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"abstract": "With primary central nervous system lymphoma (PCNSL) being a rare disease, the subtype of Burkitt lymphoma (BL) presenting as a sole CNS lesion is an even more exceptional diagnosis. A case of coexistent primary CNS Burkitt lymphoma (PCNSBL) with cerebral palsy (CP) is presented. A 55-year-old Caucasian male presented with increasing bilateral lower extremity weakness above his baseline in addition to signs of increased intracranial pressure. Four abnormal enhancing masses were detected on MRI with biopsy results consistent with Burkitt lymphoma. Complete staging workup was completed with no evidence of extra-CNS disease noted on PET/CT, bone marrow biopsy, or cerebral spinal fluid analysis. The patient was treated with intravenous as well as intrathecal chemotherapy and found to be in a complete remission at six months. Recurrence in the CNS was observed four months later with treatment consisting of whole brain radiation as well as intrathecal chemotherapy. Thirty months after diagnosis, the patient remains disease-free. To our knowledge, this is the first case of PCNSBL in the setting of CP. A review of literature regarding treatment options in this controversial setting is provided.",
"affiliations": "Section of Hematology/Oncology, West Virginia University, Morgantown, WV, USA.;Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program, West Virginia University, Morgantown, WV, USA.",
"authors": "Bower|Kathryn|K|0000-0002-8289-8103;Shah|Nilay|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2018/5869135",
"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi 10.1155/2018/5869135Case ReportPrimary CNS Burkitt Lymphoma: A Case Report of a 55-Year-Old Cerebral Palsy Patient http://orcid.org/0000-0002-8289-8103Bower Kathryn kathryn.bower@hsc.wvu.edu\n1\nShah Nilay \n2\n\n1Section of Hematology/Oncology, West Virginia University, Morgantown, WV, USA\n2Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program, West Virginia University, Morgantown, WV, USAAcademic Editor: Jeanine M. Buchanich\n\n2018 24 6 2018 2018 58691351 2 2018 16 4 2018 29 5 2018 Copyright © 2018 Kathryn Bower and Nilay Shah.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.With primary central nervous system lymphoma (PCNSL) being a rare disease, the subtype of Burkitt lymphoma (BL) presenting as a sole CNS lesion is an even more exceptional diagnosis. A case of coexistent primary CNS Burkitt lymphoma (PCNSBL) with cerebral palsy (CP) is presented. A 55-year-old Caucasian male presented with increasing bilateral lower extremity weakness above his baseline in addition to signs of increased intracranial pressure. Four abnormal enhancing masses were detected on MRI with biopsy results consistent with Burkitt lymphoma. Complete staging workup was completed with no evidence of extra-CNS disease noted on PET/CT, bone marrow biopsy, or cerebral spinal fluid analysis. The patient was treated with intravenous as well as intrathecal chemotherapy and found to be in a complete remission at six months. Recurrence in the CNS was observed four months later with treatment consisting of whole brain radiation as well as intrathecal chemotherapy. Thirty months after diagnosis, the patient remains disease-free. To our knowledge, this is the first case of PCNSBL in the setting of CP. A review of literature regarding treatment options in this controversial setting is provided.\n==== Body\n1. Introduction\nPrimary central nervous system lymphoma (PCNSL) has historically been an uncommon disease entity since it was first discovered. Recent reviews, however, indicate that cases continue to arise at increasing numbers [1–3]. Incidence rose three-fold between the years of 1973 and 1984; however, the rate of increase is currently trending toward stabilization [4]. This is perhaps due to the invention of highly active antiretroviral therapy (HAART) for acquired immunodeficiency syndrome (AIDS) as immunocompromised individuals remain at 300% increased risk for PCNSL [3], and the average age of diagnosis is 40 in the immunosuppressed population versus 55–61 years of age in those who are immunocompetent [3]. Even as the incidence of PCNSL rises, it remains a rare disease with a mere 7% incidence rate. The subset of those individuals with primary CNS Burkitt lymphoma (PCNSBL) constitutes an even scarcer population comprising just 3–5% of the PCNSL cases [1–3]. Only 36 cases of PCNSBL were found worldwide after a thorough literature review (Table 1).\n\nWith such diminutive evidence on the most effective way to treat these patients, no standard of care exists, and the chosen therapy has been anything but uniform. Many have elected various combinations of intravenous (IV) chemotherapy, intrathecal (IT) chemotherapy, and radiation therapy. A backbone of IV high-dose methotrexate (HD-MTX) proves to be the most significant prognostic variable with regard to treatment [3]. However, the optimal role for IT MTX as well as radiation has yet to be defined.\n\nRecently, there has been doubt amongst professionals whether whole brain radiation therapy (WBRT) should be implored for these patients. In those who receive WBRT, approximately 61% relapse within the radiation field, and the risk of significant neurotoxicity, is 25–35% at 5 years with death occurring in one-third of those patients [4–6]. This toxicity proves especially detrimental in individuals greater than 60 years of age [4], with recent assertions that using WBRT in children is no longer necessary or acceptable due to significant risk of long-term neurotoxicity [7]. The German PCNSL Study Group is the largest and only phase III randomized trial comparing IV chemotherapy ± WBRT which revealed no significant difference in overall survival (OS) (44.2 versus 59.0 months, p = 0.78) when WBRT was added to HD-MTX-based chemotherapy in those patients with a complete response (CR) [8]. In a subset of patients who did not reach a CR, however, the addition of WBRT did show prolonged progression-free survival (PFS) (5.0 versus 2.9 months, p = 0.002) but did reveal a difference in OS (27.4 versus 18.2 months, p = 0.119) [8].\n\nSeveral different therapeutic options, including IT chemotherapy and complete surgical resection, have also been questioned. As IV HD-MTX crosses the blood-brain barrier, many believe IT only increases toxicity with little to no additional benefit. Complete resection of the tumor has also been challenged in the past as it potentially increases neurologic deficits without any survival benefit [5]. Recently, the German PCNSL Study Group-1 (GPSG-1) trial has refuted this, stating there may be significant PFS [2]. Discrepancies may be attributed to the advances that have been made in neurosurgical techniques over the last decade [2].\n\nPatients with PCNSL have an extremely poor prognosis, with an OS of approximately 12–18 months [1, 3, 9]. Without treatment, this number dwindles to 1.5–3.3 months [10]. Therefore, it is imperative that this disease be treated with the best available option to improve the expected survival of these individuals. Here, we present a case of an adult HIV-negative male with PCNSBL in the setting of cerebral palsy (CP) and our approach to treatment with long-term follow-up.\n\n2. Case\nA 55-year-old Caucasian male with past medical history of cerebral palsy (CP) presented with nausea, vomiting, thirty-pound weight loss, and worsening bilateral lower extremity weakness for one month. A computerized tomography (CT) angiogram of the brain revealed a suprasellar mass facilitating transfer to our institution for further management. Magnetic resonance imaging (MRI) of the brain indicated abnormal enhancement along the ependymal margin of the frontal horns of the bilateral lateral ventricles with four distinct abnormal enhancing mass lesions in the hypothalamus (11 × 12 × 13 mm), pineal gland (8 × 8 × 9 mm), the trigon of the right lateral ventricle (5 × 5 × 4 mm), and the foramen of Magendie (7 × 6 × 9 mm) which demonstrated restriction diffusion indicating hypercellularity (Figure 1).\n\nAn endoscopic biopsy of the third ventricle floor lesion was performed with pathology revealing sheets of intermediate size monotonous lymphoid cells displaying high nuclear-to-cytoplasmic ratio with dispersed chromatin and indistinct nucleoli. Numerous apoptotic cells and mitotic figures with foci of necrosis were observed. The tumor cells displayed CD 20 with coexpression of CD 10 and were negative for BCL 2, BCL 6, CD 3, and CD 5. EBER in situ hybridization was also negative. Fluorescent in situ hybridization was positive for [11, 12] (MYC/IHG) fusion in 97% of the cells and loss of BCL2 in 96%. These results appeared to be consistent with Burkitt lymphoma.\n\nStaging workup was obtained which only revealed concern for extra cranial disease present at T12-L1 and L2-L3 consistent with subarachnoid nodular pial metastases on MRI of the lumbosacral spine. PET/CT disclosed no evidence of extra-CNS disease. A lumbar puncture and bone marrow biopsy were performed and found to be negative for disease. In the absence of extra-CNS disease, the patient was diagnosed with PCNSBL.\n\nPatient was started on IV HD-MTX (3.5 grams per meter squared) and cytarabine (2 grams per meter squared) per Ferreri regimen [13] with the addition of IT MTX/cytarabine every 21 days for four cycles. Dose was reduced by 25% for cycle three due to persistent cytopenias and toxicity including renal dysfunction with delayed MTX clearance. A repeat brain MRI was obtained after 6 months which indicated complete remission with no evidence of disease (Figure 2).\n\nFour months later, the patient began having generalized weakness with visual disturbances and headaches. A repeat brain MRI at that time revealed interval development of markedly abnormal signal in the pons extending to the midbrain and dorsal medulla. Repeat cerebral spinal fluid (CSF) analysis showed rare atypical lymphocytes consistent with relapse of lymphoma. He underwent WBRT, receiving 30 Gray (Gy) over 17 fractions with an additional boost to the midbrain lesion with 9 Gy in 8 fractions. Currently, he is disease-free at 30 months s/p diagnosis.\n\n3. Discussion\nTo our knowledge, our patient is the only PCNSBL case with a past medical history of CP. No literature was discovered that revealed a connection between these two diseases, and further research may be warranted if similar cases develop in the future. It would have been easy to dismiss the presenting symptoms as part of his CP; therefore, caution must be taken to not be blinded by a patient's past medical history in attempting to decipher the etiology of new symptoms. Primary CNS lymphoma should remain a consideration for those presenting with neurological symptoms regardless of their history.\n\nThe optimal treatment for PCNSBL continues to elude us, and no standard of care exists at this time. The paucity of cases provides little opportunity for randomized controlled trials; therefore, clinicians have been forced to extrapolate based upon recommendations for Burkitt lymphoma residing outside as well as PCNSL regimens. Many of the reported cases of PCNSBL used HD-MTX +/−, some variation of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy. A few studies attempted additional agents such as ifosfamide and procarbazine, but had little success. Several used IT MTX alone or in combination with cytarabine and steroids.\n\nOur treatment decision was based upon the Ferreri regimen, which is the only randomized trial for PCNSL [13]. Since our patient suffered from the added rarity of Burkitt lymphoma subtype, the addition of IT chemotherapy was made based on standard practice for extra-CNS Burkitt lymphoma as it has a high incidence of CNS penetration. While there has been some debate regarding the need for IT chemotherapy in addition to IV HD-MTX, these patients were mostly non-Burkitt type (diffuse large B cell) PCNSL. Even with the baseline cognitive deficits of our patient, he was able to tolerate an aggressive chemotherapy regimen that included IT and eventually WBRT without any permanent neurological complications to date. Although he did develop some mild delirium while hospitalized for WBRT and IT MTX after relapse, this promptly resolved prior to discharge. The decision at that time was made to withhold any further IT therapy as no further evidence of disease was present and the risk of toxicities outweighed the current benefits. He remains disease-free at 30 months.\n\nThe role of IT therapy has been challenged in the face of HD-MTX therapy being able to cross the BBB. Ferreri et al. have shown that there is no survival benefit when using IT in addition to HD-MTX with regard to PCNSL of all types, with 2-year OS rates of 51 ± 5% with IT versus 50 ± 6% without IT [14]. There are also reports of increased neurotoxicity when adding concurrent IT to HD-MTX with no survival benefit [8]. Neither of these studies separated those with Burkitt subtype, however. Therefore, our decision for IT administration was based upon extrapolation from accepted therapy for extra-CNS Burkitt lymphoma being IT MTX/Ara-C in addition to systemic chemotherapy.\n\nWe present a case of relapsed lymphoma that responded to WBRT of 30 Gray in 17 fractions with boost of 9 Gray in 8 fractions which was tolerated well with a complete response (CR), and no evidence of disease at 18 months after radiation was completed. Many studies have attempted to investigate the benefits and toxicities associated with the use of WBRT, which challenges the prior approach to this entity. There seems to be a trend away from WBRT, especially in those individuals > 60 years of age and children with no evidence of residual disease after IV chemotherapy, as long-term neurocognitive consequences have been found to outweigh the benefit gained by these patients with neurotoxicity being fatal even without evidence of recurrent disease [4].\n\nRecent studies have shown no OS benefit when adding upfront WBRT to HD-MTX-containing regimens. Ferreri et al. have shown an OS of 25 ± 4% at 2 years with WBRT alone which was significantly inferior to both MTX-containing chemotherapy as well as MTX combined with WBRT, revealing a 2-year OS of 34 ± 10% and 45 ± 3%, respectively [14]. This OS difference between WBRT with MTX versus MTX alone was not significant; therefore, it is suggested that those individuals at a high risk of neurotoxicity forego WBRT unless relapse or refractory disease is apparent. We therefore chose to forego WBRT in the initial setting, reserving it for relapsed disease in our patient. Debate also exists regarding the optimal dose of WBRT, as each study utilized different fractions and dosages. Hyperfractionation has also been noted to have increase toxicity as compared to standard dosage with neurotoxicity rates of 23% and 3.7%, respectively [5]. This has been shown to be most prevalent in those receiving > 50 Gray [9].\n\nThe concept of complete surgical resection has fallen under scrutiny in recent years as well. Previously, many subscribed to complete resection of the mass with recent reports challenging this citing an increase in postoperative neurological deficits with no OS benefit [2, 3, 15]. Currently, the decision for excision when CNS lesions are the only areas of disease is made on a case by case basis with regard to tumor location and expected postsurgical deficits.\n\nDespite adequate initial treatment with chemotherapy with or without WBRT, approximately 40–50% of PCNSL patients relapse within the first 5 years [3]. This obviates the need for obtaining better treatment modalities, not only first line but also for relapsed or refractory disease. The median post relapse survival rate approximates 2 months with a 2-year OS of 8% [3]. Our patient is now 18 months status post a second CR. A few small studies have evaluated the role of bone marrow transplant as a potential treatment for PCNSL in the relapsed and refractory setting as these individuals have a significantly increased risk of death [2, 16, 17]. Randomized phase II trials must be undertaken to thoroughly evaluate this option with regard to such a specific disease population.\n\nOur patient subscribed to the current statistics of recurrence of disease within the first five years despite a complete response to initial treatment. He is currently disease-free for 18 months after reinduction with WBRT, which is longer than the average survival of such individuals, and remains without any significant neurotoxicity. Using our approach of IV and IT chemotherapy in PCNSBL upfront and reserving WBRT for the relapsed setting, our patient has far exceeded the median post relapse survival rate. This suggests a potential benefit to our approach. Regardless of the relatively favorable outcome of our patient, it remains that clear optimal treatment continues to be elusive. Substantial advances are required with regard to PCNSBL, as it remains a significant challenge to patients and physicians alike.\n\nConflicts of Interest\nThe authors declare that there is no conflict of interest regarding the publication of this paper.\n\nFigure 1 MRI brain, T1 sagittal + gadolinium, demonstrated lesions within hypothalamus, pineal gland, trigon of the right lateral ventricle, and foramen of Magendie at diagnosis.\n\nFigure 2 MRI brain, T1 sagittal + gadolinium, revealing complete resolution of all four mass lesions after receiving IV and IT chemotherapy.\n\nTable 1 Reported PCNSBL cases. Cy: cyclophosphamide; OS: overall survival; WBRT: whole brain radiation therapy; CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone; Dex: dexamethasone; IVIG: intravenous immunoglobulin; MTX: methotrexate.\n\nAuthor\tYear\tAge/sex\tHow it is diagnosed (LP versus mass)\tTreatment and OS\t\nGawish [18]\t1976\t8/M\tLeft frontoparietal mass extending across midline and through the skull\tComplete resection with recurrence. Subtotal resection with Cy. OS of 3 years\t\nValsamis et al. [19]\t1976\t6 m/M\tLeft parietal, bilateral temporal, and post pituitary mass with abdominal and periaortic nodal involvement\tResection, steroids, WBRT, and spinal irradiation with recurrence, IT MTX. OS of 23 months\t\nTanaka et al. [20]\t1977\t49/M\tRight thalamus to midbrain mass\tSubtotal resection. OS of 4.5 years\t\nTanaka et al. [20]\t1977\t58/M\tRight temporal mass\tSubtotal resection. Recurrence. OS 3 months\t\nTanaka et al. [20]\t1977\t42/M\tLeft deep parietal to occipital mass\tPred with partial resection. Recurrence. Vincristine and Cy with radiation. Vincristine, bleomycin, Cy, steroids. OS of 2.5 years\t\nGiromini et al. [11]\t1981\t11/M\tLeft temporooccipital mass\tComplete resection\t\nHegedüs [21]\t1984\t50/F\tRight lower parietal lobe mass\tPost mortem finding\t\nKobayashi [22]\t1984\t55/F\tRight temporoparietal mass\tComplete resection. Recurrence with reresection. OS of 2 months\t\nPui et al. [23]\t1985\t6/M\tT2-5 mass\tLaminectomy and CHOP (without prednisone). OS > 2 years\t\nPui et al. [23]\t1985\t7/M\tC7-T4 mass\tLaminectomy, radiation, dex, and Cy. Recurrence. OS of 5 months\t\nPui et al. [23]\t1985\t12/M\tT7-10 mass\tLaminectomy, CHOP (substituting dex for prednisone). OS of 4 months\t\nMizugami et al. [24]\t1987\t6/M\tT10 mass\tNear complete resection, radiation, and chemotherapy. Leukemic transformation then CSF recurrence. IT MTX and cranial irradiation. OS of 20 months\t\nMizugami et al. [24]\t1987\t5/M\tEpidural T12-L4 mass\tNear complete resection, radiation, and chemotherapy with recurrence. OS of 7 months\t\nMizugami et al. [24]\t1987\t7/F\tT11 mass\tNear complete resection. Spinal radiation and chemotherapy with progression of disease. OS of 3 months\t\nShigemori et al. [25]\t1991\t49/F\tLeft frontal lobe mass\tResection, radiation, CHOP, and IT MTX. OS of >6 months\t\nTekkök et al. [12]\t1991\t5/M\tParasellar mass, extending to bilateral sphenoids and sella turcica\tPartial resection, craniospinal radiation, CHOP, and IT MTX/cytarabine/prednisone. OS > 18 months\t\nToren et al. [26]\t1994\t6/F\tCSF\tSteroids, IVIG, doxorubicin, vincristine, HD MTX, with IT MTX, cytarabine, and hydrocortisone. Changed to CHOP with MTX and IT MTX, cytarabine, hydrocortisone. OS of >2 years\t\nMora and Wollner [7]\t1999\t18/M\tT11 mass\tLaminectomy with CHOP substitute daunorubicin for doxorubicin and radiation. Relapse and refused further treatment. OS > 8 months\t\nMora and Wollner [7]\t1999\t9/M\tEpidural T9-11 mass\tLaminectomy, dex, radiation, and CHOP (substituting daunorubicin for doxorubicin). Recurrence and given chemotherapy via LSA3 protocol. Second recurrence, received palliative radiation. OS > 1 year\t\nSpath-Schwalbe et al. [27]\t1999\t40/M\tCerebellum and pons masses\tMTX and WBRT. OS > 1 year\t\nWilkening et al. [28]\t2001\t43/F\tL2-3 epidural tumor involving the dura and cauda equina\tComplete resection, radiation, IT MTX, and MTX with ifosfamide and CHOP (with dex substituted for prednisone). OS of >2 years\t\nMonabati et al. [29]\t2002\t49/F\tRight parietal mass\tComplete resection, CHOP, and craniospinal radiation. Refused further treatment. OS of >6 months\t\nDaley et al. [30]\t2003\t13/F\tL1-2 epidural mass\tComplete excision, CHOP with MTX, and IT MTX and cytarabine and steroids. OS of >5 years\t\nShehu [31]\t2003\t8/M\tLeft temporal and right orbit masses\tCy, vincristine, and MTX with IT cytosine arabinoside. OS of 11 months\t\nAbel et al. [32]\t2006\t50/M\tCentral and right thalamus mass\tUnknown\t\nGobbato et al. [15]\t2006\t38/M\tRight frontotemporoparietal subdural mass\tCraniotomy. OS of 11 days\t\nKozáková et al. [33]\t2008\t60/F\tSellar/pituitary mass\tComplete resection\t\nGu et al. [34]\t2010\t75/F\tThird and left lateral ventricle masses\tWBRT. OS of >9 months\t\nTakasu et al. [35]\t2010\t71/M\tHypothalamus and third ventricle mass\tPartial resection and WBRT\t\nJiang et al. [36]\t2011\t14/M\tRight lateral ventricle mass\tComplete resection, radiation, and MTX, vincristine, predisone, and leucovorin. OS of >18 months\t\nLim et al. [10]\t2011\t43/F\tMedulla oblongata mass, CSF involvement\tMTX, vincristine, and procarbazine with IT MTX and WBRT. OS of 7 months\t\nAkhaddar et al. [37]\t2012\t13/F\tRight infratemporal and cavernous/maxillary/sphenoethmoidal sinus mass\tChemotherapy\t\nJiang et al. [38]\t2012\t69/M\tRight temporal and occipital lobe, cervical spine, and cauda equina masses; CSF involvement\tDLBCL/BL subtype. WBRT, spinal radiation with recurrence. HD MTX and cytarabine with rituximab\t\nYoon et al. [39]\t2012\t10/M\tSuprasellar, cerebellum, and 3rd ventricle masses; CSF involvement\tHD MTX and cytarabine with IT cytarabine, MTX, and hydrocortisone. OS of >7 years\t\nYoon et al. [39]\t2012\t32 m/M\tSellar mass extending to orbit/sphenoid, CSF involvement\tHD MTX and cytarabine with IT cytarabine, MTX, and hydrocortisone. Relapse, treated with IT cytarabine, MTX, and hydrocortisone with WBRT and spinal radiation. Then received prednisone, vincristine, and cyclophosphamide with IT. OS of 9 months\t\nAlabdulsalam et al. [40]\t2014\t18/M\t4th ventricle mass\tCraniotomy with HD MTX with rituximab-CHOP and IT MTX, cytarabine, and hydrocortisone. 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Primary intracranial malignant lymphomas with particular reference to their pathogenesis Acta Pathologica Japonica 1977 27 6 927 940 343491 \n21 Hegedüs K. Burkitt-type lymphoma and reticulum-cell sarcoma. An unusual mixed form of two intracranial primary malignant lymphomas Surgical Neurology 1984 21 1 23 29 10.1016/0090-3019(84)90395-1 2-s2.0-48749138816 6359511 \n22 Kobayashi H. Sano T. Li K. Hizawa K. Primary Burkitt-type lymphoma of the central nervous system Acta Neuropathologica 1984 64 1 12 14 10.1007/BF00695600 2-s2.0-0021246794 6475493 \n23 Pui C. H. Dahl G. V. Hustu H. O. Murphy S. B. Epidural spinal cord compression as the initial finding in childhood acute leukemia and non-Hodgkin lymphoma The Journal of Pediatrics 1985 106 5 788 792 10.1016/S0022-3476(85)80357-7 2-s2.0-0022362471 3858493 \n24 Mizugami T. Mikata A. Hajikano H. Asanuma K. Ishida H. Nakamura C. Primary spinal epidural Burkitt’s lymphoma Surgical Neurology 1987 28 2 158 162 10.1016/0090-3019(87)90092-9 2-s2.0-0023394626 3603357 \n25 Shigemori M. Tokunaga T. Miyagi J. Multiple brain tumors of different cell types with an unruptured cerebral aneurysm Neurologia Medico-Chirurgica 1991 31 2 96 99 10.2176/nmc.31.96 1715044 \n26 Toren A. Mandel M. Shahar E. Primary central nervous system Burkitt’s lymphoma presenting as Guillain-Barré syndrome Medical and Pediatric Oncology 1994 23 4 372 375 10.1002/mpo.2950230410 2-s2.0-0028108106 8058010 \n27 Spath-Schwalbe E. Genvresse I. Stein H. Primary cerebral highly-malignant B-cell lymphoma of the Burkitt type Deutsche Medizinische Wochenschrift 1999 124 15 451 455 10.1055/s-2007-1024333 10326601 \n28 Wilkening A. Brack M. Brandis A. Heidenreich F. Dengler R. Weibetaenborn K. Unusual presentation of a primary spinal Burkitt’s lymphoma Journal of Neurology, Neurosurgery, & Psychiatry 2001 70 6 794 797 10.1136/jnnp.70.6.794 2-s2.0-0034979235 11385017 \n29 Monabati A. Rakei S. M. Kumar P. V. Taghipoor M. Rahimi A. Primary Burkitt lymphoma of the brain in an immunocompetent patient Journal of Neurosurgery 2002 96 6 1127 1129 10.3171/jns.2002.96.6.1127 2-s2.0-0036263062 12066916 \n30 Daley M. F. Partington M. D. Kadan-Lottick N. Odom L. F. Primary epidural Burkitt lymphoma in a child: case presentation and literature review Pediatric Hematology and Oncology 2003 20 4 333 338 10.1080/08880010390203062 2-s2.0-0038778568 12746166 \n31 Shehu B. B. Primary central nervous system Burkitt’s lymphoma presenting with proptosis Annals of Tropical Paediatrics 2003 23 4 319 320 10.1179/027249303322705812 2-s2.0-0347993998 14738582 \n32 Abel T. W. Thompson M. A. Kim J. Yenamandra A. Becher M. W. Primary central nervous system Burkitt lymphoma: report of a case confirmed with identification of t(8;14) by FISH Brain Pathology 2006 16 Supplement 1 96 97 \n33 Kozáková D. Macháleková K. Brtko P. Szépe P. Vanuga P. Pura M. Primary B-cell pituitary lymphoma of the Burkitt type: case report of the rare clinic entity with typical clinical presentation Casopis lekaru ceskych 2008 147 11 569 573 19097361 \n34 Gu Y. Hou Y. Zhang X. Hu F. Primary central nervous system Burkitt lymphoma as concomitant lesions in the third and the left ventricles: a case study and literature review Journal of Neuro-Oncology 2010 99 2 277 281 10.1007/s11060-010-0122-z 2-s2.0-77956055628 20146089 \n35 Takasu M. Takeshita S. Tanitame N. Primary hypothalamic third ventriclular Burkitt’s lymphoma: a case report with emphasis on differential diagnosis The British Journal of Radiology 2010 83 986 e43 e47 10.1259/bjr/84426981 2-s2.0-76149133648 20139257 \n36 Jiang M. Zhu J. Guan Y. Zou L. Primary central nervous system Burkitt lymphoma with non-immunoglobulin heavy chain translocation in right ventricle: case report Pediatric Hematology and Oncology 2011 28 5 454 458 10.3109/08880018.2011.566599 2-s2.0-79960148112 21615246 \n37 Akhaddar A. Zalagh M. Belfquih H. Boucetta M. Burkitt’s lymphoma: a rare cause of isolated trigeminal neuralgia in a child Child's Nervous System 2012 28 7 1125 1126 10.1007/s00381-012-1735-7 2-s2.0-84863678860 22427256 \n38 Jiang L. Li Z. Finn L. E. Primary central nervous system B cell lymphoma with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma International Journal of Clinical and Experimental Pathology 2012 5 1 72 76 22295149 \n39 Yoon J. H. Kang H. J. Kim H. Successful treatment of primary central nervous system lymphoma without irradiation in children: single center experience Journal of Korean Medical Science 2012 27 11 1378 1384 10.3346/jkms.2012.27.11.1378 2-s2.0-84872544200 23166421 \n40 Alabdulsalam A. Zaidi S. Z. A. Tailor I. Orz Y. Al-Dandan S. Primary Burkitt lymphoma of the fourth ventricle in an immunocompetent young patient Case Reports in Pathology 2014 2014 6 630954 10.1155/2014/630954 25254131\n\n",
