 0.638). The occurrence of grade 3 or higher neutropenia (69.2 vs. 93.1%, P = 0.035) and febrile neutropenia (3.8 vs. 24.1%, P = 0.054) was more common in the control arm.\n\n\nCONCLUSIONS\nERCC1 and RRM1 mRNA expression-based chemotherapy did not improve clinical outcomes in advanced NSCLC (NCT01648517).",
"affiliations": "Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-Gu, Seoul, 120-752, Korea.;Department of Biostatistics and Medical Informatics, Yonsei University College of Medicine, Seoul, Korea.;Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-Gu, Seoul, 120-752, Korea.;Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-Gu, Seoul, 120-752, Korea.;Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-Gu, Seoul, 120-752, Korea.;Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-Gu, Seoul, 120-752, Korea.;Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.;Division of Medical Oncology and Hematology, Department of Internal Medicine, School of Medicine, Kyunghee University, Seoul, Korea.;Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-Gu, Seoul, 120-752, Korea.;Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-Gu, Seoul, 120-752, Korea. nobelg@yuhs.ac.;Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-Gu, Seoul, 120-752, Korea. cbc1971@yuhs.ac.",
"authors": "Heo|Su Jin|SJ|;Jung|Inkyung|I|;Lee|Choong-Kun|CK|;Kim|Jee Hung|JH|;Lim|Sun Min|SM|;Moon|Yong Wha|YW|;Shim|Hyo Sup|HS|;Jeong|Jaeheon|J|;Kim|Joo-Hang|JH|;Kim|Hye Ryun|HR|;Cho|Byoung Chul|BC|",
"chemical_list": "D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D043823:Taxoids; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; D000077143:Docetaxel; D014747:Vinblastine; C056507:gemcitabine; D016190:Carboplatin; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; C071447:ERCC1 protein, human; D004720:Endonucleases; D000077235:Vinorelbine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-016-2968-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "77(3)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Chemotherapy; ERCC1; Non-small cell lung cancer; RRM1; mRNA expression",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D004268:DNA-Binding Proteins; D003841:Deoxycytidine; D018572:Disease-Free Survival; D000077143:Docetaxel; D004720:Endonucleases; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger; D012262:Ribonucleoside Diphosphate Reductase; D015996:Survival Rate; D043823:Taxoids; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins; D014747:Vinblastine; D000077235:Vinorelbine; D055815:Young Adult",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "539-48",
"pmc": null,
"pmid": "26811178",
"pubdate": "2016-03",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A randomized phase II trial of ERCC1 and RRM1 mRNA expression-based chemotherapy versus docetaxel/carboplatin in advanced non-small cell lung cancer.",
"title_normalized": "a randomized phase ii trial of ercc1 and rrm1 mrna expression based chemotherapy versus docetaxel carboplatin in advanced non small cell lung cancer"
} | [
{
"companynumb": "KR-CIPLA LTD.-2016KR00939",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe cutaneous adverse reaction involving various internal organs. Flare-ups after recovery from the initial presentation of DRESS are caused by relapse of drug-induced T-cell-mediated reactions. However, the specific underlying mechanism is unclear. Here, we report a case of a 60-year-old man with allopurinol-induced DRESS who suffered recurrent episodes of generalized rash with eosinophilia, which mimicked immune reconstitution inflammatory syndrome. Analysis of immunological profiles revealed that the percentages of T lymphocytes and regulatory T cells in the patient with DRESS were higher than those in healthy controls. In addition, there was a notable change in the subtype of monocytes in the patient with DRESS; the percentage of nonclassical monocytes increased, whereas that of classical monocytes decreased. Upon viral infection, nonclassical monocytes exhibited strong pro-inflammatory properties that skewed the immune response toward a Th2 profile, which was associated with persistent flare-ups of DRESS. Taken together, the results increase our understanding of the pathogenesis of DRESS as they suggest that expansion of nonclassical monocytes and Th2 cells drives disease pathogenesis.",
"affiliations": "Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea.;Laboratory of Mucosal Immunology in Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.;Laboratory of Mucosal Immunology in Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.;Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea.;Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea.;Laboratory of Mucosal Immunology in Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.",
"authors": "Kang|Sung-Yoon|SY|https://orcid.org/0000-0001-5505-3028;Kim|Jihyun|J|https://orcid.org/0000-0003-1222-0345;Ham|Jongho|J|https://orcid.org/0000-0001-9423-2053;Cho|Sang-Heon|SH|https://orcid.org/0000-0002-7644-6469;Kang|Hye-Ryun|HR|https://orcid.org/0000-0002-2317-4201;Kim|Hye Young|HY|https://orcid.org/0000-0001-5978-512X",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.5415/apallergy.2020.10.e2",
"fulltext": "\n==== Front\nAsia Pac AllergyAsia Pac AllergyAPAAsia Pacific Allergy2233-82762233-8268Asia Pacific Association of Allergy, Asthma and Clinical Immunology 10.5415/apallergy.2020.10.e2Case ReportAltered T cell and monocyte subsets in prolonged immune reconstitution inflammatory syndrome related with DRESS (drug reaction with eosinophilia and systemic symptoms) https://orcid.org/0000-0001-5505-3028Kang Sung-Yoon 1†https://orcid.org/0000-0003-1222-0345Kim Jihyun 2†https://orcid.org/0000-0001-9423-2053Ham Jongho 2https://orcid.org/0000-0002-7644-6469Cho Sang-Heon 34https://orcid.org/0000-0002-2317-4201Kang Hye-Ryun 34https://orcid.org/0000-0001-5978-512XKim Hye Young 231 Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea.2 Laboratory of Mucosal Immunology in Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.3 Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea.4 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.Correspondence to Hye-Ryun Kang. Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea. Tel: +82-2-2072 0820, Fax: +82-2-742 3291, helenmed@snu.ac.krCorrespondence to Hye Young Kim. Laboratory of mucosal immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea. Tel: +82-2-740 8970, Fax: +82-2-743 5530, hykim11@snu.ac.kr†Sung-Yoon Kang and Jihyun Kim contributed equally to this article.\n\n1 2020 17 1 2020 10 1 e215 10 2019 14 1 2020 Copyright © 2020. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.2020Asia Pacific Association of Allergy, Asthma and Clinical ImmunologyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://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.Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe cutaneous adverse reaction involving various internal organs. Flare-ups after recovery from the initial presentation of DRESS are caused by relapse of drug-induced T-cell-mediated reactions. However, the specific underlying mechanism is unclear. Here, we report a case of a 60-year-old man with allopurinol-induced DRESS who suffered recurrent episodes of generalized rash with eosinophilia, which mimicked immune reconstitution inflammatory syndrome. Analysis of immunological profiles revealed that the percentages of T lymphocytes and regulatory T cells in the patient with DRESS were higher than those in healthy controls. In addition, there was a notable change in the subtype of monocytes in the patient with DRESS; the percentage of nonclassical monocytes increased, whereas that of classical monocytes decreased. Upon viral infection, nonclassical monocytes exhibited strong pro-inflammatory properties that skewed the immune response toward a Th2 profile, which was associated with persistent flare-ups of DRESS. Taken together, the results increase our understanding of the pathogenesis of DRESS as they suggest that expansion of nonclassical monocytes and Th2 cells drives disease pathogenesis.\n\nDRESS syndromeAllopurinolHerpesvirusesImmune reconstitutionMinistry of Health and Welfarehttps://doi.org/10.13039/501100003625HI15C3083HI15C1736Seoul National University Hospitalhttps://doi.org/10.13039/50110000433204-2014-3000\n==== Body\nINTRODUCTION\nDrug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a serious cutaneous adverse event associated with constitutional symptoms [1]. Flare-up reactions can occur as a continuum from initial drug-related immune reactions. However, they can also present as a transformed T-cell-mediated hypersensitivity reaction after a patient recover from the initial manifestations. The mechanisms underlying flare-up reactions are difficult to understand because they are multifactorial and involve complex immunological components, particularly reactivation of latent viruses [23]. Currently, flare-up of DRESS is considered to be an immune reconstitution inflammatory syndrome (IRIS) associated with either discontinuation or a reduction in the dose of immunosuppressive agents [3].\n\nCASE REPORT\nA 60-year-old man with chronic kidney disease was referred to an allergy clinic for a second opinion regarding waxing/waning of the condition accompanied by generalized erythroderma for 6 months. Ten months prior to referral, he was prescribed allopurinol to treat hyperuricemia. After 3 months of treatment, he suffered a generalized maculopapular skin eruption, high fever, eosinophilia, and elevated liver enzymes. Analysis of human leukocyte antigens revealed that he harbored the HLA-B*58:01 allele, a risk marker for allopurinol-induced DRESS [4]. Allopurinol was withdrawn immediately and replaced with a systemic corticosteroid equivalent to prednisolone (1 mg/kg), along with other supportive measures. After administration of systemic corticosteroid, the rash improved gradually, and liver function and eosinophil counts returned to normal. However, he was admitted to a hospital several times due to repeated episodes of generalized eruption, which eventually manifested as erythroderma accompanied by fever, chill, facial swelling, pedal edema, and inguinal lymphadenopathy. Several attempts at steroid reduction resulted in generalized eruption followed by widespread skin exfoliation; these symptoms improved when the steroid dose was increased. Laboratory findings revealed a white blood cell count of 6.67×103/mm3 (eosinophils, 14%), a C-reactive protein level of 1.97 mg/dL (normal range, 0–0.5 mg/dL), serum creatinine value of 2.07 mg/dL (normal range, 0.5–1.2 mg/dL), and aspartate transaminase/alanine transaminase level of 15/7 IU/L. Other laboratory indexes and electrocardiogram were within normal range. Peripheral blood analysis revealed a very high load of cytomegalovirus (CMV; 10,375 copies/mL) and Epstein-Barr virus (EBV; 132,988 copies/mL). Human immunodeficiency virus (HIV) and human herpesvirus 6 (HHV-6) were not detected, but he was positive for HHV-8 (Table 1). A computed tomography scan revealed enlargement of multiple lymph nodes in the axillary, mediastinal, para-aortic, retrocaval, and aortocaval areas. A skin biopsy from the dorsum of a foot showing erythroderma revealed acanthosis with superficial perivascular lymphohistiocytic and mild eosinophilic infiltration; the tissue stained positive for HHV-8. Analysis of inguinal lymph nodes revealed an atypical vascular proliferative lesion that was positive for EBV and HHV-8; these findings are consistent with Kaposi sarcoma and ruled out the possibility of lymphoma.\n\nTable 1 Laboratory test of the patient with DRESS syndrome\nParameter\tValue\t\nHematological parameters\t\t\n\tWBC (×103/mm3)\t6.67\t\n\tEosinophils (%)\t14\t\nBiochemical parameters\t\t\n\tCRP (mg/L)\t1.97\t\n\tSerum creatinine (mg/dL)\t2.07\t\nViral infection\t\t\n\tCMV (copies/mL)\t10,375\t\n\tEBV (copies/mL)\t132,988\t\n\tHIV\t(−)\t\n\tHHV-6\t(−)\t\n\tHHV-8\t(+)\t\nDRESS, drug reaction with eosinophilia and systemic symptoms; WBC, white blood cell; CRP, C-reactive protein; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; HHV, human herpesvirus.\n\nPeripheral blood mononuclear cells (PBMCs) were isolated from the patient and from three age- and sex-matched controls. Flow cytometry analysis showed that the percentage of CD3+ T cells in the patient was higher (Fig. 1A, B) than that in controls, with a marked increase in the percentages of T cells positive for GATA3 or FOXP3, which are transcription factors representative of Th2 and regulatory T (Treg) cells, respectively. By contrast, the percentage of T-bet-positive cells, which is representative of Th1 cells, was lower in the patient than in controls (Fig. 1C, D). In parallel with this, T cells isolated from the patient showed increased production of type 2 cytokines such as interleukin (IL)-5 and IL-13, but reduced production of interferon (IFN)-γ, upon PMA/ionomycin stimulation in vitro (Fig 1E, F). Simultaneously, IL-13+ T cells from the patient showed increased production of IL-17. In vitro stimulation studies confirmed the role of the viruses detected previously. When PBMCs were stimulated with peptides derived from CMV or EBV, they secreted more IL-4 and IL-13 into the culture supernatant; however, the amount of IFN-γ remained unchanged (Fig. 1G). Next, we examined the distribution of DCs and monocytes that activate T cells by presenting antigen. Dendritic cells (CD11c+HLA-DR+) and classical monocytes (CD11b+CD14+CD16-) within the PBMC population isolated from the patient with DRESS were markedly depleted (Fig. 2A, B). By contrast, the population of nonclassical monocytes (CD11b+CD14-CD16+) expressing costimulatory molecules (CD40, CD86) was elevated (Fig. 2A-C).\n\nFig. 1 Flow cytometry analysis of lymphocyte subpopulations within the peripheral blood mononuclear cell (PBMC) population. (A) Flow cytometry analysis of B cell (CD45+CD3-CD19+) and T cell (CD45+CD3+CD19-) subsets within the PBMC population of normal controls (n=3) and the patient. Values in the diagrams indicate the percentage of the gated population. (B) Comparison of B cell, T cell, CD4+ T cell, and CD8+ T-cell populations within PBMCs from normal controls and the patient. (C) Flow cytometry analysis of transcription factor expression by T cells. (D) Expression of T-bet, GATA3, RORγt, and Foxp3 by T cells. (E) Cytokines produced by T cells, as analyzed by intracellular staining and flow cytometry. (F) Comparison of cytokine production by the cells in (E). (G) Comparison of cytokine levels in medium from PBMCs (from the controls and the patient) cultured with CMV or EBV peptides or allopurinol. Data are expressed as the mean±standard deviation. DRESS, drug reaction with eosinophilia and systemic symptoms; IFN, interferon; IL, interleukin; CMV, cytomegalovirus; EBV, Epstein-Barr virus.\nFig. 2 Comparison of mononuclear phagocyte populations within PBMCs. (A) Distribution of dendritic cells (CD45+CD15-CD11c+HLA-DR+) and monocytes (CD45+CD15-CD11b+) and their subsets within the PBMC population from normal controls (n=3) and the patient. Values in the diagrams indicate the percentage of the gated population. (B) Comparison of dendritic cell and monocyte subsets, including classical (CD45+CD15-CD11b+CD14+CD16-) monocytes, intermediate (CD45+CD15-CD11b+CD14+CD16+) monocytes, and nonclassical (CD45+CD15-CD11b+CD14-CD16+) monocytes, within PBMCs. (C) Mean fluorescence intensity of CD40 and CD86 expressed by dendritic cells and each subset of monocytes. Data are expressed as the mean±standard deviation. PBMC, peripheral blood mononuclear cell; DRESS, drug reaction with eosinophilia and systemic symptoms.\nDISCUSSION\nIRIS following withdrawal of immunosuppressive medications has been reported in both non-HIV patients and HIV-infected patients [5]. The clinical correlation between high viral load and severity of constitutional symptoms suggests that viral reactivation could be responsible for aggravating IRIS symptoms. It is proposed that drug metabolite-induced hypogammaglobulinemia and B-cell depletion in DRESS reactivate latent viruses such as HHV-6, EBV, and CMV [6]. Our result demonstrated that IL-13+ T cells may be generated in response to reactivation of EBV and CMV following a reduction in B-cell counts and immunoglobulin production (data not shown).\n\nDRESS syndrome is induced by drug-specific T cells and corresponds to a type IV hypersensitivity with eosinophilic activation; in addition, Th2-type immune responses may be involved [7]. Here, we found that eosinophilia occurred in the skin of the patient with DRESS syndrome, and that the percentages of IL-5- and IL-13-producing T cells within the PBMC population were increased, as reported previously [8]. Moreover, there was an increase in the percentage of IL-17-expressing IL-13+ T cells within the PBMC population from the patient with DRESS, a phenotype observed in cases with severe allergic responses [9]. However, it is not clear how a small compound such as a drug activates T cells and promotes cytokine production. There are several hypotheses about the mechanism underlying T-cell activation in DRESS. Pichler [10] suggested that drugs or their metabolites act as a haptens that bind to autologous proteins and induce cellular or humoral immune responses. Shiohara et al. [11] suggested that pre-existing viral-specific T cells might cross-react with specific drugs. In addition, Criado et al. [12] reported that the viral reactivation observed in IRIS might provide danger signals to nonspecific T cells, which then induce oligoclonal expansion of drug-specific and viral-specific T cells. Treg cells are likely to play an important role in IRIS in non-HIV patients, but their role in DRESS is not completely understood [35]. During the acute phase of DRESS, Treg cells expand and possibly inhibit viral-specific immune responses, leading to viral reactivation. During the resolution phase, Treg cells lose their normal function, which may be linked to hypersensitivity to drugs and flare-up reactions [13]. In line with previous reports, our data show an increased Treg population in the DRESS patient who developed a prolonged course of IRIS. However, it is unclear whether these Treg cells were functionally intact and responsible for suppressing antiviral immune responses in this patient. Therefore, additional experiments are needed to validate the function of Treg cells.\n\nWe found a clear distinction between mononuclear cells (monocytes and dendritic cells) that play an important role in tissue homeostasis and those that elicit an immune response to invading pathogens. Under normal conditions, viral infection induces rapid differentiation of monocytes into dendritic cells [14]. However, dendritic cells were depleted from the patient with DRESS. It is noteworthy that the number of nonclassical monocytes showing high expression of costimulatory molecules was increased, while that of classical monocytes was depleted severely. Monocytes are a highly plastic and heterogeneous population of cells showing different functional phenotypes in response to environmental change. Most human monocytes (~85%–90%) are classical monocytes; the remaining ~10%–15% are further subdivided into intermediate and nonclassical subsets [15]. Classical monocytes traffic to sites of inflammation and play a major role in phagocytosis, as demonstrated by high peroxidase activity, high levels of IL-10, and low levels of tumor necrosis factor (TNF)-α in response to lipopolysaccharide (LPS) stimulation [16]. Intermediate monocytes are a transitional population that bridges the classical and nonclassical monocyte subsets and exhibits pro-inflammatory functions, including production of TNF-α and IL-1β upon stimulation by LPS [16]. Intermediate monocytes not only display both phagocytic and inflammatory functions, but also play a role in the treatment of patients with rheumatoid arthritis [1718]. Nonclassical monocytes show the strongest pro-inflammatory responses to TLR stimulation [19]. Also, CD14-CD16high monocytes in peripheral blood of DRESS patients act as precursors that show increased expression of CCR4, a skin-homing chemokine receptor; indeed, these cells migrate to the skin, present viral particles to CD4+ T cells, and induce drug allergy responses [20]. Previous reports of patients with sepsis and systemic lupus erythematosus demonstrated that nonclassical monocytes also displayed properties characteristic of antigen presenting cells, and expressed inflammatory phenotype under higher levels of pro-inflammatory cytokines and lower levels of anti-inflammatory IL-10 [18]. In the current case, virus-induced TLR7/9 signaling may contribute to activation of human nonclassical monocytes and to persistence of inflammatory responses through high expression of costimulating molecules such as CD40 and CD86, which activate T cells. However, further studies are warranted to elucidate whether these nonclassical monocytes play a role in the persistent virus-associated flare-up reactions in IRIS.\n\nTaken together, the data presented herein suggest that skewed subsets of T cells, B cells, and monocytes are responsible for strengthened Th2 inflammatory responses and vulnerability to viral reactivation in a DRESS patient who exhibited prolonged flare-ups and persistent viral reactivation despite long-term withdrawal of the culprit drug. Therefore, patients with prolonged flare-up of DRESS should be evaluated carefully with respect to associated viral reactivation and related alterations in lymphocyte and monocyte populations. Moreover, we look forward to new advances in understanding the interplay between lymphocytes and monocyte populations, and to identifying potential therapeutic targets that facilitate control of prolonged flare-up reactions in DRESS.\n\nACKNOWLEDGEMENTS\nThis study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare Affairs, Republic of Korea (HI15C3083 and HI15C1736) and from the SNUH Research Fund (04-2014-3000).\n\nConflict of Interest: The authors have no financial conflicts of interest.\n==== Refs\n1 Bocquet H Bagot M Roujeau JC Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS) Semin Cutan Med Surg 1996 15 250 257 9069593 \n2 Pichler WJ Daubner B Kawabata T Drug hypersensitivity: flare-up reactions, cross-reactivity and multiple drug hypersensitivity J Dermatol 2011 38 216 221 21342222 \n3 Sueki H Mizukawa Y Aoyama Y Immune reconstitution inflammatory syndrome in non-HIV immunosuppressed patients J Dermatol 2018 45 3 9 28944502 \n4 Kang HR Jee YK Kim YS Lee CH Jung JW Kim SH Park HW Chang YS Jang IJ Cho SH Min KU Kim SH Lee KW Adverse Drug Reaction Research Group in Korea Positive and negative associations of HLA class I alleles with allopurinol-induced SCARs in Koreans Pharmacogenet Genomics 2011 21 303 307 21301380 \n5 Shiohara T Kano Y Hirahara K Aoyama Y Prediction and management of drug reaction with eosinophilia and systemic symptoms (DRESS) Expert Opin Drug Metab Toxicol 2017 13 701 704 28633581 \n6 Kano Y Inaoka M Shiohara T Association between anticonvulsant hypersensitivity syndrome and human herpesvirus 6 reactivation and hypogammaglobulinemia Arch Dermatol 2004 140 183 188 14967790 \n7 Ogawa K Morito H Hasegawa A Daikoku N Miyagawa F Okazaki A Fukumoto T Kobayashi N Kasai T Watanabe H Sueki H Iijima M Tohyama M Hashimoto K Asada H Identification of thymus and activation-regulated chemokine (TARC/CCL17) as a potential marker for early indication of disease and prediction of disease activity in drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS) J Dermatol Sci 2013 69 38 43 23141052 \n8 Yawalkar N Shrikhande M Hari Y Nievergelt H Braathen LR Pichler WJ Evidence for a role for IL-5 and eotaxin in activating and recruiting eosinophils in drug-induced cutaneous eruptions J Allergy Clin Immunol 2000 106 1171 1176 11112902 \n9 Irvin C Zafar I Good J Rollins D Christianson C Gorska MM Martin RJ Alam R Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma J Allergy Clin Immunol 2014 134 1175 86.e7 25042748 \n10 Pichler WJ Immune pathomechanism and classification of drug hypersensitivity Allergy 2019 74 1457 1471 30843233 \n11 Shiohara T Kano Y Takahashi R Ishida T Mizukawa Y Drug-induced hypersensitivity syndrome: recent advances in the diagnosis, pathogenesis and management Chem Immunol Allergy 2012 97 122 138 22613858 \n12 Criado PR Criado RF Avancini JM Santi CG Drug reaction with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS): a review of current concepts An Bras Dermatol 2012 87 435 449 22714760 \n13 Takahashi R Kano Y Yamazaki Y Kimishima M Mizukawa Y Shiohara T Defective regulatory T cells in patients with severe drug eruptions: timing of the dysfunction is associated with the pathological phenotype and outcome J Immunol 2009 182 8071 8079 19494333 \n14 Hou W Gibbs JS Lu X Brooke CB Roy D Modlin RL Bennink JR Yewdell JW Viral infection triggers rapid differentiation of human blood monocytes into dendritic cells Blood 2012 119 3128 3131 22310910 \n15 Wong KL Tai JJ Wong WC Han H Sem X Yeap WH Kourilsky P Wong SC Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets Blood 2011 118 e16 31 21653326 \n16 Yang J Zhang L Yu C Yang XF Wang H Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases Biomark Res 2014 2 1 24398220 \n17 Wijngaarden S van Roon JA Bijlsma JW van de Winkel JG Lafeber FP Fcgamma receptor expression levels on monocytes are elevated in rheumatoid arthritis patients with high erythrocyte sedimentation rate who do not use anti-rheumatic drugs Rheumatology (Oxford) 2003 42 681 688 12709546 \n18 Mukherjee R Kanti Barman P Kumar Thatoi P Tripathy R Kumar Das B Ravindran B Non-classical monocytes display inflammatory features: validation in sepsis and systemic lupus erythematous Sci Rep 2015 5 13886 26358827 \n19 Cros J Cagnard N Woollard K Patey N Zhang SY Senechal B Puel A Biswas SK Moshous D Picard C Jais JP D'Cruz D Casanova JL Trouillet C Geissmann F Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors Immunity 2010 33 375 386 20832340 \n20 Hashizume H Fujiyama T Kanebayashi J Kito Y Hata M Yagi H Skin recruitment of monomyeloid precursors involves human herpesvirus-6 reactivation in drug allergy Allergy 2013 68 681 689 23573902\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2233-8276",
"issue": "10(1)",
"journal": "Asia Pacific allergy",
"keywords": "Allopurinol; DRESS syndrome; Herpesviruses; Immune reconstitution",
"medline_ta": "Asia Pac Allergy",
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"pubdate": "2020-01",
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"title": "Altered T cell and monocyte subsets in prolonged immune reconstitution inflammatory syndrome related with DRESS (drug reaction with eosinophilia and systemic symptoms).",
"title_normalized": "altered t cell and monocyte subsets in prolonged immune reconstitution inflammatory syndrome related with dress drug reaction with eosinophilia and systemic symptoms"
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"abstract": "BACKGROUND\nTo compare the treatment outcomes of different treatment modalities for International Federation of Gynecology and Obstetrics (FIGO) stage IB2 cervical cancer.\n\n\nMETHODS\nFrom January 2002 to July 2016, 91 patients with FIGO stage IB2 squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma of the cervix were enrolled. All of them received one of the following treatment modalities, including intensity-modulated radiotherapy (IMRT) with concurrent platinum-based chemotherapy (CCRT group, n = 27), radical surgery with or without adjuvant treatment (RH group, n = 25), or neoadjuvant chemotherapy followed by radical surgery with or without adjuvant treatment (NACT group, n = 39). Overall survival (OS), disease free survival (DFS), loco-regional failure-free survival (LRFFS) and distant metastasis-free survival (DMFS) were compared among the three different groups.\n\n\nRESULTS\nThe median follow up durations were 63.3 months for the CCRT group, 83.5 months for the NACT group, and 89.8 months for the RH group, respectively. The 5-year OS, DFS, LRFFS and DMFS for CCRT group vs. NACT group vs. RH group were 80.1% vs. 94.1% vs. 93.8% (p = 0.197), 79.5% vs. 79.3% vs. 91.0% (p = 0.401), 88.1% vs. 81.8% vs. 95.8% (p = 0.253), and 83.3% vs. 88.8% vs. 95.2% (p = 0.422). No significant prognostic factor was found in OS. Age > 48 was significant in predicting poor DFS and DMFS. The non-squamous cell carcinoma was a significant predictor of poor DFS, LRFFS and DMFS.\n\n\nCONCLUSIONS\nCCRT is a feasible therapeutic option with acceptable acute and chronic treatment-related toxicities for patients who cannot tolerate radical surgery or neoadjuvant chemotherapy.",