"fulltext_license": "CC BY",
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"medline_ta": "Case Rep Oncol Med",
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"nlm_unique_id": "101581035",
"other_id": null,
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"pubdate": "2018",
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"references": "12066916;11567816;23166421;8055462;20139257;1715044;343491;12746166;7246058;177169;6359511;19021047;21479535;9950197;22427256;16917629;3603357;25254131;20146089;21615246;22295149;10659013;23963042;12805341;1878874;12488408;19767089;11385017;978244;10326601;12034789;16525183;19097361;14738582;25716362;10707777;8058010;3858493;6475493",
"title": "Primary CNS Burkitt Lymphoma: A Case Report of a 55-Year-Old Cerebral Palsy Patient.",
"title_normalized": "primary cns burkitt lymphoma a case report of a 55 year old cerebral palsy patient"
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"abstract": "BACKGROUND\nThe use of bevacizumab in the management of glioblastoma multiforme (gbm) remains controversial. In Canada, bevacizumab is approved for the treatment of recurrent gbm. We describe a pattern of progression across treatment lines in gbm.\n\n\nMETHODS\nDuring 2008-2014, 64 patients diagnosed with gbm were treated with bevacizumab at McGill University hospitals. Of those patients, 30 (46.9%) received bevacizumab in the first line (B1L), and 34 (53.1%) received it in the second line and beyond (B2L+). The average length of treatment with bevacizumab was 24.4 weeks (range: 0-232.7 weeks). The patterns of progression were categorized as local, distant, diffuse, multifocal, or multi-pattern.\n\n\nRESULTS\nLocal progression was seen in 46.7% of B1L patients and 26.5% of B2L+ patients, distant in 3.3% and 2.9%, diffuse in 20% and 47%, multifocal in 10% and 8.8%, and multi-pattern in 3.3% and 11.8%. No differences between the groups were observed for the distant (p = 0.3) or diffuse (p = 0.4) patterns. Grades 3 and 4 adverse events in the B1L and B2L+ groups were fatigue (33.3% vs. 17.6% respectively), hypertension (26.7% vs. 5.9%), thrombocytopenia (26.7% vs. 11.8%), neutropenia (26.7% vs. 11.8%), anemia (23.3% vs. 11.8%), leucopenia (20% vs. 8.8%), deep vein thrombosis (23.3% vs. 5.9%), seizure (16.7% vs. 8.8%), brain hemorrhage (6.7% vs. <1%), and delayed wound healing (6.7% vs. 2.9%). More total grades 3 and 4 adverse events occurred in the B1L group (p = 0.000519).\n\n\nCONCLUSIONS\nIn our cohort, patterns of progression were not different in B1L and B2L+ patients. Moreover, both groups experienced similar adverse events, although more grades 3 and 4 events occurred in the B1L group, implying that severe adverse events in B1L patients could negatively affect survival outcomes.",
"affiliations": "Segal Cancer Centre, Jew ish General Hospital, McGill University, Montreal, QC.;Segal Cancer Centre, Jew ish General Hospital, McGill University, Montreal, QC.;Segal Cancer Centre, Jew ish General Hospital, McGill University, Montreal, QC.;Segal Cancer Centre, Jew ish General Hospital, McGill University, Montreal, QC.;Segal Cancer Centre, Jew ish General Hospital, McGill University, Montreal, QC.;Radiation Oncology, Jewish General Hospital, McGill University Health Centre, Montreal, QC.;Department of Oncology, McGill University Health Centre, Montreal, QC.;Neurosurgery, Montreal Neurological Institute, Montreal, QC.;Pathology, McGill University Health Centre, Montreal, QC.;Clinical Research, McGill University Health Centre, Montreal, QC.;Clinical Research, McGill University Health Centre, Montreal, QC.;Segal Cancer Centre, Jew ish General Hospital, McGill University, Montreal, QC.",
"authors": "Mamo|A|A|;Baig|A|A|;Azam|M|M|;Rho|Y S|YS|;Sahebjam|S|S|;Muanza|T|T|;Owen|S|S|;Petrecca|K|K|;Guiot|M C|MC|;Al-Shami|J|J|;Sharma|R|R|;Kavan|P|P|",
"chemical_list": null,
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"issue": "23(5)",
"journal": "Current oncology (Toronto, Ont.)",
"keywords": "Glioblastoma multiforme; adverse events; bevacizumab; patterns of progression; survival",
"medline_ta": "Curr Oncol",
"mesh_terms": null,
"nlm_unique_id": "9502503",
"other_id": null,
"pages": "e468-e471",
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"pmid": "27803607",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article",
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"title": "Progression pattern and adverse events with bevacizumab in glioblastoma.",
"title_normalized": "progression pattern and adverse events with bevacizumab in glioblastoma"
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"abstract": "This study explores underlying patterns in suicide risk factors using data mining techniques. Medical records of suicide attempters who were admitted to a teaching hospital in January 2004 - December 2006 were studied. Cluster analysis revealed hidden patterns for repeated and single attempters (n=418). Repeated attempters had a more complex clinical picture. Symptoms of psychotic illness, borderline personality disorder, and psychosomatic complaints of insomnia and headaches, reports of adverse life events such as unemployment, divorce and quarrels, experience of negative feelings, and usage of alcohol were associated with risk of repeated overdoses with benzodiazepines and paracetamol. The findings have implications for suicide assessments and interventions.",
"affiliations": "School of Health Professions, Murdoch University, 90 South St, Murdoch, WA 6150, Australia. Electronic address: C.Choo@murdoch.edu.au.;School of Information Technology and Electrical Engineering, The University of Queensland, Brisbane, QLD 4072, Australia.;School of Business and IT, James Cook University, 600 Upper Thomson Road, Singapore 574421, Singapore.;Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.",
"authors": "Choo|Carol|C|;Diederich|Joachim|J|;Song|Insu|I|;Ho|Roger|R|",
"chemical_list": null,
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"issue": "8()",
"journal": "Asian journal of psychiatry",
"keywords": "Borderline personality disorder; Cluster analysis; Data mining; Psychotic illness; Repeated suicide attempts; Risk factors",
"medline_ta": "Asian J Psychiatr",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asians; D001883:Borderline Personality Disorder; D002648:Child; D016000:Cluster Analysis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011618:Psychotic Disorders; D012307:Risk Factors; D013406:Suicide, Attempted; D055815:Young Adult",
"nlm_unique_id": "101517820",
"other_id": null,
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"pmc": null,
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"pubdate": "2014-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cluster analysis reveals risk factors for repeated suicide attempts in a multi-ethnic Asian population.",
"title_normalized": "cluster analysis reveals risk factors for repeated suicide attempts in a multi ethnic asian population"
} | [
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"companynumb": "AU-JNJFOC-20140401058",
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"abstract": "Affecting 2.5 million people worldwide, multiple sclerosis (MS) is one of the main causes of acquired disability among young adults. In French West Indies (FWI), where MS has arisen from the end of the 80's, a low therapeutic response to interferons beta1 (IFN beta1) in patients of African descent, restrains the therapeutic options. Fingolimod is a Sphingosine-1-Phosphate receptor modulator whose efficacy in the treatment of MS has recently been shown in three phase III studies. Nevertheless, data are currently lacking concerning the use of Fingolimod among populations of African descent, particularly in a real-world setting. Efficacy and safety information collected during the first two years of follow-up have been analysed retrospectively for all patients in whom Fingolimod treatment was introduced in FWI between its marketing date and December 2015. Fifty-two consecutive patients with a relapsing remitting MS started Fingolimod therapy in the FWI, according to the European guidelines. After 24 months, 40 patients were still receiving the treatment. The average Annualized Relapse Rate (ARR) dropped by 81%, and 72.5% of patients remained free from disability progression during the 24 months on Fingolimod. MS remained controlled (according NEDA 3 criteria) for 41% of patients who were still on therapy at 24 months. Nine participants presented with a moderate or major side effect. Unlike IFN beta1 therapy, Fingolimod appears to be effective in Afro-Caribbean patients in a real-world setting with a similar benefit to what has been observed in phase III studies in more selected populations.",
"affiliations": "Department of Neurology, University Hospital of Caen, Avenue de la côte de Nacre, 14033 Cedex Caen, France. Electronic address: alexisrqml@gmail.com.;Department of Neurology, University Hospital of Martinique, Route de châteauboeuf, Fort-de-France, France.;Department of Neurology, University Hospital of Pointe-à-Pitre, Route de Chauvel, 97139 Abymes, France.;Neurology, Clinique de Choisy, 97190 Le Gosier, France.;Department of Neurology, University Hospital of Martinique, Route de châteauboeuf, Fort-de-France, France.",
"authors": "de Roquemaurel|Alexis|A|;Galli|Paola|P|;Landais|Anne|A|;Avendano|Samuel|S|;Cabre|Philippe|P|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jns.2019.05.027",
"fulltext": null,
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"issn_linking": "0022-510X",
"issue": "402()",
"journal": "Journal of the neurological sciences",
"keywords": "Afro-Caribbean; Efficacy; Fingolimod; NEDA-3; Real-world; Relapsing-remitting multiple sclerosis",
"medline_ta": "J Neurol Sci",
"mesh_terms": "D000328:Adult; D018450:Disease Progression; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis; D012008:Recurrence; D012189:Retrospective Studies; D016896:Treatment Outcome; D014900:West Indies",
"nlm_unique_id": "0375403",
"other_id": null,
"pages": "180-187",
"pmc": null,
"pmid": "31158557",
"pubdate": "2019-07-15",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Fingolimod for the treatment of multiple sclerosis in French West Indies, a real-world study in patients from African ancestry.",
"title_normalized": "fingolimod for the treatment of multiple sclerosis in french west indies a real world study in patients from african ancestry"
} | [
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"abstract": "Pathologic complete response is an exceptionally rare occurrence in prostate cancer, especially in the setting of poorly differentiated cancer, with high risk and poor prognostic features. Patient reviewed and signed an informed consent. The case details were collected. Patient had PSA of 52.6 ng/dl and Gleason score 5 + 5 = 10 prostate adenocarcinoma with focal signet ring cell pattern. Genomic testing revealed pathogenic p53 and SPOP mutations. The patient received androgen deprivation therapy and six cycles of docetaxel. His PSA declined to undetectable, and radical prostatectomy (RP) showed no evidence of malignancy. The patient has discontinued all therapy and continues in remission 12 months after surgery.",
"affiliations": "Department of Oncology, Wayne State University/Karmanos Cancer Institute, Detroit, MI, USA.;Department of Pathology, Wayne State University/Karmanos Cancer Institute, Detroit, MI, USA.;Department of Pathology, Wayne State University/Karmanos Cancer Institute, Detroit, MI, USA.;Department of Radiology, Wayne State University/Karmanos Cancer Institute, Detroit, MI, USA.;Department of Urology, Detroit Medical Center, Detroit, MI, USA.",
"authors": "Vaishampayan|Ulka|U|;Shi|Dongping|D|;Abdulfatah|Eman|E|;Aoun|Hussein|H|;Wynberg|Jason|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.eucr.2019.01.018",
"fulltext": "\n==== Front\nUrol Case RepUrol Case RepUrology Case Reports2214-4420Elsevier S2214-4420(18)30397-810.1016/j.eucr.2019.01.018OncologyExceptional pathologic complete response achieved with androgen deprivation and docetaxel therapy in Gleason 10 prostate cancer Vaishampayan Ulka vaishamu@karmanos.orga∗Shi Dongping bAbdulfatah Eman bAoun Hussein cWynberg Jason da Department of Oncology, Wayne State University/Karmanos Cancer Institute, Detroit, MI, USAb Department of Pathology, Wayne State University/Karmanos Cancer Institute, Detroit, MI, USAc Department of Radiology, Wayne State University/Karmanos Cancer Institute, Detroit, MI, USAd Department of Urology, Detroit Medical Center, Detroit, MI, USA∗ Corresponding author. 4100 John R, Detroit, MI, 48201, USA. vaishamu@karmanos.org28 1 2019 3 2019 28 1 2019 23 103 105 30 11 2018 23 1 2019 © 2019 Published by Elsevier Inc.2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Pathologic complete response is an exceptionally rare occurrence in prostate cancer, especially in the setting of poorly differentiated cancer, with high risk and poor prognostic features. Patient reviewed and signed an informed consent. The case details were collected.\n\nPatient had PSA of 52.6 ng/dl and Gleason score 5 + 5 = 10 prostate adenocarcinoma with focal signet ring cell pattern. Genomic testing revealed pathogenic p53 and SPOP mutations. The patient received androgen deprivation therapy and six cycles of docetaxel. His PSA declined to undetectable, and radical prostatectomy (RP) showed no evidence of malignancy. The patient has discontinued all therapy and continues in remission 12 months after surgery.\n==== Body\nIntroduction\nPathologic complete response (pCR) is an exceptionally rare occurrence in prostate cancer, especially in the setting of poorly differentiated cancer, with high risk and poor prognostic features. Neoadjuvant androgen deprivation therapy (ADT) has been evaluated in multiple randomized trials and the results consistently showed downstaging of disease stage, decrease in positive margin rate, but no change in overall survival (OS).1 In multiple randomized studies conducted, the incidence of pCR at radical prostatectomy, has been exceedingly low, and even rarer in Gleason 10 histology, which is considered extremely high risk disease. We report a unique case that demonstrated pCR after neoadjuvant ADT and docetaxel chemotherapy.\n\nMaterials and methods\nPatient reviewed and signed an informed consent for clinical data collection from the medical record.\n\nResults\nCase history\nThe patient is a remarkably fit, pleasant 59-year-old gentleman, who was followed by urology for treatment of Peyronie's disease and was noted to have an elevated PSA of 52.6 in June 2017. The prior prostate specific antigen (PSA) was 3.5 ng/ml in July 2016. For the last 5 years the patient had annual PSA testing and his PSA level ranged from 1.9 to 3.7 ng/ml. The patient was on testosterone supplement injections since 2012 and his PSA level in July 2012 prior to starting on testosterone was 1.9 ng/ml.\n\nA prostate biopsy was performed in June 2017 and the results showed 5 of 12 cores positive for prostate adenocarcinoma. The left lateral base and left base biopsies showed Gleason score 5 + 4 = 9 adenocarcinoma involving 80% and 45% of the specimens respectively. The left lateral apex, left mid and left apex biopsies revealed Gleason score 5 + 5 = 10 adenocarcinoma involving 5%, 40% and 10% of the cores respectively. The tumor cells demonstrated focal signet ring cell pattern. Prostate, right lateral base, right lateral mid and right lateral apex and left lateral mid biopsies were negative for prostatic adenocarcinoma (Fig. 1A). The contrast enhanced CT scan demonstrated mildly enlarged retroperitoneal and upper pelvic adenopathy about 1 cm in size with the largest node in the left common iliac region being 1.2 cm in short axis [Fig. 2]. Bone scan revealed no scintigraphic evidence of metastatic disease.Fig. 1A Prostate needle core biopsy shows Gleason score 9 (5 + 4) within tumor cells and ill-defined tumor glands. Signet cell features are also seen (arrow).\n\nFig. 1A\n\nGenomic testing was conducted by Caris Inc, utilizing Next Gen sequencing on the biopsy specimens. The results revealed SPOP and TP53 mutations which appeared to be pathogenic (Table 1). No TMPRSS-ERG fusion was detected.Table 1 Genomic results on prostate biopsy.\n\nTable 1Biomarker\tTesting\tResult\t\nAndrogen Receptor/AR\tIHC\tPositive 2+, 90%\t\nAndrogen Receptor/AR\tNGS\tMutation not detected\t\nATM\tNGS\tMutation not detected\t\nBRCA1\tNGS\tMutation not detected\t\nBRCA2\tNGS\tMutation not detected\t\nPDL-1\tIHC\tNegative 0%\t\nMSI\tNGS\tStable\t\nTP53\tNGS\tMutated, PL32fs\t\nSPOP\tNGS\tMutated, Pathogenic, pFI33V\t\nPTEN\tNGS\tNo loss detected\t\nTMPRSS-ERG\tGene fusion testing\tNot detected\t\nERCC1\tIHC\tPositive, 2+, 50%\t\nTUBB3\tIHC\tNegative\t\nTumor Mutation burden\tNGS\tMegabase 9, intermediate\t\nThe clinically actionable mutations are shown in bold.\n\n\n\nThe patient was treated with ADT and 4 weeks later his PSA was <0.1 ng/ml. Docetaxel chemotherapy was administered at a dose of 75 mg/m2 intravenously every 21 days cycle for 6 doses. The toxicities noted were grade 1 alopecia and grade 1 fatigue. Patient had RP and a pCR was noted. The entire prostate was submitted for microscopic examination and revealed benign prostatic glands with atrophic changes and basal cell hyperplasia (Fig. 1B). Prominent stromal fibrosis with patchy chronic inflammation and focal acute inflammation was noted. One year post RP the patient continues to be in remission.Fig. 1B Prostatectomy specimen shows atrophic prostatic glands, patchy chronic inflammation and basal cell hyperplasia.\n\nFig. 1BFig. 2 Contrast enhanced axial CT scan image through the upper pelvis demonstrates morphologically rounded mildly enlarged common iliac lymph nodes (arrows).\n\nFig. 2\n\nTissue testing\nNext-generation sequencing\nTumor tissue slides from prostate biopsy were submitted to Caris Life Sciences, a Clinical Laboratory Improvement Amendments (CLIA), the College of American Pathologists (CAP) and the International Organization for Standardization (ISO) 15189-certified/accredited laboratory (Phoenix, AZ, USA) for molecular profiling aimed to provide molecular-guided treatment options. The molecular profiling included next-generation sequencing and immunohistochemistry. Direct sequencing was carried out on genomic DNA isolated from formalin-fixed paraffin-embedded tumor samples using the NextSeq platform (Illumina Inc., San Diego, CA, USA). A custom-designed SureSelectXT assay (Agilent Technologies, Santa Clara, CA, USA) was used for targeting 592 genes that were selected based on the COSMIC database (http://cancer.sanger.ac.uk/cosmic/browse/genome).\n\nGene fusion testing\nGene detection and fusion testing was performed on mRNA isolated from a formalin fixed paraffin embedded tumor sample using the Archer FusionPlex Solid Tumor Panel and the Illumina MiSeq. This assay id designed to detect fusions occurring at known breakpoints within tested fusion genes. Fusions occurring outside of known breakpoints in these genes may not be detected. Analytical validation of this test shows sensitivity and specificity of 98.3% and 100% respectively.\n\nComment\nNeoadjuvant therapy has the benefits of controlling the dissemination of disease earlier and of evaluating response rates at RP. It also allows patient selection for consolidative local therapy depending on the extent of response attained on systemic therapy. It enables better prognostication, saves costs and helps avert significant toxicities of long term therapies continued until progression. The impact of perioperative chemotherapy on clinical outcomes has been disappointing. SWOG 9921 showed that addition of chemotherapy with mitoxantrone and prednisone did not confer any OS benefit over that seen with adjuvant ADT.1 RTOG 0521 showed a small long term benefit favoring the use of neoadjuvant ADT and docetaxel with 4 year OS of 93% and 89% respectively in the arms with or without docetaxel.1 CALGB 90203 is evaluating the results of neoadjuvant ADT and docetaxel chemotherapy followed by RP as compared to RP alone in high risk localized prostate cancer. The clinical results of this study are still awaited and will likely shed light on the overall role of contemporary chemotherapy.2\n\nGenomic testing enables delivery of personalized therapy and is gradually gaining importance in therapeutic decisions for high risk localized prostate cancer. The case presented here demonstrated an exceptional response which is seen in 0–3% of patients in most neoadjuvant trials reported to date.3 The TMPRSS-ERG gene is androgen regulated and has demonstrated higher likelihood of response to ADT and abiraterone.4 SPOP gene mutations may predict for a likely response to docetaxel and is worthy of exploration in larger patient cohorts.5 In addition the patients with TMPRSS-ERG mutations (85% of patients with prostate cancer) almost never harbor SPOP mutations. Further investigation of the role of SPOP mutations in predicting therapeutic outcomes in prostate cancer is required.\n\nConclusion\nGenomic medicine has the potential to categorize an overarching clinical stage and diagnosis of prostate cancer into subtypes defined by patterns of therapeutic sensitivity or resistance. Exceptional responders such as this case will pave the way for defining therapeutic outcome prediction.\n\nAuthor contribution\nUV is the medical oncologist and the primary person writing and coordinating the manuscript, DS and EA were responsible for pathology review, HA was responsible for radiology review and JW was the urologist on the case. All authors have contributed to the manuscript content and reviewed and approved it.\n\nData availability statement\nThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nDisclosures\nAll authors declare that there are no competing interests.\n\nAppendix A Supplementary data\nThe following is the Supplementary data to this article:Data Profile\nData Profile \n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.eucr.2019.01.018.\n==== Refs\nReferences\n1 Shah H. Vaishampayan U. Therapy of advanced prostate cancer: targeting the androgen receptor Axis in earlier lines of treatment Targeted Oncol 13 2018 679 689 \n2 Beltran H. Wyatt A.W. Chedgy E.C. Impact of therapy on genomics and transcriptomics in high-risk prostate cancer treated with neoadjuvant docetaxel and androgen deprivation therapy Clin Cancer Res 23 2017 6802 6811 28842510 \n3 McKay R. Choueiri T.K. Taplin M.E. Rationale for and review of neoadjuvant therapy prior to radical prostatectomy for patients with high-risk prostate cancer Drugs 73 2013 1417 1430 23943203 \n4 Attard G. DeBono J.S. Logothetis C.J. Improvements in radiographic progression-free survival stratified by ERG gene status in castration-resistant prostate cancer patients treated with abiraterone Clin Cancer Res 21 2015 1621 1627 25593303 \n5 Blattner M. Liu D. Robinson B.D. SPOP mutation drives prostate tumorigenesi in vivo through coordinate regulation of PI3K/mTOR and AR signaling Cancer Cell 31 2017 436 451 28292441\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-4420",