"affiliations": "Department of Radiation Oncology, Taichung Veterans General Hospital, 40705 Taichung, Taiwan, ROC.;Department of Radiation Oncology, Taichung Veterans General Hospital, 40705 Taichung, Taiwan, ROC.;Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, 40705 Taichung, Taiwan, ROC.;Department of Radiation Oncology, Taichung Veterans General Hospital, 40705 Taichung, Taiwan, ROC.;Department of Radiation Oncology, Taichung Veterans General Hospital, 40705 Taichung, Taiwan, ROC. Electronic address: llwang1212@gmail.com.",
"authors": "Hsieh|He-Yuan|HY|;Huang|Jin-Wen|JW|;Lu|Chien-Hsing|CH|;Lin|Jin-Ching|JC|;Wang|Lily|L|",
"chemical_list": "D002945:Cisplatin",
"country": "Singapore",
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"doi": "10.1016/j.jfma.2018.01.015",
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"journal": "Journal of the Formosan Medical Association = Taiwan yi zhi",
"keywords": "Chemoradiation therapy; FIGO stage IB2 cervical carcinoma; Neoadjuvant chemotherapy; Radical hysterectomy; Surgery",
"medline_ta": "J Formos Med Assoc",
"mesh_terms": "D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D002945:Cisplatin; D005260:Female; D006801:Humans; D007044:Hysterectomy; D008875:Middle Aged; D015999:Multivariate Analysis; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D050397:Radiotherapy, Intensity-Modulated; D012189:Retrospective Studies; D016019:Survival Analysis; D013624:Taiwan; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "9214933",
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"pages": "99-108",
"pmc": null,
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"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Definite chemoradiotherapy is a competent treatment option in FIGO stage IB2 cervical cancer compared with radical surgery +/- neoadjuvant chemotherapy.",
"title_normalized": "definite chemoradiotherapy is a competent treatment option in figo stage ib2 cervical cancer compared with radical surgery neoadjuvant chemotherapy"
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"abstract": "Aromatase inhibitors are increasingly used in the treatment of early and metastatic breast cancer. They can produce various skin adverse effects but are only rarely associated with cutaneous vasculitis. We report the first case of cutaneous vasculitis clearly associated with the use of aromatase inhibitor letrozole.",
"affiliations": "Centre Pluridisciplinaire d'Oncologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.",
"authors": "Digklia|Antonia|A|;Tzika|Evangelia|E|;Voutsadakis|Ioannis A|IA|",
"chemical_list": "D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole",
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"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Aromatase inhibitors; breast cancer; cutaneous vasculitis; letrozole; skin adverse effects",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D000077289:Letrozole; D009570:Nitriles; D014230:Triazoles; D018366:Vasculitis, Leukocytoclastic, Cutaneous",
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"title": "Cutaneous leukocytoclastic vasculitis associated with letrozole.",
"title_normalized": "cutaneous leukocytoclastic vasculitis associated with letrozole"
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"abstract": "Bromocriptine and cabergoline, ergot derived dopamine receptor agonists used to treat Parkinson's disease and prolactinomas, have been associated with increased risk of cardiac valve disease. Here we present a case of iatrogenic symptomatic severe mitral regurgitation due to these drugs.",
"affiliations": null,
"authors": "D'Aloia|Antonio|A|;Piovanelli|Barbara|B|;Rovetta|Riccardo|R|;Bonadei|Ivano|I|;Vizzardi|Enrico|E|;Curnis|Antonio|A|;Metra|Marco|M|",
"chemical_list": "D000970:Antineoplastic Agents; D004873:Ergolines; D006727:Hormone Antagonists; D001971:Bromocriptine; D000077465:Cabergoline",
"country": "Italy",
"delete": false,
"doi": "10.4081/monaldi.2013.75",
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"issn_linking": "1122-0643",
"issue": "80(3)",
"journal": "Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace",
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"mesh_terms": "D000970:Antineoplastic Agents; D001971:Bromocriptine; D000077465:Cabergoline; D004359:Drug Therapy, Combination; D004873:Ergolines; D006350:Heart Valve Prosthesis; D019918:Heart Valve Prosthesis Implantation; D006727:Hormone Antagonists; D006801:Humans; D008297:Male; D008875:Middle Aged; D008944:Mitral Valve Insufficiency; D010911:Pituitary Neoplasms; D015175:Prolactinoma; D016896:Treatment Outcome",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of iatrogenic severe mitral regurgitation.",
"title_normalized": "a case of iatrogenic severe mitral regurgitation"
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... |
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"abstract": "Chemotherapy and targeted therapies are effective palliative options for numerous unresectable or metastatic cancers. However, treatment resistance inevitably develops leading to mortality. In a subset of patients, systemic therapy appears to control the majority of tumors leaving 5 or less to progress, a phenomenon described as oligoprogression. Reasoning that the majority of lesions remain responsive to ongoing systemic chemotherapy, we hypothesized that local treatment of the progressing lesions would confer a benefit. The present study describes the cases of 5 patients whose metastatic disease was largely controlled by chemotherapy. The oligoprogressive lesions (≤5) were treated with stereotactic body radiotherapy (SBRT), justifying continued use of an effective systemic regimen. A total of 5 patients with metastatic disease on chemotherapy, with ≤5 progressing lesions amenable to SBRT, were treated with ablative intent. Primary tumor site and histology were as follows: 2 with metastatic colon adenocarcinoma, 2 with metastatic rectal adenocarcinoma and 1 with metastatic pancreatic adenocarcinoma. Imaging was performed prior to SBRT and every 3 months after SBRT. In total, 4 out of the 5 patients achieved disease control for >7 months with SBRT, without changing chemotherapy regimen. The median time to chemotherapy change was 9 months, with a median follow-up time of 9 months. The patient who failed to respond developed progressive disease outside of the SBRT field at 3 months. In conclusion, the addition of SBRT to chemotherapy is an option for the overall systemic control of oligoprogressive disease.",
"affiliations": "Department of Radiation Oncology, University of Florida, Gainesville, FL 32610, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL 32610, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL 32610, USA.;University of Florida Health Proton Therapy Institute, Jacksonville, FL 32206, USA.;Department of Radiation Oncology, University of Florida, Gainesville, FL 32610, USA.;Department of Radiation Oncology, University of Florida, Gainesville, FL 32610, USA.;Department of Radiation Oncology, University of Florida, Gainesville, FL 32610, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL 32610, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL 32610, USA.;Department of Radiation Oncology, University of Florida, Gainesville, FL 32610, USA.;Department of General Surgery, University of Florida, Gainesville, FL 32610, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL 32610, USA.",
"authors": "Wray|Justin|J|;Hawamdeh|Rana Fawzi|RF|;Hasija|Nalini|N|;Dagan|Roi|R|;Yeung|Anamaria R|AR|;Lightsey|Judith L|JL|;Okunieff|Paul|P|;Daily|Karen C|KC|;George|Thomas J|TJ|;Zlotecki|Robert A|RA|;Trevino|Jose|J|;Dang|Long H|LH|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2016.5540",
"fulltext": "\n==== Front\nOncol LettOncol LettOLOncology Letters1792-10741792-1082D.A. Spandidos 10.3892/ol.2016.5540OL-0-0-5540ArticlesStereotactic body radiation therapy for oligoprogression of metastatic disease from gastrointestinal cancers: A novel approach to extend chemotherapy efficacy Wray Justin 1*Hawamdeh Rana Fawzi 2*Hasija Nalini 2Dagan Roi 3Yeung Anamaria R. 1Lightsey Judith L. 1Okunieff Paul 14Daily Karen C. 2George Thomas J. 2Zlotecki Robert A. 1Trevino Jose 4Dang Long H. 21 Department of Radiation Oncology, University of Florida, Gainesville, FL 32610, USA2 Division of Hematology and Oncology, Department of Internal Medicine, University of Florida, Gainesville, FL 32610, USA3 University of Florida Health Proton Therapy Institute, Jacksonville, FL 32206, USA4 Department of General Surgery, University of Florida, Gainesville, FL 32610, USACorrespondence to: Dr Robert A. Zlotecki, Department of Radiation Oncology, University of Florida, 2000 SW Archer Road, PO Box 100385, Gainesville, FL 32610, USA, E-mail: zlotera@ufl.edu* Contributed equally\n\n3 2017 27 12 2016 27 12 2016 13 3 1087 1094 04 4 2015 27 6 2016 Copyright: © Wray et al.2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Chemotherapy and targeted therapies are effective palliative options for numerous unresectable or metastatic cancers. However, treatment resistance inevitably develops leading to mortality. In a subset of patients, systemic therapy appears to control the majority of tumors leaving 5 or less to progress, a phenomenon described as oligoprogression. Reasoning that the majority of lesions remain responsive to ongoing systemic chemotherapy, we hypothesized that local treatment of the progressing lesions would confer a benefit. The present study describes the cases of 5 patients whose metastatic disease was largely controlled by chemotherapy. The oligoprogressive lesions (≤5) were treated with stereotactic body radiotherapy (SBRT), justifying continued use of an effective systemic regimen. A total of 5 patients with metastatic disease on chemotherapy, with ≤5 progressing lesions amenable to SBRT, were treated with ablative intent. Primary tumor site and histology were as follows: 2 with metastatic colon adenocarcinoma, 2 with metastatic rectal adenocarcinoma and 1 with metastatic pancreatic adenocarcinoma. Imaging was performed prior to SBRT and every 3 months after SBRT. In total, 4 out of the 5 patients achieved disease control for >7 months with SBRT, without changing chemotherapy regimen. The median time to chemotherapy change was 9 months, with a median follow-up time of 9 months. The patient who failed to respond developed progressive disease outside of the SBRT field at 3 months. In conclusion, the addition of SBRT to chemotherapy is an option for the overall systemic control of oligoprogressive disease.\n\nstereotactic body radiation therapychemotherapyoligoprogressionoutcomes\n==== Body\nIntroduction\nIn patients with metastatic solid tumors treated with systemic chemotherapy, targeted therapy or both, oligoprogression is a relatively new term used to describe the clinical scenario in which a solitary or a few (≤5) metastatic tumors progress, while all other sites of disease are stable or responding to the current regimen (1). The concept of oligoprogression is based in the biological principle of branched cancer evolution. Tumor biopsies and cadaveric studies have shown significant genetic heterogeneity between the primary tumor mass and metastatic lesions, and also amongst different metastatic lesions in the same patient (2–4). This genetic heterogeneity is believed to explain the mixed response to systemic therapy often observed in clinical practice.\n\nOne of the main factors that restricts the effectiveness of chemotherapy is acquired resistance. Drug resistance is a complex issue, as a number of factors affect drug sensitivity, including drug activation and inactivation, accelerated drug efflux, drug target alterations, processing of drug-induced damage, DNA methylation and apoptotic evasion (5). Chemotherapy-induced genetic events lead to the development of new drug resistance and the standard of care in this clinical scenario is typically to change the systemic therapy. This approach introduces new problems, including added expense, different toxicities, dose adjustments, different supportive care treatments, patient treatment schedule changes and potentially, decreased efficacy.\n\nStereotactic body radiotherapy (SBRT) is a highly conformal radiation technique that delivers high-dose radiation to a tumor while sparing much of the nearby normal organs in a timely manner and with excellent tolerance. Compared with conventional palliative radiation therapy, which is delivered over 10 to 15 days with the intent to control pain but not disease progression, SBRT is commonly delivered in 3 to 10 treatments with the intent of disease ablation. There is evidence that SBRT achieves local control rates in excess of 90%. A number of studies also boast long-term disease-free survival and overall survival (6–8). SBRT has become the standard treatment in numerous institutions for oligometastatic disease presentation (1–5 metastases) in coordination with definitive local therapy.\n\nFor oligoprogressive cancers, the goal of the present study was to increase the duration until out of field tumor progression, indicating prolonged efficacy of the chemotherapeutic regimen. The primary outcome was to evaluate the time from SBRT to the initiation of subsequent chemotherapy. Finally, the study also hoped to shed light on the hypothesis that SBRT may overcome treatment resistance through sterilization of the few tumor clones that evade otherwise effective systemic therapy.\n\nPatients and methods\n\nPatients\nPatients eligible for treatment presented with metastatic disease in the thorax, liver or adrenals on chemotherapy, with 5 or fewer progressive metastases smaller than 5 cm in axial diameter. The patients were amenable to SBRT with other sites of disease remaining stable on the current systemic therapy. All patients were enrolled on an institutional review board-approved prospective outcomes tracking protocol in the Department of Radiation Oncology at the University of Florida (Gainesville, FL, USA). All cases were thoroughly reviewed by the Department of Pathology at the University of Florida, and the diagnoses were clear. The majority of the treated lesions were not biopsied beyond the primary diagnosis.\n\nChemotherapy\nSystemic treatment was cancer histology-specific. The details of the individual regimens are presented with the patients' results, including the sequencing of the chemotherapy with SBRT.\n\nRadiation therapy\nAll patients received SBRT with ablative intent concurrently to each of the progressive metastatic sites. Immobilization occurred in a vacuum cushion. The gross tumor volume (GTV) and internal target volume (ITV) were defined using 4-dimensional (4D) computed tomography (CT) simulation with Pinnacle Software (Phillips, Andover, MA, USA). The GTV was defined in the 50% phase of the 4D CT and the ITV was expanded to account for breathing motion. There was no clinical target volume expansion and a 5-mm planning target volume (PTV) was isometrically expanded from the ITV. The dose specified to the GTV D95% ensured that, at minimum, 95% of the PTV was covered by the 80% isodose line. Target localization was achieved using on-board image guidance with kV cone-beam CT and computer-assisted image registration for each fraction, then confirmed by the treating physician and a medical physicist. Treatment couch repositioning was applied for all translational corrections and rotational corrections were not performed if <3 degrees in each axis. Treatment was delivered using conformal arcs or multiple fixed coplanar beams shaped with multileaf collimators. The dose per fraction and total dose were determined using the dose-volume histogram of the organs at risk; individual patient doses are described in the Results section.\n\nEndpoint\nThe primary endpoint was the progression-free interval, defined as the time from oligoprogression treated with SBRT to the initiation of a different systemic drug or regimen. Disease progression requiring a treatment change was based on radiographic or clinical progression. Patients with dosage adjustments or treatment breaks with re-initiation of the same chemotherapy were not considered to have changed chemotherapy.\n\nResults\n\nSummary of results\nA total of 5 patients were treated with SBRT for oligoprogressive disease and followed until the initiation of a new systemic therapy regimen. The group consisted of 2 patients with colon cancer, 2 with rectal cancer and 1 with pancreatic cancer. Patient characteristics are shown in Table I. At the time of SBRT, 4 patients were on second-line and 1 patient was on third-line chemotherapy. The median time from diagnosis to SBRT was 35 months (range, 11–72 months). The mean and median time to chemotherapy change from first SBRT treatment was 11.7 and 10.6 months, respectively. The median follow-up time was 10 months (range, 3–17 months). During the interval from oligoprogression to chemotherapy change, 2 patients received 2 separate courses of SBRT, while 3 patients were treated with SBRT once. After the second course of SBRT, the time to chemotherapy change was 3 and 5 months in the 2 patients, respectively. All treatments met the aforementioned criteria defined for oligometastatic disease and chemotherapy was held during SBRT. The median time from SBRT to mortality or last follow-up was 10 months (range, 5–27 months) and the time from diagnosis to mortality or last follow-up was 41 months (range, 21–90 months). There were no grade 3 or higher toxicities associated with SBRT per the Common Terminology Criteria for Adverse Events, version 4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). All patients were staged using the American Joint Committee on Cancer's Cancer Staging Manual, 7th edition (9).\n\nPatient 1\nThe patient was a 62-year-old male at the time of SBRT and had been diagnosed with stage III (T4N1M0) adenocarcinoma of the pancreas. An exploratory laparotomy was performed 10 months prior to SBRT and unresectable cancer was found invading into the origin of the gastroduodenal artery and proper hepatic artery. A FOLFIRINOX chemotherapy regimen was started consisting of 180 mg/m2 irinotecan, 2,400 mg/m2 5-fluorouracil (5-FU) via continuous intravenous infusion (CIVI) and 85 mg/m2 oxaliplatin, every 2 weeks, and 4 cycles were completed.\n\nRestaging imaging after 3 months showed an unresectable, poorly-defined mass encasing the common hepatic artery. This case was discussed at the University of Florida Gastrointestinal Interdisciplinary tumor board conference (GI TB) with recommendations to continue with systemic chemotherapy for locally advanced pancreatic cancer and withhold radiation therapy until the patient became symptomatic. Due to the disease progression, the patient was started on a new systemic chemotherapy consisting of 1,000 mg/m2 gemcitabine and 125 mg/m2 protein-bound paclitaxel (on days [D]1, 8 and 15) every 28 days. Repeat imaging after 3 cycles showed stable disease except for one ill-defined 1.3-cm liver lesion. Chemotherapy was continued, and following cycle 5, imaging showed another 2.2-cm lesion in the left hepatic lobe, with stable disease elsewhere, including the primary site and 1.3-cm liver mass.\n\nSBRT to the oligoprogressive liver metastases was delivered at a total dose of 50 Gy over 5 fractions of 10 Gy (Fig. 1). During radiation treatment, chemotherapy was withheld.\n\nFollowing SBRT, the patient requested a chemotherapy break and has since been off of systemic therapy for 10 months, with stable disease on serial CT scans. Representative imaging is presented in Fig. 2.\n\nPatient 2\nThe patient was a 48-year-old male at the time of SBRT and had been diagnosed with stage III (T3N1M0) invasive moderately-differentiated adenocarcinoma of the rectum, with an 8.7×5-cm rectal mass, 6 years prior to SBRT. The patient underwent a diverting colostomy, 6 weeks of concurrent neoadjuvant chemoradiation with 5-FU CIVI D1-5, which was delivered at an external institution, and then a resection that confirmed locally invasive adenocarcinoma. Adjuvant mFOLFOX6 (400 mg/m2 5-FU D1, 2,400 mg/m2 5-FU CIVI and oxaliplatin 85 mg/m2) was then administered at our center every 2 weeks for 3 months. The patient was under active surveillance for 3 years when imaging showed a new 17-mm right lower lobe lung nodule, a 6-mm right apical lung nodule and a 32×26-mm mesenteric lymph node mass at the level of the aortic bifurcation. Lung biopsy confirmed metastatic rectal adenocarcinoma. The patient was started on FOLFIRI-bevacizumab (2,400 mg/m2 5-FU CIVI, 200 mg/m2 5-FU, 180 mg/m2 irinotecan and 5 mg/kg bevacizumab). Irinotecan was discontinued after 2 years due to a parastomal abscess and thrombocytopenia. This regimen was continued until the patient was found to have oligoprogression in the lungs with a progressing single lung metastasis measuring 21×19 mm, and multiple other <10 mm metastases throughout each lung, which were stable.\n\nSBRT to the large lung lesion was delivered 6 years after diagnosis at a total dose of 50 Gy in 5 fractions of 10 Gy (Fig. 3). Chemotherapy was held during SBRT, and then 5-FU/bevacizumab was resumed. The patient continues to otherwise have stable disease 10 months after SBRT with no change in systemic chemotherapy.\n\nPatient 3\nThe patient was a 47-year-old female who was initially diagnosed with metastatic adenocarcinoma of the colon, with biopsy-proven liver metastases and image-diagnosed bilateral lung involvement, 15 months prior to the first course of SBRT. A left hemicolectomy was performed with 3/15 positive lymph nodes and KRAS proto-oncogene, GTPase mutation. The patient was started on chemotherapy with mFOLFOX6 (similar to patient 1) and 5 mg/kg bevacizumab. Restaging imaging after 10 months showed a progressive liver metastasis. Systemic chemotherapy was changed to FOLFIRI (135 mg/m2 irinotecan, 400 mg/m2 5-FU IV bolus and 2,400 mg/m2 5-FU CIVI) with 4 mg/kg ziv-aflibercept every 3 weeks for 3 cycles. Follow-up imaging showed disease progression in the right hilum.\n\nSBRT was delivered to the lung metastasis in the right hilum consisting of a total dose of 30 Gy in 5 fractions of 6 Gy (Fig. 4). A repeat positron emission tomography (PET)/CT scan 1 month after SBRT showed mild progression of the multiple liver and lung metastases, and the patient was restarted on FOLFIRI/ziv-aflibercept. The disease responded well with the carcinoembryonic antigen level decreasing from 450 to 75 ng/ml. The patient was maintained on this regimen with surveillance for 1 year when repeat imaging showed progression in a single pulmonary nodule. The case was discussed at the GI TB and the recommendation was to continue the same systemic chemotherapy regimen and pursue SBRT to the left hilum.\n\nSBRT was delivered to the left lung hilum metastasis at 13 months after the first course using a total of 30 Gy in 5 fractions of 6 Gy (Fig. 4). Following SBRT, the current chemotherapy regimen was re-initiated.\n\nAt 16 months after the first course and 3 months after the second course of SBRT, the patient was enrolled in a clinical trial due to disease progression. The systemic disease continues to progress despite additional changes to the treatment plan.\n\nPatient 4\nThe patient was a 60-year-old male diagnosed with stage I (T2N0M0) adenocarcinoma of the rectum 5 years prior to SBRT. The patient was treated initially with 825 mg/m2 neoadjuvant capecitabine twice daily and concurrent radiation therapy to 50.4 Gy in 1.8-Gy fractions. A transanal resection was performed and the pathological findings were consistent with adenocarcinoma. Surveillance was continued for 1 year when 4 liver metastases were found. Chemotherapy with mFOLFOX6-bevacizumab (400 mg/m2 5-FU D1, 2,400 mg/m2 5-FU CIVI, 85 mg/m2 oxaliplatin and 5 mg/kg bevacizumab) was initiated with a good response on follow-up imaging. After 11 months, a right partial hepatectomy and left wedge resection were performed for isolated recurrence, which was followed by a 14-month disease-free period on surveillance imaging.\n\nThe patient was then found to have a new liver metastasis, which was also resected. Surveillance was continued for 8 months when PET/CT showed a thickened rectal wall and enlarged perirectal lymph node, as well as a pericardial lymph node that had increased in size since a prior exam. His case was presented at the GI TB and the consensus was for mediastinal biopsy and endoscopic rectal ultrasound for the recurrent disease at the primary site. Following a mediastinal biopsy confirming adenocarcinoma, the patient was started on systemic chemotherapy with 200 mg/m2 oral capecitabine administered twice daily, plus 7.5 mg/kg intravenous bevacizumab every day for 21 days. The patient was maintained on this regimen with stable disease on follow-up imaging for 11 months when CT imaging indicated progression of the anterior mediastinal nodal disease.\n\nSBRT was delivered at a total dose of 50 Gy in 10 fractions of 5 Gy (Fig. 5). Systemic chemotherapy was continued with continued control of the disease for 11 months. Several lung nodules then developed, each <1 cm on CT imaging. SBRT to 5 progressive lung metastases was performed to a total of 50 Gy in 10 fractions of 5 Gy (Fig. 5). Following the second round of SBRT, the patient was continued on chemotherapy with serial imaging for 15 months. CT imaging indicated worsening pulmonary metastases with a large right pleural effusion and progression of the anterior mediastinal nodal metastasis. The systemic chemotherapy was changed 18 months after the first round of SBRT to single-agent panitumumab (6 mg/kg every 2 weeks), with irinotecan (180 mg/m2) subsequently added due to continued progression. The patient was subjected to other treatments, and succumbed to progressive systemic disease 2 years and 2 months from the first SBRT.\n\nPatient 5\nThe patient was a 68-year-old male who was originally diagnosed with a stage IIIC (pT3N2bM0) proximal transverse colon adenocarcinoma 3 years prior to SBRT. Staging imaging was notable for subcentimeter pulmonary nodules, but no definitive evidence of metastatic disease. The patient underwent a laparoscopic right colectomy followed by adjuvant systemic chemotherapy with standard-dose mFOLFOX-6 (85 mg/m2 oxaliplatin, 400 mg/m2 leucovorin, 400 mg/m2 5-FU bolus and 2,400 mg/m2 5-FU over 46 h) repeated every 2 weeks. Although several dose reductions were required, there was no evidence of disease progression on follow-up imaging. After a year, surveillance imaging demonstrated two enlarging mesenteric soft-tissue nodules. Chemotherapy was changed to FOLFIRI-bevacizumab (280 mg/m2 5-FU, 2,400 mg/m2 5-FU, 180 mg/m2 irinotecan and 5 mg/kg bevacizumab), with a 50% dose reduction of the 5-FU bolus. The patient had two breaks from chemotherapy due to non-cancer-related disease requiring vascular surgery and subsequent complications. After 2 years, repeat imaging revealed interval increase in size of a soft tissue mass in the mesentery with stable lung metastases, and FOLFIRI with bevacizumab was restarted without a 5-FU bolus (180 mg/m2 irinotecan, 2,400 mg/m2 5-FU CIVI and 5 mg/kg bevacizumab) with interval response consisting of stable imaging. After 4 months, surveillance imaging showed a new left adrenal nodule, which was discussed during GI TB. The consensus recommendation was for short-interval surveillance. Follow-up imaging 3 months later revealed a slight increase in the left adrenal nodule.\n\nSBRT was delivered at a total of 40 Gy in 5 fractions of 8 Gy (Fig. 6) to the left adrenal metastasis. Chemotherapy was continued during SBRT. Ziv-alfibercept (4 mg/kg) replaced bevacizumab with FOLFIRI 4 months after completing the SBRT due to systemic disease progression outside of the radiation field.