"issue": "23()",
"journal": "Urology case reports",
"keywords": null,
"medline_ta": "Urol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101626357",
"other_id": null,
"pages": "103-105",
"pmc": null,
"pmid": "30740311",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports",
"references": "23943203;25593303;28292441;28842510;30536163",
"title": "Exceptional pathologic complete response achieved with androgen deprivation and docetaxel therapy in Gleason 10 prostate cancer.",
"title_normalized": "exceptional pathologic complete response achieved with androgen deprivation and docetaxel therapy in gleason 10 prostate cancer"
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"activesubstancename": "DOCETAXEL"
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"abstract": "Iliopsoas haematoma is a rare clinical entity which can be life threatening in extreme cases. We are reporting a case of iliopsoas haematoma as a complication of hypertensive urgency. A 67-year old woman presented to emergency room with hypertensive urgency and hip pain. During hospitalisation, her haemoglobin was decreasing and on further evaluation, she did not have any signs of external bleeding and laboratory results were not suggestive of haemolysis. CT scan of abdomen and pelvis revealed a spontaneous iliopsoas haematoma. A likely explanation for this presentation in the absence of coagulopathy and trauma is very high blood pressure. Patient was on low-dose aspirin at home which could have further aggravated her bleeding due to platelet dysfunction. She was managed conservatively with blood transfusions and blood pressure was reduced to target after which she recovered.",
"affiliations": "Department of Medicine, Interfaith Medical Center, Brooklyn, New York, USA.;Department of Medicine, Interfaith Medical Center, Brooklyn, New York, USA.;Department of Medicine, Interfaith Medical Center, Brooklyn, New York, USA.",
"authors": "Yogarajah|Meera|M|http://orcid.org/0000-0002-3120-2700;Sivasambu|Bhradeev|B|;Jaffe|Eric A|EA|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin",
"country": "England",
"delete": false,
"doi": null,
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"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin; D001803:Blood Transfusion; D003924:Diabetes Mellitus, Type 2; D004630:Emergencies; D005260:Female; D006406:Hematoma; D006801:Humans; D006973:Hypertension; D016658:Psoas Muscles; D011859:Radiography; D012307:Risk Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25721829",
"pubdate": "2015-02-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20200588;20048404;19764102;8640595;15680713;11779099;22482861;16128889;4289644;16020897;17336570;17343658;9000371",
"title": "Spontaneous iliopsoas haematoma: a complication of hypertensive urgency.",
"title_normalized": "spontaneous iliopsoas haematoma a complication of hypertensive urgency"
} | [
{
"companynumb": "US-BAYER-2015-036151",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"activesubstancename": "ATORVASTATIN"
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... |
{
"abstract": "BACKGROUND\nTenofovir disoproxil fumarate (TDF) has been associated with greater incidences of bone complications, which might be modified by some concomitantly administered antiretrovirals, possibly by their effect on tenofovir concentrations. We compared bone adverse outcomes among treatment-naïve HIV-infected US veterans initiating efavirenz (EFV)-containing TDF/emtricitabine (FTC) regimens versus those initiating non-EFV-containing TDF/FTC regimens.\n\n\nMETHODS\nUsing national Veterans Health Administration clinical and administrative data sets, we identified a cohort of treatment-naïve HIV-infected veterans without bone disease who initiated therapy with TDF/FTC plus EFV, rilpivirine, elvitegravir/cobicistat, or ritonavir-boosted protease inhibitors in 2003-2015. The primary composite adverse bone outcome was the unadjusted incidence rate (IR) of osteoporosis, osteopenia, or fragility fracture (any hip, wrist, or spine fracture). To account for selection bias and confounding, we used inverse probability of treatment-weighted Cox proportional hazards regression models to calculate adjusted hazard ratios (HRs) for each outcome associated with EFV + TDF/FTC versus each non-EFV-containing TDF/FTC regimen.\n\n\nRESULTS\nOf 33,048 HIV-positive veterans, 7161 initiated a TDF/FTC-containing regimen (mean age, 50 years; baseline CD4 < 200 cells/mm3, 33.3%; HIV-1 RNA > 100,000 copies/ml, 22.3%; mean follow-up, 13.0 months). Of these, 4137 initiated EFV- and 3024 non-EFV-containing regimens. Veterans initiating EFV- versus non-EFV-containing TDF/FTC regimens had a lower IR of the composite bone outcome (29.3 vs. 41.4 per 1000 patient-years), with significant risk reductions for this outcome [HR, 0.69; 95% confidence interval (CI), 0.58-0.83] and fragility fracture (HR, 0.59; 95% CI, 0.44-0.78).\n\n\nCONCLUSIONS\nEFV + TDF/FTC is associated with a lower risk of adverse bone outcomes compared with other TDF-containing regimens in the VHA.\n\n\nBACKGROUND\nBristol-Myers Squibb.",
"affiliations": "Department of Pharmacotherapy, University of Utah, Salt Lake City, UT, USA. Joanne.Lafleur@pharm.utah.edu.;Salt Lake City VA Health Care System, Salt Lake City, UT, USA.;Bristol-Myers Squibb, Lawrenceville, NJ, USA.;Bristol-Myers Squibb, Lawrenceville, NJ, USA.;Salt Lake City VA Health Care System, Salt Lake City, UT, USA.;Department of Pharmacotherapy, University of Utah, Salt Lake City, UT, USA.;VA North Texas Health Care System, Dallas, TX, USA.;Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.;Department of Pharmacotherapy, University of Utah, Salt Lake City, UT, USA.;Bristol-Myers Squibb, Lawrenceville, NJ, USA.",
"authors": "LaFleur|Joanne|J|;Bress|Adam P|AP|;Myers|Joel|J|;Rosenblatt|Lisa|L|;Crook|Jacob|J|;Knippenberg|Kristin|K|;Bedimo|Roger|R|;Tebas|Pablo|P|;Nyman|Heather|H|;Esker|Stephen|S|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40121-018-0194-1",
"fulltext": "\n==== Front\nInfect Dis Ther\nInfect Dis Ther\nInfectious Diseases and Therapy\n2193-8229\n2193-6382\nSpringer Healthcare Cheshire\n\n29492905\n194\n10.1007/s40121-018-0194-1\nOriginal Research\nTenofovir-Associated Bone Adverse Outcomes among a US National Historical Cohort of HIV-Infected Veterans: Risk Modification by Concomitant Antiretrovirals\nLaFleur Joanne Joanne.Lafleur@pharm.utah.edu\n\n12\nBress Adam P. 23\nMyers Joel 4\nRosenblatt Lisa 4\nCrook Jacob 25\nKnippenberg Kristin 12\nBedimo Roger 67\nTebas Pablo 8\nNyman Heather 1\nEsker Stephen 4\n1 0000 0001 2193 0096 grid.223827.e Department of Pharmacotherapy, University of Utah, Salt Lake City, UT USA\n2 Salt Lake City VA Health Care System, Salt Lake City, UT USA\n3 0000 0001 2193 0096 grid.223827.e Department of Population Health Sciences, University of Utah School of Medicine, Salt Lake City, UT USA\n4 grid.419971.3 Bristol-Myers Squibb, Lawrenceville, NJ USA\n5 0000 0001 2193 0096 grid.223827.e Division of Epidemiology, University of Utah, Salt Lake City, UT USA\n6 0000 0004 0420 5441 grid.422201.7 VA North Texas Health Care System, Dallas, TX USA\n7 0000 0000 9482 7121 grid.267313.2 University of Texas Southwestern Medical Center, Dallas, TX USA\n8 0000 0004 1936 8972 grid.25879.31 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA\n28 2 2018\n28 2 2018\n6 2018\n7 2 293308\n25 8 2017\n© The Author(s) 2018\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\nIntroduction\n\nTenofovir disoproxil fumarate (TDF) has been associated with greater incidences of bone complications, which might be modified by some concomitantly administered antiretrovirals, possibly by their effect on tenofovir concentrations. We compared bone adverse outcomes among treatment-naïve HIV-infected US veterans initiating efavirenz (EFV)-containing TDF/emtricitabine (FTC) regimens versus those initiating non-EFV-containing TDF/FTC regimens.\n\nMethods\n\nUsing national Veterans Health Administration clinical and administrative data sets, we identified a cohort of treatment-naïve HIV-infected veterans without bone disease who initiated therapy with TDF/FTC plus EFV, rilpivirine, elvitegravir/cobicistat, or ritonavir-boosted protease inhibitors in 2003–2015. The primary composite adverse bone outcome was the unadjusted incidence rate (IR) of osteoporosis, osteopenia, or fragility fracture (any hip, wrist, or spine fracture). To account for selection bias and confounding, we used inverse probability of treatment-weighted Cox proportional hazards regression models to calculate adjusted hazard ratios (HRs) for each outcome associated with EFV + TDF/FTC versus each non-EFV-containing TDF/FTC regimen.\n\nResults\n\nOf 33,048 HIV-positive veterans, 7161 initiated a TDF/FTC-containing regimen (mean age, 50 years; baseline CD4 < 200 cells/mm3, 33.3%; HIV-1 RNA > 100,000 copies/ml, 22.3%; mean follow-up, 13.0 months). Of these, 4137 initiated EFV- and 3024 non-EFV-containing regimens. Veterans initiating EFV- versus non-EFV-containing TDF/FTC regimens had a lower IR of the composite bone outcome (29.3 vs. 41.4 per 1000 patient-years), with significant risk reductions for this outcome [HR, 0.69; 95% confidence interval (CI), 0.58–0.83] and fragility fracture (HR, 0.59; 95% CI, 0.44–0.78).\n\nConclusion\n\nEFV + TDF/FTC is associated with a lower risk of adverse bone outcomes compared with other TDF-containing regimens in the VHA.\n\nFunding\n\nBristol-Myers Squibb.\n\nElectronic supplementary material\n\nThe online version of this article (10.1007/s40121-018-0194-1) contains supplementary material, which is available to authorized users.\n\nKeywords\n\nEfavirenz\nFracture\nOsteoporosis\nTenofovir disoproxil fumarate\nVeterans\nhttp://dx.doi.org/10.13039/100002491 Bristol-Myers Squibb issue-copyright-statement© Springer Healthcare Ltd., part of Springer Nature 2018\n==== Body\nIntroduction\n\nPatients with HIV infection have higher rates of osteoporosis and fragility fractures than uninfected individuals, which are not completely explained by differences in traditional risk factors such as age and body mass index [1]. Randomized controlled trials and observational studies suggest that HIV infection itself and the initiation of some antiretroviral therapies (ART) may independently increase the risk of bone adverse outcomes [1–8]. For these reasons, the safety profiles of antiretroviral agents are subject to increased scrutiny in an effort to reduce treatment-related side effects in the aging HIV population.\n\nTenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) has been the main nucleos(t)ide reverse transcriptase inhibitor backbone of combination ART for more than a decade; TDF/FTC continues to be included in four of the six recommended regimens for treatment-naïve patients with HIV infection in the current Department of Health and Human Services guidelines [9]. TDF has been noted to increase the risk of fragility fractures [7, 10]. In a Veterans Health Administration (VHA) population, cumulative exposure to TDF was independently predictive of fragility fracture [11]; however, no evaluation of TDF-associated fracture risk based on concomitantly administered ART was undertaken. Very few epidemiologic studies in US populations have compared risks of bone adverse outcomes with TDF across differing TDF-containing antiretroviral regimens [12].\n\nART initiation is associated with increases in bone turnover and modest decreases in bone mineral density (BMD) [13], which are greater with TDF-containing regimens. BMD loss with TDF is amplified when coadministered with boosted protease inhibitors (PIs), but effects are less certain when coadministered with other antiretroviral agents [7, 10, 14–25]. For example, in the AIDS Clinical Trials Group (ACTG) A5224s substudy of ACTG A5202, spine BMD loss was significantly greater in those receiving ritonavir-boosted atazanavir (ATV) + TDF/FTC (−3.1%) than in those receiving efavirenz (EFV) + TDF/FTC (−1.7%; P = 0.035) [7]. However, the clinical relevance of these observations (increased fracture risk) remains uncertain.\n\nRegarding fracture risk, available data from randomized controlled trials are limited by the small sample sizes and short observation periods of individual trials and the lack of specific reporting of fragility fractures [26]. Thus, despite differences in BMD across regimens in ACTG A5224s, fractures (all traumatic) were uncommon, and rates were similar across regimens [7]. In contrast, one recent large cohort study of commercial claims data showed lower fracture incidence rates (IRs) for EFV + TDF/FTC compared with elvitegravir/cobicistat (EVG/c)/TDF/FTC, rilpivirine (RPV) + TDF/FTC, and the overall HIV population in the database [12].\n\nThe lower BMD loss and fracture risk with EFV-containing TDF/FTC regimens compared with other third agents combined with TDF/FTC may relate to differences in drug-drug and drug-food interactions across these regimens. Tenofovir plasma concentrations are increased by 22–37% when TDF is taken with PIs [27, 28], cobicistat [29], or RPV [30]. The bioavailability of tenofovir is also increased by up to 40% with concomitant food intake [28, 31]. Certain TDF regimens, including RPV, EVG/c, and boosted PIs, are taken with food [32–34]. Conversely, EFV + TDF/FTC is taken in the fasted state, and no clinically relevant drug-drug interactions have been reported between TDF and either EFV or FTC. Therefore, we hypothesized that EFV + TDF/FTC could result in a lower incidence of bone adverse outcomes compared with these other TDF-containing regimens.\n\nThe purpose of this analysis was to compare the incidence of bone adverse outcomes among treatment-naïve HIV-infected US veterans without bone disease who initiated different TDF-containing regimens.\n\nMethods\n\nStudy Design and Data Sets\n\nUsing a national cohort of US veterans, we conducted a population-based historical cohort study using VHA databases containing clinical, pharmacy, and administrative data from more than 150 VHA hospitals and 850 outpatient clinics nationwide [35]. We obtained demographic, laboratory, diagnosis, and utilization data from the Veterans Affairs (VA) Corporate Data Warehouse (CDW), including medical SAS data sets for in- and outpatient encounter data, CDW’s raw pharmacy data, and Decision Support Systems and CDW’s laboratory data. To conduct the analyses, data sets were housed in the VA Informatics and Computing Infrastructure environment, which enables access to data and tools for reporting and analysis in a secure workspace to ensure veterans’ privacy and data security. This article does not contain any studies with human participants or animals performed by any of the authors. The University of Utah Institutional Review Board and the Salt Lake City VA Health Care System Office of Research and Development approved this study.\n\nPatients\n\nThe cohort included all HIV-infected antiretroviral-naïve veterans without bone disease who initiated TDF/FTC plus a third antiretroviral agent of interest (see Exposures section) during the period 2003–2015. A validated algorithm [36] with a sensitivity of 86% and positive predictive value of 87% [37] was used to exclude patients with evidence of prior ART received outside of the VHA, which included the following criteria: exposure to any antiretroviral agents during a 1-year period before the index date (the pre-index period), patients whose index ART regimen was a “salvage” regimen (i.e., composed of both a PI and an NNRTI or composed of 5 or more agents), and patients whose HIV RNA levels before the index date were low enough (< 500 copies/ml) to suggest prior antiretroviral exposure. Veterans were identified for inclusion by an available index date for the first pharmacy fill for one of the third agents of interest and if they fulfilled the following criteria at the index date: (1) aged ≥ 18 years; (2) at least 6 months of pre-index date VHA activity including in- or outpatient services; (3) no evidence of prior treatment including fills for antiretrovirals in the 6 months before the index date; (4) no evidence of prior bone disease (defined as diagnosis of osteoporosis/osteopenia by International Classification of Disease diagnosis codes, Current Procedural Terminology codes, or classification by bone mineral density test result). Codes used to identify patients with HIV infection are shown in Supplemental Digital Content, Table 1.Table 1 Unadjusted baseline characteristics among HIV-infected veterans receiving initial ART with differing TDF/FTC-containing regimens\n\n\tInitial ART Containing TDF/FTC Plus\t\nEFV (n = 4137)\tNon-EFVa (n = 3024)\tEVG/c (n = 232)\tRPV (n = 171)\tRTV-boosted PI (n = 2621)\t\nDemographics and physical\t\n Age, years, mean ± SD\t50 ± 10\t49 ± 9.8\t49 ± 13\t47 ± 13\t50 ± 9.3\t\n Male\t4002 (96.7)\t2903 (96.0)\t221 (95.3)\t161 (94.2)\t2521 (96.2)\t\n Married\t337 (8.1)\t221 (7.3)\t26 (11.2)\t20 (11.7)\t175 (6.7)\t\n Race\t\n White\t1240 (30.0)\t911 (30.1)\t73 (31.5)\t48 (28.1)\t790 (30.1)\t\n Black\t2492 (60.2)\t1762 (58.3)\t124 (53.4)\t104 (60.8)\t1534 (58.5)\t\n Hispanic\t260 (6.3)\t207 (6.8)\t19 (8.2)\t10 (5.8)\t178 (6.8)\t\n Asian\t34 (0.8)\t28 (0.9)\t5 (2.2)\t2 (1.2)\t21 (0.8)\t\n Other\t22 (0.5)\t28 (0.9)\t2 (0.9)\t2 (1.2)\t24 (0.9)\t\n Missing\t89 (2.2)\t88 (2.9)\t9 (3.9)\t5 (2.9)\t74 (2.8)\t\n BMI (kg/m2, mean ± SD)\t26 ± 5.0\t25 ± 5.1\t26 ± 5.6\t27 ± 5.3\t25 ± 5.1\t\nPre-indexb† prognostic indices\t\n CD4+ count, cells/mm3\t\t\t\t\t\t\n < 200\t1286 (31.1)\t1103 (36.5)\t60 (25.9)\t23 (13.5)\t1020 (38.9)\t\n 200–299\t698 (16.9)\t477 (15.8)\t33 (14.2)\t30 (17.5)\t414 (15.8)\t\n 300–399\t634 (15.3)\t342 (11.3)\t34 (14.7)\t11 (6.4)\t297 (11.3)\t\n 400–499\t401 (9.7)\t222 (7.3)\t24 (10.3)\t33 (19.3)\t165 (6.3)\t\n ≥ 500\t588 (14.2)\t426 (14.1)\t61 (26.3)\t63 (36.8)\t302 (11.5)\t\n Missing\t530 (12.8)\t454 (15.0)\t20 (8.6)\t11 (6.4)\t423 (16.1)\t\nHIV viral load, copies/ml\t\n < 10,000\t1184 (28.6)\t950 (31.4)\t65 (28.0)\t68 (39.8)\t817 (31.2)\t\n 10,000–100,000\t1434 (34.7)\t940 (31.1)\t78 (33.6)\t67 (39.2)\t795 (30.3)\t\n > 100,000\t913 (22.1)\t686 (22.7)\t61 (26.3)\t15 (8.8)\t610 (23.3)\t\n Missing\t606 (14.6)\t448 (14.8)\t28 (12.1)\t21 (12.3)\t399 (15.2)\t\nPre-indexb renal function\t\n eGFR, ml/min/1.73 m2\t\t\t\t\t\t\n ≥ 90\t2193 (53.0)\t1552 (51.3)\t143 (61.6)\t108 (63.2)\t1301 (49.6)\t\n 60–89\t1360 (32.9)\t985 (32.6)\t73 (31.5)\t54 (31.6)\t858 (32.7)\t\n 30–59\t164 (4.0)\t123 (4.1)\t3 (1.3)\t4 (2.3)\t116 (4.4)\t\n 15–29\t5 (0.1)\t7 (0.2)\t0 (0.0)\t0 (0.0)\t7 (0.3)\t\n < 15\t39 (0.9)\t53 (1.8)\t0 (0.0)\t0 (0.0)\t53 (2.0)\t\n Missing\t376 (9.1)\t304 (10.1)\t13 (5.6)\t5 (2.9)\t286 (10.9)\t\nPre-indexb comorbid diagnoses\t\n CAD/CVD\t447 (10.8)\t280 (9.3)\t28 (12.1)\t13 (7.6)\t239 (9.1)\t\n Heart failure\t132 (3.2)\t62 (2.1)\t5 (2.2)\t2 (1.2)\t55 (2.1)\t\n Dyslipidemia\t659 (15.9)\t412 (13.6)\t50 (21.6)\t29 (17.0)\t333 (12.7)\t\n Hypertension\t1521 (36.8)\t910 (30.1)\t83 (35.8)\t64 (37.4)\t763 (29.1)\t\n Diabetes mellitus\t561 (13.6)\t358 (11.8)\t30 (12.9)\t19 (11.1)\t309 (11.8)\t\n Chronic kidney diseasec\t281 (6.8)\t169 (5.6)\t16 (6.9)\t9 (5.3)\t144 (5.5)\t\n End-stage renal diseased\t15 (0.4)\t12 (0.4)\t1 (0.4)\t0 (0.0)\t11 (0.4)\t\n Fracture\t30 (0.7)\t20 (0.7)\t4 (1.7)\t1 (0.6)\t15 (0.6)\t\n Viral hepatitis\t1122 (27.1)\t902 (29.8)\t59 (25.4)\t42 (24.6)\t801 (30.6)\t\n Tuberculosis\t52 (1.3)\t46 (1.5)\t1 (0.4)\t2 (1.2)\t43 (1.6)\t\n Psychiatric disorder\t1495 (36.1)\t1384 (45.8)\t119 (51.3)\t104 (60.8)\t1161 (44.3)\t\n Depression\t962 (23.3)\t878 (29.0)\t83 (35.8)\t68 (39.8)\t727 (27.7)\t\n Schizophrenia\t140 (3.4)\t194 (6.4)\t12 (5.2)\t9 (5.3)\t173 (6.6)\t\n Bipolar disorder\t635 (15.3)\t648 (21.4)\t61 (26.3)\t63 (36.8)\t524 (20.0)\t\n Psychosis\t231 (5.6)\t308 (10.2)\t26 (11.2)\t18 (10.5)\t264 (10.1)\t\n Posttraumatic stress disorder\t366 (8.8)\t379 (12.5)\t39 (16.8)\t52 (30.4)\t288 (11.0)\t\n Tobacco usee\t1279 (30.9)\t918 (30.4)\t70 (30.2)\t77 (45.0)\t771 (29.4)\t\n Alcohol abuse\t946 (22.9)\t725 (24.0)\t59 (25.4)\t51 (29.8)\t615 (23.5)\t\nMedications\t\n Methadone\t49 (1.2)\t70 (2.3)\t2 (0.9)\t2 (1.2)\t66 (2.5)\t\n Proton pump inhibitors\t1179 (28.5)\t713 (23.6)\t56 (24.1)\t23 (13.5)\t634 (24.2)\t\n Bisphosphonates\t8 (0.2)\t9 (0.3)\t0 (0.0)\t0 (0.0)\t9 (0.3)\t\n Testosterone\t66 (1.6)\t51 (1.7)\t2 (0.9)\t3 (1.8)\t46 (1.8)\t\nData are n (%) unless otherwise indicated\n\naNon-EFV includes the EVG/c, RPV, and RTV-boosted PI groups\n\nbPre-index comorbidities and clinical characteristics were identified in the 6–12-month pre-index period\n\ncDefined as either a chronic kidney disease diagnosis or two consecutive measures of eGFR < 60 ml/min/1.73 m2 occurring at least 30 days apart\n\ndDefined as either a diagnosis of end-stage renal disease, kidney transplant, or dialysis\n\neIncludes abuse, dependence, rehabilitation, and toxicity related to tobacco\n\nART antiretroviral therapy, BMI body mass index, CAD coronary artery disease, CVD cerebrovascular disease, EFV efavirenz, eGFR estimated glomerular filtration rate, EVG/c elvitegravir/cobicistat, FTC emtricitabine, PI protease inhibitor (atazanavir, darunavir, or lopinavir), RPV rilpivirine, RTV ritonavir, SD standard deviation, TDF tenofovir disoproxil fumarate\n\nExposures\n\nExposures of interest included TDF/FTC (either as a fixed-dose combination or as separate agents) plus one of the following agents: EFV, EVG/c, RPV, or any one of three ritonavir-boosted PIs (i.e., ATV, lopinavir, or darunavir). For regimens with separate dosage forms, the third agent must have overlapped with the backbone within 30 days. For boosted or enhanced regimens (EVG/c and RTV-boosted PIs), the third agent must have also overlapped with the booster/enhancer for the patient to be classified as taking the regimen. Discontinuation of the regimen was defined as having a gap of at least 30 days for either the third agent or the backbone; patients who discontinued their regimen were censored on the first day of the first 30-day gap following the end of the prior days’ supply received by the patient.\n\nOutcomes\n\nThe primary composite outcome was a bone adverse event defined as a diagnosis of osteoporosis; a BMD T-score in the osteoporotic or osteopenic ranges for the femoral neck, total spine, distal radius, or total hip; or a diagnosis or procedure code for likely fragility fracture (any hip, wrist/forearm, or spine fracture). BMD T-scores were extracted from patient radiology dual-energy X-ray absorptiometry (DEXA) reports and clinical notes using a previously developed natural language processing tool, with accuracy in the range of 90.4–92.8% [38, 39]. All codes used to identify outcomes of interest are provided in Supplemental digital content, Table 2.\n\nCovariates\n\nTo control for confounding and selection bias, we measured baseline covariates that were selected on the basis of potential associations with treatment and/or outcomes, as found in published literature and based on prior clinical knowledge of ART and HIV. These included baseline demographics, baseline HIV laboratory measures, baseline BMD measures and related diagnoses, lifestyle exposures, other comorbidities, medication exposures, and calendar year of the index regimen. All covariates were identified over a 12-month look-back period preceding the index date. Specific definitions for all covariates are provided in the Supplemental digital content, Table 3.\n\nStatistical Analysis\n\nWe calculated baseline characteristics overall and by treatment group and used standardized mean differences (SMDs) to compare differences between groups, with SMDs outside the bounds of ± 0.1 indicating meaningful differences [40]. We calculated crude IRs of bone adverse outcomes per 1000 patient-years of exposure and associated exact 95% confidence intervals (CIs) in the unweighted cohort assuming a Poisson distribution. To control for confounding by indication and selection bias, we used inverse probability of treatment weighting (IPTW) for each patient [41]. Weighted Cox proportional hazards regression models were used to estimate adjusted hazard ratios (HRs) for bone outcomes associated with EFV + TDF/FTC compared with EVG/c + TDF/FTC, RPV + TDF/FTC, ritonavir-boosted PIs + TDF/FTC, and all non-EFV regimens combined. To reduce risk of bias, model variability, and unreliable CIs, we excluded any group with < 5 events from analysis comparisons. We used IPTW in the primary analysis; however, if covariate balance was not achieved with IPTW, we conducted a sensitivity analysis using matching weights, which are less sensitive to residual and unmeasured confounding. All analyses were done in SAS version 9.2 (SAS Institute, Cary, NC).