\n\nDiscussion\nThe present study describes the cases of 5 patients with metastatic cancer treated with SBRT for oligoprogressive disease with the goal of delaying the requirement to transition to subsequent lines of chemotherapy. This goal was achieved in 4 out of 5 patients, each of whom was able to remain on pre-SBRT systemic therapy beyond 7 months without progression warranting a change in chemotherapy. SBRT was well-tolerated and there were no grade 3 or higher toxicities from SBRT, enabling continuation of the same systemic chemotherapy with sustained quality of life. Ongoing disease control is being performed with the same systemic regimen in 2 of the patients, and 1 patient has remained off chemotherapy for 8 months. Additionally, 2 of the patients developed disease progression after 16 and 18 months, 1 of whom has since succumbed. Furthermore, 1 patient was found to have widespread disease progression at the 3-month follow-up imaging.\n\nBiologically, this approach appears to be intuitive since treatment resistance results from cancer adaptations and mutations, which induce subsequent clonal selection (10). However, systemic treatment changes to account for local clonal evolution creates new challenges. Systemic therapeutic options are finite and further mutations accumulate after each line of therapy, as new selection forces are applied even to clones that previously were static and responding to previous treatment. By eradicating resistant, oligoprogressive sub-clones, prematurely discontinuing otherwise effective systemic therapy may be avoided. Significant clinical benefit may be obtained if the duration of each of line of systemic therapy is extended prior to changing to a new regimen. Historically, surgical debulking has been the only way to provide durable disease control for oligometastatic disease, but for a number of patients this carries some morbidity and requires recovery time off of systemic therapy, which allows progression of otherwise stable metastatic disease. Additionally, the surgical recovery of hepatic metastasectomy may stimulate otherwise stable growth factors potentially accelerating disease progression. In the modern era, SBRT has become a novel approach to achieve non-invasive debulking or ablation and has been reported in patients treated with targeted therapy to control their widely metastatic disease (1,11–13).\n\nIn a retrospective series (sequential publications including the same patients), Gan et al (11) and Weickhardt et al (1) described the cases of 33 patients administered crizotinib for metastatic non-small cell lung cancer with anaplastic lymphoma kinase-positive tumors. In total, 14 patients exhibited extracranial progression in 4 or fewer tumor sites that were treated with SBRT, yielding excellent local control rates and an increased time to widespread progression. Those patients who were able to continue taking crizotinib for over 12 months experienced significantly higher overall survival times.\n\nStraka et al (13) described the case of a patient with metastatic renal cell carcinoma who developed a solitary area of progression in an adrenal metastasis whilst being administered sunitinib. Rather than switching to a different systemic therapy, SBRT was used to treat the progressing tumor. Sunitinib was then be administered for another 8 months prior to the occurrence of more widespread progression. A Canadian, multi-institutional, single-arm, prospective, phase 2 trial (OZM-053; clinicaltrials.gov identifier NCT02019576) is currently being conducted to study the use of SBRT in metastatic renal cell carcinoma patients who develop oligoprogression whilst being administered first-line sunitinib therapy. SBRT is being used to treat ≤5 progressing tumors, with ≤3 progressing soft-tissue metastases.\n\nFinally, Iyengar et al (12) recently published a prospective phase II trial employing SBRT in patients on second-line erlotinib to debulk progressive metastatic disease. This study is subtly different compared with the others in that every site of metastatic disease was treated with SBRT prior to initiation of erlotinib after the patients failed first-line chemotherapy. Nonetheless, an increase in progression-free (14.7 months) and overall (20.4 months) survival times was shown compared with historical benchmarks.\n\nAll these studies employed targeted biologically active tyrosine kinase inhibitors, but to the best of our knowledge, no previously published study has indicated that this approach would be beneficial in patients on systemic chemotherapy. Iyengar et al (12) used SBRT following systemic treatment failure, but did not continue the current regimen; they instead initiated a targeted agent once debulking was accomplished.\n\nThere are several limitations of the present series, including the small patient population treated in this manner and the lack of a comparison group. Despite these limitations, this study provides proof of principle and clinical rationale for considering the thoughtful use of SBRT for treatment of oligoprogressive disease in select situations where continuation of an otherwise effective systemic chemotherapy is reasonable.\n\nOne of the greatest strengths of the present study is the novel approach to evaluating the efficacy of the treatment by measuring the time from the treatment with SBRT to the change in chemotherapy. This is an innovative strategy to evaluate progressive metastatic disease treatment efficacy and we advocate for systemic change in this arena. Future studies will benefit from this approach, as patients in the metastatic setting often experience short overall survival times and the intent of the treatment is to extend quality of life, which may be difficult to prove significant, since it is difficult to objectively measure. Furthermore, once patients enroll in a hospice and decide to discontinue therapy, the endpoint of overall survival is no longer relevant. Other endpoints such as health care resource utilization, pharmacoeconomic analyses and patient-reported quality of life should be considered as correlative endpoints in future studies.\n\nTo summarize, the current study presents the cases of 5 patients who achieved an extended, high quality of life following SBRT delivered to increase the duration of effective systemic chemotherapy, with no significant toxicity. We believe that this strategy will improve the duration of effective chemotherapy and allow for increased, high quality longevity in a select group of patients with oligoprogression.\n\nFigure 1. Stereotactic body radiotherapy (SBRT) treatment plan for patient 1. (A) A computed tomography image of the treatment plan with isodose volumes shown. (B) A dose-volume histogram of the SBRT plan with pertinent structures shown. GTV, gross tumor volume; ITV, internal target volume; PTV, planning target volume.\n\nFigure 2. Representative imaging for patient 1. (A) A computed tomography (CT) image of the untreated primary and metastatic disease prior to stereotactic body radiotherapy (SBRT). (B) A CT image of the untreated primary and metastatic disease 3 months after SBRT. (C) A CT image of the untreated primary and metastatic disease 9 months after SBRT.\n\nFigure 3. Stereotactic body radiotherapy (SBRT) treatment plan for patient 2. (A) A computed tomography (CT) image of the treatment plan with isodose volumes shown. (B) A dose-volume histogram of the SBRT plan with pertinent structures shown. GTV, gross tumor volume; ITV, internal target volume; PTV, planning target volume.\n\nFigure 4. Stereotactic body radiotherapy (SBRT) treatment plans for patient 3. (A) SBRT course 1: A computed tomography (CT) image of the treatment plan with isodose volumes shown. (B) SBRT course 2: A dose-volume histogram of the SBRT plan with pertinent structures shown. (C) SBRT course 2: A CT image of the treatment plan with isodose volumes shown. (D) SBRT course 2: A dose-volume histogram of the SBRT plan with pertinent structures shown. GTV, gross tumor volume; ITV, internal target volume; PTV, planning target volume.\n\nFigure 5. Stereotactic body radiotherapy (SBRT) treatment plans for patient 3. (A) SBRT course 1. A computed tomography (CT) image of the treatment plan with isodose volumes shown. (B) SBRT course 2. A dose-volume histogram of the SBRT plan with pertinent structures shown. (C) SBRT course 2. A combined dose-volume histogram of the SBRT plan with pertinent structures shown. All GTVs and PTVs are shown. (D) SBRT course 2. A CT image of the treatment plan, including all treated metastases, with isodose volumes shown. GTV, gross tumor volume; ITV, internal target volume; PTV, planning target volume.\n\nFigure 6. Steretactic body radiotherapy (SBRT) treatment plan for patient 5. (A) A computed tomography (CT) image of the treatment plan with isodose volumes shown. (B) A dose-volume histogram of the SBRT plan with pertinent structures shown. GTV, gross tumor volume; ITV, internal target volume; PTV, planning target volume.\n\nTable I. Patient characteristics and outcomes for 5 patients treated with SBRT for oligoprogression.\n\nPatient no.\tAge at first SBRT, years/gender\tTime from diagnosis to first SBRT, months\tPrimary site and histology\tChemotherapy agents at the time of SBRT\tFirst SBRT total dose and fraction size, Gy\tSite of first SBRT (number of metastases)\tMonths from first SBRT to changes in chemotherapy\tSecond SBRT total dose and fraction size, Gy\tSite of second SBRT (number of metastases)\tMonths from second SBRT to changes in chemotherapy regimen\t\n1\t62/male\t11\tPancreatic adenocarcinoma\tGemcitabine, nab-paclitaxel\t 50/10\tLiver (1)\t10\tN/A\tN/A\tN/A\t\n2\t48/male\t73\tRectal adenocarcinoma\tBevacizumab, leucovorin, 5-FU\t 50/10\tLung (1)\t10\tN/A\tN/A\tN/A\t\n3\t49/female\t15\tColon adenocarcinoma\tIrinotecan, aflibercept\t30/6\tRight hilum (1)\t17\t30/6\tLeft hilum (1)\t4\t\n4\t60/male\t63\tRectal adenocarcinoma\tCapecitabine, bevacizumab\t50/5\tAnterior mediastinum (1)\t17\t50/5\tLung (5)\t5\t\n5\t68/male\t35\tColon adenocarcinoma\tFOLFIRI, bevacizumab\t40/8\tAnterior mediastinum (1)\t 3\tN/A\tN/A\tN/A\t\nAll patients\t\t\n Mean (range)\t\t\t\t\t44 (30–50)\t1 (1)\t11.7\t40\t3.5\t4.6\t\n Median (range)\t\t\t\t\t50 (30–50)\t1 (1)\t10 (3–17)\t40 (30–50)\t3.5 (1–5)\t4\t\nSBRT, stereotactic body radiation therapy; 5-FU, 5-fluorouracil; FOLFIRI, leucovorin, 5-FU and irinotecan; N/A, not applicable.\n==== Refs\nReferences\n1 Weickhardt AJ Scheier B Burke JM Gan G Lu X Bunn PA Jr Aisner DL Gaspar LE Kavanagh BD Doebele RC Camidge DR Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer J Thorac Oncol 7 1807 1814 2012 10.1097/JTO.0b013e3182745948 23154552 \n2 Gerlinger M Rowan AJ Horswell S Larkin J Endesfelder D Gronroos E Martinez P Matthews N Stewart A Tarpey P Intratumor heterogeneity and branched evolution revealed by multiregion sequencing N Engl J Med 366 883 892 2012 10.1056/NEJMoa1113205 22397650 \n3 Ding L Ellis MJ Li S Larson DE Chen K Wallis JW Harris CC McLellan MD Fulton RS Fulton LL Genome remodelling in a basal-like breast cancer metastasis and xenograft Nature 464 999 1005 2010 10.1038/nature08989 20393555 \n4 Yachida S Jones S Bozic I Antal T Leary R Fu B Kamiyama M Hruban RH Eshleman JR Nowak MA Distant metastasis occurs late during the genetic evolution of pancreatic cancer Nature 467 1114 1117 2010 10.1038/nature09515 20981102 \n5 Wilson TR Longley DB Johnston PG Chemoresistance in solid tumours Ann Oncol 17 (Suppl 10) x315 x324 2006 10.1093/annonc/mdl280 17018746 \n6 Milano MT Katz AW Zhang H Okunieff P Oligometastases treated with stereotactic body radiotherapy: Long-term follow-up of prospective study Int J Radiat Oncol Biol Phys 83 878 886 2012 10.1016/j.ijrobp.2011.08.036 22172903 \n7 Takeda A Sanuki N Tsurugai Y Oku Y Aoki Y Stereotactic body radiotherapy for patients with oligometastases from colorectal cancer: Risk-adapted dose prescription with a maximum dose of 83–100 Gy in five fractions J Radiat Res 3 16 2016 (Epub ahead of print) 10.1093/jrr/rrw029 \n8 Filippi AR Guerrera F Badellino S Ceccarelli M Castiglione A Guarneri A Spadi R Racca P Ciccone G Ricardi U Ruffini E Exploratory analysis on overall survival after either surgery or stereotactic radiotherapy for lung oligometastases from colorectal cancer Clin Oncol (R Coll Radiol) 28 505 512 2016 10.1016/j.clon.2016.02.001 26899780 \n9 Edge S Byrd DR Compton CC Fritz AG Greene FL Trotti A American Joint Committee on Cancer AJCC Cancer Staging Manual 8th Springer New York, NY 2010 \n10 Talmadge JE Clonal selection of metastasis within the life history of a tumor Cancer Res 67 11471 11475 2007 10.1158/0008-5472.CAN-07-2496 18089772 \n11 Gan GN Weickhardt AJ Scheier B Doebele RC Gaspar LE Kavanagh BD Camidge DR Stereotactic radiation therapy can safely and durably control sites of extra-central nervous system oligoprogressive disease in anaplastic lymphoma kinase-positive lung cancer patients receiving crizotinib Int J Radiat Oncol Biol Phys 88 892 898 2014 10.1016/j.ijrobp.2013.11.010 24462383 \n12 Iyengar P Kavanagh BD Wardak Z Smith I Ahn C Gerber DE Dowell J Hughes R Abdulrahman R Camidge DR Phase II trial of stereotactic body radiation therapy combined with erlotinib for patients with limited but progressive metastatic non-small-cell lung cancer J Clin Oncol 32 3824 3830 2014 10.1200/JCO.2014.56.7412 25349291 \n13 Straka C Kim DW Timmerman RD Pedrosa I Jacobs C Brugarolas J Ablation of a site of progression with stereotactic body radiation therapy extends sunitinib treatment from 14 to 22 months J Clin Oncol 31 e401 e403 2013 10.1200/JCO.2012.47.7455 23796996\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1792-1074",
"issue": "13(3)",
"journal": "Oncology letters",
"keywords": "chemotherapy; oligoprogression; outcomes; stereotactic body radiation therapy",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "1087-1094",
"pmc": null,
"pmid": "28454218",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article",
"references": "25349291;23154552;24462383;17018746;20393555;20981102;26983981;22397650;22172903;26899780;18089772;23796996",
"title": "Stereotactic body radiation therapy for oligoprogression of metastatic disease from gastrointestinal cancers: A novel approach to extend chemotherapy efficacy.",
"title_normalized": "stereotactic body radiation therapy for oligoprogression of metastatic disease from gastrointestinal cancers a novel approach to extend chemotherapy efficacy"
} | [
{
"companynumb": "US-ACCORD-049535",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "Paclitaxel combined with bevacizumab yields significantly better progression-free survival (PFS) in patients with metastatic breast cancer than paclitaxel alone. Here, we report a case of stage IV breast cancer with multiple liver, lung, and bone metastases maintaining a long-term partial response (PR) with tri-weekly paclitaxel plus bevacizumab administration. A 46- year-old woman treated with endocrine therapy for 21 months for multiple metastases in her lungs and bones detected 4 years after surgery for left breast cancer was referred to our hospital. New metastases were discovered in her liver. She received paclitaxel (l 90 mg/m/(2)) on days 1, 8, and 15 combined with bevacizumab (10 mg/kg) on days 1 and 15 every 4 weeks. However, during the first 3 courses, the administration of paclitaxel on day 8 was postponed to 1 to 2 weeks because of severe neutropenia. We began tri-weekly administration of paclitaxel plus bevacizumab. She continued receiving the treatment for about 1 year, without severe side effects. The PR state with good performance status was maintained. We suggest that the tri-weekly administration of paclitaxel plus bevacizumab is an effective way to maintain long-term efficacy.",
"affiliations": "Dept. of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine.",
"authors": "Okamoto|Akiko|A|;Nakatsukasa|Katsuhiko|K|;Fujita|Yoshifumi|Y|;Sugimoto|Riho|R|;Sakaguchi|Kouichi|K|;Taguchi|Tetsuya|T|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "42(3)",
"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; D000068258:Bevacizumab; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D017239:Paclitaxel",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "343-6",
"pmc": null,
"pmid": "25812504",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A case of stage IV breast cancer with long-term partial response treated with tri-weekly paclitaxel plus bevacizumab.",
"title_normalized": "a case of stage iv breast cancer with long term partial response treated with tri weekly paclitaxel plus bevacizumab"
} | [
{
"companynumb": "JP-AMGEN-JPNSP2015035224",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "Topical steroid use is common, but its association with Cushing syndrome is rare. We report the rapid development of iatrogenic Cushing syndrome in a patient on ritonavir who applied a moderate-potency topical steroid cream, triamcinolone, on his genital mucosa for treatment of phimosis.\nClinical and diagnostic challenges associated with topical steroid use are presented and discussed.\nA 41-year-old man with human immunodeficiency virus infection on stable antiretroviral therapy that included ritonavir, a cytochrome P450 3A4 inhibitor, presented with new onset diabetes and development of overt cushingoid features over a 4-week period. He reported no known history of steroid use. A midnight salivary cortisol using a quantitative enzyme immunoassay was obtained and reported at >15.0 μg/dL (normal, <0.112 μg/dL). However, free cortisol in a 24-hour urine collection was undetectable by high-performance liquid chromatography and morning plasma cortisol was also unexpectedly low at 1.1 μg/dL (normal, 4.5 to 23.0 μg/dL). Further investigation revealed that the patient had been applying a topical cream with triamcinolone acetonide (0.1%) on the glans penis for treatment of phimosis. The salivary enzyme immunoassay for cortisol appears to have detected the absorbed triamcinolone, a compound known to cross-react with cortisol in this assay.\nThis case raises awareness on the severe metabolic consequence resulting from the seemingly benign use of a topical steroid medication when applied to the genital mucosa in the setting of stable therapy with ritonavir and illustrates the limitations of salivary cortisol enzyme immunoassays for the evaluation of Cushing syndrome in this setting.",
"affiliations": null,
"authors": "Purser|Jeremy D|JD|;Riachy|Ruba|R|;Blanton|Lucas S|LS|;Belalcazar|L Maria|LM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4158/ACCR-2020-0375",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2376-0605",
"issue": "6(6)",
"journal": "AACE clinical case reports",
"keywords": null,
"medline_ta": "AACE Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101670593",
"other_id": null,
"pages": "e346-e348",
"pmc": null,
"pmid": "33244500",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "20972726;18334580;26955131;23970582;18991509;6020682;24895495;29108449;25284850;17163820;21501034;19602555;10509596;17550962",
"title": "RAPID DEVELOPMENT OF IATROGENIC CUSHING SYNDROME IN A PATIENT ON RITONAVIR: THE ADVERSE METABOLIC CONSEQUENCE OF TOPICAL STEROID USE.",
"title_normalized": "rapid development of iatrogenic cushing syndrome in a patient on ritonavir the adverse metabolic consequence of topical steroid use"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-2022-032826",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE ACETONIDE"
},
... |
{
"abstract": "BACKGROUND\nAn accidental durotomy is a recognised and not infrequent complication of lumbar spine surgery, and may lead to postoperative low-pressure headaches, pseudomeningocele and CSF leak. Conventional postoperative management involves a period of flat bed rest. There is no agreement as to the need for and duration of postoperative bed rest. This study aims to determine whether the duration of flat bed rest alters the rate of these complications.\n\n\nMETHODS\nThis is a retrospective study. All patients who underwent surgery for degenerative spinal disease between May 2010 and May 2011 were reviewed. All patients who incurred an accidental durotomy and who were repaired using fibrin glue were included in this study. Their notes were reviewed for evidence of complications for a minimum of 12 months after surgery. The following complications were identified: postural headache, pseudomeningocele, CSF leak wound infection, subdural haematoma.\n\n\nRESULTS\nEight hundred and eighty-nine patients underwent lumbar spine surgery. Sixty-one (6.8%) patients suffered an accidental durotomy and were repaired with fibrin glue. Twenty-six patients were mobilised on the first postoperative day, 9 patients on the second, and a further 26 patients were mobilised on the third postoperative day or later. The overall incidence of complications related to the durotomy was 18%. There was no statistical significance between the day of mobilisation and the rate of complication (p = 0.433).\n\n\nCONCLUSIONS\nA longer period of mandatory bed rest does not decrease the rate of complications. Patients should be mobilised as soon as they can. This could potentially reduce the length of hospital stay and the cost of aftercare.",
"affiliations": "Department of Neurosurgery, Salford Royal NHS Foundation Trust , Salford , UK.",
"authors": "Low|Jacob Chen Ming|JC|;von Niederhäusern|Belinda|B|;Rutherford|Scott A|SA|;King|Andrew T|AT|",
"chemical_list": "D015718:Fibrin Tissue Adhesive; D014014:Tissue Adhesives",
"country": "England",
"delete": false,
"doi": "10.3109/02688697.2013.798858",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-8697",
"issue": "27(6)",
"journal": "British journal of neurosurgery",
"keywords": null,
"medline_ta": "Br J Neurosurg",
"mesh_terms": "D001510:Bed Rest; D015331:Cohort Studies; D004388:Dura Mater; D004434:Early Ambulation; D005260:Female; D015718:Fibrin Tissue Adhesive; D006801:Humans; D007431:Intraoperative Complications; D008161:Lumbosacral Region; D008297:Male; D019636:Neurodegenerative Diseases; D019635:Neurosurgical Procedures; D010865:Pilot Projects; D012189:Retrospective Studies; D013131:Spine; D014014:Tissue Adhesives",
"nlm_unique_id": "8800054",
"other_id": null,
"pages": "800-2",
"pmc": null,
"pmid": "23724795",
"pubdate": "2013-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pilot study of perioperative accidental durotomy: does the period of postoperative bed rest reduce the incidence of complication?",
"title_normalized": "pilot study of perioperative accidental durotomy does the period of postoperative bed rest reduce the incidence of complication"
} | [
{
"companynumb": "GB-BAXTER-2014BAX046870",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FIBRINOGEN HUMAN\\THROMBIN HUMAN"
},
"drugaddi... |
{
"abstract": "Introduction. It is rare for actinic or squamous cell carcinoma (SCC) in situ to metastasize. Case Presentation. A 67-year-old male had a significant medical history including severe psoriatic arthritis treated with UVB, methotrexate, and rapamycin. He had twenty-five different skin excisions of actinic keratosis four of which were invasive SCC. Our patient developed shortness of breath necessitating a visit to the emergency department. A CT scan of his chest revealed a mass in the right lower lung. A subsequent biopsy of the mass revealed well-differentiated SCC. He underwent thoracoscopic surgery with wedge resection of the lung lesion. Discussion. Actinic keratosis (AK) is considered precancerous and associated with UV exposure. It exists as a continuum of progression with low potential for malignancy. The majority of invasive SCCs are associated with malignant progression of AK, but only 5-10% of AKs will progress to malignant potential. Conclusion. In this case, a new finding of lung SCC in the setting of multiple invasive actinic cutaneous SCC associated with a history of extensive UV light exposure and immunosuppression supports a metastatic explanation for lung cancer.",
"affiliations": "Department of Medicine, Sky Ridge Medical Center, Lone Tree, CO, USA.;Department of Surgery, Berkshire Medical Center, Pittsfield, MA, USA.;Department of Surgery, Berkshire Medical Center, Pittsfield, MA, USA.",
"authors": "Meter|Monet E|ME|;Nye|David J|DJ|0000-0002-0153-8289;Galvez|Christian R|CR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2017/4176071",
"fulltext": "\n==== Front\nCase Rep SurgCase Rep SurgCRISCase Reports in Surgery2090-69002090-6919Hindawi 10.1155/2017/4176071Case ReportSuspected Pulmonary Metastasis of Actinic Cutaneous Squamous Cell Carcinoma Meter Monet E. \n1\nhttp://orcid.org/0000-0002-0153-8289Nye David J. \n2\n\n*\nGalvez Christian R. \n2\n1Department of Medicine, Sky Ridge Medical Center, Lone Tree, CO, USA2Department of Surgery, Berkshire Medical Center, Pittsfield, MA, USA*David J. Nye: dnye@bhs1.orgAcademic Editor: Angelo Carretta\n\n2017 13 3 2017 2017 41760715 10 2016 30 12 2016 9 2 2017 Copyright © 2017 Monet E. Meter et al.2017This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nIntroduction. It is rare for actinic or squamous cell carcinoma (SCC) in situ to metastasize. Case Presentation. A 67-year-old male had a significant medical history including severe psoriatic arthritis treated with UVB, methotrexate, and rapamycin. He had twenty-five different skin excisions of actinic keratosis four of which were invasive SCC. Our patient developed shortness of breath necessitating a visit to the emergency department. A CT scan of his chest revealed a mass in the right lower lung. A subsequent biopsy of the mass revealed well-differentiated SCC. He underwent thoracoscopic surgery with wedge resection of the lung lesion. Discussion. Actinic keratosis (AK) is considered precancerous and associated with UV exposure. It exists as a continuum of progression with low potential for malignancy. The majority of invasive SCCs are associated with malignant progression of AK, but only 5–10% of AKs will progress to malignant potential. Conclusion. In this case, a new finding of lung SCC in the setting of multiple invasive actinic cutaneous SCC associated with a history of extensive UV light exposure and immunosuppression supports a metastatic explanation for lung cancer.\n==== Body\n1. Introduction\nCutaneous squamous cell carcinoma (SCC) is the second most common skin cancer [1], accounting for 20% of all cutaneous malignancies [2], with risk factors that include accumulation of sun and other UV exposure, and immunocompromised [2]. It is the most common cancer capable of metastatic spread [3]. SCC includes many histopathologic subtypes, each associated with various behaviors, courses, and prognoses [1, 2, 4]. Although potential to metastasize is increased for high grade subtypes such as nonactinic SCC, it rarely occurs in patients with actinic or SCC in situ [1, 2], with only 5–10% ever progressing to invasive SCC over a five-year period [2, 4]. In this case, a new finding of lung SCC in the setting of multiple invasive actinic cutaneous SCC and history of extensive UV light exposure and immunosuppression supports a metastatic explanation for the lung cancer.\n\n2. Case Presentation\nThe patient is a 67-year-old male with severe psoriatic arthritis involving his entire body but sparing his face, who has undergone 800+ UVB treatments over his 40-year-history of the condition and who has likewise been treated at various times with methotrexate and rapamycin for this autoimmune disease. He also has a long and significant past medical history of multiple, recurrent cutaneous SCC. Twenty-five of these lesions have been removed, nine of which were within the past 2 years, and at least four of which were invasive, albeit resected with negative margins. At least one lesion was classified as actinic keratosis.\n\nHe recently presented to the BMC Emergency Department complaining of sudden onset shortness of breath after exertion, without chest pain, wheezing, productive cough, or calf pain. Given his family history of thromboembolic disease and his own remote history of deep vein thrombosis with subsequent pulmonary embolism (PE), his care team moved to rule out a recurrence of this process and possible hypercoagulable disorder. Labs showed troponins were within normal limits, but an elevated D-dimer of 437 ng/mL. An EKG showed normal sinus rhythm with multiple PACs. A chest X-ray revealed mild cardiomegaly but no infiltrates. A computed tomography angiography (Figure 1) found no PE but revealed an ovoid 3.2 × 2.2 cm costophrenic angle mass of the right lower lung lobe with no evidence of hilar or mediastinal lymphadenopathy. His symptoms resolved without treatment. He was stable on discharge and referred to a pulmonary specialist for evaluation of the lung nodule.\n\nA month later, a CT-guided biopsy was performed by Interventional Radiology, which confirmed the diagnosis of keratinizing, well-differentiated SCC and extensive necrosis. Of note were several scattered lesions of cutaneous SCC on the patient's abdomen and back at the time of this procedure, one of which was oozing, that the patient did not believe required attention at this time. Given the question of metastasis, a staging positron emission tomography (PET) scan was performed, revealing hypermetabolic foci in addition to the known lung mass with a max standardized uptake value (SUV) of 3.9 (Figure 2). SUV is a measurement of how metabolically active a tissue is. As the SUV increases there is a higher association with cancer.\n\nIntensely hypermetabolic nodular lesion within the subcutaneous soft tissue of the left anterior/inferior chest wall inferior to left axilla measuring 2.6 × 1.7 cm—suspicious for malignant lymph node (Figure 3).\n\nAt least seven additional scattered cutaneous nodular foci in the right and left superior back, right inferior back, and right and bilateral inferior midline areas of the anterior abdomen, any of which could represent SCC (Figure 4).\n\nThe patient subsequently underwent right subxiphoid video-assisted thoracoscopic surgery (VATS) in which a wedge excision of the right lower lobe was performed. A thoracostomy tube was inserted. Excision of the left chest wall nodule was also performed. The lung SCC (Figures 5–7) is histopathologically similar to biopsies of prior cutaneous SCC (Figures 8 and 9). The right lower lung mass was negative when stained with TTF-1. TTF-1 would stain positive for adenocarcinoma. A p63 stain would identify SCC from any site and that was positive on the lung sample. TTF-1 and p63 staining was not performed on the cutaneous SCC lesions. There are no markers that would identify or exclude a primary lung tumor that has metastasized to the skin.\n\nPrior to completion of the pathology report, it was unclear if the left anterior/inferior lymph nodule malignancy is in fact a metastasis, related to the right lower lobe lung SCC, or a separate, primary, synchronous tumor such as a skin carcinoma. Pathologic examination of the nodule did show it to be of histologically higher grade than the lung or skin SCC (Figure 10). The lung was TTF-1 negative for adenocarcinoma and p63 positive for SCC.\n\n3. Discussion\nThe singularity of this lung lesion might suggest its occurrence as a primary SCC of the lung. However, the appearance on preoperative imaging (Figure 1) suggests metastasis from any of numerous primary cutaneous SCC due to its very well-circumscribed edges and “cannonball” appearance. A primary SCC of the lung would typically appear on CT imaging as a speculated lesion. The location of the lesion is also in the periphery of the lung, while this type of lung cancer usually arises centrally with hilar vessel and bronchiolar invasion. Additionally, primary SCC of the lung is highly associated with cigarette smoking or other environmental exposure [2], of which this patient has no history.\n\nActinic keratosis (AK) is considered precancerous and associated with UV exposure but exists as a continuum of progression with low potential for malignancy [2]. The majority (97%) of invasive SCCs are associated with malignant progression of AK, but only 5–10% of AKs will progress to malignant potential [2]. However, even invasive SCC is considered indolent, and metastatic potential is still only 0.5% [2]. More poorly differentiated SCC and lesions over 2 cm possess increased potential to metastasize [1, 2, 4] and, in this group, do so at a rate of 11–47.3% [1]. Dermal and subcutaneous involvement increase probability of metastasis sevenfold [2]. In this case, despite the absence of nonactinic SCC with higher metastatic potential, the risk for metastasis in this patient is exponentially increased given his unique set of risk factors: continued exposure to UV light, his immune-suppressing drug regiment, his propensity to develop multiple, recurrent primary cutaneous SCCs with invasive qualities, his history of very large (~3–9 cm width) and deep cutaneous tumors, and his self-reported delay to treatment of his present cutaneous lesions [2, 4].\n\nThe right lower lung mass was negative when stained with TTF-1. TTF-1 would stain positive for adenocarcinoma [5]. A p63 stain would identify SCC from any site and that was positive on the lung sample. TTF-1 and p63 staining was not performed on the cutaneous SCC lesions. There are no markers that would identify or exclude a primary lung tumor that has metastasized to the skin.\n\nNo markers are currently in use to reliably distinguish primary versus secondary SCC, as both cutaneous and lung SCC possess the same measured markers [3, 6] although the novel Pathfinder TG, Metastases versus Primary Tumors (MvP) test developed by RedPath Integrated Pathology, may be useful in this case.\n\n4. Conclusion\nGiven this patient's unique set of circumstances and risk factors—the size, invasive nature and sheer number of his past skin tumors, the location and radiographic appearance of the lung mass, and histologic similarity to his cutaneous SCC—the possibility of a rare occurrence of metastasis of actinic cutaneous SCC to the lung from prior or current cutaneous SCC is plausible. Despite being a solitary lesion, the patient's negative history of smoking or environmental exposure would make a primary lung SCC less likely.\n\nCompeting Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Computed tomography angiography of the thorax showing well-circumscribed, ovoid “cannonball” costophrenic mass in right lower lung lobe, consistent with appearance of metastasis.\n\nFigure 2 PET scan identifies costophrenic lung mass as peripherally hypermetabolic with relatively ametabolic central region, likely cavitation from necrosis (max SUV 3.9).\n\nFigure 3 PET scan identifies intensely hypermetabolic nodular lesion on the left lateral chest wall inferior to left axilla, highly suspicious for malignancy (max SUV 12.5).\n\nFigure 4 PET scan identifies intensely hypermetabolic cutaneous lesion of the back. This patient has a history of multiple hypermetabolic cutaneous lesions with excisions.\n\nFigure 5 Normal lung tissue with intact alveolar spaces adjacent to the keratinizing squamous cell carcinoma, which, here, is more moderately differentiated and more clearly characteristic of SCC [2]. The tumor measures 4.5 × 3.7 × 2.2 cm, and the distal border of the tumor invades the pleura.\n\nFigure 6 SCC invasion of bronchus. Note the intact pseudostratified ciliated columnar epithelium of the bronchial wall to the left and upper right of the image, while the lower right portion shows the tumor breaking through the bronchial wall and invading the bronchial lumen.\n\nFigure 7 Angioinvasion—SCC has engulfed all muscles layers of a large blood vessel wall. Only the endothelium of the tunica intima remains intact.\n\nFigure 8 Left chest invasive cutaneous SCC measuring 9.8 cm, excised a few years ago, revealing desmoplastic reaction and deep invasion into subcutaneous fat, a strong predictor of metastasis [1]. Moderately differentiated.\n\nFigure 9 Right shoulder invasive cutaneous SCC measuring 7.8 cm, excised a few years ago, showing “nests” of deep dermal and subcutaneous invasion [2].\n\nFigure 10 Left chest wall lymph node measuring 3.0 × 2.5 × 1.7 cm poorly differentiated, higher grade squamous cell carcinoma. Extranodal invasion is suspected but not definitive.\n==== Refs\n1 Kwon S. Dong Z. M. Wu P. C. Sentinel lymph node biopsy for high-risk cutaneous squamous cell carcinoma: clinical experience and review of literature World Journal of Surgical Oncology 2011 9, article 80 10.1186/1477-7819-9-80 2-s2.0-79960560469 \n2 Yanofsky V. R. Mercer S. E. Phelps R. G. Histopathological variants of cutaneous squamous cell carcinoma: a review Journal of Skin Cancer 2011 2011 13 210813 10.1155/2011/210813 \n3 Tirino V. Camerlingo R. Franco R. The role of CD133 in the identification and characterisation of tumour-initiating cells in non-small-cell lung cancer European Journal of Cardio-thoracic Surgery 2009 36 3 446 453 10.1016/j.ejcts.2009.03.063 2-s2.0-68749092099 19464919 \n4 Renzi C. Caggiati A. Mannooranparampil T. J. Sentinel lymph node biopsy for high risk cutaneous squamous cell carcinoma: case series and review of the literature European Journal of Surgical Oncology 2007 33 3 364 369 10.1016/j.ejso.2006.10.017 2-s2.0-33947636745 17129703 \n5 Pereira T. C. Share S. M. Magalhães A. V. Silverman J. F. Can we tell the site of origin of metastatic squamous cell carcinoma? An immunohistochemical tissue microarray study of 194 cases Applied Immunohistochemistry and Molecular Morphology 2011 19 1 10 14 10.1097/PAI.0b013e3181ecaf1c 2-s2.0-78650804445 20823766 \n6 Patel G. K. Yee C. L. Terunuma A. Identification and characterization of tumor-initiating cells in human primary cutaneous squamous cell carcinoma Journal of Investigative Dermatology 2012 132 2 401 409 10.1038/jid.2011.317 2-s2.0-84855941324 22011906\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2017()",
"journal": "Case reports in surgery",
"keywords": null,
"medline_ta": "Case Rep Surg",
"mesh_terms": null,
"nlm_unique_id": "101580191",
"other_id": null,
"pages": "4176071",
"pmc": null,
"pmid": "28386508",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "21771334;17129703;22011906;21234325;20823766;19464919",
"title": "Suspected Pulmonary Metastasis of Actinic Cutaneous Squamous Cell Carcinoma.",
"title_normalized": "suspected pulmonary metastasis of actinic cutaneous squamous cell carcinoma"
} | [
{
"companynumb": "US-ACCORD-050597",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Objectives: Up to 40% of inflammatory bowel disease (IBD) patients treated with anti-TNF drugs lose response within 1 year of treatment, therefore requiring drug optimization. Although higher drug trough levels (TLs) are associated with sustained clinical outcomes, there are concerns that they may be associated with a higher risk of adverse events (AEs). The aim was to evaluate the presence of a possible association between drug TLs and the occurrence of AEs in IBD patients treated with anti-TNF drugs.Methods: We retrospectively studied a cohort of 113 IBD patients treated with adalimumab or infliximab, of whom 27 were in combination therapy with immunosuppressants. TLs were measured using a homogeneous mobility shift assay.Results: During a median follow-up of 16 months (range 1-144), we observed 103 AEs occurring in 58 patients. We found no statistically significant difference (p = .21) in median TLs between patients who did 6.7 mcg/mL; range 0.0-36.2) or did not (7.7 mcg/mL; range 0.0-20.7) experience an AE. No difference was observed in the rate of AEs between patients in mono- or combination therapy (p = .38), as well as between elderly (i.e., >65 years) and younger patients (p = .32). Considering a TL cutoff of 7 mcg/mL for infliximab and 12 mcg/mL for adalimumab, or even double these TL values, we observed no statistically significant difference in the rate of AEs occurrence.Conclusion: Our study suggests that, when clinically required, anti-TNF drug dosage may be increased without particular concerns regarding the risk of AEs occurrence in IBD patients, even in patients on combination therapy and elderly ones.",
"affiliations": "Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy.;Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy.;Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy.;Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy.;Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy.;Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy.;Gastroenterolgy Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.;Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy.;Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy.",
"authors": "Bodini|Giorgia|G|;Demarzo|Maria Giulia|MG|;Saracco|Margherita|M|;Coppo|Claudia|C|;De Maria|Costanza|C|;Baldissarro|Isabella|I|;Savarino|Edoardo|E|;Savarino|Vincenzo|V|http://orcid.org/0000-0001-6803-1952;Giannini|Edoardo G|EG|http://orcid.org/0000-0001-8526-837X",
"chemical_list": "D007166:Immunosuppressive Agents; D000069285:Infliximab; D000068879:Adalimumab",
"country": "England",
"delete": false,
"doi": "10.1080/00365521.2019.1666914",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0036-5521",
"issue": "54(10)",
"journal": "Scandinavian journal of gastroenterology",
"keywords": "Infliximab; adalimumab; loss of response; therapeutic drug monitoring",
"medline_ta": "Scand J Gastroenterol",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D015212:Inflammatory Bowel Diseases; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0060105",
"other_id": null,
"pages": "1220-1225",
"pmc": null,
"pmid": "31553630",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "High anti-TNF alfa drugs trough levels are not associated with the occurrence of adverse events in patients with inflammatory bowel disease.",
"title_normalized": "high anti tnf alfa drugs trough levels are not associated with the occurrence of adverse events in patients with inflammatory bowel disease"
} | [
{
"companynumb": "IT-JNJFOC-20180404726",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
"... |
{
"abstract": "In the literature, many cases of coronavirus disease 2019 (COVID-19) positive pregnancies have been observed, mostly with mild findings, but there is limited evidence about perinatal transition and early COVID-19 positive newborns. In this case, severe acute respiratory syndrome coronavirus 2 reverse transcription-polymerase chain reaction results were studied from samples obtained from the placenta, amniotic fluid, cord blood and postoperative breast milk - that were obtained while avoiding contamination and preserved appropriately - of a cesarean section performed under anesthesia on a woman with previous cesarean section and gestational diabetes mellitus history. This patient who presented to our emergency gynecology clinic with membrane rupture was infected with severe acute respiratory syndrome coronavirus 2 two weeks before delivery but was not treated as the disease was asymptomatic. In addition, literature data in line with this topic were evaluated to demonstrate that there was generally no perinatal transmission over 34 weeks of gestation.",
"affiliations": "Department of Obstetrics and Gynecology, Saglik Bilimleri University Umraniye Training and Research Hospital, Istanbul, Turkey.;Department of Obstetrics and Gynecology, Saglik Bilimleri University Umraniye Training and Research Hospital, Istanbul, Turkey.;Operation Room Services, Uskudar University, Istanbul, Turkey.;Department of Obstetrics and Gynecology, Maternal-Fetal Unit, Saglik Bilimleri University Umraniye Training and Research Hospital, Istanbul, Turkey.",
"authors": "Palalioglu|Rabia M|RM|;Mahammadaliyeva|Aytakin|A|;Erbiyik|Halil I|HI|;Muhcu|Murat|M|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.14584",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "47(2)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "coronavirus disease 2019; pregnancy; reverse transcription-polymerase chain reaction; severe acute respiratory syndrome coronavirus 2; vertical transmission",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000328:Adult; D058345:Asymptomatic Infections; D000086382:COVID-19; D005260:Female; D005322:Fetal Membranes, Premature Rupture; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011263:Pregnancy Trimester, Third; D013902:Radiography, Thoracic; D000086402:SARS-CoV-2",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "838-842",
"pmc": null,
"pmid": "33258171",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "COVID-19 in third trimester may not be as scary as you think, it can be innocent: Evaluating vertical transmission from a COVID-19 positive asymptomatic pregnant woman with early membrane rupture.",
"title_normalized": "covid 19 in third trimester may not be as scary as you think it can be innocent evaluating vertical transmission from a covid 19 positive asymptomatic pregnant woman with early membrane rupture"
} | [
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-303292",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN ANHYDROUS"
},
... |
{
"abstract": "OBJECTIVE\nTo report a case of ipilimumab-associated life-threatening diarrhea responding quickly to a single dose of infliximab.\n\n\nMETHODS\nA 67-year-old man presented 3 weeks after his second dose of ipilimumab with severe diarrhea, acute kidney injury, and hypotension. After 2 days of high-dose corticosteroids and supportive care, he continued to have 2.8 L of stool output per day (grade 4 National Cancer Institute Common Terminology Criteria for Adverse Events). The patient was transferred to the medical intensive care unit requiring endotracheal intubation because of concerns of worsening mental status, metabolic acidosis, and increased work of breathing, with a serum bicarbonate concentration of <5 mmol/L. Despite aggressive fluid resuscitation and a sodium bicarbonate infusion, he remained hypotensive and hyponatremic with persistent premature ventricular contractions. On the evening of day 3, infliximab (5 mg/kg) was given, resulting in a rapid decrease in diarrhea. After 48 hours, the acidosis was corrected and electrolytes, renal function, and fluid status were improving. At discharge, diarrhea, acute kidney injury, and acidosis had resolved, and he was discharged on a slow steroid taper.\n\n\nCONCLUSIONS\nAutoimmune colitis is a described immune-related adverse event of ipilimumab. Prompt recognition, initiation of steroids, and supportive therapy are key to the management of diarrhea. Infliximab should be considered early in steroid-nonresponsive or life-threatening diarrhea.\n\n\nCONCLUSIONS\nInfliximab is a life-saving intervention in patients with ipilimumab-induced diarrhea.",
"affiliations": "University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA.",
"authors": "Merrill|Steven P|SP|;Reynolds|Paul|P|;Kalra|Avash|A|;Biehl|Jason|J|;Vandivier|R William|RW|;Mueller|Scott W|SW|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D005765:Gastrointestinal Agents; D000074324:Ipilimumab; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028014528152",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "48(6)",
"journal": "The Annals of pharmacotherapy",
"keywords": "critically ill; diarrhea; immune-colitis; infliximab; ipilimumab; melanoma",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001327:Autoimmune Diseases; D003092:Colitis; D016638:Critical Illness; D003967:Diarrhea; D005765:Gastrointestinal Agents; D006801:Humans; D007022:Hypotension; D000069285:Infliximab; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "806-10",
"pmc": null,
"pmid": "24651165",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Early administration of infliximab for severe ipilimumab-related diarrhea in a critically ill patient.",
"title_normalized": "early administration of infliximab for severe ipilimumab related diarrhea in a critically ill patient"
} | [
{
"companynumb": "US-JNJFOC-20140516667",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "The BRAF-V600E mutation has been established as a signature alteration occurring almost universally in hairy cell leukemia. Moreover, it can be detected in a small percentage of patients with non-small cell lung cancer. We report the case of a patient with a metastatic BRAF-V600E-mutated lung adenocarcinoma suffering from concomitant hairy cell leukemia. The identification of an identical BRAF mutation in both malignancies raises physiopathological considerations and might offer unique therapeutic strategies for this group of patients.",
"affiliations": "Klinik für Onkologie, Hämatologie und Palliativmedizin, Marien Hospital Düsseldorf, Düsseldorf, Germany.;Klinik für Onkologie, Hämatologie und Palliativmedizin, Marien Hospital Düsseldorf, Düsseldorf, Germany.;Klinik für Onkologie, Hämatologie und Palliativmedizin, Marien Hospital Düsseldorf, Düsseldorf, Germany.;Klinik für Strahlentherapie, Marien Hospital Düsseldorf, Düsseldorf, Germany.;Institut für Pathologie, Krankenhaus Düren, Düren, Germany.;Klinik für Onkologie, Hämatologie und Palliativmedizin, Marien Hospital Düsseldorf, Düsseldorf, Germany.;Klinik für Onkologie, Hämatologie und Palliativmedizin, Marien Hospital Düsseldorf, Düsseldorf, Germany.",
"authors": "Mitsogianni|Maria|M|;Mitsimponas|Nikolaos|N|;Crespo|Felipe|F|;Hartmann|Karl Axel|KA|;Klosterhalfen|Bernd|B|;Haase|Sabine|S|;Giagounidis|Aristoteles|A|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000486640",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 2960694810.1159/000486640cro-0011-0109Case ReportConcomitant Non-Small Cell Lung Cancer and Hairy Cell Leukemia in a Patient Harboring BRAF-V600E Mutation in Both Tissues: A Case Report Mitsogianni Maria a*Mitsimponas Nikolaos aCrespo Felipe aHartmann Karl Axel bKlosterhalfen Bernd cHaase Sabine aGiagounidis Aristoteles aaKlinik für Onkologie, Hämatologie und Palliativmedizin, Marien Hospital Düsseldorf, Düsseldorf, GermanybKlinik für Strahlentherapie, Marien Hospital Düsseldorf, Düsseldorf, GermanycInstitut für Pathologie, Krankenhaus Düren, Düren, Germany*Dr. Maria Mitsogianni, Klinik für Onkologie, Hämatologie und Palliativmedizin, Marien Hospital Düsseldorf, Rochusstrasse 2, DE-40479 Düsseldorf (Germany), E-Mail maria_mitsogianni@hotmail.comJan-Apr 2018 14 2 2018 14 2 2018 11 1 109 113 8 1 2018 8 1 2018 Copyright © 2018 by S. Karger AG, Basel2018This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.The BRAF-V600E mutation has been established as a signature alteration occurring almost universally in hairy cell leukemia. Moreover, it can be detected in a small percentage of patients with non-small cell lung cancer. We report the case of a patient with a metastatic BRAF-V600E-mutated lung adenocarcinoma suffering from concomitant hairy cell leukemia. The identification of an identical BRAF mutation in both malignancies raises physiopathological considerations and might offer unique therapeutic strategies for this group of patients.\n\nKeywords\nBRAF-V600E mutationDriver mutationsNon-small cell lung cancerLung adenocarcinomaHairy cell leukemia\n==== Body\nIntroduction\nLung cancer is one of the most common cancer types and the leading cause of cancer-related deaths worldwide [1]. More than 80% of lung cancers can be classified as non-small cell lung cancer (NSCLC) [1], whereas adenocarcinoma is the most common histological subtype, accounting for 40% of all lung cancer cases [2]. In the last years, the identification of various oncogenic mutations in lung adenocarcinoma has enabled a better understanding of its pathogenesis and led to new effective targeted therapies for different molecularly defined subgroups [3, 4]. One of these alterations is the mutation of the BRAF gene, which occurs in 1.6–4.9% of NSCLC [3]. BRAF is an isoform of the RAF family of serine/threonine kinases and acts as mediator between RAS and the MAPK signaling pathway [5, 6]. BRAF activation by RAS results in a series of intracellular metabolic events regulating the cell cycle. Mutations in BRAF lead to permanent activation of the MAPK cascade and, therefore, stimulate cellular proliferation [6]. In general, BRAF has been shown to act as a driver oncogene in a wide range of malignant tumors [7, 8]. The most commonly detected mutation consists of a valine to glutamate substitution at codon 600 of exon 15 (V600E) [7, 8]. The BRAF-V600E mutation is the predominant alteration in malignancies such as melanoma, differentiated thyroid cancer, as well as hairy cell leukemia (HCL) [7, 9, 10]. Lung adenocarcinoma, on the other hand, presents a significant heterogeneity among BRAF mutations, with approximately only 50% presenting as V600E [7, 11]. The case reported here describes the concomitant occurrence of HCL in a patient with a BRAF-V600E-mutated lung adenocarcinoma.\n\nCase Presentation\nA 55-year-old man with a smoking history of approximately 30 pack-years was diagnosed with a tumor of the left lower lobe and underwent VATS lobectomy. Histological analysis confirmed the diagnosis of a poorly differentiated lung adenocarcinoma and further molecular diagnostics detected a mutation for BRAF-V600E. Cancer staging revealed a UICC stage Ib (pT2a, pN0, cM0) and adjuvant chemotherapy was advised but rejected by the patient.\n\nFive months later, the patient was admitted with dysphagia, fatigue, and weight loss. Computerized tomography revealed a relapse with pulmonary, lymphatic, and peritoneal metastases as well as direct infiltration of the esophagus and pharynx. At this time, peripheral blood counts were within normal limits. Palliative systemic therapy with cisplatin, vinorelbine, and bevacizumab as well as radiation of the esophagus were initiated.\n\nAfter 2 months of treatment, progressive symptomatic anemia (hemoglobin 7.4 g/dL) and severe neutropenia (absolute neutrophil count 270/μL) as well as recurrent bacterial infections were observed. The bone marrow biopsy revealed an extended infiltration by a low-grade non-Hodgkin lymphoma. Immunohistological analysis and molecular pathology detected the characteristic BRAF-V600E mutation and the diagnosis of HCL was confirmed [12, 13]. Additional immunotherapy with rituximab was initiated, resulting in normalization of the neutrophil count and improvement of anemia.\n\nHowever, in the following months, the patient developed cerebral metastasis of the NSCLC, which persisted despite radiotherapy of the neurocranium and led to death 6 months after the relapse of the disease.\n\nDiscussion\nIn our report, we present a patient with a BRAF-V600E-mutated lung adenocarcinoma who developed HCL after relapse of the disease. To the best of our knowledge, this is the first reported case of a patient diagnosed with a combination of these two BRAF-V600E-mutated malignancies.\n\nA possible association of HCL with other secondary tumors such as colorectal and renal cell carcinoma was first described many years ago [14]. The identification of the BRAF-V600E mutation as a somatically acquired signature alteration occurring universally in HCL [7, 9, 10] as well as a commonly detected mutation in a series of solid tumors [7] further supported the hypothesis of a unique pathogenic mechanism in various malignant diseases. A number of patient cases with two different synchronous or metachronous BRAF-mutated malignancies have subsequently been described.\n\nFor example, a case report by Shah et al. [15] illustrated a possible connection between neuroendocrine-differentiated colorectal cancer and HCL. The patient presented by the authors was diagnosed with BRAF-V600E-mutated metastatic neuroendocrine colon cancer several years after successful treatment of HCL. Bone marrow biopsy showed no sign of a new or recurrent hematological disease and next-generation sequencing revealed no BRAF-V600E mutation of the bone marrow, excluding the possibility of a germline mutation in that patient. This case confirms that somatic mutations of the BRAF gene in different cell types resulting in different malignancies can be observed in one individual, despite the rarity of such a combination.\n\nA conclusion based on molecular testing alone is not always reliable. Schlick et al. [16] described the isolation of a BRAF-V600E mutation in a patient with NSCLC and HCL, whereas in that case immunohistochemical analysis using the monoclonal anti-BRAF-V600E (VE1) antibody revealed that the mutation detected in the lung specimen was falsely positive due to contamination with leukemic hairy cells. Although such a contamination cannot be excluded in our case, it would be unlikely, since the mutated NSCLC occurred several months before the development of any bone marrow deficiency signs.\n\nIt needs to be pointed out that the mere occurrence of two malignancies in a single patient with the same molecular aberration, be it synchronous or metachronous, does not at all imply them to be causatively linked. Independent mutations in two different histological tissues are perfectly possible and may occur at any given point in time. In the present case, a germline BRAF mutation was not ruled out. However, its presence seems unlikely given that affected patients are most often diagnosed during childhood and display distinctive facial dysmorphia, reduced growth, cardiac defects, skeletal and ectodermal anomalies as well as cognitive dysfunctions, all of which were not present in our patient.