\n\nResults\n\nPatient Characteristics\n\nA total of 7161 patients met all eligibility criteria (Fig. 1). Of these, 4137 initiated EFV and 3024 initiated non-EFV regimens, including 232 with EVG/c, 171 with RPV, and 2621 with ritonavir-boosted PIs. At baseline, 26 (0.4%) had received a bisphosphonate (Table 1). For all unadjusted comparisons, psychiatric disorders were overrepresented in those receiving non-EFV-containing regimens versus EFV-containing regimens (Fig. 2 and Supplemental digital content Table 4). After IPTW, covariate balance was achieved among all variables for EFV versus all non-EFV combined (Fig. 2), versus EVG/c (Supplemental digital content, Fig. 1A), and versus ritonavir-boosted PIs (Supplemental digital content, Fig. 1B). For EFV versus RPV, the covariate balance was achieved for 83.0% of variables (Supplemental digital content, Fig. 1C). Mean (standard deviation) follow-up times were 13.0 (19.2) months overall and 15.0 (21.2), 7.6 (7.6), 10.0 (10.5), and 10.5 (16.7) months for EFV, EVG/c, RPV, and ritonavir-boosted PIs, respectively. Corresponding median (interquartile range; min–max) values were 5.0 (2.0–14.2; 0.1–127.7), 5.7 (2.1–17.9; 0.1–110.3), 4.6 (2.1–10.4; 0.2–34.6), 5.9 (2.8–13.4; 0.5–48.3), and 4.2 (1.8–10.7; 0.1–127.7) months.Fig. 1 Patient selection according to eligibility criteria. ART antiretroviral therapy, ATV atazanavir, BMI body mass index, DRV darunavir, EFV efavirenz, EVG/c elvitegravir/cobicistat, FTC emtricitabine, LPV lopinavir, PI protease inhibitor (atazanavir, darunavir, or lopinavir), RPV rilpivirine, RTV ritonavir, TDF tenofovir disoproxil fumarate, VHA Veterans Health Administration. *Bone disease defined as diagnosis of osteoporosis/osteopenia by international classification of disease diagnosis codes, current procedural terminology codes, or classification by bone mineral density test result\n\nFig. 2 Baseline demographics: verification that IPT weighting achieves baseline covariate balance between TDF/FTC-containing regimens with EFV versus all non-EFV. CAD/CVD coronary artery disease/cerebrovascular disease, CKD chronic kidney disease, EFV efavirenz, eGFR estimated glomerular filtration rate, FTC emtricitabine, IPT inverse probability of treatment, TDF tenofovir disoproxil fumarate\n\nIncidence and Risk of Any Bone Outcome\n\nThe unadjusted (crude) IRs and adjusted HRs for all comparisons are summarized in Fig. 3. The crude IR of the composite bone outcome was lower in the EFV group than in the EVG/c, RPV, and ritonavir-boosted PI groups. In adjusted analyses, EFV was associated with a statistically significant 31% lower risk of the composite bone outcome than non-EFV groups combined, 25% lower than RPV, and 30% lower than the ritonavir-boosted PI group.Fig. 3 Unadjusted incidence rates and IPTW adjusted hazard ratios of bone adverse outcomes among patients treated with different TDF/FTC-containing regimens with at least five events per group. CI confidence interval, CVD cerebrovascular disease, diag. diagnosis, EFV efavirenz, EVG/c elvitegravir/cobicistat, FTC emtricitabine, IPTW inverse probability of treatment weighting, PI protease inhibitor (atazanavir, darunavir, or lopinavir), PY patient-years, RPV rilpivirine, RTV ritonavir, TDF tenofovir disoproxil fumarate, – insufficient events to calculate hazard ratio. aMeasured at the femoral neck, total spine, distal radius, or total hip\n\nIncidence and Risk of Osteoporosis or Osteopenia\n\nThe crude IR for osteoporosis was lower for EFV compared with all other regimens. In adjusted analyses, EFV was associated with a statistically significant 36% lower risk of osteoporosis than non-EFV groups combined, 53% lower than EVG/c, and 35% lower than the ritonavir-boosted PI group. Too few events were observed with RPV to make comparisons. The crude IR of osteopenia was lower for EFV compared with EVG/c, but for all other comparisons IRs were similar. In adjusted analyses, the risk of osteopenia was similar between EFV and the ritonavir-boosted PI group (too few events were observed to report comparisons for EVG/c or RPV). When combining osteoporosis and osteopenia events, EFV was associated with a 21% lower risk compared with the ritonavir-boosted PI group. Frequencies of available pre- and post-index DEXA scans as well as baseline characteristics by DEXA scan status are presented in the Supplemental digital content, Tables 6 and 7, respectively.\n\nIncidence and Risk of Fracture\n\nThe crude IR of fragility fractures was lower for EFV compared with EVG/c, RPV, and ritonavir-boosted PIs. In adjusted analyses, risk differences were statistically significant for EFV versus all non-EFV combined (41% lower), RPV (57% lower), and ritonavir-boosted PIs (40% lower).\n\nOf the individual fracture outcomes, EFV had a lower incidence compared with each non-EFV regimen for all fracture sites in all comparisons except for hip fractures with ritonavir-boosted PIs, which had too few events to make comparisons. In adjusted analyses, this corresponded to statistically significant reduced risks for EFV compared with all non-EFV regimens combined for vertebral fracture (51% lower) and wrist/forearm fracture (60% lower). Significantly lower risks were also observed versus ritonavir-boosted PIs for vertebral fracture (48% lower) and wrist/forearm fracture (60% lower). Too few events were observed for individual fracture outcomes to make comparisons with EVG/c or RPV.\n\nFor a summary of event numbers, time to events and follow-up times for all bone adverse outcomes, see Supplemental digital content, Table 5.\n\nSensitivity Analysis\n\nIn matching weight analyses, the risks of any bone outcome or fracture for RPV versus EFV showed a similar magnitude, suggesting the IPTW findings were robust regarding residual confounding present for 7/47 (14.9%) of variable comparisons for EFV versus RPV.\n\nDiscussion\n\nEFV + TDF/FTC was generally associated with lower risks of bone adverse outcomes compared with TDF-containing regimens with EVG/c, RPV, or ritonavir-boosted PIs in the VHA cohort over an average follow-up time of 13.0 months. These findings suggest that patients with HIV infection receiving EFV + TDF/FTC, which has no known drug-drug interactions with TDF or FTC, or drug-food interactions, may be at lower overall risk of bone adverse outcomes compared with those receiving TDF-containing regimens with EVG/c, RPV, or ritonavir-boosted PIs.\n\nThis study is the first to identify an association between EFV + TDF/FTC use among veterans and a reduced risk of bone adverse outcomes versus other TDF-containing regimens. These findings confirm those of Nkhoma et al. [12], who conducted a large claims database analysis of bone fractures associated with TDF/FTC and various third agents (although adjusted analyses were not possible because of insufficient numbers of fracture events). Nkhoma et al. [12] found a lower fracture IR with EFV + TDF/FTC (3.4 per 1000 patient-years) compared with RPV + TDF/FTC (3.6 per 1000 patient-years) or with EVG/c + TDF/FTC (4.4 per 1000 patient-years). The IRs in this study followed the same general trend as in Nkhoma et al. [12], but were higher in magnitude, possibly because the current study was conducted in a higher-risk population in a relatively closed, integrated care network.\n\nCobicistat, rilpivirine, and ritonavir increase serum creatinine and decrease the estimated glomerular filtration rate (GFR) via inhibition of renal tubular transporters [42, 43], but this does not appear to affect actual GFR as measured by iohexol clearance [44]. Therefore, the bone effects we observed were more likely due to relative differences in tenofovir exposure across the evaluated regimens. Both RPV/FTC/TDF and EVG/COBI/FTC/TDF are recommended to be administered with food, which increases tenofovir exposure compared with fasting administration [33, 34]. In addition, both protease inhibitors (including RTV) [45] and cobicistat [46] increase tenofovir exposure by inhibition of intestinal P-gp-mediated efflux of TDF. Taken together, these effects on tenofovir exposure may have contributed to the increased risk of adverse bone outcomes that we observed with EVG/c/FTC/TDF, RPV/TDF/FTC, and RTV-boosted PIs in this analysis.\n\nFor patients with a high risk of bone adverse outcomes, the use of the novel formulation tenofovir alafenamide (TAF) or abacavir has been associated with lower BMD losses at the time of therapy initiation compared with TDF [9]. TAF, a prodrug of tenofovir, is associated with a 91% lower plasma tenofovir concentration than that following TDF administration while maintaining higher intracellular tenofovir concentrations in peripheral blood mononuclear cells for HIV suppression [47]. Biomarkers of bone turnover appear to be less affected by TAF-containing regimens compared with TDF-containing regimens. TAF is now recommended in HIV treatment guidelines [9], and its use is being preferred to TDF by HIV-care providers concerned about bone toxicity of TDF in the aging HIV population.\n\nGiven the ongoing widespread use of EFV + TDF/FTC and the absence of an EFV co-formulation with TAF, the results of the current study may reassure physicians and their patients about the bone safety of this combination. Moreover, where alternatives to TDF are limited (such as in resource-limited settings), or where use of generic EFV or TDF as a cost reduction strategy is available, or where EFV + TDF/FTC is available through the Medicines Patent Pool, the choice of a third agent remains critical to long-term safety. The reduced risk of bone adverse outcomes for EFV + TDF/FTC found in this study is of high relevance, especially in resource-limited settings where the cost effectiveness of the fixed-dose combination has achieved widespread use [48]. However, while it appears that EFV + TDF/FTC has a lower risk for bone adverse outcomes than PIs and other boosted regimens in combination with TDF/FTC, our study is not generalizable to the use of unboosted integrase inhibitors, for which additional research is needed.\n\nOther options to counter antiretroviral-associated BMD loss include vitamin D/calcium and/or zoledronic acid supplementation. Vitamin D/calcium supplementation lessened BMD loss among patients receiving EFV + TDF/FTC over 48 weeks [21, 23], and single-dose zoledronic acid administered at the initiation of a PI-containing TDF/FTC regimen can prevent the initial BMD loss [49]. These options, together with careful antiretroviral choice, should be considered between patients and health care providers, taking into account the drug resistance profile, treatment history, other comorbidities, and the risk or tolerability of side effects.\n\nStrengths and limitations of this study are those common to large epidemiologic studies. The main strengths of our study were its large sample size and detailed data from VHA data sets, as well as the use of a natural language-processing tool, which allowed us to extract BMD results from radiology and clinical notes. Our study also has limitations. The VHA population was more than 95% male, which limits generalizability to female populations that could be affected differently by the predictors identified in our study. Follow-up times were short, which may have led to underascertainment of relevant bone adverse outcomes; however, statistically significant between-regimen differences for relevant bone adverse outcomes were noted despite these follow-up times. Moreover, other data have demonstrated that the incidence of fracture is highest during the first and second years after ART initiation, tailing off thereafter [50]; fracture risk among men with HIV infection is higher among older individuals [51] as was the case in this VA population. Thus, we consider that follow-up times in the current study were sufficient to detect differences in BMD and fracture risk. Although IPTW was successfully used to adjust for selection bias and measured confounders for all comparisons with the exception of EFV versus RPV, the potential for unmeasured confounders and incomplete adjustment for measured confounders cannot be ruled out. For example, patients with a range of psychiatric disorders were less likely to be prescribed EFV-containing regimens across all comparisons (Fig. 2 and Supplemental digital content, Fig. 1), likely because of channeling bias consequent to the side effect profile of EFV in patients with severe psychiatric symptoms [52]. Various psychiatric disorders, such as schizophrenia and depression, and psychotropic medications are associated with BMD loss and an increased risk of fracture [53]. However, our method of controlling for confounding effectively balanced the observed differences in these measured characteristics. Specifically, the six psychiatric covariates examined were balanced after IPTW for the EFV versus EVG/c and EFV versus ritonavir-boosted PI comparisons. For the EFV versus RPV comparison, only one remained imbalanced after IPTW, and this was by a small margin (SMD of 0.102). In addition, the more conservative matching weights analyses produced qualitatively similar results to those using IPTW, making it highly unlikely that channeling bias affected our results. Finally, as in any retrospective observational study, causal associations cannot be proven; thus, these findings require confirmation in further prospective studies.\n\nConclusion\n\nIn conclusion, EFV + TDF/FTC was generally associated with a lower incidence of bone adverse outcomes, including osteoporosis, any major fracture, vertebral fracture, and wrist/forearm fracture, compared with other TDF/FTC-containing regimens in the VHA. The third agent in antiretroviral regimens may have a significant effect on the risk of bone adverse events associated with TDF.\n\nElectronic supplementary material\n\nBelow is the link to the electronic supplementary material. Supplementary material 1 (PDF 512 kb)\n\nFunding\n\nThis work was supported by Bristol-Myers Squibb by a grant to the University of Utah. The article processing charges were also funded by Bristol-Myers Squibb.\n\nAuthorship\n\nAll authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.\n\nAuthor Contribution\n\nJoanne LaFleur, Adam P. Bress, Joel Myers, Lisa Rosenblatt, Roger Bedimo, Pablo Tebas, Heather Nyman, and Stephen Esker contributed to the conception and design of the study. Joanne LaFleur, Adam P. Bress, Kristin Knippenberg, and Jacob Crook contributed to data collection. Joanne LaFleur, Adam P. Bress, Kristin Knippenberg, and Jacob Crook contributed to data analysis. Joanne LaFleur, Adam P. Bress, Joel Myers, Lisa Rosenblatt, Roger Bedimo, Pablo Tebas, Heather Nyman, and Stephen Esker contributed to data interpretation. All authors contributed to writing and editing the manuscript.\n\nEditorial Assistance\n\nEditorial Assistance was provided by Julian Martins of inScience Communications, Springer Healthcare, which was funded by Bristol-Myers Squibb.\n\nDisclosures\n\nThis work was supported by Bristol-Myers Squibb by a grant to the University of Utah. Joanne LaFleur received some salary support from this grant and declares no intellectual property rights related to this research. Outside of the funded work, over the last 3 years, the following organizations provided research grants to the University of Utah and Joanne LaFleur worked on those projects and/or received salary or other types of support that were funded by those grants: Gilead Sciences, Inc., Anolinx LLC, Skaggs Foundation, and Agency for Healthcare Research and Quality. Adam P. Bress received some salary support from this grant and declares no intellectual property rights related to this research. Outside of the funded work, over the last 3 years, the following organizations provided research grants to the University of Utah, and Adam P. Bress worked on those projects and/or received salary or other types of support that were funded by those grants: Gilead Sciences, and National Heart, Lung, and Blood Institute (NHLBI). Joel Myers is an employee of, and owns stock in, Bristol-Myers Squibb. Lisa Rosenblatt is an employee of, and owns stock in, Bristol-Myers Squibb. Jacob Crook received some salary support from this grant and declares no intellectual property rights related to this research. Outside of the funded work, over the last 3 years, the following organizations provided research grants to the University of Utah and Jacob Crook worked on those projects and/or received salary or other types of support that were funded by those grants: Cubist, Gilead Sciences, Inc., Anolinx LLC, Skaggs Foundation, Agency for Healthcare Research and Quality, and Utah Department of Health. Kristin Knippenberg received some salary support from this grant and declares no intellectual property rights related to this research. Outside of the funded work, over the last 3 years, the following organizations provided research grants to the University of Utah and Kristin Knippenberg worked on those projects and/or received salary or other types of support that were funded by those grants: Gilead Sciences, Inc., Anolinx LLC, Skaggs Foundation, Agency for Healthcare Research and Quality, and Utah Department of Health. Roger Bedimo has received grants and research support awarded to the Veterans Affairs North Texas Healthcare System from Merck & Co; he has served as a scientific advisor for Bristol-Myers Squibb, Merck & Co, Inc., and Theratechnologies, Inc. Pablo Tebas has served as a scientific advisor to Merck & Co, Inc., and is a member of an adjudication committee in a vaccine trial sponsored by Glaxo. Heather Nyman received some salary support and travel expenses from this grant and declares no intellectual property rights related to this research; she has also received consultancy honoraria from Otsuka and Fresenius. Stephen Esker is an employee of, and owns stock in, Bristol-Myers Squibb.\n\nCompliance with Ethics Guidelines\n\nThis article does not contain any studies with human participants or animals performed by any of the authors. The University of Utah Institutional Review Board and the Salt Lake City VA Health Care System Office of Research and Development approved this study.\n\nData Availability\n\nThe data sets generated during and/or analyzed during the current study are not publicly available because of compliance with Veteran Healthcare Administration restrictions on data sharing.\n\nPrevious Presentation\n\nThese data were previously presented in poster form at Infectious Disease Week (IDWeek) October 26–30, 2016, New Orleans, LA.\n\nOpen Access\n\nThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\n\nEnhanced Content\n\nTo view enhanced content for this article go to 10.6084/m9.figshare.5887165.\n==== Refs\nReferences\n\n1. 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Wohl DA Orkin C Doroana M Change in vitamin D levels and risk of severe vitamin D deficiency over 48 weeks among HIV-1-infected, treatment-naive adults receiving rilpivirine or efavirenz in a Phase III trial (ECHO) Antivir Ther. 2014 19 2 191 200 10.3851/IMP2721 24430534\n24. Sax PE DeJesus E Mills A Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks Lancet 2012 379 9835 2439 2448 10.1016/S0140-6736(12)60917-9 22748591\n25. Zolopa A Sax PE DeJesus E A randomized double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: analysis of week 96 results J Acquir Immune Defic Syndr 2013 63 1 96 100 10.1097/QAI.0b013e318289545c 23392460\n26. Bedimo R Rosenblatt L Myers J Systematic review of renal and bone safety of the antiretroviral regimen efavirenz, emtricitabine, and tenofovir disoproxil fumarate in patients with HIV infection HIV clinical trials. 2016 17 6 246 266 10.1080/15284336.2016.1243363 27809711\n27. Jullien V Treluyer JM Rey E Population pharmacokinetics of tenofovir in human immunodeficiency virus-infected patients taking highly active antiretroviral therapy Antimicrob Agents Chemother 2005 49 8 3361 3366 10.1128/AAC.49.8.3361-3366.2005 16048948\n28. Gilead Sciences. Prescribing information for VIREAD® (tenofovir disoproxil fumarate). http://www.gilead.com/~/media/files/pdfs/medicines/hiv/viread/viread_pi.pdf?la=en. Accessed 19 Oct 2017.\n29. European Commission Health and Food Safety. Tybost Product Characteristics. Available at http://ec.europa.eu/health/documents/community-register/2015/20150210131020/anx_131020_en.pdf. Accessed 2 May 2016.\n30. Hoetelmans R, Van Heeswijk R, Kestens Dea. Pharmacokinetic interaction between the novel nonnucleoside reverse transcriptase inhibitor (NNRTI) TMC278 and tenofovir disoproxil fumarate (TDF) in healthy volunteers. In: 3rd IAS conference on HIV pathogenesis, treatment and prevention, Brazil, July 2005, abstract WePe3.3C15.\n31. Zimmermann AE Pizzoferrato T Bedford J Morris A Hoffman R Braden G Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions Clin Infect Dis 2006 42 2 283 290 10.1086/499048 16355343\n32. Bristol Myers Squibb, Gilead Sciences. Prescribing information for ATRIPLA® (efavirenz/tenofovir disoproxil fumarate/emtricitabine). http://packageinserts.bms.com/pi/pi_atripla.pdf. Accessed 19 Oct 2017.\n33. Gilead Sciences. Prescribing information for COMPLERA® (rilpivirine/tenofovir disoproxil fumarate/emtricitabine). https://gilead.com/~/media/files/pdfs/medicines/hiv/complera/complera_pi.pdf. Accessed 19 Oct 2017.\n34. Gilead Sciences. Prescribing information for STRIBILD® (elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine). http://www.gilead.com/~/media/files/pdfs/medicines/hiv/stribild/stribild_pi.pdf?la=en. Accessed 19 Oct 2017.\n35. Veterans Health Administration Office of Research and Development. Office of Research & Development. Available from http://www.research.va.gov/default.cfm. Accessed 24 Feb 2017.\n36. Braithwaite RS Kozal MJ Chang CC Adherence, virological and immunological outcomes for HIV-infected veterans starting combination antiretroviral therapies AIDS. 2007 21 12 1579 1589 10.1097/QAD.0b013e3281532b31 17630553\n37. Gandhi NR Tate JP Rodriguez-Barradas MC Validation of an algorithm to identify antiretroviral-naive status at time of entry into a large, observational cohort of HIV-infected patients Pharmacoepidemiol Drug Saf 2013 22 9 1019 1025 23836591\n38. LaFleur J DuVall SL Willson T Analysis of osteoporosis treatment patterns with bisphosphonates and outcomes among postmenopausal veterans Bone 2015 78 174 185 10.1016/j.bone.2015.04.022 25896952\n39. LaFleur J, Ginter T, Curtis JR, et al. A novel method for obtaining bone mineral densities from a dataset of radiology reports and clinic notes: natural language processing in a national cohort of postmenopausal veterans. Presented at the 2013 annual meeting of the American Society for Bone and Mineral Research (ASBMR), Baltimore Convention Center, Baltimore, Maryland; 2013, October 4–7. http://www.asbmr.org/education/AbstractDetail?aid=99cbf7b6-f3c3-49c4-9984-0ba2962f1812. Accessed 13 Oct 2017.\n40. Austin PC Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples Stat Med 2009 28 25 3083 3107 10.1002/sim.3697 19757444\n41. Robins JM Hernan MA Brumback B Marginal structural models and causal inference in epidemiology Epidemiology. 2000 11 5 550 560 10.1097/00001648-200009000-00011 10955408\n42. Maggi P Montinaro V Mussini C Novel antiretroviral drugs and renal function monitoring of HIV patients AIDS Rev. 2014 16 3 144 151 25102336\n43. Lepist EI Zhang X Hao J Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat Kidney Int 2014 86 2 350 357 10.1038/ki.2014.66 24646860\n44. German P Liu HC Szwarcberg J Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function J Acquir Immune Defic Syndr 2012 61 1 32 40 10.1097/QAI.0b013e3182645648 22732469\n45. Tong L Phan TK Robinson KL Effects of human immunodeficiency virus protease inhibitors on the intestinal absorption of tenofovir disoproxil fumarate in vitro Antimicrob Agents Chemother 2007 51 10 3498 3504 10.1128/AAC.00671-07 17664327\n46. Lepist EI Phan TK Roy A Cobicistat boosts the intestinal absorption of transport substrates, including HIV protease inhibitors and GS-7340, in vitro Antimicrob Agents Chemother 2012 56 10 5409 5413 10.1128/AAC.01089-12 22850510\n47. Ruane PJ DeJesus E Berger D Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults J Acquir Immune Defic Syndr 2013 63 4 449 455 10.1097/QAI.0b013e3182965d45 23807155\n48. Pinheiro Edos S Antunes OA Fortunak JM A survey of the syntheses of active pharmaceutical ingredients for antiretroviral drug combinations critical to access in emerging nations Antiviral Res 2008 79 3 143 165 10.1016/j.antiviral.2008.05.001 18571246\n49. Ofotokun I Titanji K Lahiri CD A single-dose zoledronic acid infusion prevents antiretroviral therapy-induced bone loss in treatment-naive HIV-infected patients: a phase IIb trial Clin Infect Dis 2016 63 5 663 671 10.1093/cid/ciw331 27193748\n50. Yin MT Kendall MA Wu X Fractures after antiretroviral initiation AIDS. 2012 26 17 2175 2184 10.1097/QAD.0b013e328359a8ca 22951635\n51. Triant VA Brown TT Lee H Grinspoon SK Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system J Clin Endocrinol Metab 2008 93 9 3499 3504 10.1210/jc.2008-0828 18593764\n52. Bristol Myers Squibb. Prescribing information for SUSTIVA® (efavirenz). http://packageinserts.bms.com/pi/pi_sustiva.pdf. Accessed 19 Oct 2017.\n53. Brown MJ Mezuk B Brains, bones, and aging: psychotropic medications and bone health among older adults Curr Osteoporos Rep. 2012 10 4 303 311 10.1007/s11914-012-0121-4 23001917\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2193-6382",
"issue": "7(2)",
"journal": "Infectious diseases and therapy",
"keywords": "Efavirenz; Fracture; Osteoporosis; Tenofovir disoproxil fumarate; Veterans",
"medline_ta": "Infect Dis Ther",
"mesh_terms": null,
"nlm_unique_id": "101634499",
"other_id": null,
"pages": "293-308",
"pmc": null,
"pmid": "29492905",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": "16048948;16355343;21522014;19531929;23836591;24646860;23001917;24384588;24278992;23392460;19424051;22951635;25872972;24430534;18571246;17630553;22748591;27193748;17664327;25102336;24871454;26355674;20828304;17086056;23835510;27941989;23899468;25265073;19757444;22301411;22850510;18195566;23807155;21606537;10955408;18593764;21398272;24660840;22732469;21320923;26075752;27809711;25896952",
"title": "Tenofovir-Associated Bone Adverse Outcomes among a US National Historical Cohort of HIV-Infected Veterans: Risk Modification by Concomitant Antiretrovirals.",
"title_normalized": "tenofovir associated bone adverse outcomes among a us national historical cohort of hiv infected veterans risk modification by concomitant antiretrovirals"
} | [
{
"companynumb": "US-GILEAD-2018-0345511",
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"abstract": "Bullous pemphigoid (BP) is an autoimmune blistering disorder that predominantly affects the elderly. Treatment regimens typically include topical and systemic immunosuppressive medications. Although effective, systemic corticosteroids are sometimes poorly tolerated in the elderly patient, contributing to the overall morbidity and mortality of BP. Dupilumab is a monoclonal antibody targeting interleukin 4 receptor alpha (IL4R?), approved for the treatment of atopic dermatitis, as well as moderate to severe asthma and chronic rhinosinusitis with nasal polyposis. In recent reports, dupilumab has been successfully used off-label to treat a variety of pruritic disorders, including chronic spontaneous urticaria [1], anal and genital itch [2], allergic contact dermatitis [3], and prurigo nodularis [4, 5]. We report here a case of an elderly patient with refractory BP whose symptoms of pruritus and blistering became well-controlled with the addition of dupilumab to the treatment regimen.",
"affiliations": "Department of Dermatology, University of California San Diego, San Diego, CA. chorme@ucsd.edu.",
"authors": "Seidman|Jason S|JS|;Eichenfield|Dawn Z|DZ|;Orme|Charisse M|CM|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; C582203:dupilumab",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "1087-2108",
"issue": "25(11)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D004351:Drug Resistance; D004804:Eosinophils; D006801:Humans; D008297:Male; D010391:Pemphigoid, Bullous; D011537:Pruritus; D018418:Th2 Cells",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32045153",
"pubdate": "2019-11-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dupilumab for bullous pemphigoid with intractable pruritus.",
"title_normalized": "dupilumab for bullous pemphigoid with intractable pruritus"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP004762",
"fulfillexpeditecriteria": "2",
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
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{
"abstract": "Isoniazid and rifampicin are used for management of tuberculosis. Acute poisoning due to isoniazid overdose is associated with repetitive generalized tonic-clonic seizures and severe metabolic acidosis. In toxic doses, rifampicin is known to produce hepatic, renal, hematological disorders, and convulsions. Sometimes, it may produce red man syndrome. We report a case of fatal poisoning with isoniazid and rifampicin. The case was characterized by late presentation, lactic acidosis, and renal failure.",
"affiliations": "Department of Nephrology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India.",
"authors": "Sridhar|A|A|;Sandeep|Y|Y|;Krishnakishore|C|C|;Sriramnaveen|P|P|;Manjusha|Y|Y|;Sivakumar|V|V|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0971-4065.103930",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-22-38510.4103/0971-4065.103930Case ReportFatal poisoning by isoniazid and rifampicin Sridhar A. Sandeep Y. Krishnakishore C. Sriramnaveen P. Manjusha Y. Sivakumar V. Department of Nephrology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, IndiaAddress for correspondence: Dr. V. Sivakumar, Department of Nephrology, Sri Venkateswara Institute of Medical Sciences, Tirupati, India. E-mail: sa_vskumar@yahoo.comSep-Oct 2012 22 5 385 387 Copyright: © Indian Journal of Nephrology2012This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Isoniazid and rifampicin are used for management of tuberculosis. Acute poisoning due to isoniazid overdose is associated with repetitive generalized tonic-clonic seizures and severe metabolic acidosis. In toxic doses, rifampicin is known to produce hepatic, renal, hematological disorders, and convulsions. Sometimes, it may produce red man syndrome. We report a case of fatal poisoning with isoniazid and rifampicin. The case was characterized by late presentation, lactic acidosis, and renal failure.\n\nFatal poisoningisoniazidrifampicin\n==== Body\nIntroduction\nAcute poisoning due to isoniazid and rifampicin overdose is often associated with generalized tonic-clonic seizures, altered sensorium, renal, hepatic dysfunctions, and severe metabolic acidosis. Sometimes with rifampicin ingestion, typical red man syndrome is also described. The prognosis and outcome depends on rapid diagnosis and timely management of complications. We herein report a fatal poisoning due to isoniazid and rifampicin.\n\nCase Report\nA 31-year-old male was brought with a history of vomiting, altered sensorium, and generalized tonic-clonic seizures, following ingestion of tablets of Isoniazid (9 gm) and rifampicin (6.75 gm). He was initially managed elsewhere and reached our emergency 32 h after ingestion. At presentation, patient was in shock, respiratory distress, and comatosed. He was immediately intubated and intravenous fluids and vasopressors support for shock was administered. Evaluation revealed orange and red color urine (no other features of red man syndrome), high anion gap metabolic acidosis due to lactic acidosis, rhabdomyolysis, renal, and hepatic dysfunction. Investigative work-up was tabulated [Table 1]. We could not measure blood levels of Isoniazid and rifampicin because of non-availability and the diagnosis of poisoning was considered depending on history, used labeled drug strips, and clinical features. Initially, patient received acute peritoneal dialysis support for 28 h as he was in shock, and subsequently when his blood pressure improved he was changed over to sustained low efficiency dialysis (SLED) support. Patient also received oral pyridoxine (as intravenous preparation is not available) in almost equal quantity to the quantity of isoniazid ingested. Despite all efforts, patient succumbed after 4 days.\n\nTable 1 The values of various parameters in the patient blood and urine samples at admission\n\nDiscussion\nAccidental or intentional isoniazid poisoning manifests as generalized tonic-clonic seizures metabolic seizures and coma. Isoniazid is a hydrazid derivative of isonicotinic acid, and is absorbed rapidly from gastrointestinal tract reaching peak levels in 1-2 h. The distribution volume is 0.6-0.7 L/kg. It is excreted in 24 h in subjects with a normal renal function. Metabolism takes place by enzymatic acetylation and hydrolysis is in liver. The plasma half-life is 0.5-1.6 h by fast acetylation and 2.5 h by slow acetylation.[1] Isoniazid toxicity occurs with doses as low as 10 to 30 mg/kg. The manifestation being nausea, vomiting, blurred vision, and slurred speech. A dose over 20 mg/kg may be associated with hallucination, recurrent seizures, metabolic acidosis hypotension, and coma. Death may occur at doses of over 50 mg/kg.[1] The metabolite of isoniazid, isoniazid hydrazone is produced by dehydrazination that inhibits formation of pyridoxal-5 phosphate from pyridoxine by inhibiting pyridoxine phosphokinase competitively. The other metabolite of isoniazid such as hydrazines and hydrazides formed by acetylation and hydrolysis also inhibits pyridoxal-5 phosphate. Pyridoxal-5 phosphate is a cofactor in gamma amino butyric acid (GABA) synthesis from glutamic acid by decarboxylation. Thus, the metabolite of isoniazid inhibits formation of pyridoxal-5 phosphate and ultimately decreases GABA production. The decrease in GABA is associated with seizures and other central nervous manifestation.[1–3] Isoniazid inhibits conversion of lactate to pyruvate which in turn results in lactic acidosis. The seizures activity further aggravates lactate accumulation and increase lactic acidosis. Acetyl hydrazine metabolite of isoniazid is hepatotoxic. Sometimes, isoniazid (INH) also causes hyperglycemia by blocking specific steps in Krebs cycle that requires nicotinamide adenine dinucleotide and also from stimulating glucagon secretion. Thus, isoniazid toxicity manifests with central nervous dysfunction and hepatic dysfunction with metabolic abnormalities such as lactic acidosis, hyperglycemia, and hyperkalemia.[1–3] Despite the reported efficacy of hemodialysis and peritoneal dialysis in isoniazid poisoning, closer scrutiny revealed that only 9.2% of dose is dialyzable and the rest is handled through hepatic metabolism. However, metabolites of isoniazid are rapidly cleared through normal kidney, and hence forced diuresis is preferred to accelerate isoniazid clearance.[4]\n\nRifampicin in toxic doses is known to produce gastrointestinal, hepatic, renal dysfunction, hematological, and central nervous system manifestation. It often presents with metabolic acidosis, convulsions, thrombocytopenia, cholestatic jaundice, oliguric renal failure, and redman syndrome. The typical features of red man syndrome are glowing red discoloration of skin, facial, and periorbital odema. The toxicology findings are attributed to high concentration of rifampicin and two major metabolites 25-desacetyl rifampicin and 3-formylrifamycin. The toxic effects have been described with ingestion of 9-12 g and 14-15 g of rifampicin in various situation.[56] About 70-80% of rifampicin is bound to protein and is distributed throughout body. The diacetyl metabolite is less toxic and its aqueous solubility results in better elimination in bile. In general, rifampicin is well tolerated by man even in very high doses and intoxication, with fatal outcomes being exceptional. However, when there is a liver disease with inadequate liver function, the enzyme capacity of liver becomes inadequate for complete metabolism of rifampicin to its desacetyl form. This results in accumulation of unchanged rifampicin that is more toxic and results in fatal poisoning.[56] rifampicin is not significantly removed by hemodialysis in view of large molecular weight, wide distribution in tissue, and high (80%) protein binding. However, rifampicin has rapid hepatic clearance.[7]\n\nIn certain situations, toxic over-dosage of Isoniazid and rifampicin in combination has been recorded. In such situations, patients presented with variety of manifestation such as convulsions, altered sensoruim, coma, metabolic acidosis, rhabdomyolysis, renal failure, and variable hepatotoxicity. In terms of management, apart from general measures such as providing airway by intubation, gastric lavage with activated charcoal, correction of metabolic acidosis by soda bicarb, and measures to correct hypotension and hyperkelemia.\n\nPyridoxine supplementation has been found to be useful in the management of neurological complication of isoniazid. In general, pyridoxine is given in doses equal to the amount of isoniazid ingested, and is given intravenous over 30-60 min for patients without seizures and over 3-5 min in patients with seizures. The dose can be repeated at 5-20 min interval until seizures cease.[48]\n\nConclusion\nIn conclusion, we report a case of fatal poisoning from Isoniazid and rifampicin combination, with detailed literature review. With increasing usage of antituberculosis drugs, and in view of increasing prevalence of various forms of tuberculosis in community, it may be prudent to educate health-care providers and immediate relatives to bring the patient in case of accidental or suicidal poisoning at the earliest for timely management, and also to ensure the availability of intravenous preparation of pyridoxine in all centers and availability of monitoring blood levels of isoniazid and rifampicin in selected centers. The late referral, shock, severe lactic acidosis, and renal failure would have been contributory for fatal outcome in our patient. Isoniazid poisoning should be suspected in all patients where symptoms are coma and seizures especially in those who have access to isoniazid.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\n1 Topcu I Yentur EA Kefi A Ekici NZ Sakarya M Sezures metabolic acidosis and coma resulting from acute isoniazid intoxication Anesth Intensive Care 2005 33 518 20 \n2 Tai WP Yue H Hu PJ Coma caused by isoniazid poisoning in a patient treated with pyridoxine and hemodialysis Adv Ther 2008 25 1085 8 18807228 \n3 Agrawal RL Dwivedi NC Agrawal M Jain S Agrawal A Accidental isoniazid poisoning: A report Indian J Tuberc 2008 55 94 6 18516826 \n4 Kumar L Singhi PD Pereira BJ Singh U Sakhuja V Chugh KS Accidental poisoning with isoniazid and rifampicin in an infant: Role of peritoneal dialysis Nephrol Dial Transplant 1989 4 156 7 2496358 \n5 Cheng J Fock KM Chua KL Reversible hepatic and renal damage from rifampin overdose: A case report Singapore Med J 1988 29 306 8 3187586 \n6 Plomp TA Battista HJ Unterdorfer H Van Ditmarsch WC Maes RA A case of fatal poisoning by rifampicin Arch Toxicol 1981 48 245 52 7316759 \n7 Malone RS Fish DN Spiegel DM Childs JM Peloquin CA The effect of hemodialysis on isoniazid, rifampin, pyrazinamide, and ethambutol Am J Respir Crit Care Med 1999 159 1580 4 10228130 \n8 Spalding CT Buss WC Toxic overdose of isoniazid, rifampicin and ethambutol Eur J Clin Pharmacol 1986 30 381 2 3732380\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "22(5)",
"journal": "Indian journal of nephrology",
"keywords": "Fatal poisoning; isoniazid; rifampicin",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
"other_id": null,
"pages": "385-7",
"pmc": null,
"pmid": "23326053",
"pubdate": "2012-09",
"publication_types": "D002363:Case Reports",
"references": "16119496;7316759;10228130;3732380;18807228;3187586;18516826;2496358",
"title": "Fatal poisoning by isoniazid and rifampicin.",
"title_normalized": "fatal poisoning by isoniazid and rifampicin"
} | [
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"companynumb": "PHHY2013IN024917",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugadditional": null,
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"abstract": "This case report describes an extremely rare cause of small bowel obstruction. A female patient who was liver transplanted seven years earlier and had been in immunosuppressive therapy since then presented with clinical and radiological manifest small bowel obstruction and surgery followed. The surgical finding was a segment near the terminal ileum with three separate stenoses in which the most oral was causing the obstruction. Histology evaluation of the stenoses revealed infiltration of lymphoid tissue and the stenoses tested positive on Epstein-Barr virus. The patient was later confirmed to be suffering from post-transplant lymphoproliferative disease.",
"affiliations": "Berggreensgade 16, 2100 København Ø. afschmiegelow@hotmail.com.",
"authors": "Schmiegelow|Amalie|A|;Klein|Mads|M|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Denmark",
"delete": false,
"doi": null,
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"issn_linking": "0041-5782",
"issue": "176(44)",
"journal": "Ugeskrift for laeger",
"keywords": null,
"medline_ta": "Ugeskr Laeger",
"mesh_terms": "D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D045823:Ileus; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D008232:Lymphoproliferative Disorders; D008875:Middle Aged",
"nlm_unique_id": "0141730",
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"pmid": "25354009",
"pubdate": "2014-10-27",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Small bowel obstruction caused by immunosuppressive therapy after a liver transplant.",
"title_normalized": "small bowel obstruction caused by immunosuppressive therapy after a liver transplant"
} | [
{
"companynumb": "DK-BAUSCH-BL-2018-009326",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
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"activesubstancename": "PREDNISOLONE"
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... |
{
"abstract": "Ovarian insufficiency is a major long-term adverse event, following the administration of a myeloablative conditioning regimen, and occurring in >80% of children and adolescents receiving such treatment for malignant or non-malignant disease. Cryopreservation of ovarian tissue is currently offered to preserve the fertility of these young patients. At least 35 live births have been reported after transplantation of cryopreserved ovarian tissue in adult patients, but the procedure remains unproven for ovarian tissue harvested at a prepubertal or pubertal age. We report here the first live birth after autograft of cryopreserved ovarian tissue in a woman with primary ovarian failure after a myeloablative conditioning regimen as part of a hematopoietic stem cell transplantation performed for homozygous sickle-cell anemia at age 14 years. This first report of successful fertility restoration after the graft of ovarian tissue cryopreserved before menarche offers reassuring evidence for the feasibility of the procedure when performed during childhood.",
"affiliations": "Research Laboratory on Human Reproduction, Faculty of Medicine, Université Libre de Bruxelles (ULB), Campus Erasme, CP636, 808 route de Lennik, 1070 Brussels, Belgium Fertility Clinic, Department of Obstetrics and Gynaecology, Erasme Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium idemeest@ulb.ac.be.;Gynecology Clinic, Department of Obstetrics and Gynaecology, Erasme Hospital, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium.;Department of Hematology-Oncology, Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), 1020 Brussels, Belgium.;Research Laboratory on Human Reproduction, Faculty of Medicine, Université Libre de Bruxelles (ULB), Campus Erasme, CP636, 808 route de Lennik, 1070 Brussels, Belgium Present address: Instituto Marqués, Assisted Reproduction Service, Manuel Girona 33, MASIA, 08034 Barcelona, Spain.;Research Laboratory on Human Reproduction, Faculty of Medicine, Université Libre de Bruxelles (ULB), Campus Erasme, CP636, 808 route de Lennik, 1070 Brussels, Belgium Fertility Clinic, Department of Obstetrics and Gynaecology, Erasme Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium Present address: Nivelles Hospital, Rue Samiette, 1400 Nivelles, Belgium.;Department of Endocrinology, Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), 1020 Brussels, Belgium.;Research Laboratory on Human Reproduction, Faculty of Medicine, Université Libre de Bruxelles (ULB), Campus Erasme, CP636, 808 route de Lennik, 1070 Brussels, Belgium Fertility Clinic, Department of Obstetrics and Gynaecology, Erasme Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium.;Research Laboratory on Human Reproduction, Faculty of Medicine, Université Libre de Bruxelles (ULB), Campus Erasme, CP636, 808 route de Lennik, 1070 Brussels, Belgium Department of Endocrinology, Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), 1020 Brussels, Belgium.;Department of Hematology-Oncology, Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), 1020 Brussels, Belgium.",
"authors": "Demeestere|Isabelle|I|;Simon|Philippe|P|;Dedeken|Laurence|L|;Moffa|Federica|F|;Tsépélidis|Sophie|S|;Brachet|Cecile|C|;Delbaere|Anne|A|;Devreker|Fabienne|F|;Ferster|Alina|A|",
"chemical_list": "D019653:Myeloablative Agonists",
"country": "England",
"delete": false,
"doi": "10.1093/humrep/dev128",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-1161",
"issue": "30(9)",
"journal": "Human reproduction (Oxford, England)",
"keywords": "childhood; fertility preservation; live birth; ovarian tissue cryopreservation; transplantation",
"medline_ta": "Hum Reprod",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell; D064592:Autografts; D015925:Cryopreservation; D005260:Female; D059247:Fertility Preservation; D006801:Humans; D050498:Live Birth; D019653:Myeloablative Agonists; D010053:Ovary; D011247:Pregnancy; D016649:Primary Ovarian Insufficiency; D014182:Transplantation, Autologous",
"nlm_unique_id": "8701199",
"other_id": null,
"pages": "2107-9",
"pmc": null,
"pmid": "26062556",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Live birth after autograft of ovarian tissue cryopreserved during childhood.",
"title_normalized": "live birth after autograft of ovarian tissue cryopreserved during childhood"
} | [
{
"companynumb": "BE-SA-2015SA141686",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN"
},
"drugadditio... |
{
"abstract": "We report a benzonatate overdose in a teenager resulting in life-threatening toxicity to increase awareness of this overdose, and discuss recent pediatric warnings and labeling information provided by the US Food and Drug Administration (FDA). After an overdose of benzonatate, a 13-yr-old female presented to our emergency department with coma, seizures, hypotension, prolonged QT interval on electrocardiogram, and metabolic acidosis. Benzonatate is an antitussive medication with sodium channel-blocking properties and local anesthetic effects on the respiratory stretch receptors due to a tetracaine-like metabolite. Overdose is reported to cause coma, seizures, hypotension, tachycardia, ventricular dysrhythmias, and cardiac arrest. The FDA recently issued a Drug Safety Communication warning that accidental benzonatate ingestion in children younger than 10 years of age have increased risk of death and added the new information to the Warnings and Precautions section of benzonatate's label.",
"affiliations": "Division of Emergency Medicine, Department of Pediatrics, Children's Medical Center of Dallas, Dallas, Texas ; University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.",
"authors": "Thimann|Daniel A|DA|;Huang|Craig J|CJ|;Goto|Collin S|CS|;Feng|Sing-Yi|SY|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5863/1551-6776-17.3.270",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1551-6776",
"issue": "17(3)",
"journal": "The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG",
"keywords": "AERS, Adverse Event Reporting System; ECG, electrocardiogram; ED, emergency department; EMS, emergency medical services; FDA, Food and Drug Administration; altered mental status; benzonatate; metabolic acidosis; pediatrics; seizures",
"medline_ta": "J Pediatr Pharmacol Ther",
"mesh_terms": null,
"nlm_unique_id": "101089851",
"other_id": null,
"pages": "270-3",
"pmc": null,
"pmid": "23258970",
"pubdate": "2012-07",
"publication_types": "D016428:Journal Article",
"references": "19121573;19892505;2774240;20490746;3788039;9865240;18431127;16810015;11762966",
"title": "Benzonatate toxicity in a teenager resulting in coma, seizures, and severe metabolic acidosis.",
"title_normalized": "benzonatate toxicity in a teenager resulting in coma seizures and severe metabolic acidosis"
} | [
{
"companynumb": "US-PFIZER INC-2016535294",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CHLORPHENIRAMINE\\DEXTROMETHORPHAN"
},
"druga... |
{
"abstract": "OBJECTIVE\nTreatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin is associated with increased risk of upper gastrointestinal bleeding. There is little evidence on the risk of lower gastrointestinal bleeding with NSAIDs, antiplatelet agents (APAs), or anticoagulants. We aimed to quantify the relative risk (RR) of upper and lower gastrointestinal bleeding associated with use of NSAIDs, APAs, or anticoagulants.\n\n\nMETHODS\nWe performed a case-control study that used data collected from consecutive patients hospitalized for gastrointestinal bleeding (563 upper, mean age, 63.6 ± 16.7 years and 415 lower, mean age, 70.8 ± 13.8 years), confirmed by endoscopy or other diagnostic procedures. Unhospitalized patients were used as controls (n = 1008) and matched for age, hospital, and month of admission. Drug use was considered current when taken within 7 days or less before hospitalization. RRs and 95% confidence intervals (CIs) were estimated by unconditional logistic regression analysis.\n\n\nRESULTS\nUse of anticoagulants, low-dose aspirin, and other drugs (non-aspirin-APA, 82.3% thienopiridines) was associated with upper and lower gastrointestinal bleeding; the risk was 2-fold higher for anticoagulants (RR, 4.2; 95% CI, 2.9-6.2) than for low-dose aspirin (RR, 2.1; 95% CI, 1.4-3.3) or other non-aspirin-APA drugs (RR, 2.0; 95% CI, 1.6-2.6). NSAID use was also associated with increased risk of gastrointestinal bleeding and greater for upper (RR, 2.6; 95% CI, 2.0-3.5) than lower gastrointestinal bleeding (RR, 1.4; 95% CI, 1.0-1.9). Use of proton pump inhibitors was associated with reduced risk of upper, but not lower, gastrointestinal bleeding.\n\n\nCONCLUSIONS\nAnticoagulants, low-dose aspirin, NSAIDs, and other non-aspirin-APA drugs are associated with increased risk of upper and lower gastrointestinal bleeding. Use of anticoagulants appears to be the strongest risk factor for gastrointestinal bleeding.",