\n\nThe existence of a common pathogenic pathway as evidenced by a somatic alteration of the BRAF gene in different malignancies can offer the possibility of a unique therapeutic strategy. For example, inhibitors of the BRAF/MAPK pathway have been proven to effectively treat HCL [17, 18]. Moreover, BRAF-targeted therapy is being widely used in the treatment of malignant melanoma [19]. In a case report by Blachly et al. [20], a patient suffering from malignant melanoma and HCL, both BRAF-V600E-mutated, achieved long-term complete remission under treatment with the BRAF-inhibitor dabrafenib. Of course, it has to be pointed out that BRAF-V600E alterations are much more common in melanoma compared to NSCLC [7]. Therefore, it can be assumed that the probability of BRAF-V600E-mutated melanoma and HCL in one individual is higher than the one of the combination described in our report.\n\nHowever, since BRAF inhibitors have been shown to be a valuable therapeutic option for patients with BRAF-mutated NSCLC [21, 22] (the combination of dabrafenib and trametinib having been approved by the FDA), efficient treatment of patients with BRAF-mutated NSCLC and HCL with a single BRAF-targeted therapy remains a realistic scenario. Further research is needed in order to detect the frequency of co-occurrence of these malignancies as well as the group of patients that could profit from a targeted personalized therapy.\n\nStatements of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n==== Refs\nReferences\n1 Yoon SM Shaikh T Hallman M Therapeutic management options for stage III non-small cell lung cancer World J Clin Oncol 2017 Feb 8 (1) 1 20 28246582 \n2 Shi J Hua X Zhu B Ravichandran S Wang M Nguyen C Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study PLoS Med 2016 Dec 13 (12) e1002162 27923066 \n3 Oxnard GR Binder A Jänne PA New targetable oncogenes in non-small-cell lung cancer J Clin Oncol 2013 Mar 31 (8) 1097 104 23401445 \n4 Park SJ More S Murtuza A Woodward BD Husain H New Targets in Non-Small Cell Lung Cancer Hematol Oncol Clin North Am 2017 Feb 31 (1) 113 29 27912827 \n5 Cantwell-Dorris ER O'Leary JJ Sheils OM BRAFV600E implications for carcinogenesis and molecular therapy Mol Cancer Ther 2011 Mar 10 (3) 385 94 21388974 \n6 Cardarella S Ogino A Nishino M Butaney M Shen J Lydon C Clinical and biologic features associated with BRAF mutations in non-small cell lung cancer Clin Cancer Res 2013 Aug 19 (16) 4532 40 23833300 \n7 Hall RD Kudchadkar RR BRAF mutations signaling, epidemiology, and clinical experience in multiple malignancies Cancer Contr 2014 Jul 21 (3) 221 30 \n8 Sánchez-Torres JM Viteri S Molina MA Rosell R BRAF mutant non-small cell lung cancer and treatment with BRAF inhibitors Transl Lung Cancer Res 2013 Jun 2 (3) 244 50 25806238 \n9 Tiacci E Trifonov V Schiavoni G Holmes A Kern W Martelli MP BRAF mutations in hairy-cell leukemia N Engl J Med 2011 Jun 364 (24) 2305 15 21663470 \n10 Arcaini L Zibellini S Boveri E Riboni R Rattotti S Varettoni M The BRAF V600E mutation in hairy cell leukemia and other mature B-cell neoplasms Blood 2012 Jan 119 (1) 188 91 22072557 \n11 Cui G Liu D Li W Fu X Liang Y Li Y A meta-analysis of the association between BRAF mutation and nonsmall cell lung cancer Medicine (Baltimore) 2017 Apr 96 (14) e6552 28383426 \n12 Quest GR Johnston JB Clinical features and diagnosis of hairy cell leukemia Best Pract Res Clin Haematol 2015 Dec 28 (4) 180 92 26614896 \n13 Tiacci E Pettirossi V Schiavoni G Falini B Genomics of Hairy Cell Leukemia J Clin Oncol 2017 Mar 35 (9) 1002 10 28297625 \n14 Nielsen B Braide I Hasselbalch H Evidence for an association between hairy cell leukemia and renal cell and colorectal carcinoma Cancer 1992 Oct 70 (8) 2087 90 1394039 \n15 Shah H McPherson K Mansour A Ramirez-Santrich C Nassiri M Shahda S Neuroendocrine Differentiation of a Primary BRAF Mutant Colon Cancer in a Patient With a History of Hairy Cell Leukemia Clin Colorectal Cancer 2016 Dec 15 (4) e235 9 27117521 \n16 Schlick K Troch M Placher-Sorko G Faber V Neureiter D Berghoff AS A patient diagnosed with BRAF-mutated non-small cell lung cancer and hairy cell leukemia at last, which entity is really carrying the BRAF mutation? Ann Hematol 2015 Feb 94 (2) 345 6 25055797 \n17 Sarvaria A Topp Z Saven A Current Therapy and New Directions in the Treatment of Hairy Cell Leukemia: A Review JAMA Oncol 2016 Jan 2 (1) 123 9 26513168 \n18 López-Rubio M Garcia-Marco JA Current and emerging treatment options for hairy cell leukemia Onco Targets Ther 2015 Aug 8 2147 56 26316784 \n19 Luke JJ Flaherty KT Ribas A Long GV Targeted agents and immunotherapies: optimizing outcomes in melanoma Nat Rev Clin Oncol 2017 Aug 14 (8) 463 82 28374786 \n20 Blachly JS Lozanski G Lucas DM Grever MR Kendra K Andritsos LA Cotreatment of hairy cell leukemia and melanoma with the BRAF inhibitor dabrafenib J Natl Compr Canc Netw 2015 Jan 13 (1) 9 13 25583765 \n21 Baik CS Myall NJ Wakelee HA Targeting BRAF-Mutant Non-Small Cell Lung Cancer: From Molecular Profiling to Rationally Designed Therapy Oncologist 2017 Jul 22 (7) 786 96 28487464 \n22 Myall NJ Neal JW Cho-Phan CD Zhou LY Stehr H Zhou L Long-Term Survival of a Patient With Non-Small-Cell Lung Cancer Harboring a V600E Mutation in the BRAF Oncogene Clin Lung Cancer 2016 Mar 17 (2) e17 21 26776917\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "11(1)",
"journal": "Case reports in oncology",
"keywords": "BRAF-V600E mutation; Driver mutations; Hairy cell leukemia; Lung adenocarcinoma; Non-small cell lung cancer",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "109-113",
"pmc": null,
"pmid": "29606948",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "28374786;27912827;25583765;21663470;28383426;26316784;25055797;26513168;24955706;23833300;26776917;28487464;26614896;27117521;21388974;28297625;27923066;23401445;28246582;22072557;25806238;1394039",
"title": "Concomitant Non-Small Cell Lung Cancer and Hairy Cell Leukemia in a Patient Harboring BRAF-V600E Mutation in Both Tissues: A Case Report.",
"title_normalized": "concomitant non small cell lung cancer and hairy cell leukemia in a patient harboring braf v600e mutation in both tissues a case report"
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"abstract": "Continuous infusion of vecuronium is a commonly used technique for patients requiring prolonged neuromuscular blockade for mechanical ventilation. As compared with older neuromuscular blocking agents, it confers the advantages of rapid excretion and intermediate duration of action. Prolongation of neuromuscular blockade and muscle weakness are the known complications of continuous vecuronium infusion. This report attempts to describe polyuria, as a hitherto unknown complication of vecuronium infusion, which can occur due to the mannitol present in commercially available preparation of vecuronium bromide.",
"affiliations": "1Department of Anaesthesia, Gian Sagar Medical College, Patiala, India; 2Department of Anaesthesia and Critical Care Medicine (Trauma), All India Institute of Medical Sciences, New Delhi, India; and 3Department of Anaesthesia and Intensive Care, Post Graduate Institute of Medical Education and Research, Chandigarh, India.",
"authors": "Haldar|Rudrashish|R|;Samanta|Sukhen|S|;Singla|Ankush|A|",
"chemical_list": "D003473:Neuromuscular Nondepolarizing Agents; D008353:Mannitol; D014673:Vecuronium Bromide",
"country": "United States",
"delete": false,
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"issue": "23(2)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000328:Adult; D003919:Diabetes Insipidus; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008353:Mannitol; D003473:Neuromuscular Nondepolarizing Agents; D011141:Polyuria; D014673:Vecuronium Bromide",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e588-90",
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"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intractable Polyuria Mimicking Diabetes Insipidus-Source Traced to Vecuronium Infusion.",
"title_normalized": "intractable polyuria mimicking diabetes insipidus source traced to vecuronium infusion"
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"companynumb": "IN-MYLANLABS-2016M1021069",
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"activesubstancename": "VECURONIUM BROMIDE"
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"abstract": "Triple-negative breast cancer (TNBC) classified by transcriptional profiling as the mesenchymal subtype frequently harbors aberrations in the phosphoinositide 3-kinase (PI3K) pathway, raising the possibility of targeting this pathway to enhance chemotherapy response. Up to 30% of mesenchymal TNBC can be classified histologically as metaplastic breast cancer, a chemorefractory group of tumors with a mixture of epithelial and mesenchymal components identifiable by light microscopy. While assays to identify mesenchymal TNBC are under development, metaplastic breast cancer serves as a clinically identifiable surrogate to evaluate potential regimens for mesenchymal TNBC.\nTo assess safety and efficacy of mammalian target of rapamycin (mTOR) inhibition in combination with liposomal doxorubicin and bevacizumab in patients with advanced metaplastic TNBC.\nPhase 1 study with dose escalation and dose expansion at the University of Texas MD Anderson Cancer Center of patients with advanced metaplastic TNBC. Patients were enrolled from April 16, 2009, to November 4, 2014, and followed for outcomes with a cutoff date of November 1, 2015, for data analysis.\nLiposomal doxorubicin, bevacizumab, and the mTOR inhibitors temsirolimus or everolimus using 21-day cycles.\nSafety and response. When available, archived tissue was evaluated for aberrations in the PI3K pathway.\nFifty-two women with metaplastic TNBC (median age, 58 years; range, 37-79 years) were treated with liposomal doxorubicin, bevacizumab, and temsirolimus (DAT) (N = 39) or liposomal doxorubicin, bevacizumab, and everolimus (DAE) (N = 13). The objective response rate was 21% (complete response = 4 [8%]; partial response = 7 [13%]) and 10 (19%) patients had stable disease for at least 6 months, for a clinical benefit rate of 40%. Tissue was available for testing in 43 patients, and 32 (74%) had a PI3K pathway aberration. Presence of PI3K pathway aberration was associated with a significant improvement in objective response rate (31% vs 0%; P = .04) but not clinical benefit rate (44% vs 45%; P > .99).\nUsing metaplastic TNBC as a surrogate for mesenchymal TNBC, DAT and DAE had notable activity in mesenchymal TNBC. Objective response was limited to patients with PI3K pathway aberration. A randomized trial should be performed to test DAT and DAE for metaplastic TNBC, as well as nonmetaplastic, mesenchymal TNBC, especially when PI3K pathway aberrations are identified.",
"affiliations": "Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston.;Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston.;Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston.;Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston.;Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston5Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston6Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Biostatistics, The University of Texas MD Anderson Cancer Center, Houston.;Pediatrics, The University of Texas MD Anderson Cancer Center, Houston.;Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston.;Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston9Health Services Research, The University of Texas MD Anderson Cancer Center, Houston.;Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston.;Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston.;Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston10Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, La Jolla.;Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston.;Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston4Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston.",
"authors": "Basho|Reva K|RK|;Gilcrease|Michael|M|;Murthy|Rashmi K|RK|;Helgason|Thorunn|T|;Karp|Daniel D|DD|;Meric-Bernstam|Funda|F|;Hess|Kenneth R|KR|;Herbrich|Shelley M|SM|;Valero|Vicente|V|;Albarracin|Constance|C|;Litton|Jennifer K|JK|;Chavez-MacGregor|Mariana|M|;Ibrahim|Nuhad K|NK|;Murray|James L|JL|;Koenig|Kimberly B|KB|;Hong|David|D|;Subbiah|Vivek|V|;Kurzrock|Razelle|R|;Janku|Filip|F|;Moulder|Stacy L|SL|",
"chemical_list": "D053492:Elafin; C506806:PI3 protein, human; D047428:Protein Kinase Inhibitors; C506643:liposomal doxorubicin; D000068258:Bevacizumab; D011092:Polyethylene Glycols; C401859:temsirolimus; D004317:Doxorubicin; D000068338:Everolimus; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.1001/jamaoncol.2016.5281",
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"issn_linking": "2374-2437",
"issue": "3(4)",
"journal": "JAMA oncology",
"keywords": null,
"medline_ta": "JAMA Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D004317:Doxorubicin; D053492:Elafin; D000068338:Everolimus; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D011092:Polyethylene Glycols; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D064726:Triple Negative Breast Neoplasms",
"nlm_unique_id": "101652861",
"other_id": null,
"pages": "509-515",
"pmc": null,
"pmid": "27893038",
"pubdate": "2017-04-01",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": null,
"title": "Targeting the PI3K/AKT/mTOR Pathway for the Treatment of Mesenchymal Triple-Negative Breast Cancer: Evidence From a Phase 1 Trial of mTOR Inhibition in Combination With Liposomal Doxorubicin and Bevacizumab.",
"title_normalized": "targeting the pi3k akt mtor pathway for the treatment of mesenchymal triple negative breast cancer evidence from a phase 1 trial of mtor inhibition in combination with liposomal doxorubicin and bevacizumab"
} | [
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"companynumb": "PHHY2017US067774",
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"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
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"drugadditional": "3",
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{
"abstract": "A 61-year-old woman presented with sudden vision loss from a left anterior optic neuropathy in the context of severely elevated intraocular pressure after starting topical steroids for anterior uveitis related to herpes zoster ophthalmicus (HZO). The strong temporal relationship between the vision loss and elevated IOP suggested the vision loss was related to nonarteritic anterior ischemic optic neuropathy (NAION). Anterior chamber paracentesis did not detect varicella zoster virus (VZV) and magnetic resonance imaging of the orbits was normal. Her vision remained stable and the optic disc edema resolved within 3 months. The occurrence of NAION following an acute elevation of intraocular pressure (IOP) is well-documented in the context of surgical procedures, glaucoma, uveitis and trauma. This case indicates that not every optic neuropathy in close temporal relationship with HZO is directly attributable to the virus. NAION may also occur after steroid-related IOP spikes and ophthalmologists should ensure that patients on topical steroids are closely monitored for ocular complications.",
"affiliations": "Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.;Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada.",
"authors": "Yuan|Po Hsiang|PH|;Micieli|Jonathan A|JA|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000511100",
"fulltext": "\n==== Front\nCase Rep Ophthalmol\nCase Rep Ophthalmol\nCOP\nCase Reports in Ophthalmology\n1663-2699 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000511100\ncop-0012-0011\nCase Report\nNonarteritic Anterior Ischemic Optic Neuropathy following Herpes Zoster Ophthalmicus and Steroid-Related Intraocular Pressure Spike\nYuan Po Hsiang a Micieli Jonathan A. bcd* aFaculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada\nbDepartment of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada\ncDivision of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada\ndKensington Vision and Research Centre, Toronto, Ontario, Canada\n*Jonathan A. Micieli, Kensington Vision and Research Centre, 340 College Street, Suite 501, Toronto, ON, M5T 3A9 (Canada), jmicieli@kensingtonhealth.org\nJan-Apr 2021 \n7 1 2021 \n7 1 2021 \n12 1 11 15\n3 7 2020 20 8 2020 2021 Copyright © 2021 by S. Karger AG, Basel2021This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.A 61-year-old woman presented with sudden vision loss from a left anterior optic neuropathy in the context of severely elevated intraocular pressure after starting topical steroids for anterior uveitis related to herpes zoster ophthalmicus (HZO). The strong temporal relationship between the vision loss and elevated IOP suggested the vision loss was related to nonarteritic anterior ischemic optic neuropathy (NAION). Anterior chamber paracentesis did not detect varicella zoster virus (VZV) and magnetic resonance imaging of the orbits was normal. Her vision remained stable and the optic disc edema resolved within 3 months. The occurrence of NAION following an acute elevation of intraocular pressure (IOP) is well-documented in the context of surgical procedures, glaucoma, uveitis and trauma. This case indicates that not every optic neuropathy in close temporal relationship with HZO is directly attributable to the virus. NAION may also occur after steroid-related IOP spikes and ophthalmologists should ensure that patients on topical steroids are closely monitored for ocular complications.\n\nKeywords\nNAIONIschemic optic neuropathyIntraocular pressureHerpes zoster\n==== Body\nIntroduction\nVision loss is a rare complication of herpes zoster ophthalmicus (HZO) and can be a result of anterior segment of posterior segment involvement. Optic neuropathy is a rare complication of HZO seen in less than 0.5% of cases and can be anterior (associated with optic disc edema) or retrobulbar [1]. The diagnosis of herpes zoster optic neuropathy (HZON) is diagnosed in patients who develop an optic neuropathy in close temporal relationship with HZO with other causes of optic neuropathy being excluded. Supportive evidence for the diagnosis is helpful by means of magnetic resonance imaging (MRI) of the orbits with contrast demonstrating enhancement of the optic nerve in retrobulbar cases, or the detection of varicella zoster virus (VZV) in the aqueous humor or cerebrospinal fluid (CSF) [1]. However, the yield of detection of VZV in the CSF is low, especially in anterior cases. Treatment consists of oral or intravenous antivirals and the use of systemic corticosteroids remains controversial [1]. Patients with HZO may develop an anterior optic neuropathy that is not directly related to VZV, but secondarily related to HZO by means of other ocular complications. We report a case of nonarteritic anterior ischemic optic neuropathy (NAION) related to HZO, which was likely secondary to the development of a steroid response and elevated intraocular pressure (IOP) for the treatment of anterior uveitis. This indicates that not every optic neuropathy in close temporal relationship to HZO is directly related to the virus.\n\nCase Report\nA 61-year-old woman was seen in neuro-ophthalmology consultation for a left optic neuropathy. She had a history of hypertension and was taking amlodipine. She developed left HZO 1 month prior to presentation with skin lesions on the left forehead and tip and side of her nose. She was treated with valacyclovir 1 g PO TID for 10 days. She saw an ophthalmologist 3 days later and was found to have anterior uveitis (1+ cells), an intraocular pressure of 18, and was started on prednisolone acetate 1% eye drops QID. This was continued and the examination remained stable 1 week later. Two weeks later, she developed left eye pain and worsening vision. She saw an ophthalmologist and was found to have an intraocular pressure of 52 mm Hg without any signs of uveitis. Her refraction was −1.00 +0.50 × 172 OD and −1.50 +0.50 × 180 OS and the gonioscopy revealed open angles, grade 3 (Shaffer system) with the trabecular meshwork visible for 360 degrees in both eyes. She was started on acetazolamide 250 mg PO QID, brimonidine-timolol eye drops BID and topical prednisolone acetate was discontinued given the likelihood of a steroid response. Follow-up the next day revealed an improved intraocular pressure of 16, but she was noted to have a new relative afferent pupillary defect and optic disc edema in the left optic nerve. A neuro-ophthalmology consultation was requested. Acetazolamide and brimonidine-timolol eye drops were discontinued.\n\nNeuro-ophthalmology assessment revealed a visual acuity of 20/20 OD and 20/100 OS, a left RAPD, and Humphrey visual field testing demonstrated a left inferior altitudinal visual field defect (Fig. 1a). Anterior segment revealed no signs of uveitis and dilated fundus examination demonstrated a normal appearing right optic nerve with a cup-to-disc ratio of 0.1 and left diffuse optic disc edema. Optical coherence tomography of the retinal nerve fiber layer showed an average thickness of 84 μm OD and 182 μm OS (Fig. 1b). The differential diagnosis considered was a left anterior optic neuropathy related to herpes zoster or NAION related to the recent IOP elevation. An anterior chamber paracentesis was performed and VZV was not detected by real-time PCR. She had an MRI of the brain and orbits with contrast that did not show enhancement of the optic nerves and was normal. Complete blood count, erythrocyte sedimentation rate and C-reactive protein were normal. She was treated with valacyclovir 1 g PO TID for 1 month as a precaution, but her vision did not improve. At 3-month follow-up, she continued to have a left inferior altitudinal visual field defect and the left optic disc edema had resolved.\n\nDiscussion\nVision loss is a feared complication of HZON and may affect almost any part of the eye including the anterior and posterior segments [1]. This may be a result of direct involvement of VZV or a secondary inflammatory component. This case highlights that optic nerve complications from VZV may not be due to direct involvement of the virus but can be a secondary result of another ocular complication. Our patient developed NAION related to elevated IOP that likely disrupted the perfusion to the optic nerve head. This was unlikely to be a direct result of the virus for a number of reasons including the absence of detectable virus in the aqueous humor by PCR, the absence of any optic nerve enhancement on orbital MRI with contrast and the absence of any improvement in her visual field, which is typical of NAION, despite antiviral treatment [2]. The patient also had a history of hypertension and a disc-at-risk, which is a requirement for the development of NAION [3]. The optic disc edema resolved in the expected time course for NAION, and the patient had no other signs or symptoms of another optic neuropathy. There was also a clear temporal relationship between the IOP spike and the loss of vision. Although CSF was not obtained, this would be an extremely low-yield test, especially with no retrobulbar involvement seen on MRI.\n\nNAION has been previously described to develop in response to elevated IOP and subsequent disruption to the optic nerve head perfusion pressure [4, 5, 6]. This has been well-described in a number of situations including after ophthalmological procedures, acute glaucoma, hypertensive uveitis, or the administration of steroid eye drops [7, 8, 9, 10, 11]. Cases of ophthalmological procedures include cataract extraction complicated by capsular block, pars plana vitrectomy for macular hole, and trabeculectomy complicated by NAION have been described [7, 8, 9]. NAION after intravitreal injections have also been presumed to be related to elevated intraocular pressure, although the IOP has not been routinely measured in most of these cases [12]. The presumed mechanism of NAION after cataract surgery has also been thought to be related to elevated IOP, which is elevated intraoperatively and sometimes postoperatively [13]. Acute primary angle closure and traumatic angle recession glaucoma has been reported to be complicated by NAION and may be bilateral and severe [10, 11]. We were unable to retrieve any previously reported case of NAION secondary to herpes zoster anterior uveitis, but cases after Posner-Schlossman syndrome (PSS) have been described. Similar to our case, the PSS cases all had IOP in excess of 50 mmHg and some cases were in individuals younger than 50 years of age [5, 10]. We were unable to retrieve any cases of NAION that developed after steroid-related IOP spikes.\n\nElevated intraocular pressure is well-known complication of topical steroids and to a lesser extent systemic and topical steroid treatment [14, 15]. This typically onsets around 3–6 weeks after the initiation of topical steroids and is thought to be related to increased resistance to aqueous outflow at the trabecular meshwork. The mechanism of this IOP elevation is unclear but the discontinuation of steroid treatment predictably triggers the reversal of IOP elevation back to baseline [14]. Complications of elevated IOP, not only include glaucoma, but may also result in retinal vein occlusions, corneal edema and as we have shown in this case, NAION. It is important that ophthalmologists closely monitor patients on topical steroids since NAION may be a rare and irreversible complication of their use. This may even occur in younger patients who may be taking topical steroids postoperatively for eye surgery or for ocular inflammatory disorders. Treatment of steroid-induced ocular hypertension typically involves discontinuation of the steroid and use of topical and systemic IOP-lowering medications. The elevation of IOP in our patient was likely related to topical steroid use since there was no active inflammation at the time of vision loss and the IOP responded promptly to the discontinuation of steroids.\n\nIn summary, the development of an optic neuropathy in close temporal relationship may not necessarily be related to VZV. We report a case of steroid-induced ocular hypertension for initial treatment of herpes zoster-related anterior uveitis that was complicated by NAION. Patients on topical steroids should be closely monitored since irreversible optic nerve damage may occur in this context.\n\nStatement of Ethics\nThis study was carried out in accordance with the World Medical Association Declaration of Helsinki. Verbal and written consent were obtained from the patient.\n\nConflict of Interest Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nNo funding was received.\n\nAuthor Contributions\nConception and design (P.H.Y., J.A.M.), data extraction (P.H.Y., J.A.M.), manuscript preparation (P.H.Y.), final approval (J.A.M.). All authors have seen and approved the final version of the manuscript for publication.\n\nFig. 1 a Humphrey 24–2 SITA-Fast visual fields demonstrating a left inferior altitudinal visual field defect. b Optical coherence tomography of the retinal nerve fiber layer (RNFL) at presentation with left eye vision loss demonstrating an elevated RNFL due to optic disc edema in the left eye.\n==== Refs\nReferences\n1 Kedar S Jayagopal LN Berger JR Neurological and ophthalmological manifestations of varicella zoster virus J Neuroophthalmol 2019 6 39 (2) 220 31 30188405 \n2 Hayreh SS Ischemic optic neuropathy Prog Retin Eye Res 2009 1 28 (1) 34 62 19063989 \n3 Tsai RK Liu YT Su MY Risk factors of non-arteritic anterior ischemic optic neuropathy (NAION): ocular or systemic Kaohsiung J Med Sci 1998 4 14 (4) 221 5 9589616 \n4 Slavin ML Margulis M Anterior ischemic optic neuropathy following acute angle-closure glaucoma Arch Ophthalmol 2001 8 119 (8) 1215 11483097 \n5 Kim R Van Stavern G Juzych M Nonarteritic anterior ischemic optic neuropathy associated with acute glaucoma secondary to Posner-Schlossman syndrome Arch Ophthalmol 2003 1 121 (1) 127 8 12523901 \n6 Choudhari NS George R Kankaria V Sunil GT Anterior ischemic optic neuropathy precipitated by acute primary angle closure Indian J Ophthalmol 2010 Sep-Oct 58 (5) 437 40 20689205 \n7 Cunha LP Cunha LV Costa CF Monteiro ML Nonarteritic anterior ischemic optic neuropathy following pars plana vitrectomy for macular hole treatment: case report Arq Bras Oftalmol 2016 Sep-Oct 79 (5) 342 5 27982219 \n8 Lee H Kim CY Seong GJ Ma KT A case of decreased visual field after uneventful cataract surgery: nonarteritic anterior ischemic optic neuropathy Korean J Ophthalmol 2010 2 24 (1) 57 61 20157417 \n9 Kawashima H Nagai N Shinoda H Tsubota K Ozawa Y Optic neuropathy causing vertical unilateral hemianopsia after pars plana vitrectomy for a macular hole: A case report Medicine (Baltimore) 2018 4 97 (17) e0321 29702978 \n10 Irak I Katz BJ Zabriskie NA Zimmerman PL Posner-Schlossman syndrome and nonarteritic anterior ischemic optic neuropathy J Neuroophthalmol 2003 12 23 (4) 264 7 14663306 \n11 Nahum Y Newman H Kurtz S Rachmiel R Nonarteritic anterior ischemic optic neuropathy in a patient with primary acute angle-closure glaucoma Can J Ophthalmol 2008 12 43 (6) 723 4 19020646 \n12 Battaglia Parodi M Iacono P Cascavilla ML Zucchiatti I Kontadakis DS Vergallo S Sequential anterior ischemic optic neuropathy and central retinal artery and vein occlusion after ranibizumab for diabetic macular edema Eur J Ophthalmol 2010 Nov-Dec 20 (6) 1076 8 20954148 \n13 Yang HK Park SJ Byun SJ Park KH Hwang JM Risk of Nonarteritic Anterior Ischemic Optic Neuropathy After Cataract Surgery Am J Ophthalmol 2019 11 207 343 50 31415735 \n14 Becker B Mills DW Elevated intraocular pressure following corticosteroid eye drops JAMA 1963 9 185 (11) 884 6 14043096 \n15 Bernstein HN Mills DW Becker B Steroid-induced elevation of intraocular pressure Arch Ophthalmol 1963 7 70 (1) 15 8 13967695\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1663-2699",