"affiliations": "Servicio de Aparato Digestivo, Hospital Clínico, University of Zaragoza, Zaragoza, Spain; CIBERehd, Barcelona, Spain. Electronic address: alanas@unizar.es.;CIBERehd, Barcelona, Spain.;Servicio de Aparato Digestivo, Hospital Clínico, University of Zaragoza, Zaragoza, Spain.;Servicio de Aparato Digestivo, Hospital Universiatrio Miguel Servet, Zaragoza, Spain.;CIBERehd, Barcelona, Spain; Hospital Donostia, San Sebastian, Spain.;CIBERehd, Barcelona, Spain; Servicio de Aparato Digestivo, Corporació Sanitària Universitària, Sabadell, Barcelona, Spain.;CIBERehd, Barcelona, Spain; Servicio de Aparato Digestivo, Hospital La Fe, Valencia, Spain.;Servicio de Aparato Digestivo, Hospital Costa del Sol, Marbella, Spain.;CIBERehd, Barcelona, Spain; Gastroenterología, Hospital de Valme, Sevilla, Spain.;Servicio de Aparato Digestivo, Hospital Clínico, University of Zaragoza, Zaragoza, Spain.;Servicio de Aparato Digestivo, Hospital Clínico, University of Zaragoza, Zaragoza, Spain.;Centro Español de Investigación Farmacoepidemiológica, Madrid, Spain.",
"authors": "Lanas|Ángel|Á|;Carrera-Lasfuentes|Patricia|P|;Arguedas|Yolanda|Y|;García|Santiago|S|;Bujanda|Luis|L|;Calvet|Xavier|X|;Ponce|Julio|J|;Perez-Aísa|Ángeles|Á|;Castro|Manuel|M|;Muñoz|Maria|M|;Sostres|Carlos|C|;García-Rodríguez|Luis A|LA|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1542-3565",
"issue": "13(5)",
"journal": "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association",
"keywords": "Colon; Complication; Intestine; Peptic Ulcer; Side Effect; Small Bowel; Stomach",
"medline_ta": "Clin Gastroenterol Hepatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants; D016022:Case-Control Studies; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D011446:Prospective Studies; D018570:Risk Assessment",
"nlm_unique_id": "101160775",
"other_id": null,
"pages": "906-12.e2",
"pmc": null,
"pmid": "25460554",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants.",
"title_normalized": "risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti inflammatory drugs antiplatelet agents or anticoagulants"
} | [
{
"companynumb": "ES-JNJFOC-20150514087",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RANITIDINE\\RANITIDINE HYDROCHLORIDE"
},
"drugadd... |
{
"abstract": "Social media data are being increasingly used for population-level health research because it provides near real-time access to large volumes of consumer-generated data. Recently, a number of studies have explored the possibility of using social media data, such as from Twitter, for monitoring prescription medication abuse. However, there is a paucity of annotated data or guidelines for data characterization that discuss how information related to abuse-prone medications is presented on Twitter.\n\n\n\nThis study discusses the creation of an annotated corpus suitable for training supervised classification algorithms for the automatic classification of medication abuse-related chatter. The annotation strategies used for improving interannotator agreement (IAA), a detailed annotation guideline, and machine learning experiments that illustrate the utility of the annotated corpus are also described.\n\n\n\nWe employed an iterative annotation strategy, with interannotator discussions held and updates made to the annotation guidelines at each iteration to improve IAA for the manual annotation task. Using the grounded theory approach, we first characterized tweets into fine-grained categories and then grouped them into 4 broad classes-abuse or misuse, personal consumption, mention, and unrelated. After the completion of manual annotations, we experimented with several machine learning algorithms to illustrate the utility of the corpus and generate baseline performance metrics for automatic classification on these data.\n\n\n\nOur final annotated set consisted of 16,443 tweets mentioning at least 20 abuse-prone medications including opioids, benzodiazepines, atypical antipsychotics, central nervous system stimulants, and gamma-aminobutyric acid analogs. Our final overall IAA was 0.86 (Cohen kappa), which represents high agreement. The manual annotation process revealed the variety of ways in which prescription medication misuse or abuse is discussed on Twitter, including expressions indicating coingestion, nonmedical use, nonstandard route of intake, and consumption above the prescribed doses. Among machine learning classifiers, support vector machines obtained the highest automatic classification accuracy of 73.00% (95% CI 71.4-74.5) over the test set (n=3271).\n\n\n\nOur manual analysis and annotations of a large number of tweets have revealed types of information posted on Twitter about a set of abuse-prone prescription medications and their distributions. In the interests of reproducible and community-driven research, we have made our detailed annotation guidelines and the training data for the classification experiments publicly available, and the test data will be used in future shared tasks.",
"affiliations": "Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.;Department of Biomedical Informatics, School of Medicine, Emory University, Atlanta, GA, United States.;Department of Emergency Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.;Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.",
"authors": "O'Connor|Karen|K|0000-0001-7709-3813;Sarker|Abeed|A|0000-0001-7358-544X;Perrone|Jeanmarie|J|0000-0002-3396-6333;Gonzalez Hernandez|Graciela|G|0000-0002-6416-9556",
"chemical_list": "D055553:Prescription Drugs",
"country": "Canada",
"delete": false,
"doi": "10.2196/15861",
"fulltext": "\n==== Front\nJ Med Internet Res\nJ. Med. Internet Res\nJMIR\nJournal of Medical Internet Research\n1439-4456 1438-8871 JMIR Publications Toronto, Canada \n\nv22i2e15861\n32130117\n10.2196/15861\nOriginal Paper\nOriginal Paper\nPromoting Reproducible Research for Characterizing Nonmedical Use of Medications Through Data Annotation: Description of a Twitter Corpus and Guidelines\nEysenbach Gunther Tang Lu Foufi Vasiliki O'Connor Karen MShttps://orcid.org/0000-0001-7709-38131Department of Biostatistics, Epidemiology and InformaticsPerelman School of MedicineUniversity of PennsylvaniaBlockley Hall423 Guardian DrivePhiladelphia, PA, 19095United States1 2155738089karoc@pennmedicine.upenn.edu Sarker Abeed PhD2https://orcid.org/0000-0001-7358-544X Perrone Jeanmarie MD3https://orcid.org/0000-0002-3396-6333 Gonzalez Hernandez Graciela PhD1https://orcid.org/0000-0002-6416-9556 \n1 \nDepartment of Biostatistics, Epidemiology and Informatics\nPerelman School of Medicine\nUniversity of Pennsylvania\nPhiladelphia, PA\nUnited States\n\n\n2 \nDepartment of Biomedical Informatics\nSchool of Medicine\nEmory University\nAtlanta, GA\nUnited States\n\n\n3 \nDepartment of Emergency Medicine\nPerelman School of Medicine\nUniversity of Pennsylvania\nPhiladelphia, PA\nUnited States\n\nCorresponding Author: Karen O'Connor karoc@pennmedicine.upenn.edu\n2 2020 \n26 2 2020 \n22 2 e1586113 8 2019 31 10 2019 14 11 2019 15 12 2019 ©Karen O'Connor, Abeed Sarker, Jeanmarie Perrone, Graciela Gonzalez Hernandez. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 26.02.2020.2020This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in the Journal of Medical Internet Research, is properly cited. The complete bibliographic information, a link to the original publication on http://www.jmir.org/, as well as this copyright and license information must be included.Background\nSocial media data are being increasingly used for population-level health research because it provides near real-time access to large volumes of consumer-generated data. Recently, a number of studies have explored the possibility of using social media data, such as from Twitter, for monitoring prescription medication abuse. However, there is a paucity of annotated data or guidelines for data characterization that discuss how information related to abuse-prone medications is presented on Twitter.\n\nObjective\nThis study discusses the creation of an annotated corpus suitable for training supervised classification algorithms for the automatic classification of medication abuse–related chatter. The annotation strategies used for improving interannotator agreement (IAA), a detailed annotation guideline, and machine learning experiments that illustrate the utility of the annotated corpus are also described.\n\nMethods\nWe employed an iterative annotation strategy, with interannotator discussions held and updates made to the annotation guidelines at each iteration to improve IAA for the manual annotation task. Using the grounded theory approach, we first characterized tweets into fine-grained categories and then grouped them into 4 broad classes—abuse or misuse, personal consumption, mention, and unrelated. After the completion of manual annotations, we experimented with several machine learning algorithms to illustrate the utility of the corpus and generate baseline performance metrics for automatic classification on these data.\n\nResults\nOur final annotated set consisted of 16,443 tweets mentioning at least 20 abuse-prone medications including opioids, benzodiazepines, atypical antipsychotics, central nervous system stimulants, and gamma-aminobutyric acid analogs. Our final overall IAA was 0.86 (Cohen kappa), which represents high agreement. The manual annotation process revealed the variety of ways in which prescription medication misuse or abuse is discussed on Twitter, including expressions indicating coingestion, nonmedical use, nonstandard route of intake, and consumption above the prescribed doses. Among machine learning classifiers, support vector machines obtained the highest automatic classification accuracy of 73.00% (95% CI 71.4-74.5) over the test set (n=3271).\n\nConclusions\nOur manual analysis and annotations of a large number of tweets have revealed types of information posted on Twitter about a set of abuse-prone prescription medications and their distributions. In the interests of reproducible and community-driven research, we have made our detailed annotation guidelines and the training data for the classification experiments publicly available, and the test data will be used in future shared tasks.\n\nprescription drug misusesocial mediasubstance abuse detectionnatural language processingmachine learninginfodemiologyinfoveillance\n==== Body\nIntroduction\nBackground\nSocial media has provided a platform for internet users to share experiences and opinions, and the abundance of data available has turned social networking websites into valuable resources for research. Social media chatter encapsulates knowledge regarding diverse topics such as politics [1], sports [2], and health [3]. A 2015 report by the Pew Research Center [4] suggested that 37% of adults online in the United States considered health to be one of the most interesting topics. Users seek and share health-related information on social media regularly, resulting in the continuous generation of knowledge regarding health conditions, drugs, interventions, and health care policies. Social media has become an important source of data, particularly for public health monitoring because the data generated can be collected and processed in near real-time to make population-level estimates. Consequently, social media data have been used for conducting health-related studies such as tracking the spread of contagious diseases such as influenza [5], predicting depression [6], understanding and characterizing people’s health-related choices such as diet [7], and discovering the potential adverse or beneficial effects of medications [8].\n\nAlthough the volume of data in social media is attractive, owing to the various complexities associated with the data, such as the use of nonstandard language and the presence of misspellings, advanced natural language processing (NLP) pipelines are required for automated knowledge discovery from this resource. These pipelines typically require the application of machine learning approaches, supervised or unsupervised, for information classification and extraction. Unsupervised approaches such as topic modeling are capable of automatically identifying themes associated with health topics from large unlabeled datasets [9]. However, as targeted applications of social media data are being explored, supervised methods are becoming increasingly popular. Supervised machine learning methods are generally more accurate than unsupervised approaches for targeted tasks (eg, adverse drug reaction detection [10] and user sentiment classification [11]), but they require the manual annotation of large datasets. Over the recent years, public releases of manually annotated datasets have significantly contributed to community-driven development of data-centric solutions to important research problems lying at the intersection of data science and health, and these community efforts have been instrumental in progressing toward the benchmarks for these tasks [12].\n\nThe importance of building high-quality datasets and annotation processes cannot be overstated—the reliability of the systems and their performance estimates depend directly on it. When annotating datasets for training machine learning algorithms, the standard approach is to have multiple annotators annotate the same sample of data and then compute agreement among the different annotators. Interannotator agreement (IAA) measures provide estimates about how well defined a task is, its level of difficulty, and the ceiling for the performance of automated approaches (ie, it is assumed to be impossible for an automated system to be better than human agreement). IAA values reported for social media–based annotation tasks are often relatively low [13] compared with other data sources because information in social media can be presented in unique ways, often without sufficient context (eg, due to length limitations, as in the case of Twitter). Although significant attention of the informatics research community is directed toward improving machine learning performance numbers—such as F-measure, recall, precision, and accuracy—on standardized datasets, relatively less attention has been paid to improve the qualities of the datasets that are standardized. On the basis of our significant past experience in social media–based NLP and machine learning research, we have established some best practices for preparing health-related research datasets.\n\nGuidelines and Corpus Development\nOne of the most important steps in preparing high-quality corpora is the development of detailed and consistent annotation guidelines that are followed by all the annotators involved. Methodically prepared annotation guidelines for a target task have multiple advantages, as outlined below:\n\nThey enable the annotation process to be more consistent, leaving fewer decisions to the subjective judgments of different annotators. Consequently, this also inevitably improves IAA, naturally raising the performance ceilings for automated systems.\n\nWell-defined guidelines document the clinical or public health purposes of the studies, enabling researchers from informatics or computer science domains to better understand the high-level objectives of the studies, thereby helping bridge the gap between the domains.\n\nData science approaches to health-related problems are seeing incremental development (ie, as one problem is addressed successfully, additional follow-up problems are addressed). Therefore, well-defined annotation guidelines can be crucial to enable extensions of the annotated corpora for future studies.\n\nDatasets for a specific problem (eg, adverse drug event detection [10,14,15]) are often developed by distinct teams and can be in different languages. If detailed annotation guidelines are prepared and published for each problem, with sufficient explanation behind the decisions made by the annotating team, the guidelines can be used by different research groups. This could facilitate the use of combined datasets and allow systems trained on one dataset to be ported to the others.\n\nThe considerations documented within the annotation guidelines of one study can be beneficial for research teams developing corpora for other tasks, as they can follow identical standards or make similar considerations.\n\nIn addition to datasets and automated systems that are valuable for the health informatics research community, detailed explanations of methods and justifications for annotation guidelines can impact data-centric automation—particularly for domain-specific problems, where the potential for automation is at the exploratory or early development phase.\n\nIn this paper, we discuss the preparation of a dataset from Twitter involving misuse- and abuse-prone prescription medications. Prescription medication misuse and abuse, and more generally, drug abuse, is currently a major epidemic globally, and the problem has received significant attention particularly in the United States in recent years because of the opioid crisis. Given the enormity of the problem and the obstacles associated with the active monitoring of drug abuse, recent publications have suggested the possibility of using innovative sources for close-to-real-time monitoring of the crisis [16], particularly social media, where prescription medications, their use, and misuse are publicly discussed [17,18].\n\nPrescription Medication Abuse and Social Media\nThe contribution of prescription medications in the broader drug abuse crisis has been well documented and understood over the recent years. Nonmedical use of prescription medications may result in an array of adverse effects, from nonserious ones such as vomiting to addiction and even death. A significant portion of emergency department visits are due to nonmedical use of prescription medications [19]. Distinct classes of prescription medications are misused or abused with differing intents—stimulants such as Adderall, for example, are often used for performance enhancement, whereas opioids, depressants, and benzodiazepines are typically used for the sensations they produce [20]. A 2016 report focusing on the threat of drug abuse published by the Drug Enforcement Agency suggested that the number of deaths involving prescription medications has overtaken those from illicit drugs such as cocaine and heroin combined, for every year since 2002 [21]. The report also stated that approximately 52 people die each day in the United States from prescription medication overdose—a number that has only increased since the publication of the report. A report by the Centers for Disease Control and Prevention showed that of over 40,000 drug overdose deaths in 2013, more than 20,000 were due to prescription drugs [22]. Understandably, the misuse of certain prescription medications, such as opioids, has resulted in more dire consequences than others. Statistics from the WONDER database [23] suggest that the increasing sales in prescription opioids correlate with the steady increase in opioid overdose deaths over 15 years. Unfortunately, because of the absence of effective, timely surveillance approaches, the problem posed by prescription opioids was not fully understood before it reached the level of a national crisis. Recent advances in NLP, social media mining, and, broadly, data science present us with the opportunity of using public social media data as a complementary resource for monitoring and studying prescription medication use and abuse.\n\nIn this paper, we do not distinguish between prescription drug misuse and abuse and use these terms interchangeably to represent all types of nonmedical use. There are, however, subtle differences between the definitions of the terms. Misuse is defined by the National Institutes of Health (NIH) National Institute on Drug Abuse (NIDA) as a form of nonmedical use that involves “taking a medication in a manner or dose other than prescribed; taking someone else’s prescriptions, even if for a legitimate medical complaint such as pain”; whereas abuse is defined as “taking a medication to feel euphoria (ie, to get high)” [20]. Although misuse is the contrary or improper use of prescribed drugs, which maybe intentional or unintentional, abuse is intentional use for nonmedical purposes [24]. When it comes to the misuse and abuse of prescription medications, as opposed to illicit drugs, social media may provide unprecedented insights because the population-level extent and mechanisms of abuse for different prescription drugs are not known a priori. Our overarching focus is to create a Twitter dataset that enables the training of supervised systems to automatically characterize medication abuse–related chatter for large-scale analysis. Publicly available discussions regarding prescription medication abuse may enable us to discover emerging abuse-prone medications, novel methods of abuse, and other related information. Although some data-centric approaches have been published in recent times for leveraging social media data for monitoring prescription medication abuse, there is a lack of (1) clear descriptions of how abuse information is presented in public social media (eg, Twitter), (2) annotated datasets usable for automatic characterization of social media chatter associated with abuse-prone medications, and (3) thorough annotation guidelines that may serve as the groundwork for long-term future research on this topic.\n\nWe present here an analysis of how prescription medication abuse information is presented on Twitter, the details of a large-scale annotation process that we have conducted, annotation guidelines that may be used for future annotation efforts, and a large annotated dataset involving various abuse-prone medications that we envision will drive community-driven data science and NLP research on the topic. Although we primarily focus on the annotation process, guidelines, and the data, we also illustrate the utility of the corpus by presenting the performances of several supervised classification approaches, which will serve as strong baselines for future research.\n\nMethods\nData Selection and Collection\nIn consultation with the toxicology expert of our study (JP), we selected 20 medications (generic) to include in the study. We selected drugs belonging to the classes of prescription medications that have been identified as more commonly abused: opioids (including those used for medication-assisted treatment), benzodiazepines, atypical antipsychotics, central nervous system stimulants, and gamma-aminobutyric acid analogs. Table 1 shows the drug categories, generic names, and brand names for the drugs included in this study. All data were collected from Twitter through the public streaming application programming interface (API). The Twitter API allows data collection in real time through the use of keywords. We used the brand and generic names as keywords, as well as common spelling variants for these keywords generated automatically through a data-centric misspelling generator [25]. We only kept tweets that were in English as per the metadata that was available with them during collection. Starting with a large random sample from the entire collected dataset, we applied further filtering to generate a manageable sample for manual annotation. The tweets were filtered by removing retweets and short tweets only with links. After the collection, a sample of the data was selected for preliminary manual inspection. This inspection involved simply reading a set of tweets to (1) ensure that all medications of interest were included, (2) identify which medications occurred too many times, and (3) check if any noisy nondrug keywords had been introduced during the misspelling generation process leading to the collection of large volumes of irrelevant data. During the sampling and analysis, we discovered that stimulants were particularly overrepresented in social media chatter (eg, Adderall was mentioned almost as frequently as stopwords such as the, of, and in the collected dataset). So, we undersampled tweets mentioning stimulants for the final annotation set using random selection without replacement. This set was then passed to the annotators for guideline development and annotation.\n\nThe protocol for this study was reviewed by the University of Pennsylvania’s institutional review board and was determined to meet the criteria for exempt human subjects research as all data collected and used are publicly available. In the examples presented in this paper, all identifiers have been removed, and slight modifications have been made to tweets to protect the anonymity of users.\n\nTable 1 Main drug categories, generic names, and brand names for prescription medications included in this study.\n\nDrug category\tGeneric name\tBrand name(s)\t\nOpioids\tOxycodone\tOxycontin, Percocet\t\nMethadone\tDolophine\t\nMorphine\tAvinza\t\nTramadol\tConzip\t\nHydrocodone\tVicodin, Zohydro\t\nBuprenorphine\tSuboxone\t\nBenzodiazepines\tDiazepam\tValium\t\nAlprazolam\tXanax\t\nClonazepam\tKlonopin\t\nLorazepam\tAtivan\t\nAtypical antipsychotics\tOlanzapine\tZyprexa\t\nRisperidone\tRisperdal\t\nAripiprazole\tAbilify\t\nAsenapine\tSaphris\t\nQuetiapine\tSeroquel\t\nCentral nervous system stimulants\tAmphetamine mixed salts\tAdderall\t\nLisdexamfetamine\tVyvanse\t\nMethylphenidate\tRitalin\t\nGABAa analogs\tGabapentin\tNeurontin\t\nPregabalin\tLyrica\t\naGABA: gamma-aminobutyric acid.