"issue": "12(1)",
"journal": "Case reports in ophthalmology",
"keywords": "Herpes zoster; Intraocular pressure; Ischemic optic neuropathy; NAION",
"medline_ta": "Case Rep Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101532006",
"other_id": null,
"pages": "11-15",
"pmc": null,
"pmid": "33613245",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "20689205;12523901;31415735;29702978;9589616;30188405;20157417;19063989;19020646;27982219;13967695;20954148;14663306;11483097;14043096",
"title": "Nonarteritic Anterior Ischemic Optic Neuropathy following Herpes Zoster Ophthalmicus and Steroid-Related Intraocular Pressure Spike.",
"title_normalized": "nonarteritic anterior ischemic optic neuropathy following herpes zoster ophthalmicus and steroid related intraocular pressure spike"
} | [
{
"companynumb": "CA-ALLERGAN-2122209US",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "1",
... |
{
"abstract": "Digoxin is widely used to manage heart failure and atrial fibrillation, and requires careful patient monitoring to avoid toxicity. Vision disturbances are a specific indicator of toxicity and may be the initial sign. Treatment depends on the patient's clinical presentation.",
"affiliations": "Office of Bassam Haddad, MD, Jersey City, NJ, USA.",
"authors": "Dobkowski|Darlene|D|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D007140:Immunoglobulin Fab Fragments; C050199:digoxin antibodies Fab fragments; D004077:Digoxin",
"country": "United States",
"delete": false,
"doi": "10.1097/01.jaa.0000430341.17896.d8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0893-7400",
"issue": "26(6)",
"journal": "JAAPA : official journal of the American Academy of Physician Assistants",
"keywords": null,
"medline_ta": "JAAPA",
"mesh_terms": "D000368:Aged; D000889:Anti-Arrhythmia Agents; D001281:Atrial Fibrillation; D004077:Digoxin; D006073:Gout; D006801:Humans; D007140:Immunoglobulin Fab Fragments; D008297:Male; D051436:Renal Insufficiency, Chronic; D014786:Vision Disorders",
"nlm_unique_id": "9513102",
"other_id": null,
"pages": "30-2",
"pmc": null,
"pmid": "23805590",
"pubdate": "2013-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An older man with gout and vision changes.",
"title_normalized": "an older man with gout and vision changes"
} | [
{
"companynumb": "US-AUROBINDO-AUR-APL-2021-024483",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALLOPURINOL"
},
"drugadditional": nul... |
{
"abstract": "OBJECTIVE\nTo investigate nystagmus and other visual system abnormalities among children exposed to opiates and benzodiazepines in utero.\n\n\nMETHODS\nRetrospective case series comprising clinical examination and case note review of 25 children with nystagmus and reduced vision who were exposed to controlled drugs during pregnancy.\n\n\nRESULTS\nTwenty-four children were exposed to opiates, of whom 13 were also exposed to diazepam. One child was exposed to diazepam alone. All children had horizontal nystagmus, which was either fine pendular or jerk type. The nystagmus had a latent element in 4 children and 8 adopted a compensatory head posture. Where the time of onset of nystagmus was known, it was always prior to 6 months of age. At least 9 children (36%) had delayed visual maturation. The mean initial logarithm of the minimum angle of resolution binocular best-corrected visual acuity (BCVA) was 0.54 at an average of 22 months of age. Thirteen children were followed up for 6 months or longer and their BCVA improved to 0.4 at an average age of 48 months. The nystagmus was clinically improved in only 5 patients. Electroretinogram testing was normal in the 4 children tested. The only ocular structural abnormality was binocular optic nerve hypoplasia in 2 children.\n\n\nCONCLUSIONS\nExposure to opiates and benzodiazepines in utero may be associated with permanent nystagmus and reduced visual acuity. This is most likely the result of insult(s) to the central nervous system rather than the eyes.",
"affiliations": "Royal Victoria Infirmary, Newcastle, United Kingdom.",
"authors": "Gupta|Manish|M|;Mulvihill|Alan O|AO|;Lascaratos|Gerassimos|G|;Fleck|Brian W|BW|;George|Nick D|ND|",
"chemical_list": "D053610:Opiate Alkaloids; D003975:Diazepam",
"country": "United States",
"delete": false,
"doi": "10.3928/01913913-20110308-01",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0191-3913",
"issue": "49(1)",
"journal": "Journal of pediatric ophthalmology and strabismus",
"keywords": null,
"medline_ta": "J Pediatr Ophthalmol Strabismus",
"mesh_terms": "D002675:Child, Preschool; D003975:Diazepam; D004596:Electroretinography; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D009759:Nystagmus, Pathologic; D053610:Opiate Alkaloids; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012189:Retrospective Studies; D019966:Substance-Related Disorders; D014786:Vision Disorders; D015348:Vision, Binocular; D014792:Visual Acuity",
"nlm_unique_id": "7901143",
"other_id": null,
"pages": "58-63",
"pmc": null,
"pmid": "21417186",
"pubdate": "2012",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Nystagmus and reduced visual acuity secondary to drug exposure in utero: long-term follow-up.",
"title_normalized": "nystagmus and reduced visual acuity secondary to drug exposure in utero long term follow up"
} | [
{
"companynumb": "GB-ACTAVISPR-2014-16757",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIAZEPAM"
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"drugadditional": null,
... |
{
"abstract": "The management of critically ill Cushing's disease (CD) patients is extremely challenging. Pasireotide is indicated for the treatment of CD patients when pituitary surgery is unfeasible or has not been curative, but no data are available about the use of this drug as pre-operative treatment in critically ill patients. We report the effects of presurgical pasireotide therapy in CD patients in whom hypercortisolism caused life-threatening hypokalemia, alkalosis, and cardio-respiratory complications precluding surgical approach. Clinical, biochemical, and radiological data of two critically ill patients with ACTH-secreting pituitary macroadenoma, before and during first-line presurgical pasireotide treatment (600 μg s.c. bid). During the first 21 days of treatment, pasireotide therapy induced a rapid, partial decrease of plasma ACTH, serum cortisol, and urinary free cortisol levels, with the consequent normalization of serum potassium concentration and arterial blood gases parameters, in both the patients. They did not experience unmanageable side effects and underwent endoscopic transsphenoidal surgery after 4 weeks of effective treatment. Pre-operative MRI evaluation did not show pituitary tumor shrinkage. Surgical cure of CD was obtained in the first patient, while debulking allowed the pharmacological control of hypercortisolism in the second case. We suggest that pasireotide can induce a rapid improvement of clinical and metabolic conditions in critically ill CD patients in whom surgical approach is considered hazardous and need to be delayed.",
"affiliations": "Department of Clinical and Experimental Medicine - Endocrinology Unit, University of Messina, Messina, Italy.;Department of Clinical and Experimental Medicine - Endocrinology Unit, University of Messina, Messina, Italy.;Department of Clinical and Experimental Medicine - Endocrinology Unit, University of Messina, Messina, Italy.;Department of Clinical and Experimental Medicine - Endocrinology Unit, University of Messina, Messina, Italy. francesco.ferrau1@gmail.com.;Department of Human Pathology Gaetano Barresi - Section of Anatomic Pathology, University of Messina, Messina, Italy.;Department of Neuroscience - Neurosurgery Unit, University of Messina, Messina, Italy.;Department of Neuroscience - Neurosurgery Unit, University of Messina, Messina, Italy.;Department of Neuroscience - Neurosurgery Unit, University of Messina, Messina, Italy.",
"authors": "Cannavo|S|S|;Messina|E|E|;Albani|A|A|;Ferrau|F|F|;Barresi|V|V|;Priola|S|S|;Esposito|F|F|;Angileri|F|F|",
"chemical_list": "D000970:Antineoplastic Agents; D013004:Somatostatin; C517782:pasireotide",
"country": "United States",
"delete": false,
"doi": "10.1007/s12020-015-0601-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-008X",
"issue": "52(3)",
"journal": "Endocrine",
"keywords": "ARDS; Cushing’s disease; Hypercortisolism; Pituitary tumors; Somatostatin analogs",
"medline_ta": "Endocrine",
"mesh_terms": "D049913:ACTH-Secreting Pituitary Adenoma; D000236:Adenoma; D000328:Adult; D000970:Antineoplastic Agents; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D016638:Critical Illness; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D047748:Pituitary ACTH Hypersecretion; D057234:Preoperative Period; D013004:Somatostatin; D016896:Treatment Outcome",
"nlm_unique_id": "9434444",
"other_id": null,
"pages": "481-7",
"pmc": null,
"pmid": "25877016",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20463350;21752886;19289534;25624013;24415169;22397653;22573933;23564942;12943521;25743263;20829621;25012159;22577107;25500791;18957506;24980037;23564338;22918543;22652826;24576201;23733372;23192246;24272603;23345100;18413427;18264630",
"title": "Clinical management of critically ill patients with Cushing's disease due to ACTH-secreting pituitary macroadenomas: effectiveness of presurgical treatment with pasireotide.",
"title_normalized": "clinical management of critically ill patients with cushing s disease due to acth secreting pituitary macroadenomas effectiveness of presurgical treatment with pasireotide"
} | [
{
"companynumb": "PHHY2016IT079673",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "POTASSIUM CHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "Hypocalcaemia is a rare complication of calcium channel blocker overdose, having been reported only once previously (J Toxicol Clin Toxicol, 1992, 30, 309). In this article, we report a case of a 37-year-old woman who developed hypocalcaemia after a verapamil overdose, review the literature and propose a mechanism for this rare finding.",
"affiliations": "Department of Internal Medicine, University of California, Davis, Sacramento, CA, USA.",
"authors": "Price|David|D|;Radke|Joshua|J|;Albertson|Timothy|T|",
"chemical_list": "D002121:Calcium Channel Blockers; D014700:Verapamil; D002118:Calcium",
"country": "England",
"delete": false,
"doi": "10.1111/bcpt.12121",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1742-7835",
"issue": "114(2)",
"journal": "Basic & clinical pharmacology & toxicology",
"keywords": null,
"medline_ta": "Basic Clin Pharmacol Toxicol",
"mesh_terms": "D000328:Adult; D002118:Calcium; D002121:Calcium Channel Blockers; D016638:Critical Illness; D062787:Drug Overdose; D005260:Female; D006801:Humans; D006996:Hypocalcemia; D016896:Treatment Outcome; D014700:Verapamil",
"nlm_unique_id": "101208422",
"other_id": null,
"pages": "217-21",
"pmc": null,
"pmid": "24034162",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Hypocalcaemia after an occult calcium channel blocker overdose: a case report and literature review.",
"title_normalized": "hypocalcaemia after an occult calcium channel blocker overdose a case report and literature review"
} | [
{
"companynumb": "US-GLENMARK GENERICS INC.-2014GMK011976",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VERAPAMIL HYDROCHLORIDE"
},
"dr... |
{
"abstract": "BACKGROUND\nFelty syndrome is a rare and life-threatening type of rheumatoid arthritis (RA).\nA patient with RA had skin rash and subcutaneous hemorrhage, with a significant decrease in blood hemoglobin (Hb), white blood cell count (WBC), and blood platelet count (BPC).\nThe patient had a history of RA, splenomegaly, decreased Hb, WBC, BPC, and normal immunological indexes, combined with a series of bone marrow related tests and genetic tests.\n\n\nMETHODS\nShe was given high-doses of glucocorticoids intravenously, followed by oral prednisone and cyclosporine maintenance therapy.\n\n\nRESULTS\nHer symptoms were resolved within 2 weeks after the start of immunosuppression. After 2 weeks of discharge, the Hb, WBC, BPC basically returned to normal, and prednisone gradually decreased.\n\n\nCONCLUSIONS\nFelty syndrome is a rare complication of RA. Reductions in Hb, WBC, BPC, and subcutaneous hemorrhage should be considered strongly as the possibility of Felty syndrome. Multi-disciplinary diagnosis and related tests of bone marrow and genes are helpful for diagnosis and correct treatment.",
"affiliations": "The First Affiliated Hospital of GuangDong Pharmaceutical University.;Department of traditional Chinese medicine, southern theater general hospital, the Chinese People's Liberation Army, Guangzhou, China.;Department of traditional Chinese medicine, southern theater general hospital, the Chinese People's Liberation Army, Guangzhou, China.",
"authors": "Wu|Peng|P|;Sun|Weifeng|W|;Li|Jing|J|",
"chemical_list": "D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000023608",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD \n\nMD-D-19-09872\n10.1097/MD.0000000000023608\n23608\n6900\nResearch Article\nClinical Case Report\nRheumatoid arthritis patients with peripheral blood cell reduction should be evaluated for latent Felty syndrome\nA case reportWu Peng MD, PhDa∗ Sun Weifeng MD, PhDb Li Jing MD, PhDb Saranathan. Maya a The First Affiliated Hospital of GuangDong Pharmaceutical University\nb Department of traditional Chinese medicine, southern theater general hospital, the Chinese People's Liberation Army, Guangzhou, China.\n∗ Correspondence: Peng Wu, Department of Intergrated Chinese and with Western Medicine, The First Affiliated Hospital of GuangDong Pharmaceutical University, 19 Nonglinxia Road, Yuexiu District, Guangzhou, Guangdong 510010, China (e-mail: wpeng23@163.com).\n18 12 2020 \n18 12 2020 \n99 51 e2360819 12 2019 11 10 2020 10 11 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nFelty syndrome is a rare and life-threatening type of rheumatoid arthritis (RA).\n\nPatient concerns:\nA patient with RA had skin rash and subcutaneous hemorrhage, with a significant decrease in blood hemoglobin (Hb), white blood cell count (WBC), and blood platelet count (BPC).\n\nDiagnoses:\nThe patient had a history of RA, splenomegaly, decreased Hb, WBC, BPC, and normal immunological indexes, combined with a series of bone marrow related tests and genetic tests.\n\nInterventions:\nShe was given high-doses of glucocorticoids intravenously, followed by oral prednisone and cyclosporine maintenance therapy.\n\nOutcomes:\nHer symptoms were resolved within 2 weeks after the start of immunosuppression. After 2 weeks of discharge, the Hb, WBC, BPC basically returned to normal, and prednisone gradually decreased.\n\nLessons:\nFelty syndrome is a rare complication of RA. Reductions in Hb, WBC, BPC, and subcutaneous hemorrhage should be considered strongly as the possibility of Felty syndrome. Multi-disciplinary diagnosis and related tests of bone marrow and genes are helpful for diagnosis and correct treatment.\n\nKeywords\nFelty syndromeglucocorticoidperipheral blood cellrheumatoid arthritisOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nFelty syndrome is a rare and special type of rheumatoid arthritis (RA) that is typically characterized by arthritis, neutropenia, and splenomegaly. Common symptoms include systemic lymphadenopathy, anemia, thrombocytopenia, and lower-extremity ulcers.[13] Latent Felty syndrome has a higher mortality rate than RA because clinicians cannot detect the leukopenia in time, leading to delayed treatment. Related studies have shown that Felty syndrome is common in patients with a long history of RA (>10 years). However, for patients with a short RA history and no clinical signs or symptoms, Felty syndrome is often easily missed or misdiagnosed, leading to delayed treatment.[5,14,19] Therefore, here, we report the case of a patient with a short history of RA (<1 year) that presented as subcutaneous hemorrhage and decreased hemoglobin (Hb), WBC, and blood platelet count (BPC). After the exclusion of other systemic diseases, the final diagnosis was Felty syndrome. Treatment with glucocorticoids and immunosuppressive agents reduced the peripheral blood cell count and healed the skin.\n\n2 Case presentation\nThe study was approved by the Human Body Protection Agency Review Board of the Southern Theater General Hospital and followed the principles of the Helsinki Declaration. The patient provided written informed consent and has agreed to publish the case.\n\nIn December 2017, a 48-year-old woman developed repeated pain in the thumb and metacarpophalangeal joints, forefinger metacarpophalangeal joints, proximal interphalangeal joints, bilateral wrist joints, and bilateral shoulder joints with a morning stiffness of 1.5 h. Pain symptoms were relieved after symptomatic treatment in the hospital. In April 2018, she visited our department. Laboratory values were as follows: anti-CCP antibody, 401.00 U/mL; erythrocyte sedimentation rate, 40.00 mm/h; C-reactive protein, 6.7 mg/L; rheumatoid factor, negative; anti-RA33 antibody, negative; and anti-“O” test, negative. She was subsequently diagnosed with RA. Treatment with meloxicam dispersible tablets 7.5 mg/day, methotrexate (MTX) 10 mg/week, leflunomide (LEF) 20 mg/night, prednisone 7.5 mg/day at 8 am for 2 weeks alleviated her symptoms of joint swelling and pain. However, she reduced the medication amount due to stomach discomfort. Three days prior to presenting, the patient developed a red rash on the chest, abdomen, and back that partially merged into an area with obvious itchiness. A rash then developed on the hips and feet. Later, subcutaneous sputum and ecchymoses appeared on the lower extremities, particularly the bilateral calves. A small amount of petechia appeared on the upper limbs without pain, itching and bleeding gums, at which point she visited our outpatient clinic.\n\nThe patient's vital signs were stable at admission, but routine bloodwork showed the following: WBC, 2.09 × 109/L; neutrophils, 0.85 × 109/L; red blood cells, 1.46 × 1012/L; Hb, 45 g/L, BPC, 13 × 109/L ↓ (Table 1). Thus, we discontinued all drugs. After the dermatology consultation, drug dermatitis, and purpura were considered, and she was given desonide ointment and ebastine tablets for anti-allergy treatment. A hematology consultation determined that blood system diseases could not be ruled out. A bone marrow puncture was recommended. Due to the patient's critical situation, symptomatic treatment including the infusion of 2 units of red blood cells and 15 units of platelets and a methylprednisolone 120 mg intravenous drip for 3 days were given (Fig. 1). On the fourth day of admission, the lower-extremity subcutaneous ecchymosis decreased, the rash on the chest and abdomen faded significantly, the back and foot rashes were slightly better, and the WBC, Hb, and BPC values were significantly improved (Table 1). The relevant examinations continued. The Coombs test, electrolyte, and total biochemical findings were normal. The fibrinogen was 4.5 g/L (reference value, 2–4 g/L), while partial clotting activity enzyme time was 45.2 s (reference value, 28–44 s). The rheumatoid immune index results showed no obvious abnormalities (Table 2). The bone marrow puncture results showed that myelodysplastic syndrome (MDS) should be considered (Fig. 2). An abdominal B-ultrasound showed that the spleen was ∼158 × 47 mm and the rib was about 49 mm. The liver, gallbladder, pancreas, kidneys, and so on showed no obvious abnormalities. On the seventh day after admission, the patient developed a systemic rash and significantly reduced WBC, Hb, and BPC values (Table 1). A bone marrow flow test showed 0.15% normal myeloid naive cells in the bone marrow samples and abnormal granulocyte differentiation and development; thus, MDS was not excluded. The genetic examination revealed three chromosomal abnormalities. A database search and literature review confirmed that the three abnormalities were not related to the pathological changes associated with malignant blood diseases. Gain (14q) is included in the normal population chromosome copy number variation polymorphism database, while two uniparental disomies (Xq) were included in the normal population uniparental disomy database. Analysis of bone marrow karyotype showed that this patient's specimen was analyzed for 2 metaphase cells after culture. No abnormal chromosome clones were found. Because few metaphase cells were available for analysis, review of the elective period recommended. After the temporary administration of granulocyte colony-stimulating factor as whitening treatment and the administration of prednisone 30 mg/day and cyclosporine 50 mg 2 times/day, the patient's rash and sputum point subsided significantly. On the 10th day, the WBC, Hb, and BPC steadily increased (Table 1). Combined with the patient's clinical manifestations and related test results, MDS was excluded and Felty syndrome was diagnosed (Fig. 1). The treatment of prednisone 30 mg/day, cyclosporine 50 mg 2 times/day was continued. On the 10th day, the peripheral blood cell count continued to rise steadily and the patient was discharged on the 15th day. A reexamination 2 weeks after the patient was discharged from the hospital showed the WBC, Hb, and BPC were basically normal, so the prednisone was gradually reduced and the outpatient treatment was continued.\n\nTable 1 Patient's laboratory test results during hospitalization and follow-up (abnormal values in bold).\n\nBlood test\tAdmission\tDay 4\tDay 7\tDay 10\tDay 15\t2 week after discharge\t\nWBC (4.0–10.0) × 109/L\t2.09\t6.05\t2.7\t3.85\t6.27\t6.74\t\nNeutrophils % (0.5–0.7)\t0.85\t4.25\t1.39\t1.93\t3.62\t3.74\t\nRBC (3.5–5.0 × 1012/L)\t1.46\t1.98\t0.19\t1.71\t2.36\t3.74\t\nHb (110–150 g/L)\t45\t61\t58\t51\t80\t111\t\nPLT (100–300) × 109/L)\t13\t21\t27\t62\t78\t120\t\nScr (44–97 umol/L)\t47\t48\t49\t46\t43\t45\t\nBUN (3.2–7.1 mmol/L)\t1.9\t3.2\t3.5\t3.2\t3.6\t3.3\t\nALT (0–40 U/L)\t20\t23\t22\t25\t29\t24\t\nAST (0–40 U/L)\t27\t23\t25\t23\t26\t25\t\nLDH (100–300 U/L)\t243\t249\t265\t243\t253\t233\t\nSugar (3.9–6.1 mmol/L)\t5.5\t5.8\t4.9\t4.8\t5.2\t4.3\t\nALB (35–51 g/L)\t41\t38\t39\t42\t43\t44\t\nUPQ (≤150 mg/24 h)\t0.10\t0.18\t0.04\t0.02\t0.03\t0.06\t\nuric acid (89–357 μmol/L)\t325\t300\t329\t276\t289\t342\t\nK (3.5–5.5 mmol/L)\t3.7\t3.5\t3.6\t3.7\t3.9\t4.4\t\nNa (135–145 mmol/L)\t139\t138\t140\t141\t138\t140\t\nCl (96.00–106.00 mmol/L)\t105\t102\t98\t101\t99\t103\t\nESR (0–20 mm/h)\t22\t15\t14\t16\t10\t8\t\nCRP (0.068–8.2 mg/L)\t59.8\t25\t6\t3\t5\t4\t\nFg (2–4g/L)\t4.5\t3.8\t3.2\t3.5\t3.7\t3.2\t\nPTT (28.00–44.00 S)\t45.2\t43\t40\t43\t39\t42\t\nProcalcitonin (<0.5 ug/L)\t0.08\t0.04\t0.03\t0.02\t0.04\t0.02\t\nFigure 1 Diagnosis and treatment progress of the patient. (A) Neut = neutrophils, RBC = red blood cells, WBC = white blood cell. (B) Hb = blood hemoglobin, PLT = platelet.\n\nTable 2 Patient's immunological data.\n\nName\tImmunological data\t\nC3 (0.80–1.20 g/L)\t1.01\t\nC4 (0.44–0.66 g/L)\t0.275\t\nIgG (6–16 g/L)\t8.14\t\nIgM (40–345 mg/dL)\t0.45\t\nIgA ((76–390 mg/dL)\t1.85\t\nAnti-Un Ab (<1:160)\t4.82\t\nAnti-ds-DNA Ab (negative)\tNegative\t\nAnti-Sm Ab (negative)\tNegative\t\nAnti-SSA Ab (negative)\tNegative\t\nAnti-SSB Ab (negative)\tNegative\t\nAnti-caIgM (negative)\tNegative\t\nAnti-caIgG (negative)\tNegative\t\nAnti-ma Ab (negative)\tNegative\t\nAGBM Ab (negative)\tNegative\t\nAnti-p3 Ab (negative)\tNegative\t\nAnti-B2IgG (negative)\tNegative\t\nAnti-B2IgM (negative)\tNegative\t\nFigure 2 Bone marrow aspiration results (day 4 bone marrow aspiration).\n\n3 Discussion\nFelty syndrome is common in patients with a history of RA longer than 10 years. For those patients with a short onset time and atypical clinical symptoms, a missed or incorrect diagnosis is not uncommon. Therefore, early diagnosis is of great significance for the treatment and prognosis of Felty syndrome.[18] Felty syndrome can be confused with immune system diseases like systemic lupus erythematosus (SLE) and Sicca syndrome (SS), blood system diseases like MDS and aplastic anemia (AA), digestive system diseases such as cirrhosis and adverse drug reactions.[9,18]\n\nIn this case, the patient developed a decreasing peripheral blood cell count and some skin symptoms. Upon admission, the cause of the peripheral blood cell reduction was unclear since drugs or SLE, MDS, AA, or other diseases may cause such decreases. However, in each case, it can be treated with glucocorticoids, so methylprednisolone 120 mg was given to treat it.[11] Since the disease onset, there were no photoallergic symptoms, nervous system involvement, oral ulcers, kidney damage, dry eyes, dry mouth, caries, repeated parotid swelling, or other symptoms. Although reduced WBC, Hb, and BPC were seen, no hemolytic anemia was noted. The laboratory results showed that Coomb's test was negative, while a rheumatoid immunological examination showed no obvious abnormalities, thereby excluding other rheumatoid immune system diseases such as SLE and SS.[12] Because the patient had a history of RA, the possibility of Felty syndrome was considered. Blood system diseases such as MDS and AA can decrease peripheral blood cell counts. Therefore, bone marrow puncture is of great significance for the differential diagnosis. In this case, the patient underwent two bone marrow punctures, and it was not ruled out that the decrease in the blood triads was caused by MDS, so further tests like bone marrow biopsy, bone marrow flow, bone marrow chromosome, and genetic examinations are necessary.[12,24] Since the patient refused to undergo a bone marrow biopsy, only bone marrow flow, bone marrow chromosome, and genetic examinations were performed. The results suggested that it was unlikely to have been caused by MDS. After a multi-disciplinary consultation, doctors believed that MDS could not explain the splenomegaly, so malignant hematological diseases such as MDS and AA are excluded, making the diagnosis more likely Felty syndrome. MTX can cause many adverse reactions, including reduced WBC, Hb, and BPC, but the resulting myelosuppression is reversible.[8] The most common adverse reactions of LEF include digestive tract reaction, rash, hair loss, weight loss, and liver and kidney dysfunction but rarely decreases WBC or platelet blood count.[10] This patient had a short-term (2-week) history of MTX and LEF use and experienced gastrointestinal adverse reactions. She subsequently reduced the dosage herself and experienced a series of signs including rash and subcutaneous ecchymosis. Combined with splenomegaly visualized on abdominal B-ultrasound, lack of portal hypertension, and normal liver and kidney function, it is unlikely that the decrease in WBC, Hb, and BPC was caused by adverse drug reactions. After the exclusion of these diseases, Felty syndrome was diagnosed and treated.\n\nThe cause of the peripheral blood cell reduction in Felty syndrome is not fully understood. Neutropenia, the most common symptom, may be related to the presence of granulocyte-specific anti-nuclear factor (GS-ANF). The positive rate of GS-ANF in patients with Felty syndrome is reportedly as high as 75% to 100%, while that in RA patients is only 25% to 30%.[16,20] At the same time, the presence of IgG-like granulocyte antibodies in peripheral blood of patients with Felty syndrome can further destroy granulocytes, decreasing their ability to phagocytose immune complexes, while T-cell activation can inhibit granulocyte production. Similar to RA patients, anemia is common in patients with Felty syndrome. Splenomegaly can cause thrombocytopenia, the mechanism of which may be related to factors like decreased platelet production, spleen retention, peripheral platelet depletion, and peripheral immune-mediated platelet destruction.[2]\n\nA special type of RA, Felty syndrome is treated similarly to RA, with the treatment being mainly divided into glucocorticoids and slow-acting anti-rheumatic drugs. However, due to the lack of evidence-based medicine, most are empirical drugs.[13,18] Glucocorticoids are widely used to treat Felty syndrome because of their strong anti-inflammatory and immunosuppressive effects. As a traditional drug for patients with significantly reduced WBC, Hb, and BPC, large doses of hormones combined with gamma-globulin can be given.[11] In this case, gamma-globulin shock therapy was rejected due to the patient's economic level. After the condition stabilizes, the glucocorticoids should be gradually reduced. Immunosuppressive drugs can be used to treat Felty syndrome. Both MTX and LEF can improve joint and vascular inflammation in patients with Felty syndrome.[4,26] Sulfasalazine suppositories can directly inhibit or even kill the activated immunoactive cells, and they have positive impacts on pain relief and disease control.[3] Some clinical trial results have shown that cyclophosphamide effectively treats Felty syndrome, but the resulting reduction in granulocytes limits its use.[15] However, the significant reductions in WBC, Hb, and BPC limit the use of immunosuppressive agents. As a second-line drug, cyclosporine inhibits T-cell activation by inhibiting calcineurin and can be used in patients with blood system diseases such as leukopenia and thrombocytopenia.[1,17] Therefore, in our case, cyclosporine was administered. The peripheral blood cell count returned to normal after 2 weeks of follow-up, while the skin lesion symptoms completely disappeared.\n\nIn recent years, biological agents have been widely used to treat various rheumatic immune diseases. Currently, the most widely used agent is rituximab (RTX), a monoclonal antibody to CD20 that can fight mature B cells and has been approved for the treatment of complex RA. Related studies have shown that RTX can be used to successfully treat Felty syndrome with infection or ulceration.[5,13,23] Among them, the use of RTX to reduce WBC, Hb, and BPC remains controversial. Lekharaju, Fragoso, and other authors[6,7,20,21,25] indicated that RTX can successfully reverse the decreased WBC and neutropenia in patients with Felty syndrome, while reports by Sordet C and Salama[20,22] were unable to conclude that RTX can successfully reverse WBC reductions and neutropenia in patients with Felty syndrome. However, the overall results demonstrated that RTX still has a high successful rate for treating refractory Felty syndrome.\n\nWe reported here the case of a patient with a short-term (<1 year) duration of LA plus latent Felty syndrome with a reduced peripheral blood cell count and skin symptoms. The main purpose of this study was to emphasize that, when the reduction of peripheral blood cell count in the absence of the common symptoms of RA such as arthritis occurs, the possibility of Felty syndrome should be considered and the diagnosis confirmed quickly. Active intervention would positively affect patient prognosis. We can gain some experience and inspiration from this case. First of all, if blood counts decrease in a case of newly developed RA, clinicians should be alert to the possibility of latent Felty syndrome. Second, bone marrow puncture is recommended in routine examinations to rule out blood system diseases. Third, multidisciplinary communication helps with the early diagnosis of Felty syndrome. Fourth, for the treatment of Felty syndrome according to the patient's condition, active glucocorticoids and gamma-globulin shocks are beneficial to controlling the disease. Fifth, patients in whom conventional immunosuppressive agents and glucocorticoids are ineffective should be actively treated with biological agents such as RTX.\n\nAuthor contributions\nConceptualization: Weifeng Sun.\n\nWriting – original draft: Peng Wu.\n\nWriting – review & editing: Peng Wu, Jing Li.\n\nAbbreviations: AA = aplastic anemia, BPC = blood platelet count, Hb = blood hemoglobin, MDS = myelodysplastic syndrome, RA = rheumatoid arthritis, SLE = systemic lupus erythematosus, SS = Sicca syndrome, WBC = white blood cell.\n\nHow to cite this article: Wu P, Sun W, Li J. Rheumatoid arthritis patients with peripheral blood cell reduction should be evaluated for latent Felty syndrome: A case report. Medicine. 2020;99:51(e23608).\n\nThe authors have no conflict of interests to disclose.\n\nThe datasets generated during and/or analyzed during the present study are publicly available.\n\nALB = albumin, BUN = blood urea nitrogen, Fg = fibrinogen, LY = lymphocyte, PLT = platelet, PTT = partial thromboplastin time, Scr = serum creatinine, TT = thrombin time, UPQ = 24 h Urinary Protein Quantity.\n\nAGBM Ab = antiglomerular basement membrane antibody, Anti-B2IgG = anti-B2-glycoprotein 1 antibody IgG, Anti-B2IgM = anti-B2-glycoprotein 1 antibody IgM, Anti-caIgG = anti-cardiolipase antibodyIgG, Anti-ds-DNA Ab = anti double stranded DNA antibody, Anti-caIgM = anti-cardiolipase antibody IgM, Anti-ma Ab = anti-myeloperoxidase antibody, Anti-p3Ab = anti-protease 3 antibody, Anti-Un Ab = antinuclear antibodies.\n==== Refs\nReferences\n[1] Vitali C Sciuto M Bombardieri S \nImmunotherapy in rheumatoid arthritis: a review\n. Int J Artif Organs \n2018 ;16 : Suppl 5 : 196 –200\n.\n[2] Savola P Oscar B Olson T \nSomatic stat3 mutations in felty syndrome: an implication for a common pathogenesis with large granular lymphocyte leukaemia\n. Haematologica \n2018 ;103 :304 –12\n.29217783 \n[3] Alpay-Kanitez N Pehlivan O Omma A \nFavorable retention rates and safety of conventional anti-rheumatic drugs in older patients with rheumatoid arthritis\n. Medicine (Baltimore) \n2020 ;99 :e19696 .32311948 \n[4] Aslam F Cheema RS Feinstein M \nNeutropaenia and splenomegaly without arthritis: think rheumatoid arthritis\n. BMJ Case Rep \n2018 ;2018 : doi: 10.1136/bcr-2018-225359 .\n[5] Ayzenberg M Shenberger KN \nSuccessful treatment of a large cutaneous ulcer and improvement in the hematologic manifestations of Felty syndrome with Rituximab\n. J Clin Rheumatol \n2014 ;20 :440 –1\n.25417682 \n[6] Brown LE Sampath S Ryan F \nFELTY'S SYNDROME IN RHEUMATOID FACTOR POSITIVE POLYARTICULAR JUVENILE IDIOPATHIC ARTHRITIS: THE ROLE OF RITUXIMAB[C]//Conference of the \n2015 .\n[7] Chandra PA Margulis Y Schiff C \nRituximab is useful in the treatment of Felty's syndrome\n. Am J Ther \n2008 ;15 :321 –2\n.18645332 \n[8] Furuya T Totokawa S Nakajima A \nAdverse effects of low-dose methotrexate therapy in rheumatoid arthritis\n. J Rheumatol \n1996 ;36 :746 –52\n.\n[9] Jakez-Ocampo J Atisha-Fregoso Y Llorente L \nPancytopenia as manifestation of nonarticular Felty syndrome\n. J Clin Rheumatol \n2018 ;doi: 10.1097/RHU.0000000000000906 .\n[10] Kanbe K Inoue K Chiba J \nThe side-effects and efficacy of leflunomide in Japanese patients with rheumatoid arthritis\n. APLAR J Rheumatol \n2015 ;8 :114 –8\n.\n[11] Kuhn A Bonsmann G Anders HJ \nThe diagnosis and treatment of systemic lupus erythematosus\n. Dtsch Arztebl Int \n2015 ;112 :423 –32\n.26179016 \n[12] Miano M Dufour C \nThe diagnosis and treatment of aplastic anemia: a review\n. Int J Hematol \n2015 ;101 :527 –35\n.25837779 \n[13] Puksic S Mitrovic J Morovic-Vergles J \nRituximab: a safe treatment in a patient with refractory Felty syndrome and recurrent infections‘\n. J Clin Rheumatol \n2017 ;23 :70 –1\n.28002164 \n[14] Mohammad BO Kam N Mojtaba A \nFelty's syndrome\n. Insights Updates \n2014 ;8 :129 –36\n.\n[15] Negrei C Bojinca V Balanescu A \nManagement of rheumatoid arthritis: impact and risks of various therapeutic approaches (Review)\n. Exp Ther Med \n2016 ;11 :1177 –83\n.27073419 \n[16] Onyewotu II Onyemelukwe GC Okpapi JU \nFelty's syndrome in a Nigerian\n. Trop Geogr Med \n1991 ;43 :238 –41\n.1750123 \n[17] Patel D Delivery SWJD \nRecent advances in cyclosporine drug delivery: challenges and opportunities\n. Drug Deliv Transl Res \n2019 ;9 :1067 –81\n.31144214 \n[18] Patel R Akhondi H \nFelty Syndrome\n. Treasure Island, FL : StatPearls ; 2020 .\n[19] Godhwani S Gruber BL Finzel K \nA case of rheumatoid arthritis with Felty syndrome complicated by late-onset ankylosing spondylitis and psoriatic arthritis: a potpourri of rheumatic diseases\n. J Clin Rheumatol \n2015 ;21 :53 –5\n.25539441 \n[20] Sarp U Ataman S \nA beneficial long-term and consistent response to rituximab in the treatment of refractory neutropenia and arthritis in a patient with Felty syndrome\n. J Clin Rheumatol \n2014 ;20 :398 .25275774 \n[21] Shipley E Héraud A Hennette A \nEfficacy of rituximab in Felty's syndrome\n. Joint Bone Spine \n2008 ;75 :621 –2\n.18805034 \n[22] Sordet C Gottenberg J-E Hellmich B \nLack of efficacy of rituximab in Felty's syndrome\n. Ann Rheum Dis \n2005 ;64 :332 –3\n.15647445 \n[23] Wang CR Chiu YC Chen YC \nSuccessful treatment of refractory neutropenia in Felty's syndrome with rituximab\n. Scandinavian Journal of Rheumatology \n2017 \n1 .\n[24] Wang YN Zhuang JL Zhao WL \nClinical analysis of Sweet syndrome with myelodysplasia syndrome\n. Zhonghua Yi Xue Za Zhi \n2016 ;96 :1755 –7\n.27356643 \n[25] Weinreb N Rabinowitz A Dellaripa PF \nBeneficial response to rituximab in refractory Felty syndrome\n. J Clin Rheumatol \n2006 ;12 :48 .\n[26] Wijesinghe H Galappatthy P De Silva R \nLeflunomide is equally efficacious and safe compared to low dose rituximab in refractory rheumatoid arthritis given in combination with methotrexate: results from a randomized double blind controlled clinical trial\n. BMC Musculoskelet Disord \n2017 ;18 :310 .28724365\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "99(51)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D016572:Cyclosporine; D005258:Felty Syndrome; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D008875:Middle Aged; D011241:Prednisone",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e23608",
"pmc": null,
"pmid": "33371095",
"pubdate": "2020-12-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rheumatoid arthritis patients with peripheral blood cell reduction should be evaluated for latent Felty syndrome: A case report.",
"title_normalized": "rheumatoid arthritis patients with peripheral blood cell reduction should be evaluated for latent felty syndrome a case report"
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"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-279937",
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"occurcountry": "CN",
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"activesubstancename": "LEFLUNOMIDE"
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"abstract": "OBJECTIVE\nTo report a case of filamentary keratitis (FK) successfully treated with autologous serum tears and to review the pathogenesis and management of FK.\n\n\nMETHODS\nCase report including high-resolution anterior segment optical coherence tomography and filament histopathology.\n\n\nMETHODS\nA 61-year-old Hispanic man presented with pain and photophobia of the right eye. He was found to have a corneal epithelial defect and a small peripheral infiltrate 4 months after Laser Assisted in situ Keratomileusis. After resolution of the epithelial defect, he developed FK. Over a 4-month period, conservative management with aggressive lubrication, lid hygiene, topical corticosteroids, topical cyclosporine, bandage contact lenses, and oral doxycycline failed to resolve the corneal filaments. Notably, treatment with 20% autologous serum tears, four times daily, led to a sustained resolution of the FK within 1 week.\n\n\nCONCLUSIONS\nThis case demonstrates the complexity of FK management and introduces autologous serum tears as a viable management option when conservative approaches to this condition fail.",
"affiliations": "Department of Ophthalmology (S.P.R., M.R., S.D., C.L.K., A.G.), Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL; and Department of Ophthalmology (A.G.), Miami Veterans Affairs Medical Center, Miami, FL.",
"authors": "Read|Sarah P|SP|;Rodriguez|Marianeli|M|;Dubovy|Sander|S|;Karp|Carol L|CL|;Galor|Anat|A|",
"chemical_list": "D009077:Mucins",
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"doi": "10.1097/ICL.0000000000000217",
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"issn_linking": "1542-2321",
"issue": "43(5)",
"journal": "Eye & contact lens",
"keywords": null,
"medline_ta": "Eye Contact Lens",
"mesh_terms": "D003315:Cornea; D004847:Epithelial Cells; D006801:Humans; D007634:Keratitis; D008297:Male; D008875:Middle Aged; D009077:Mucins; D044967:Serum; D013666:Tears; D041623:Tomography, Optical Coherence",
"nlm_unique_id": "101160941",
"other_id": null,
"pages": "e16-e18",
"pmc": null,
"pmid": "26657665",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treatment of Refractory Filamentary Keratitis With Autologous Serum Tears.",
"title_normalized": "treatment of refractory filamentary keratitis with autologous serum tears"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2015US-108673",
"fulfillexpeditecriteria": "1",
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"abstract": "Respiratory syncytial virus (RSV) is responsible for significant morbidity and mortality in the lung transplant population. Oral and aerosolized ribavirin may improve outcomes in lung transplant patients with RSV; however, data relating ribavirin concentrations in plasma and intracellular ribavirin triphosphate (iRTP) concentrations in blood and bronchoalveolar lavage (BAL) fluid cells with efficacy and safety are lacking. We describe ribavirin and iRTP concentrations within various compartments in two adult lung transplant recipients with RSV who were sampled throughout successful treatment courses with oral and inhaled ribavirin. In patient 1, iRTP BAL concentrations decreased by 45% over 3 days after changing inhaled ribavirin to oral (6.32 to 3.43 pmol/106 cells). In patient 2, iRTP BAL concentrations were 103 pmol/106 cells after 5 days of oral followed by 5 days of inhaled ribavirin. Further study is needed to describe ribavirin pharmacokinetics in the respiratory compartment to inform clinical use of ribavirin for respiratory viruses.",
"affiliations": "Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA.;Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA.;Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA.;Department of Medicine-Pulmonary Sciences and Critical Care, University of Colorado School of Medicine, Aurora, CO, USA.;Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA.;Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA.",
"authors": "Mueller|Scott W|SW|https://orcid.org/0000-0003-1238-8199;Kiser|Tyree H|TH|;Morrisette|Taylor|T|;Zamora|Martin R|MR|;Lyu|Dennis M|DM|;Kiser|Jennifer J|JJ|",
"chemical_list": "D000998:Antiviral Agents; D011122:Polyphosphates; D012254:Ribavirin; C005692:triphosphoric acid",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13464",
"fulltext": null,
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"issn_linking": "1398-2273",
"issue": "23(1)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "concentration; lung transplant; respiratory syncytial virus; ribavirin; ribavirin triphosphate",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000998:Antiviral Agents; D001992:Bronchoalveolar Lavage Fluid; D006801:Humans; D016040:Lung Transplantation; D011122:Polyphosphates; D018357:Respiratory Syncytial Virus Infections; D012254:Ribavirin; D016896:Treatment Outcome",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13464",
"pmc": null,
"pmid": "32920958",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Ribavirin and cellular ribavirin-triphosphate concentrations in blood and bronchoalveolar lavage fluid in two lung transplant patients with respiratory syncytial virus.",
"title_normalized": "ribavirin and cellular ribavirin triphosphate concentrations in blood and bronchoalveolar lavage fluid in two lung transplant patients with respiratory syncytial virus"
} | [
{
"companynumb": "US-009507513-2010USA010460",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
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"drug": [
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"actiondrug": "6",
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"activesubstancename": "RIBAVIRIN"
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... |
{
"abstract": "C3 glomerulopathy (C3G) is a rare, but severe glomerular disease with grim prognosis. The complex pathogenesis is just unfolding, and involves acquired as well as inherited dysregulation of the alternative pathway of the complement cascade. Currently, there is no established therapy. Treatment with the C5 complement inhibitor eculizumab may be a therapeutic option. However, due to rarity of the disease, parameters predicting treatment response remain largely unknown.\n\n\n\nSeven patients with C3G (five with C3 glomerulonephritis and two with dense deposit disease) were treated with eculizumab. Subjects underwent biopsy before enrollment. The histopathology, clinical data, and response to eculizumab treatment were analyzed. The key parameters to determine outcome were changes of serum creatinine and urinary protein over time.\n\n\n\nAfter treatment with eculizumab, four subjects showed significantly improved or stable renal function and urinary protein. A positive response occurred between 2 weeks and 6 months after therapy initiation. One subject (with allograft recurrent C3 glomerulonephritis) initially showed a positive response, but relapsed when eculizumab was discontinued, and did not respond after re-initiation of treatment. Two subjects showed impaired renal function and increasing urinary protein despite therapy with eculizumab.\n\n\n\nEculizumab may be a therapeutic option for a subset of C3G patients. The response to eculizumab is heterogeneous, and early as well as continuous treatment may be necessary to prevent disease progression. These findings emphasize the need for studies identifying genetic and functional complement abnormalities that may help to guide eculizumab treatment and predict response.",
"affiliations": "Department of Nephrology, Medical Center-University of Freiburg, Germany, Hugstetter Strasse 55, 79106, Freiburg, Germany.;Department of Nephrology, Medical Center-University of Freiburg, Germany, Hugstetter Strasse 55, 79106, Freiburg, Germany.;Department of Pneumology, Medical Center-University of Freiburg, Germany, Killianstrasse 4, 79106, Freiburg, Germany.;Department of Pathology, Medical Center-University of Freiburg, Germany, Breisacher Strasse 115A, 79106, Freiburg, Germany.;Department of Pediatrics and Adolescent Medicine, Medical Center-University of Freiburg, Germany, Heiliggeiststrasse 1, 79106, Freiburg, Germany.;Center for Human Genetics, Bioscientia, Ingelheim, Germany, Konrad-Adenauer-Strasse 17, 55218, Ingelheim, Germany.;Department of Nephrology, Medical Center-University of Freiburg, Germany, Hugstetter Strasse 55, 79106, Freiburg, Germany.;Department of Nephrology, Medical Center-University of Freiburg, Germany, Hugstetter Strasse 55, 79106, Freiburg, Germany. elke.neumann-haefelin@uniklinik-freiburg.de.",
"authors": "Welte|Thomas|T|;Arnold|Frederic|F|;Kappes|Julia|J|;Seidl|Maximilian|M|;Häffner|Karsten|K|;Bergmann|Carsten|C|;Walz|Gerd|G|;Neumann-Haefelin|Elke|E|0000-0001-5893-4293",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D003176:Complement C3; C481642:eculizumab",
"country": "England",
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"doi": "10.1186/s12882-017-0802-4",
"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central London 80210.1186/s12882-017-0802-4Research ArticleTreating C3 glomerulopathy with eculizumab Welte Thomas thomas.welte@uniklinik-freiburg.de 1Arnold Frederic frederic.arnold@uniklinik-freiburg.de 1Kappes Julia julia.kappes@uniklinik-freiburg.de 2Seidl Maximilian maximilian.seidl@uniklinik-freiburg.de 3Häffner Karsten karsten.haeffner@uniklinik-freiburg.de 4Bergmann Carsten carsten.bergmann@bioscientia.de 5Walz Gerd gerd.walz@uniklinik-freiburg.de 1http://orcid.org/0000-0001-5893-4293Neumann-Haefelin Elke +49 761 270 35590elke.neumann-haefelin@uniklinik-freiburg.de 11 0000 0000 9428 7911grid.7708.8Department of Nephrology, Medical Center–University of Freiburg, Germany, Hugstetter Strasse 55, 79106 Freiburg, Germany 2 0000 0000 9428 7911grid.7708.8Department of Pneumology, Medical Center–University of Freiburg, Germany, Killianstrasse 4, 79106 Freiburg, Germany 3 0000 0000 9428 7911grid.7708.8Department of Pathology, Medical Center–University of Freiburg, Germany, Breisacher Strasse 115A, 79106 Freiburg, Germany 4 0000 0000 9428 7911grid.7708.8Department of Pediatrics and Adolescent Medicine, Medical Center–University of Freiburg, Germany, Heiliggeiststrasse 1, 79106 Freiburg, Germany 5 Center for Human Genetics, Bioscientia, Ingelheim, Germany, Konrad-Adenauer-Strasse 17, 55218 Ingelheim, Germany 12 1 2018 12 1 2018 2018 19 731 5 2017 18 12 2017 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nC3 glomerulopathy (C3G) is a rare, but severe glomerular disease with grim prognosis. The complex pathogenesis is just unfolding, and involves acquired as well as inherited dysregulation of the alternative pathway of the complement cascade. Currently, there is no established therapy. Treatment with the C5 complement inhibitor eculizumab may be a therapeutic option. However, due to rarity of the disease, parameters predicting treatment response remain largely unknown.\n\nMethods\nSeven patients with C3G (five with C3 glomerulonephritis and two with dense deposit disease) were treated with eculizumab. Subjects underwent biopsy before enrollment. The histopathology, clinical data, and response to eculizumab treatment were analyzed. The key parameters to determine outcome were changes of serum creatinine and urinary protein over time.\n\nResults\nAfter treatment with eculizumab, four subjects showed significantly improved or stable renal function and urinary protein. A positive response occurred between 2 weeks and 6 months after therapy initiation. One subject (with allograft recurrent C3 glomerulonephritis) initially showed a positive response, but relapsed when eculizumab was discontinued, and did not respond after re-initiation of treatment. Two subjects showed impaired renal function and increasing urinary protein despite therapy with eculizumab.\n\nConclusions\nEculizumab may be a therapeutic option for a subset of C3G patients. The response to eculizumab is heterogeneous, and early as well as continuous treatment may be necessary to prevent disease progression. These findings emphasize the need for studies identifying genetic and functional complement abnormalities that may help to guide eculizumab treatment and predict response.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12882-017-0802-4) contains supplementary material, which is available to authorized users.\n\nKeywords\nC3 glomerulopathyC3 glomerulonephritisDense deposit diseaseComplementEculizumabhttp://dx.doi.org/10.13039/501100001659Deutsche Forschungsgemeinschaftissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nC3 glomerulopathy (C3G) is a recent description of a disease characterized by uncontrolled activation of the alternative complement pathway leading to predominantly glomerular deposition of complement C3 and C3 fragments [1–4] and characteristic histo-pathological features for membranoproliferative glomerulonephritis (MPGN). Based on electron microscopy analysis, C3G can be subclassified as dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). A distinction is made to MPGN caused by immune complex mediated dysregulation of the classical complement cascade, although both disease spectra share common pathophysiological features [5]. Patients present with varying levels of urinary protein and/or hematuria. Concomitant loss of renal function leads to end-stage renal disease (ESRD) in many cases.\n\nC3G is a rare disease with an estimated incidence of 1–2 cases per million [6]. Renal prognosis is poor with very few reports of spontaneous remission [7] and a vast majority of progression to ESRD with rates of up to 50% within a decade, and recurrence rates of 45–60% in allografts [8–12]. A cohort study with 80 patients identified age > 16 years, DDD subtype, and crescentic GN as predictors for ESRD [6].\n\nDysregulation of the alternative complement cascade plays a primary role in the pathogenesis of C3G and atypical hemolytic uremic syndrome (aHUS). Uncontrolled activation of the alternative complement pathway is driven by inherited mutations in complement proteins and cofactors (e.g. C3, CFB, CFH, CFI, CFHR1–5), or by acquired defects (e.g. CFH, CFB, C3 convertase autoantibodies) [13–16]. While aHUS results from dysregulation of complement factors on cell surfaces (the ‘solid phase’) [17] leading to global endothelial damage, C3G seems to occur after activation of the alternative complement pathway in the fluid phase [14, 15, 18].\n\nIn contrast to immune complex mediated MPGN, which is managed by treating underlying infections, autoimmune diseases, or cancer, treatment strategies in the setting of C3G are still evolving. So far, no generally effective treatment has been identified [19]. Treatment of C3G with immunosuppression (e.g. calcineurin inhibitors, cyclophosphamide, mycophenolate mofetil, or rituximab) [9, 20–23], plasma infusion [24], or plasmapheresis [25] has been described in small cohorts with inconclusive results. With the emerging role of complement in C3G, complement-modulating agents have added new therapeutic options. Eculizumab is a monoclonal humanized antibody that binds C5 and prevents assembly of the membrane attack complex (C5b-9) thereby blocking the final complement cascade. Several case reports and one open-label study showed a potential benefit of eculizumab for patients with C3G [22, 26–39].\n\nIn this study, we characterize clinical and pathological features of seven patients with C3G (five with C3GN, two with DDD), evaluate their treatment response to eculizumab, and discuss critical features of their individual therapeutic outcome.\n\nMethods\nData were collected from medical records. Inclusion criteria were age > 18 years, histopathological diagnosis of C3G, and treatment with eculizumab (Soliris; Alexion Pharmaceuticals, Cheshire, CT). Seven patients (five with C3GN, two with DDD) treated with eculizumab between 2013 and 2016 for C3G were enrolled in the study. Data were collected from the time of treatment initiation until last follow-up. Outcome measurements were change of kidney function, and urinary protein over time.\n\nPositive treatment response was defined as >30% decrease of serum creatinine, urinary protein, or hematuria after 3 months of treatment. Stable disease was defined as serum creatinine, urinary protein, or hematuria between ±30% after 3 months of treatment. Negative treatment response was defined as increase >30% of serum creatinine, urinary protein, or hematuria after 3 months of treatment.\n\nTreatment with Angiotensin converting enzyme inhibitors (ACEI), or angiotensin receptor blockers (ARB) was administered to all patients for blood pressure control and reduction of urinary protein. However, disease progression warranted for specific treatment in all patients.