\n\nGuidelines and Annotation\nIn a preliminary study that paved the way for a long-term project [26], we performed binary annotation of potential medication abuse tweets. In that study, we classified 6400 tweets from 3 abuse-prone medications and 1 non–abuse-prone medication (control medication) as either abuse indicating or non-abuse indicating for use in the training and testing of automatic classifiers. The guidelines from that study served as the foundation for this study. In addition, the familiarity we gained from that study regarding the information available in the discussions of potential prescription drug abuse informed our decision to expand the number of categories for this classification task. Our annotation entailed labeling tweets into 1 of 4 categories: potential abuse or misuse, non-abuse consumption, drug mention only, and unrelated. The annotators were given the following definitions, with examples, to assist in determining the classification of the tweets:\n\nPotential Abuse or Misuse (A): These tweets contain possible indications that the user is abusing or is seeking to abuse or misuse the medication. The user may have a valid prescription for the medication, but their manner of use is indicative of abuse or misuse, or the medication may have been obtained illegally. We also include in this category tweets that can possibly indicate abuse without confirming evidence. As the end goals of this project are to identify all potential mentions of nonmedical or improper drug use by users, we do not differentiate between misuse and abuse.\n\nNon-abuse Consumption (C): These tweets indicate that the user has a valid prescription for the medication and is taking the medication as prescribed, or is seeking to obtain the medication for a valid indicated reason. Tweets should be placed in this category when there is evidence of possible consumption, but there is no evidence of abuse or misuse. This category only applies to personal consumption.\n\nDrug Mention Only (M): In these tweets, the mention of the medication name is not related to wanting, needing, or using the medication either as prescribed or misuse or abuse. For example, these tweets may be sharing information or news about the medication, jokes, movie or book titles, or lines from movies or songs. This category also includes mentions of use by a third person that do not indicate abuse or misuse by that person.\n\nUnrelated (U): These tweets mention the medication keywords, but they do not represent the drug and refer to something else.\n\nWe decided on these categories and built our initial guidelines using the grounded theory approach [27] whereby each tweet was categorized in terms of the topic of its content, which were eventually mapped to one of the above categories. We trained 4 annotators using the developed guidelines for the manual categorization of the tweets; 2 of the annotators were the primary authors of the guidelines (AU1 and AU2) and the remaining 2 were expert annotators with past experience in similar annotation tasks (AN1 and AN2). The annotation task was started as an iterative process both for training purposes and to test the efficacy and clarity of the guidelines over a small initial dataset. The annotators were instructed to code each tweet into only one category and were asked to create brief notes stating their thought process for instances in which coding was difficult or where they felt that the reason for their decision was not obvious. The notes were used to assist in adjudication and for error analysis, and they helped to highlight areas in which the guidelines were not clear. We executed a total of 4 such iterations over the same dataset, refining the guidelines at each iteration and expanding them to make distinctions between the different categories more explicit.\n\nFrom the initial topic categorization of the tweets, we added identifying markers that could be found within the tweets to help determine their classifications. With the exception of unrelated, these markers were, in effect, all the subcategories identified during annotator training and manual review of the ways users may express use, potential abuse or misuse, consumption, or just the mention of a medication.\n\nFor example, an identifying marker of abuse or misuse is the explicit or implied mention of consuming a higher dose of medication than prescribed:\n\nlet's see how fast a double dose of hydrocodone will knock me out\n\nthewaitinggameAn identifying marker of consumption is the taking of a prescribed medication as indicated with no evidence of it being abused or misused:\n\nI was prescribed Ritalin by my doctor to help me. i feel more hyper than focused\n\nMeanwhile, a tweet categorized as mention gives no indication that the person mentioning the medication is taking the medication themselves:\n\nthe adderall tweets are not even funny to me. if you saw what i see daily at work it wouldn't be funny to you either.\n\nTextbox 1 presents some examples of the descriptions of the identified subcategories, or markers, within each of the broader categories, or classes, detailing the various ways in which abuse-indicating and other information are shared on Twitter. Although we did not code the tweets’ subcategories during annotation, their descriptions and examples were provided in the annotation guidelines, which helped the annotators to be consistent in their decisions. Consequently, the thorough breakdown of these subcategories, or markers, improved agreement between the different annotators. The full annotation guidelines used by the annotators, with details and examples of each subcategory within the 4 classes, are made available with this publication (Multimedia Appendix 1).\n\nThe creation of the gold standard corpus commenced after consistent levels of agreement between the annotators were achieved. The corpus of tweets was divided into 3 overlapping sets ensuring that each tweet was annotated at least twice, with some being annotated 3 times. The annotations were completed by 3 expert annotators trained on the guidelines (AU1, AN1, and AN2). The annotators coded each tweet according to the entire text contained in the tweet by following the guidelines established to distinguish between classes. There were no further annotations at the subtweet level. The disagreements from each set were annotated by a fourth annotator (AU2) for resolution. For the tweets that were annotated by 3 annotators, majority agreement was used to resolve disagreements. In the event that all 3 annotators disagreed on the classification, they were reviewed and resolved by AU2. An overview of the process is shown in Figure 1.\n\nExamples of the descriptions of subcategories or identifying markers for each category from the classification guidelines.\n\n1. Potential Abuse or Misuse (A)\n\n\nThe tweet explicitly states that the user has taken or is going to take the medication to experience certain feelings (ie, to get high) or that the user experienced certain feelings in the past.\n\nThe tweet expresses that the user has or is going to coingest a medication with other prescription medications or illicit drugs or alcohol or coffee (or other substances).\n\nThe tweet expresses a mechanism of intake that is typically associated with abuse or misuse.\n\n\n2. Non-abuse Consumption (C)\n\n\nThe user mentions side effects of the drug, but there is no implication that these are the result of misusing or abusing the drug.\n\nIn the tweet, the user expresses a want for the medication for a condition that matches its indicated use.\n\n\n3. Drug Mention Only (M)\n\n\nThe tweet conveys some information about the medication but contains no indication that the user is taking or wants to take the medication.\n\nThe mention of the medication is from a song, book or movie, or some other cultural reference.\n\nThe mention of the medication is being used in a joking or a hypothetical statement.\n\n\n4. Unrelated (U)\n\n\nThe only tweets that belong to this category are those that include a drug/medication name as keyword, but the keyword is referring to something else and not the drug/medication. It can be, for example, a person’s name or a misspelling of something else.\n\nFigure 1 Overview of the creation of the annotation guideline and the iterative annotation process.\n\nAutomatic Classification\nTo demonstrate the utility of the corpus for training systems for automatic classification of medication abuse–related Twitter chatter, we performed a set of supervised classification tasks. Our intent with these experiments was to illustrate that machine learning algorithms are trainable using this dataset and establish a set of baseline performance metrics that can be used as reference for future research. We split the annotated dataset into 2 at approximately 80:20 ratio and used the larger set (13,172/16,443, 80.11%) for training and the smaller set (3271/16,443, 19.89%) for evaluation.\n\nWe experimented with 4 classifiers—multinomial naive Bayes (NB), random forest (RF), support vector machines (SVM), and deep convolutional neural network (dCNN). Our extensive past work on social media mining for health research and social media text classification has demonstrated that identifying the best classification strategy requires elaborate experimentation and is best identified by means of community-driven efforts such as shared tasks [12]. Therefore, for the purposes of this study, we did not attempt to identify the optimal classification strategy or perform elaborate feature engineering. Instead, we optimized the specific classifier parameters using 10-fold cross validation over the training sets and only used basic features. For the first 3 classifiers, we used word n-grams (n=1-3) and word clusters [26] as features following basic preprocessing of the texts (lowercasing and stemming). For the dCNN classifier, we used a 3-layer network, and we further split the training set into approximately 80-20 splits and used the larger set for training and the smaller set for validation. We used pregenerated dense word vectors (embeddings) [28] for representing the tweets. All experiments were performed using Python sci-kit learn [29] (NB, RF, and SVM classifiers) and Google’s TensorFlow [30] (dCNN), and the results are presented in the next section.\n\nResults\nGuidelines and Annotation\nIn total, a sample of 16,443 tweets were selected for annotation from more than 1 million posts collected from April 2013 to July 2018. This rather arbitrary number of tweets resulted from the various filtering methods (eg, removing short tweets and undersampling tweets with stimulants) that we applied on a much larger random sample of about 50,000 tweets. Before undersampling, approximately three-quarters of the retrieved tweets mentioned stimulants, and only approximately one-fifth of them were kept following the sampling process. From this chosen set, 517 randomly selected tweets were used in the initial iterations for improving agreement and developing the guidelines. These were then adjudicated and added to the gold standard corpus. The rest of the corpus was split into 3 sets containing 15,405 (set 1), 8016 (set 2), and 6906 tweets (set 3). In addition, a fourth set contained overlapping tweets that were annotated by all 3 of the annotators (set 4). All these sets had an arbitrary number of overlapping tweets with at least one other set, which the annotators were not aware of during annotation. Pairwise IAA, measured using Cohen kappa [31], ranged from 0.681 to 0.971. For the set of tweets with more than two annotators, IAA was measured using Fleiss kappa [32] and was 0.904. IAA for the different sets are reported in Table 2. The final distribution of classes in the corpus, following the completion of the entire annotation process, was 2636 misuse or abuse (16.03%, 2133 in the training set, 503 in the evaluation set), 4587 consumption (27.90%, 3668 in the training set, 919 in the evaluation set), 8565 mention only (52.09%, 6843 in the training set, 1722 in the evaluation set), and 655 unrelated (3.98%, 528 in the training set, 127 in the evaluation set). Figure 2 shows the distribution of tweets and the classes per medication category in the entire collection. The training set tweet texts, along with other resources, will be made available with the final version of this paper [33]. Note that to preserve anonymity of the original posters of the tweets, we will add an additional layer of masking by reposting the tweet texts from our own Twitter profile and sharing the IDs of the tweets posted by this account, along with a download script (written in python). In addition to keeping the original posters anonymous, this method of data sharing will ensure long-term availability of the tweets. We will preserve the test/evaluation set for use in community-driven efforts such as shared tasks.\n\nAn analysis of the disagreements suggested that they were somewhat evenly distributed across the categories of interest. Over the first 3 sets, there were a total of 3631 disagreements among the annotators, 1082 (29.80%) were disagreements between abuse or mention classifications, 1160 (31.95%) were between abuse or consumption, 1186 (32.66%) were between consumption or mention, and the remaining 203 (5.59%) were disagreements between unrelated or all other categories. The analyses also showed that the disagreements did not result from the annotators’ incorrect interpretations of the guidelines but from their interpretations of the tweets. We, therefore, concluded that it was unlikely that we could further increase the IAA by updating or modifying the annotation guidelines.\n\nTable 2 Annotation agreement results.\n\nSet\tAnnotators\tTweets, n\tAgreement, n (%)\tIAAa\t\n1\tAN1+AU1\t15,405\t13,560 (88.02)\t0.815\t\n2\tAN1+AN2\t8016\t6414 (80.02)\t0.681\t\n3\tAU1+AN2\t6906\t6709 (97.15)\t0.953\t\n4\tAN1+AN2+AU1\t6906\t—c\t0.904b\t\naInterannotator agreement.\n\nbFleiss Kappa.\n\ncNot applicable.\n\nFigure 2 Distribution of tweets in the annotated corpus by annotation category and drug class.\n\nAutomatic Classification\nTable 3 presents the results of the classification experiments, showing the F1 scores per class, the overall accuracy, and 95% CIs for the accuracy. The RF and SVM classifiers particularly show promising performances, without any feature engineering or parameter tuning. The performance on the abuse class is particularly lower, as expected, because of the low number of instances belonging to this class.\n\nTable 3 Class-specific F1 scores, overall accuracy, and 95% CIs for the accuracy for 4 classifiers.\n\nClassifier\tAbuse\tConsumption\tMention\tUnrelated\tCorrect predictions and accuracy (N=3271), n (%)\t95% CI\t\nNBa\t0.51\t0.66\t0.77\t0.81\t2257 (69.00)\t67.4-70.6\t\nSVMb\t0.53\t0.67\t0.82\t0.78\t2388 (73.00)\t71.4-74.5\t\nRFc\t0.30\t0.66\t0.81\t0.79\t2352 (71.90)\t70.3-73.4\t\ndCNNd\t0.35\t0.64\t0.79\t0.16\t2355 (72.00)\t70.3-73.5\t\naNB: naive Bayes.\n\nbSVM: support vector machine.\n\ncRF: random forest.\n\nddCNN: deep convolutional neural network.\n\nDiscussion\nTweet Contents and Sources of Disagreements\nThe iterative process undertaken for our guideline development was crucial to concretize the definitions for each of the classes and identify sample tweets presenting a multiplicity of types of information for each class, and to reduce decision-making uncertainties among the annotators. Through the process, we raised IAA from 0.569 in the first round to a combined average of 0.861, which can be interpreted as an “almost perfect agreement” [34]. Though we were able to increase overall agreement with improvements to the guidelines, the short and context-lacking nature of many tweets makes it hard to eliminate disagreements entirely. There are many tweets that do not unambiguously meet the requirements stated as identifying markers so that they can be definitively categorized, and the annotators must rely on their background knowledge and judgment. Table 4 shows several examples of difficult-to-categorize tweets and the eventual category assigned following disagreement resolution, along with justification for it. A more detailed listing of these examples is provided in the full guidelines (Multimedia Appendix 1).\n\nTable 4 Examples of difficult-to-annotate instances.\n\nTweet\tCategory\tJustification\t\ngeneric xanax and adderall look way too alike. oh no what have i done...?\tCa\tThere is inexplicit evidence that the user took the medication, although there is no evidence of abuse.\t\nGoing by a restaurant before 10:30 and not stopping to get breakfast is how you know you're on Vyvanse\tC\tThere is inexplicit evidence that the user took the medication, although there is no evidence of abuse.\t\nif this tweet sticks i'll eat my shorts (made of adderall)\tAb\tThe user is expressing an intent to abuse, with an inexplicit indication that he/she has access to the medication.\t\ni always freak out before a speech, always... this is the part where i'm supposed to ask my gp for zoloft or roofies but nooo,\tMc\tThe user is expressing that he/she does not have access to the medication and expressing a situation.\t\ni swear vyvanse got you finishing things you didn't know you had to doo #justironedmysocks\tC\tThe tweet expresses the effect of Vyvanse more like a side effect, with no evidence or hint to indicate that the drug is being abused.\t\nso glad i did my research and never let anyone convince me to take tysabri or gilenya. dr. was so informative!\tM\tThe user is expressing that he or she never took the medication.\t\nvyvanse i love you so much omg like i want to marry you i want to love you\tC\tThe user is expressing love for Vyvanse, although never really expressing or hinting at possible abuse. If there was any hint of abuse, this tweet would be labeled as such.\t\ntook double dose vyvanse today by accident. i'mbouncinall around.\tA\tAlthough the misuse is unintentional, the user is expressing certain sensations brought about by the drug, so it was considered to be abuse-indicating. This is another borderline case.\t\naC: Non-abuse consumption.\n\nbA: Potential abuse or misuse.\n\ncM: Drug mention only.\n\nWe also performed a word-level analysis to better understand how the contents of the tweets belonging to the 4 classes differed, if at all. We found that the consumption tweets contain more health-related terms (eg, pain, anxiety, sleep, and doctor), whereas the unrelated tweets contain mostly irrelevant terms (eg, song, Anderson, and Hollywood). There are similarities in the word frequencies in the abuse or misuse and mention categories, indicating that discussion about abusing medications is not remarkably different from general discussions about the medications. This adds to the difficulty of accurately classifying the tweets belonging to the smaller abuse or misuse class.\n\nIn addition to the word-level similarities between the abuse or misuse and mention classes, the ambiguity in the language and the lack of context within the tweets leave them open to subjective interpretation, which affects the annotation process itself. These interpretations are troublesome when there can be multiple meanings in the clues that are present. For example, a tweet may have no explicit mention of abuse, but the use of certain keywords (eg, popped) or the situation may suggest that there might be misuse or abuse involved (possible abuse). However, it is not unreasonable that the use of such expressions would also be adopted by a patient taking their medication in the prescribed manner, making it difficult for the annotators to decide when it should be considered abuse and when it should be considered consumption. We sought to mitigate the effect of this uncertainty on the quality of the corpus by double, or even triple, annotating each tweet to achieve consensus.\n\nUtility of Annotation Guideline and Data\nThe key objective behind creating detailed annotation guidelines and making them publicly available is to ensure the reproducibility of the annotation experiments. This is of particular importance for health-related data, from public social media or other sources such as electronic health records, which may have restrictions on public sharing, requiring researchers from different institutions to annotate their own data. For example, Twitter requires researchers to make a reasonable effort to remove data that are no longer in the public sphere. Therefore, data used in the training and testing of corpora may not be available as time passes, as users may delete tweets or change the privacy settings of their profiles. For a task such as the one we address here, new data may need to be collected and annotated in the future by other researchers (eg, to have comparable training data or to have a sample size with enough power to effectively train a machine learning classifier). The same is true if tweets mentioning medications not included in our sample are to be annotated for the same purpose in the future. Having a thorough, standardized annotation guideline may guide future annotation efforts. Furthermore, making the guidelines generalizable to the task rather than the data allows the methods to be transferred to other sources of similar social media data, such as Reddit or Facebook, so comparisons can be made about the utility of each source.\n\nThe expansion of the classes did decrease the accuracy we achieved from our prior pilot study [26] in which we modeled the problem as a binary classification one and had obtained lower IAA. The higher IAA raises the performance ceiling for supervised classification systems on these data. We have presented a set of automatic classification experiments and results, and, interestingly, the SVM classifier outperforms the dCNN classifier. The deep learning system particularly underperforms on the classes with few instances, which is a phenomenon we have observed in past classification tasks. The optimal classification strategy for such social media–based datasets is typically discovered via community-driven efforts such as shared tasks [12], and our objective is to enable that with this dataset. The identification of prescribed consumers of the medications may allow us to identify those users who later exhibit signs of abusing or misusing the medication and also potentially study long-term effects of such behavior. We leave these tasks as future work. The identification of mentions only and unrelated tweets will allow us to develop better filtering methods to ensure that a higher quality corpus is used for data collection and analysis, thus reducing the potential for biases and misleading conclusions [35].\n\nPrincipal Findings\nThe principal findings and outcomes of the work described in this paper are summarized as follows:\n\nCreation of annotated data that will be used to promote community-driven research focusing on social media mining for prescription medication abuse research. We have made the manually labeled training data available with this manuscript, and the evaluation set will be used to evaluate systems via shared tasks [12].\n\nWe have provided elaborate descriptions about how prescription medication misuse or abuse is discussed on Twitter for a number of medications. Our detailed annotation guideline may be used by others to contribute more annotated datasets involving additional sets of medications.\n\nThe machine learning results mentioned in the paper present strong baseline and benchmark results for future systems trained and evaluated on this dataset.