\n\nAll patients gave informed consent for eculizumab treatment. The study was approved by the Ethics Committee of the University Medical Center, Freiburg, Germany. Before eculizumab administration, all patients received meningococcal vaccinations. Eculizumab was given according to aHUS standard treatment protocol [40]. Briefly, eculizumab was administered weekly at a dose of 900 mg (week 1–4), followed by eculizumab every other week at a dose of 1200 mg (from week 5). No serious side effects were reported. Serum creatinine and urinary protein levels were monitored regularly. Reference ranges for serum creatinine levels were defined for men as 0.84–1.25 mg/dl, for women as 0.66–1.09 mg/dl. Reference ranges for urinary protein were defined as <0.15 g/g. Due to the small study population, no statistical analysis was performed. Data are presented for each individual case.\n\nResults\nPatient characteristics\nThe report includes five patients (all white Caucasians) with C3GN (two males and three females) and two patients with DDD (both female, Table 1). Three patients had recurring allograft C3G. One patient was diagnosed with de novo allograft C3GN after kidney transplantation with ESRD due to focal segmental glomerulosclerosis (FSGS). Four patients received immunosuppressive agents prior to eculizumab with varying success. The mean age at diagnosis was 29 years (range = 14–59 years). At diagnosis all subjects had either impaired renal function (mean serum creatinine 2 mg/dl; range = 0.8–3.3 mg/dl) and/or elevated levels of urinary protein (urinary protein to creatinine ratio [UPCR] 3.6 g/g; range = 0.3–5.4 g/g). All patients presented with varying levels of hematuria.Table 1 Patient characteristics and treatment response\n\n\t\nC3GN1\n\t\nC3GN2\n\t\nC3GN3\n\t\nDDD1\n\t\nC3GN4\n\t\nDDD2\n\t\nC3GN5\n\t\nnative/grafta\tgraft\tnative\tgraft\tnative\tgraft\tnative\tnative\t\nBaseline SCr (mg/dl)\t1.9\t2.3\t2.1\t1.5\t3.3\t2.1\t0.8\t\nBaseline UPCR (g/g)\t5.4\t0.3\t0.3\t5.0\t3.4\t5.4\t5.6\t\nBaseline hematuriab (0–4)\t4\t4\t3\t4\t4\t4\t2\t\nTherapy\t\npre Tx\n\nnone\tnone\t\npre Tx\n\nprednisone, MMF, azathioprine\tnone\t\npre Tx\n\ncyclo-\nsporine A, cyclophos-phamide\tnone\tPEX, FFP, immune-globulins, prednisone, MMF [25]\t\n\npost Tx\n\nprednisone, tacrolimus, MMF, rituximab\t\t\npost Tx\n\nprednisone, tacrolimus, MMF (graft)\t\t\npost Tx\n\nprednisone, tacrolimus, MMF, cyclophos-phamide, PEX [41] (graft)\t\t\t\nTime to graft relaps (months)\t48\t–\t3\t–\tde novo C3GN 135 months post Tx\t–\t–\t\nTime diagnosis to eculizumab (months)\t144 (native); 0 (graft)\t7\t88 (native); 2 (graft)\t128\t2 (graft)\t7\t11\t\nTreatment duration (months)\t27\t26\t9\t24\t3; 3\t16\t28\t\nResponse SCr\tstable\tyes\tstable\tstable\tinitially yes; recurrence no\tinitially stable; ultimately no\tno\t\nResponse UPCR\tyes\tstable\tstable\tinitially yes; ultimately stable\tinitially yes; recurrence no\tinitially stable; ultimately no\tno\t\nResponse hematuria\tstable\tyes\tstable\tyes\tstable\tyes\tyes\t\nAbbreviations: FFP fresh frozen plasma, MMF mycophenolate mofetil, PEX plasmapheresis, Tx kidney transplantation\n\nanative: applies to native kidney; graft: applies to kidney transplant\n\nbhematuria measured by urine dipstic (scale from 0 to 4)\n\n\n\nCourse of C3G disease\nPatient C3GN1 was diagnosed with C3GN in his/her late thirties, 4 years after receiving an allogenic kidney transplant (baseline creatinine 1.6 mg/dl post transplantation; immunosuppression with tacrolimus, MMF [mycophenolate mofetil], and prednisone) due to ESRD of MPGN (initial diagnosis 11 years earlier with classification as MPGN type I). The patient presented with elevated levels of serum creatinine (1.9 mg/dl), urinary protein (5–6 g/g), and hematuria. The kidney biopsy revealed discrete glomerular fibrosis, mesangial hypercellularity, lymphocyte infiltration, and pronounced C3 staining in accordance with C3GN (Table 2). Complement assays showed complement activation with low C3 levels (Additional file 1: Table S2). Additionally, C3 convertase autoantibodies were detected (C3 nephritic factors, C3NeF; Table 2). Immunosuppression was maintained with prednisone, tacrolimus, and MMF. One-time administration of rituximab did neither affect creatinine levels nor urinary protein. Treatment with eculizumab over 27 months maintained stable kidney transplant function (serum creatinine levels of 1.6–2.2 mg/dl), greatly improved urinary protein (0.2–0.4 g/g), and led to stable hematuria (Fig. 1a). Complement testing at week 17 and 43 of treatment suggested effective complement blockade (CH50 < 10 IE/ml, ref. range 20–50 IE/ml; Additional file 1: Table S2).Table 2 Histo-pathology, genetic and autoantibody testing\n\n\t\nC3GN1\n\t\nC3GN2\n\t\nC3GN3\n\t\nDDD1\n\tC3GN4 1st biopsy\tC3GN4 2nd biopsy\t\nDDD2\n\tC3GN5 1st biopsy\tC3GN5 2nd biopsy\t\nLight microscopy\t\n Glomerula (n)\t20\t15\t3\t8\t25\t13\t11\t24\t19\t\n Global sclerosis (%)\t5\t7\t0\t0\t56\t38\t9\t4\t16\t\n Partial sclerosis (%)\t0\t0\t0\t0\t0\t15\t91\t13\t0\t\n IF/TAa (%)\t5\t10\t0\t5\t5\t25\t30\t10\t10\t\n Crescents (%)\t0\t0\t0\t0\t0\t0\t0\t0\t0\t\n Mesangial proliferation\tpos\tpos\tpos\tpos\tpos\tpos\tneg\tpos\tpos\t\n Leukocyte infiltrationb (0–3)\t2\t2\t1\t0\t1\t2\t0\t1\t0\t\nImmunofluorescencec\t\n C3 (0–3)\t3\t2\t3\t2\t2\t3\t2\t3\t3\t\n C4d (0–3)\tNT\tNT\t0\tNT\t0\t0\tNT\tNT\tNT\t\n C5b-9 (0–3)\t2\t1\t2\tNT\t1\t1\t1\tNT\t2\t\n IgA (0–3)\t1\t1\t0\t1\t0\t0\t1\t0\t0\t\n IgG (0–3)\t1\t0\t1\t1\t0\t0\t0\t1\t2, κ light chain, mouse pos\t\n IgM (0–3)\t1\t2\t1\t1\t1\t1\t2\t1\t1\t\nElectron microscopy\t\n DDD deposits\tneg\tneg\tneg\tpos\tneg\tneg\tpos\tNT\tneg\t\nGenetic analysis\t\n CFH\tNT\tNT\tneg\tneg\tneg\tneg\tneg\t\t\n CFI\tNT\tneg\tneg\tNT\tHET c.1322A > G\tneg\tneg\t\t\n CFB\tNT\tNT\tNT\tNT\tNT\tneg\tNT\t\t\n CFHR1–5\tNT\tNT\tneg\tNT\tHET del cfhr1, 3\tHET CFHR5 c.832G > A\tneg\t\t\n MCP\tNT\tneg\tneg\tNT\tneg\tneg\tneg\t\t\n C3\tNT\tNT\tHET c.2203C > T\tneg\tneg\tneg\tneg\t\t\n COL4A3\tNT\tNT\tNT\tNT\tHET c.4484A > G\tNT\tNT\t\t\nAutoantibodies\t\n C3Nef\tpos\tpos\tneg\tneg\tpos\tneg\tpos\t\t\n C3b\tNT\tpos\tNT\tNT\tNT\tNT\tNT\t\t\n CFH\tpos\tpos\tNT\tNT\tneg\tneg\tNT\t\t\n CFI\tneg\tNT\tNT\tNT\tneg\tNT\tNT\t\t\nAbbreviations: del deletion, HET heterozygous, NT not tested\n\nainterstitial fibrosis and tubular atrophy\n\nbleukocyte infiltration was graded on a scale from 0 to 3\n\ncantibody staining was graded on a scale from 0 to 3\n\nFig. 1 Positive response to eculizumab treatment in C3G patients. Graphs show treatment response to eculizumab. Column charts show applied eculizumab dose (low column: 900 mg; high column: 1200 mg). Line charts display serum creatinine levels (black; SCr; mg/dl), and urinary protein levels (grey; UPCR; g/g) over time (weeks). a Patient C3GN1. b Patient C3GN2. Dashed lines show the period of time (12 weeks) where eculizumab was paused. c Patient C3GN3. Dashed lines show the period of time (4 weeks) where eculizumab was paused. d Patient DDD1\n\n\n\nPatient C3GN2 with a history of HIV infection (HAART had been successfully applied to control HIV infection) presented with serum creatinine levels of 2.3 mg/dl, urinary protein levels of 0.3 g/g, and hematuria in his/her early forties. Kidney biopsy revealed global mesangial and endocapillary hypercellularity with discrete glomerular sclerosis. Immunofluorescence and electron microscopy revealed distinct C3 deposition with little to no immunoglobulin deposition (Table 2) leading to the diagnosis of C3GN. Complement analysis showed increased C3 turnover and sMAC formation (Additional file 1: Table S3). Antibody and genetic testing showed no pathologic mutations, but identified antibodies against C3NeF, C3b, and CFH (Table 2). Eculizumab treatment resulted in an improvement of renal function with slightly improved serum creatinine levels at 1.2–1.7 mg/dl and low range urinary protein (0.1–0.2 g/g; Fig. 1b). Notably, a short interruption of eculizumab treatment for 12 weeks led to a dramatic increase of urinary protein (maximum urinary protein levels 1.8 g/g), worsened renal function (maximum serum creatinine levels 2.2 mg/dl), and enhanced sMAC formation (maximum sMAC levels 914 ng/dl). Re-initiation of eculizumab promptly reduced urinary protein (0.1–0.3 g/g), restored kidney function (serum creatinine levels 1.4–1.8 mg/dl), and improved hematuria.\n\nPatient C3GN3 presented with relapsing C3GN in his/her mid-thirties, 3 months after receiving allogenic kidney transplantation (post transplantation creatinine 1.5 mg/dl; immunosuppression with tacrolimus, MMF, and prednisone) due to ESRD of C3GN (initial diagnosis 7 years earlier). Previous treatment approaches included prednisone, MMF, and azathioprine. The patient presented with elevated serum creatinine (2.1 mg/dl), discrete urinary protein (0.3 g/g), and hematuria (Additional file 1: Table S4). Transplant kidney biopsy revealed no signs of graft rejection, but showed mesangial proliferation, lymphocyte infiltration and predominant C3 staining without immunoglobulin deposition (Table 2). Electron microscopy confirmed relapsing C3GN. Antibody and genetic testing revealed neither autoantibodies nor pathophysiological relevant mutations in any of the known disease genes (Table 2). Notably a heterozygous variant change of questionable pathophysiological relevance in exon 17 of C3 was detected (detailed discussion Additional file 1: Text S1). Treatment with eculizumab stabilized kidney function (serum creatinine 1.9–2.2 mg/dl), urinary protein (0.25–0.35 g/g), and hematuria (Fig. 1c). Immunosuppression was maintained with prednisone, tacrolimus, and MMF. Of note, eculizumab had to be paused for 4 weeks due to immunosuppression-induced agranulocytosis.\n\nPatient DDD1 presented in his/her early twenties with impaired renal function (serum creatinine 1.5 mg/dl), nephrotic range urinary protein (5.7 g/g), and hematuria. Complement analysis showed activation of the alternative pathway and high sMAC levels (Additional file 1: Table S5). A kidney biopsy at the department of pediatric nephrology 10 years before had shown mesangial proliferation, and prominent C3 staining with little immunoglobulin staining. Electron microscopy confirmed DDD (Table 2). Antibody analysis and genetic testing identified neither autoantibodies against C3NeF, nor pathophysiological relevant mutations in CFH (Table 2). Treatment with eculizumab stabilized kidney function (serum creatinine 1.1–1.3 mg/dl) and initially improved urinary protein (2.2–2.7 g/g). Hematuria levels significantly decreased. However, urinary protein deteriorated after 87 weeks of therapy (3.0–3.7 g/g) (Fig. 1d). Blood pressure was carefully controlled and within normal range.\n\nPatient C3GN4 presented with de novo C3GN at the in his/her early twenties. He had received a kidney transplant due to FSGS with ESRD 10 years earlier. In line with the initial diagnosis of FSGS an immunosuppressive therapy with prednisone, cyclosporine, and cyclophosphamide had been administered. One month following kidney transplantation, the patient had been successfully treated with cyclophosphamide and plasmapheresis due to relapsing FSGS [41]. 11 years after transplantation, laboratory testing showed a gradual loss of transplant function with elevated serum creatinine (3.3 mg/dl), prominent urinary protein (3.4 g/g), and hematuria. Transplant kidney biopsy revealed glomerular sclerosis, mesangial and endocapillary proliferation. Immunofluorescence and electron microscopy confirmed the diagnosis of de novo C3GN (Table 2; C3GN4, 1st biopsy). Further analysis showed activation of the alternative pathway and a weakly positive C3NeF (Additional file 1: Table S6). Genetic testing revealed heterozygous changes of unknown clinical significance in CFI and COL4A3 (Table 2, detailed discussion Additional file 1: Text S2).\n\nImmunosuppression after kidney transplantation was maintained with prednisone, tacrolimus, and MMF. After administration of eculizumab, kidney transplant function and urinary protein greatly improved. Serum creatinine levels stabilized at 1.6–1.8 mg/dl and urinary protein levels at 1 g/g. However after 3 months of treatment, eculizumab was stopped due to lack of compliance. 1.5 years later the patient presented again with relapsing disease, serum creatinine levels of 3 mg/dl, and urinary protein of 4.3 g/g. A second kidney biopsy showed progressing glomerular sclerosis, and immunofluorescence revealed complement deposition but no IgG. (Table 2; C3GN4, 2nd biopsy). Treatment with eculizumab was reapplied. Hematuria levels remained stable, however serum creatinine and urinary protein levels further increased, and treatment with eculizumab was discontinued after 3 months (Fig. 2a).Fig. 2 Negative response to eculizumab treatment in C3G patients. Graphs show treatment response to eculizumab. Column charts show applied eculizumab dose (low column: 900 mg; high column: 1200 mg). Line charts display serum serum creatinine levels (black; SCr; mg/dl), and urinary protein levels (grey; UPCR; g/g) over time (weeks). a Patient C3GN4. Dashed lines show the period of time (1.5 years) where eculizumab was paused. b Patient DDD2. c Patient C3GN5. Dashed lines show the period of time (17 weeks) where eculizumab was paused\n\n\n\nPatient DDD2 presented with elevated serum creatinine levels (2.1 mg/dl), nephrotic range urinary protein (5.4 g/g), and hematuria at the in his/her late fifties (Additional file 1: Table S7). Kidney biopsy displayed mesangial proliferation, lymphocyte infiltration, and discrete glomerular sclerosis. Immunofluorescence showed distinct C3 staining with little immunoglobulin staining. Electron microscopy found dense deposits in accordance with DDD (Table 2). Further diagnostic workup revealed alternative pathway complement activation but no autoantibodies against C3NeF and CFH. Genetic analysis detected a heterozygous missense variant in CFHR5 (Table 2, detailed discussion in Additional file 1: Text S3). Treatment with eculizumab was initiated stabilizing kidney function at serum creatinine levels of 2 mg/dl and urinary protein levels of 2 g/g. However, in the following months kidney function and urinary protein deteriorated. Thus, treatment with eculizumab was terminated and dialysis was initiated (Fig. 2b).\n\nPatient C3GN5 presented in his/her mid-teens with nephrotic range urinary protein (5.6 g/g), normal renal function (serum creatinine levels 0.8 mg/dl), and hematuria. Kidney biopsy showed pronounced glomerular sclerosis, mesangial proliferation, and distinct C3 staining with little immunoglobulin deposition. Electron microscopy confirmed the diagnosis of C3GN (Table 2, C3GN5, 1st and 2nd biopsy). Complement analysis revealed extensive activation of the alternative pathway with low C3 levels (Additional file 1: Table S8). Antibody and genetic testing detected C3NeF, but no mutation in known disease genes (Table 2). Treatment with plasmapheresis, plasma infusion, prednisone, and MMF had initially induced reduction of urinary protein (details published in [25]). Due to deterioration of urinary protein (5.6 g/g) eculizumab therapy was initiated. With the initiation of eculizumab, MMF was stopped but was readministered after 2.5 months since urinary protein increased. A follow-up biopsy after 1 year of eculizumab treatment revealed glomerular IgG, and κ light chain deposition with identical staining pattern for mouse antibodies (Table 2, C3GN5, 2nd biopsy). Since eculizumab is a humanized monoclonal antibody with human IgG2/IgG4 heavy and κ light chain, and mouse variable regions [42], this glomerular antibody deposition may reflect eculizumab. A break of 17 weeks due to insurance payment negotiations led to a dramatic increase of urinary protein (> 15 g/g) and decline of renal function. Reinitiation of eculizumab could not halt disease progression (Fig. 2c).\n\nDiscussion\nWe analyzed data of five patients with C3GN and two patients with DDD treated with eculizumab. The study population included patients with atypical history (patient C3GN2 had a history of HIV infection, patient C3GN4 presented with de novo C3GN in the kidney graft, and patient DDD2 presented in his/her late fifties). We observed heterogeneous treatment response (Table 1): Four patients showed either improved or stable kidney function, and three patients did not respond. These latter cases also involved patient C3GN4 who initially responded to eculizumab but showed disease progression in the second treatment attempt. Treatment response varied between 2 weeks and 6 months. This is in line with published literature as previous studies also reported varying response rates (Additional file 1: Table S1); [22, 26–39], although published literature shows a clear publication bias towards positive results. Our study supports that eculizumab can be a successful treatment option for at least some patients with C3G.\n\nAlthough the numbers are small, this study indicates that timing and duration of treatment seem to be important factors for the effectiveness. As described in patient C3GN2, short treatment breaks may result in reversible loss of kidney function and urinary protein, while longer breaks (patients C3GN4 and C3GN5) can result in disease progression, deterioration of kidney function, and treatment resistance. This is in line with recent publications showing that treatment brakes may result in relapsing disease [39, 43]. Our study also supports the notion that eculizumab is less likely to improve disease outcome in patients with more severe glomerular sclerosis and interstitial fibrosis. Especially patient C3GN4, who initially was successfully treated with eculizumab showed pronounced renal damage (> 50% glomerular sclerosis and IF/TA 25%) after a treatment break of 1.5 years, and resuming eculizumab treatment did not halt progression. In several studies, old age, renal impairment at presentation, and severe glomerular pathology were identified as predictors of ESRD in patients with C3G [6, 44]. While kidney biopsies provide important clues, systematic evaluation schemes are needed and correlation to treatment response and clinical outcome should be evaluated.\n\nSeveral markers have been investigated that may help to evaluate efficacy of eculizumab. sMAC levels have been suggested as serum marker for the activity of the alternative complement pathway and treatment response to eculizumab [28]. However, several C3G cases have been reported with normal pre-treatment sMAC levels [5, 28, 36], and in several reports treatment response of C3G patients was heterogeneous without correlation to pre-treatment sMAC levels or the course of sMAC levels during eculizumab treatment [28, 29, 36]. In general, this questions sMAC levels as a treatment parameter. Further studies with detailed complement analyses are needed to guide therapeutic interventions.\n\nInterestingly, we observed controlled hematuria in our collective. Two patients (C3GN2 and DDD1) with decline in hematuria also paralleled improved kidney function suggesting reduced glomerular inflammation. A recent study also reported improved creatinine and partial reduction of hematuria in seven pediatric patients treated with eculizumab for DDD [36]. But, in two patients with deteriorating kidney function, hematuria partially receded (DDD2 and C3GN5). Additional research is needed to define clinical parameter for treatment response in C3G patients.\n\nOf note, high range urinary protein might also lead to accelerated renal elimination of eculizumab and therefore weaken treatment response to eculizumab since therapeutic drug levels might not be maintained. In these cases, careful evaluation of complement activity such as CH50 as an indicator of total complement activity or eculizumab serum concentrations might be helpful in order to detect possible underdosing.\n\nIn contrast to aHUS, where eculizumab represents a successful therapy [40], response rates in C3G patients are heterogeneous. C3G and aHUS share uncontrolled activation of the alternative complement pathway and pathophysiological key regulators, such as mutations in complement factors or autoantibodies. However, the two diseases display fundamental differences: In aHUS, complement activation occurs on endothelial surfaces, leading to endothelial damage and thrombus formation. In C3G, complement activation occurs predominantly in the fluid phase resulting in excess formation of activated C3 and cleavage products, which are deposited in the kidney and raise glomerular damage [44]. Despite eculizumab-driven blockage of the terminal complement cascade, upstream C3 cleavage products may cause continuing glomerular damage. This provides reasons for diverging response rates to eculizumab in aHUS and C3G. Therefore, further studies evaluating other complement inhibitors such as the emerging group of C3-convertase inhibitors are needed. In this context, genetic and immunologic screening with registration of relevant mutations, such as the CFHR5 genotype of patient DDD2 in C3G databases, is crucial for understanding the pathophysiology and correlating genetic features with treatment response.\n\nSince treatment with eculizumab in C3G patients as well as in aHUS likely needs to be maintained lifelong, long-term effects such as glomerular eculizumab deposition as seen in patient C3GN5 and a previous study [45] have to be monitored. In this regard, the follow-up periods of this study as well as published literature (Additional file 1: Table S1) are too short to draw conclusions.\n\nThe time to allograft recurrence in the two reported patients varies widely (in patient C3GN1 disease repalsed after 3 years, and in patient C3GN3 after 3 months), which is in line with previous reports [12]. Rituximab has been discussed as a treatment option in autoantibody positive transplant recurrent C3G [46]. In our study (patient C3GN1), it did not affect disease progression and a previous report showed poor outcome [12]. However, reported numbers are too small to draw conclusions. As reported in this and previous studies (Additional file 1: Table S1), allograft recurrent C3GN can be treated with eculizumab. As recurrence rates are high, close clinical monitoring is especially important in this group.\n\nThis study has several limitations, the major being the retrospective character and the lack of standardized follow-up, including genetic and serologic testing. Also the multitude of therapeutic approaches prior to therapy with eculizumab both in this study and published literature (Additional file 1: Table S1) complicate the interpretation of the clinical course. This is mainly due to the rarity of C3 glomerulopathy, and consequently underlines the need to prospectively collect data of patients with C3G.\n\nConclusions\nTogether, our series and previous case reports suggest that early diagnosis and continuous treatment might be necessary to affect the outcome of C3G. Treatment with eculizumab may be successful in some patients. Prospective long-term studies will be required to identify parameters that predict response to therapy.\n\nAdditional file\n\nAdditional file 1: Text S1. Summary of genetic testing of patient C3GN3.\nText S2. Summary of genetic testing of patient C3GN4.\nText S3. Summary of genetic testing of patient DDD2. Table S1. Details on published cases with patient characteristics, and treatment response. Table S2. Details on treatment and response of patient C3GN1. Table S3. Details on treatment and response of patient C3GN2. Table S4. Details on treatment and response of patient C3GN3. Table S5. Details on treatment and response of patient DDD1. Table S6. Details on treatment and response of patient C3GN4. Table S7. Details on treatment and response of patient DDD2. Table S8. Details on treatment and response of patient C3GN5. (DOCX 155 kb)\n\n\n\n\nAbbreviations\nACEIAngiotensin converting enzyme inhibitors\n\naHUSatypical hemolytic uremic syndrome\n\nARBAngiotensin receptor blockers\n\nC3GC3 glomerulopathy\n\nC3GNC3 glomerulonephritis\n\nC3NeFC3 nephritic factor\n\nCyACyclosporine A\n\nDDDDense deposit disease\n\nDEAP-HUSDeficiency of complement factor H-related plasma proteins and autoantibody positive form of hemolytic uremic syndrome\n\nDelDeletion\n\neGFRestimated glomerular filtration rate\n\nESRDEnd-stage renal disease\n\nFFPFresh frozen plasma\n\nHETHeterozygous\n\nHIVHuman immunodeficiency virus\n\nHOMHomozygous\n\nIF/TAInterstitial fibrosis and tubular atrophy\n\nMPGNMembranoproliferative glomerulonephritis\n\nNTNot tested\n\nPEXPlasmapheresis\n\nSCrSerum creatinine\n\nsMACsoluble membrane attack complex\n\nUPCRUrinary protein to serum protein ratio\n\nElectronic supplementary material\n\nThe online version of this article (10.1186/s12882-017-0802-4) contains supplementary material, which is available to authorized users.\n\nAcknowledgements\nNot applicable\n\nFunding\nENH, CB, and GW are funded by the Deutsche Forschungsgemeinschaft (DFG; DFG KFO201 to GW and ENH).\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article [and its supplementary information files]. Information on specific age and gender for each patient will not be shared to ensure patient confidentiality.\n\nAuthors’ contributions\nTW designed the study and performed data analysis. TW, FA, JK, and ENH wrote the first draft of the article. MS performed histo-pathological examination of kidney biopsies. CB performed genetic analysis. GW, KH and ENH participated in patient diagnosis, treatment, and critically reviewed and edited the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nAll patients gave written informed consent for eculizumab treatment. The study was approved by the Ethics Committee of the University Medical Center, Freiburg, Germany (reference number #400/16).\n\nConsent for publication\nNot applicable\n\nCompeting interests\nGW and CB have received honoraria for participating in Alexion Pharmaceuticals advisory board meetings. Alexion Pharmaceuticals was not involved in drafting, editing or publication of this study. CB is an employee of Bioscientia.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Sethi S Fervenza FC Membranoproliferative glomerulonephritis--a new look at an old entity N Engl J Med 2012 366 12 1119 1131 10.1056/NEJMra1108178 22435371 \n2. Sethi S Nester CM Smith RJ Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion Kidney Int 2012 81 5 434 441 10.1038/ki.2011.399 22157657 \n3. Bomback AS Appel GB Pathogenesis of the C3 glomerulopathies and reclassification of MPGN Nat Rev Nephrol 2012 8 11 634 642 10.1038/nrneph.2012.213 23026947 \n4. Pickering MC D'Agati VD Nester CM Smith RJ Haas M Appel GB Alpers CE Bajema IM Bedrosian C Braun M C3 glomerulopathy: consensus report Kidney Int 2013 84 6 1079 1089 10.1038/ki.2013.377 24172683 \n5. 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Thomas S Ranganathan D Francis L Madhan K John GT Current concepts in C3 glomerulopathy Indian J Nephrol 2014 24 6 339 348 10.4103/0971-4065.134089 25484526\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "19(1)",
"journal": "BMC nephrology",
"keywords": "C3 glomerulonephritis; C3 glomerulopathy; Complement; Dense deposit disease; Eculizumab",
"medline_ta": "BMC Nephrol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D003176:Complement C3; D005260:Female; D005921:Glomerulonephritis; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "7",
"pmc": null,
"pmid": "29329521",
"pubdate": "2018-01-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "21601923;26221755;26895476;24464478;24908321;16612335;24178974;23892798;22435382;21215749;22435371;22233157;25530108;22403278;23026947;23738544;15889282;22435383;21415311;10775078;24799306;26316621;22677550;21422921;23479095;24408225;15800116;22456601;23689905;28236143;24172683;26759144;25484526;25986912;22105967;24367026;24672732;24472365;24536001;26754737;22157657;27989322;24357668;18971369;17989688;25796589",
"title": "Treating C3 glomerulopathy with eculizumab.",
"title_normalized": "treating c3 glomerulopathy with eculizumab"
} | [
{
"companynumb": "DE-ALEXION-A201800915",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
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"activesubstancename": "ECULIZUMAB"
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