\n\nComparison With Prior Work\nA number of recent studies, including our preliminary studies on the topic [18,26,36], have explored the possibility of using social media for monitoring prescription medication abuse and have validated that it can serve as a potentially useful resource. Studies have suggested that reports of prescription medication misuse, including the use of specific formulations, temporal trends of abuse, and geolocation-based trends can potentially be discovered from social media—information that is not available from other sources because these are not voluntarily reported to health practitioners or agencies. Early studies have primarily attempted manual methods for qualitatively and quantitatively verifying the presence of abuse-related data from social media [18,37]. Later efforts attempted to automate the process of detection via NLP and machine learning approaches, or explore other aspects related to misuse (eg, user sentiments) [26,38]. Although there is consensus regarding the presence of valuable information in social media data, there is a lack of consistent methodologies for mining the information. Unsupervised approaches, for example, are suitable for analyzing data snapshots but not portable across time periods because of the evolving nature of the social media sphere. Due to the need for large training sets and the time and expense related to manually creating these datasets, weak supervision approaches have been explored as a means to create larger, albeit noisier, training data. However, these approaches may still require some labeled data or domain expertise to generate the data programming or feature labels [39,40]. The training data generated by these approaches may degenerate the performance over baseline approaches using only labeled data [41]. There is also a lack of publicly available annotated data that can be readily used by health informatics researchers to develop data-centric systems, or annotation standards using which consistent datasets can be built across institutions. Although supervised classification approaches have been shown to be promising for automatic detection of prescription medication abuse–related posts, the performances reported by systems are typically low for this task even when compared with other social media–based text classification tasks [26,42,43]. A contributing factor to these relatively low performances is the IAA rates that are typically low. For example, 2 recent papers reported IAA rates ranging from 0.45 to 0.46 for manual annotation [44,45] but no follow-up work to better define the annotation task or guidelines to improve the rates. We believe that the root of the problem of low agreement rates for this task is the lack of understanding or agreement regarding how users express medication abuse, or what constitutes misuse vs medical use. This problem does not exist, for example, in the task of illicit drug abuse annotation, in which any consumption can be regarded as abuse. In the case of prescription medications, it has to be determined if the drug is being consumed, and, if yes, if there is evidence of nonmedical consumption. The issue of such low agreement rates must be addressed for laying the foundations of long-term research on this topic and before releasing datasets for community-driven development of solutions. We attempt to address this as the primary focus of this paper by elaborately describing the chatter on Twitter, discussing annotation decisions and a guideline, and illustrating the utility of the developed corpus by presenting the results of several machine learning experiments.\n\nLimitations\nThe study has several limitations, particularly in terms of scope. Only Twitter data are included in this study and the accompanying dataset, although data on misuse or abuse are also available from other social networks such as Instagram and Reddit [46,47]. We have included 20 abuse-prone medications although in reality there are other medications and categories of medications that are also prone to misuse or abuse. In addition, our study did not include illicit drugs, which is another branch of social media–based drug abuse research that has received considerable attention over recent years. We included medication names (generic and trade) and their common misspellings, but we did not use any street names for data collection. Future research may focus on including more illicit medication and establish annotation guidelines relevant for them, similar to our work presented here. We also included only the tweets that were in the English language, which limits the use of these data for training systems for English text only. However, our guidelines may be followed by future researchers to create annotated datasets in other languages. From the perspective of demographic representation, social media users are different from the actual population, with a larger representation of young people than older people.\n\nConclusions\nIn this paper, we discussed how users present information about prescription medication abuse and consumption on Twitter, described the iterative annotation of a large corpus containing 16,443 tweets, outlined our annotation guidelines that we have made available along with this publication, and presented the performance of several baseline classifiers over a sample of the corpus to demonstrate its utility. In our annotation guideline, we identified and defined 4 possible broad categories of topics of discussion related to abuse-prone prescription medications: potential abuse or misuse, non-abuse consumption, mention only, and unrelated. The guidelines were improved over a series of iterations of annotation and reviewed until we reached an agreeable level of consistency in our annotations. Through this process, we created a high-quality annotated corpus that can serve as the standardized dataset for future research on the topic. We expect that our annotation strategy, guidelines, and dataset will provide a significant boost to community-driven data-centric approaches for the task of monitoring prescription medication misuse or abuse monitoring from Twitter. Considering the growing problem of drug abuse, social media–based research may provide important unprecedented insights about the problem and perhaps even enable the discovery of novel abuse-prone medications or medication combinations.\n\nResearch reported in this publication was supported by NIDA of the NIH under award number R01DA046619. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.\n\nAuthors' Contributions: KC led the annotation process and the guideline preparation, served as an annotator, and contributed to the writing of the manuscript. AS performed some annotation and disagreement resolution, conducted the classification experiments, and wrote significant portions of the manuscript. JP provided domain expertise for the study, finalized medications to be included, reviewed the guidelines, and contributed to the writing of the manuscript. GG provided high-level guidance to the project and contributed to the writing of the manuscript.\n\nConflicts of Interest: None declared.\n\nAppendix\nMultimedia Appendix 1 Full annotation guidelines.\n\n Abbreviations\ndCNNdeep convolutional neural network\n\nIAAinterannotator agreement\n\nNBnaive Bayes\n\nNIDANational Institute on Drug Abuse\n\nNIHNational Institutes of Health\n\nNLPnatural language processing\n\nRFrandom forest\n\nSVMsupport vector machine\n==== Refs\n1 Bennett WL The Personalization of Politics Ann Am Acad Pol Soc Sci 2012 644 1 20 39 10.1177/0002716212451428 \n2 Parganas P Anagnostopoulos C Chadwick S 'You’ll never tweet alone': Managing sports brands through social media J Brand Manag 2015 22 7 551 68 10.1057/bm.2015.32 \n3 Xu WW Chiu I Chen Y Mukherjee T Twitter hashtags for health: applying network and content analyses to understand the health knowledge sharing in a Twitter-based community of practice Qual Quant 2014 49 4 1361 80 10.1007/s11135-014-0051-6 \n4 Kennedy B Funk C Pew Research Center 2015 12 11 2019-03-16 Public Interest in Science and Health Linked to Gender, Age and Personalityhttps://www.pewresearch.org/science/2015/12/11/public-interest-in-science-and-health-linked-to-gender-age-and-personality/ \n5 Paul MJ Dredze M Broniatowski D Twitter improves influenza forecasting PLoS Curr 2014 10 28 6 pii: ecurrents.outbreaks.90b9ed0f59bae4ccaa683a39865d9117 10.1371/currents.outbreaks.90b9ed0f59bae4ccaa683a39865d9117 10.1371/currents.outbreaks.90b9ed0f59bae4ccaa683a39865d9117 25642377 \n6 Eichstaedt JC Smith RJ Merchant RM Ungar LH Crutchley P Preoţiuc-Pietro D Asch DA Schwartz HA Facebook language predicts depression in medical records Proc Natl Acad Sci U S A 2018 10 30 115 44 11203 8 10.1073/pnas.1802331115 30322910 30322910 \n7 de Choudhury M Sharma S Kiciman E Characterizing Dietary Choices, Nutrition, and Language in Food Deserts via Social Media Proceedings of the 19th ACM Conference on Computer-Supported Cooperative Work & Social 2016 2 CSCW'16 February 27–March 2, 2016 San Francisco, California, USA 1157 70 10.1145/2818048.2819956 \n8 Sarker A Ginn R Nikfarjam A O'Connor K Smith K Jayaraman S Upadhaya T Gonzalez G Utilizing social media data for pharmacovigilance: a review J Biomed Inform 2015 4 54 202 12 10.1016/j.jbi.2015.02.004 25720841 25720841 \n9 Paul MJ Dredze M Discovering health topics in social media using topic models PLoS One 2014 9 8 e103408 10.1371/journal.pone.0103408 25084530 25084530 \n10 Sarker A Gonzalez G Portable automatic text classification for adverse drug reaction detection via multi-corpus training J Biomed Inform 2015 2 53 196 207 10.1016/j.jbi.2014.11.002 25451103 25451103 \n11 Bobicev V Sokolova M Mouhoub M Langlais P Confused and thankful: multi-label sentiment classification of health forums Advances in Artificial Intelligence 2017 Cham Springer 284 9 \n12 Sarker A Belousov M Friedrichs J Hakala K Kiritchenko S Mehryary F Han S Tran T Rios A Kavuluru R de Bruijn B Ginter F Mahata D Mohammad S Nenadic G Gonzalez-Hernandez G Data and systems for medication-related text classification and concept normalization from Twitter: insights from the Social Media Mining for Health (SMM4H)-2017 shared task J Am Med Inform Assoc 2018 10 1 25 10 1274 83 10.1093/jamia/ocy114 30272184 30272184 \n13 Ritter A Cherry C Dolan WB Data-Driven Response Generation in Social Media Proceedings of the 2011 Conference on Empirical Methods in Natural Language Processing 2011 EMNLP'11 July 27–31, 2011 Edinburgh, Scotland, UK 583 93 \n14 Morlane-Hon F Grouin C Zweigenbaum P Identification of Drug-Related Medical Conditions in Social Media Proceedings of the Tenth International Conference on Language Resources and Evaluation 2016 LREC'16 23-28 May, 2016 Portorož, Slovenia 2022 8 \n15 Segura-Bedmar I Martínez P Revert R Moreno-Schneider J Exploring Spanish health social media for detecting drug effects BMC Med Inform Decis Mak 2015 15 Suppl 2 S6 10.1186/1472-6947-15-S2-S6 26100267 \n16 Kolodny A Frieden TR Ten steps the federal government should take now to reverse the opioid addiction epidemic J Am Med Assoc 2017 10 24 318 16 1537 8 10.1001/jama.2017.14567 29049522 \n17 Hanson CL Cannon B Burton S Giraud-Carrier C An exploration of social circles and prescription drug abuse through Twitter J Med Internet Res 2013 9 6 15 9 e189 10.2196/jmir.2741 24014109 24014109 \n18 Shutler L Nelson LS Portelli I Blachford C Perrone J Drug Use in the Twittersphere: A Qualitative Contextual Analysis of Tweets About Prescription Drugs J Addict Dis 2015 34 4 303 10 10.1080/10550887.2015.1074505 26364675 26364675 \n19 Substance Abuse and Mental Health Services Administration 2013 2 13 2020-01-03 Highlights of the 2011 Drug Abuse Warning Network (DAWN) Findings on Drug-Related Emergency Department Visitshttps://www.samhsa.gov/data/sites/default/files/DAWN127/DAWN127/sr127-DAWN-highlights.htm \n20 National Institute on Drug Abuse 2016 2020-01-03 Misuse of Prescription Drugshttps://www.drugabuse.gov/publications/misuse-prescription-drugs/overview \n21 Drug Enforcement Administration 2016 11 1 2020-01-03 2016 National Drug Threat Assessment Summaryhttps://www.dea.gov/documents/2016/11/01/2016-national-drug-threat-assessment \n22 Centers for Disease Control and Prevention 2015 2020-01-03 National Vital Statistics System: Mortality Datahttps://www.cdc.gov/nchs/nvss/deaths.htm \n23 Centers for Disease Control and Prevention 2016 2020-01-03 Wide-ranging Online Data for Epidemiologic Research (WONDER)https://healthdata.gov/dataset/wide-ranging-online-data-epidemiologic-research-wonder \n24 Vowles KE McEntee ML Julnes PS Frohe T Ney JP van der Goes DN Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis Pain 2015 4 156 4 569 76 10.1097/01.j.pain.0000460357.01998.f1 25785523 25785523 \n25 Sarker A Gonzalez-Hernandez G An unsupervised and customizable misspelling generator for mining noisy health-related text sources J Biomed Inform 2018 12 88 98 107 10.1016/j.jbi.2018.11.007 30445220 30445220 \n26 Sarker A O'Connor K Ginn R Scotch M Smith K Malone D Gonzalez G Social Media Mining for Toxicovigilance: Automatic Monitoring of Prescription Medication Abuse from Twitter Drug Saf 2016 3 39 3 231 40 10.1007/s40264-015-0379-4 26748505 26748505 \n27 Martin PY Turner BA Grounded theory and organizational research J Appl Behav Sci 1986 22 2 141 57 10.1177/002188638602200207 \n28 Sarker A Gonzalez G A corpus for mining drug-related knowledge from Twitter chatter: Language models and their utilities Data Brief 2017 2 10 122 31 10.1016/j.dib.2016.11.056 27981203 27981203 \n29 Pedregosa F Varoquaux G Gramfort A Michel V Thirion B Scikit-learn: Machine Learning in Python J Mach Learn Res 2011 12 2011 2825 30 \n30 Abadi M Barham P Chen J Chen Z Davis A Dean J Devin M Ghemawat S Irving G Isard M Kudlur M Levenberg J Monga R Moore S Murray DG Steiner B Tucker P Vasudevan V Warden P Wicke M Yu Y Zheng X TensorFlow: A System for Large-scale Machine Learning Proceedings of the 12th USENIX Symposium on Operating Systems Design and Implementation 2016 OSDI’16 November 2–4, 2016 Savannah, GA, USA 265 83 \n31 Cohen J A coefficient of agreement for nominal scales Educ Psychol Meas 1960 20 1 37 46 10.1177/001316446002000104 \n32 Fleiss JL Measuring nominal scale agreement among many raters Psychol Bull 1971 76 5 378 82 10.1037/h0031619 \n33 Sarker A Sarker Lab 2019-12-24 PM Abuse Data – JMIRhttps://sarkerlab.org/pm_abuse_data/ \n34 Viera AJ Garrett JM Understanding interobserver agreement: the kappa statistic Fam Med 2005 5 37 5 360 3 15883903 15883903 \n35 Kim Y Huang J Emery S Garbage In, Garbage Out: data collection, quality assessment and reporting standards for social media data use in health research, infodemiology and digital disease detection J Med Internet Res 2016 2 26 18 2 e41 10.2196/jmir.4738 26920122 26920122 \n36 Hanson CL Burton SH Giraud-Carrier C West JH Barnes MD Hansen B Tweaking and tweeting: exploring Twitter for nonmedical use of a psychostimulant drug (Adderall) among college students J Med Internet Res 2013 4 17 15 4 e62 10.2196/jmir.2503 23594933 23594933 \n37 Davey Z Schifano F Corazza O Deluca P Psychonaut Web Mapping Group e-Psychonauts: conducting research in online drug forum communities J Ment Health 2012 8 21 4 386 94 10.3109/09638237.2012.682265 22823094 22823094 \n38 Daniulaityte R Chen L Lamy FR Carlson RG Thirunarayan K Sheth A ' When 'Bad' is 'Good' ': identifying personal communication and sentiment in drug-related tweets JMIR Public Health Surveill 2016 10 24 2 2 e162 10.2196/publichealth.6327 27777215 27777215 \n39 Ratner A De Sa C Wu S Selsam D Ré C Data Programming: creating large training sets, quickly Adv Neural Inf Process Syst 2016 29 3567 75 29872252 \n40 Bringer E Israeli A Ratner A Ré C Osprey: Weak Supervision of Imbalanced Extraction Problems without Code ACM Reference Format Proceedings of the 3rd International Workshop on Data Management for End-to-End Machine 2019 DEEM'19 June 30, 2019 Amsterdam, Netherlands ACM 1 11 10.1145/3329486.3329492 \n41 Li Y Guo L Zhou Z Towards safe weakly supervised learning IEEE Trans Pattern Anal Mach Intell 2019 6 12 - 10.1109/TPAMI.2019.2922396 31199253 \n42 Jenhani F Gouider MS Said LB A hybrid approach for drug abuse events extraction from Twitter Procedia Computer Science 2016 96 1032 40 10.1016/j.procs.2016.08.121 \n43 McNaughton EC Black RA Zulueta MG Budman SH Butler SF Measuring online endorsement of prescription opioids abuse: an integrative methodology Pharmacoepidemiol Drug Saf 2012 10 21 10 1081 92 10.1002/pds.3307 22777908 22777908 \n44 Bigeard E Grabar N Thiessard F Detection and analysis of drug misuses. A study based on social media messages Front Pharmacol 2018 9 791 10.3389/fphar.2018.00791 10.3389/fphar.2018.00791 30140224 30140224 \n45 Anderson LS Bell HG Gilbert M Davidson JE Winter C Barratt MJ Win B Painter JL Menone C Sayegh J Dasgupta N Using social listening data to monitor misuse and nonmedical use of Bupropion: a content analysis JMIR Public Health Surveill 2017 2 1 3 1 e6 10.2196/publichealth.6174 28148472 28148472 \n46 Pandrekar S Chen X Gopalkrishna G Srivastava A Saltz M Saltz J Wang F Social media based analysis of opioid epidemic using Reddit AMIA Annu Symp Proc 2018 2018 867 76 30815129 30815129 \n47 Cherian R Westbrook M Ramo D Sarkar U Representations of codeine misuse on instagram: Content analysis JMIR Public Health Surveill 2018 3 20 4 1 e22 10.2196/publichealth.8144 29559422 29559422\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1438-8871",
"issue": "22(2)",
"journal": "Journal of medical Internet research",
"keywords": "infodemiology; infoveillance; machine learning; natural language processing; prescription drug misuse; social media; substance abuse detection",
"medline_ta": "J Med Internet Res",
"mesh_terms": "D003625:Data Collection; D017408:Guidelines as Topic; D006801:Humans; D055553:Prescription Drugs; D061108:Social Media",
"nlm_unique_id": "100959882",
"other_id": null,
"pages": "e15861",
"pmc": null,
"pmid": "32130117",
"pubdate": "2020-02-26",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "26100267;25785523;22777908;25084530;28148472;26748505;25642377;31199253;25720841;29559422;30322910;25451103;22823094;30272184;26364675;30815129;27777215;30445220;15883903;24014109;29872252;26920122;27981203;30140224;29049522;23594933",
"title": "Promoting Reproducible Research for Characterizing Nonmedical Use of Medications Through Data Annotation: Description of a Twitter Corpus and Guidelines.",
"title_normalized": "promoting reproducible research for characterizing nonmedical use of medications through data annotation description of a twitter corpus and guidelines"
} | [
{
"companynumb": "US-OTSUKA-2020_012518",
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"activesubstancename": "ARIPIPRAZOLE"
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... |
{
"abstract": "Pediatric-onset multiple sclerosis (MS) has a highly active and aggressive course, which can have a devastating effect on the physical and cognitive functioning of a child if not treated appropriately with effective disease-modifying drugs. The optimal treatment strategy of pediatric MS is currently unknown and debate continues as to whether treatment escalation or initiation of a highly active therapy provides a better outcome. Here, we present the case of a 16-year-old female diagnosed with highly active relapsing-remitting MS (age at onset: 14 years) who received first-line treatment with fingolimod within 1 year of the first recorded symptom. Since starting fingolimod, the course of the disease has essentially been stable. No new or active lesions were observed in magnetic resonance imaging scans performed at 3 and 12 months after starting fingolimod, and treatment was well tolerated. These data suggest that, in this case, early treatment with first-line fingolimod was able to slow disease progression.",
"affiliations": "Department of Neurology and Regional Referral Multiple Sclerosis Centre, University-Hospital San Luigi, Orbassano, Italy. mcapobianco1972@gmail.com.;Department of Neurology and Regional Referral Multiple Sclerosis Centre, University-Hospital San Luigi, Orbassano, Italy.;Department of Neurology and Regional Referral Multiple Sclerosis Centre, University-Hospital San Luigi, Orbassano, Italy.",
"authors": "Capobianco|Marco|M|http://orcid.org/0000-0003-2501-2932;Bertolotto|Antonio|A|;Malucchi|Simona|S|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride",
"country": "Italy",
"delete": false,
"doi": "10.1007/s10072-020-05027-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-1874",
"issue": "42(Suppl 1)",
"journal": "Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology",
"keywords": "Disease progression; Fingolimod; First-line treatment; Pediatric-onset multiple sclerosis",
"medline_ta": "Neurol Sci",
"mesh_terms": "D000293:Adolescent; D002648:Child; D018450:Disease Progression; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents; D008279:Magnetic Resonance Imaging; D009103:Multiple Sclerosis; D020529:Multiple Sclerosis, Relapsing-Remitting; D016896:Treatment Outcome",
"nlm_unique_id": "100959175",
"other_id": null,
"pages": "25-28",
"pmc": null,
"pmid": "33712907",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25680425;29157395;29523094;25142460;25878006;19139299;17582070;23155206;31913090;22146610;27572855;30333163;30207920;31467033",
"title": "Fingolimod as first-line treatment in pediatric-onset multiple sclerosis: a case report.",
"title_normalized": "fingolimod as first line treatment in pediatric onset multiple sclerosis a case report"
} | [
{
"companynumb": "IT-MYLANLABS-2021M1059989",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FINGOLIMOD"
},
"drugadditional": "3",
... |
{
"abstract": "The potent immunosuppressive drugs used by transplant recipients place them at risk of infections. Data on infective endocarditis (IE) in the setting of renal transplantation (RT) are sparse. We describe a 36-year-old woman referred to a tertiary medical center for evaluation of elevated creatinine levels 1 month after a second RT. Work-up revealed the presence of all four of Duke's criteria: fever, persistent bacteremia, new-onset tricuspid regurgitation, and masses suspected to be vegetation attached to the tricuspid annulus. Symptoms resolved with antibiotic treatment and fluids. Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) revealed hypermetabolic absorption in the femoral vascular graft that had been used for hemodialysis prior to transplantation. The graft was removed by open surgery, and the patient was discharged home in good condition with continued antibiotic treatment. Review of the literature yielded 73 previously reported cases of IE in renal transplant recipients. Several differences were noted from IE in the general population: lower male predominance, younger age (<60 years), absence in most cases of a preexisting structural cardiac anomaly, and more variable causative pathogens. Our case also highlights the importance of FDG-PET/CT for detecting the source of IE and alerts clinicians to the sometimes unexpected course of the disease in renal transplant recipients.",
"affiliations": "Department of Internal Medicine F (Recanati), Rabin Medical Center-Beilinson, Petach Tikva, Israel.;Department of Internal Medicine F (Recanati), Rabin Medical Center-Beilinson, Petach Tikva, Israel.;Department of Internal Medicine F (Recanati), Rabin Medical Center-Beilinson, Petach Tikva, Israel.;Department of Internal Medicine F (Recanati), Rabin Medical Center-Beilinson, Petach Tikva, Israel.",
"authors": "Nardi Agmon|Inbar|I|http://orcid.org/0000-0001-7995-789X;Goldberg|Elad|E|;Cohen|Eytan|E|;Krause|Ilan|I|",
"chemical_list": "D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12786",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "19(6)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "graft infection; infective endocarditis; renal transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D001807:Blood Vessel Prosthesis; D004697:Endocarditis, Bacterial; D005260:Female; D005263:Femoral Artery; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D000072078:Positron Emission Tomography Computed Tomography; D016459:Prosthesis-Related Infections; D019275:Radiopharmaceuticals; D006435:Renal Dialysis",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28981185",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Infective endocarditis in the setting of renal transplantation: Case report and review of the literature.",
"title_normalized": "infective endocarditis in the setting of renal transplantation case report and review of the literature"
} | [
{
"companynumb": "IL-ASTELLAS-2018US006112",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "De novo malignancy, including primary lung cancer, is one of the limitations to long-term survival after liver transplantation. The purpose of this study was to describe patients who developed de novo lung cancer after living-donor liver transplantation (LDLT) and investigate their clinicopathological features as well as the feasibility of surgical resection.\n\n\n\nWe investigated 554 patients who underwent LDLT.\n\n\n\nDe novo lung cancer after LDLT was observed in five (0.9%) out of 554 studied patients: four men and one woman, aged 61-78 years (mean=67 years). All four men had a smoking history. Clinical stages of de novo lung cancer were stage IA in three patients, and stage IB and IV in one patient each. Three out of five patients underwent pulmonary lobectomy and pathological stage was IA in two patients and IIA in one. All patients who underwent surgery stopped immunosuppressive therapy 1 day preoperatively and restarted on postoperative day 1. There were no serious postoperative complications. All three patients are still alive without any recurrence, with survival ranging from 8 to 29 months, with an average of 16.3 months after diagnosis of lung cancer.\n\n\n\nAlthough the study population was small, these results suggest that pulmonary lobectomy of de novo lung cancer after LDLT, even under immunosuppressive conditions, is a feasible procedure and may yield a survival benefit.",
"affiliations": "Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan fshoji@surg2.med.kyushu-u.ac.jp.;Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.",
"authors": "Shoji|Fumihiro|F|;Toyokawa|Gouji|G|;Harada|Noboru|N|;Itoh|Shinji|S|;Harimoto|Norifumi|N|;Ikegami|Toru|T|;Okamoto|Tatsuro|T|;Soejima|Yuji|Y|;Yoshizumi|Tomoharu|T|;Maehara|Yoshihiko|Y|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.11608",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "37(5)",
"journal": "Anticancer research",
"keywords": "De novo lung cancer; living-donor liver transplantation; surgical resection",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D019520:Living Donors; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "2619-2623",
"pmc": null,
"pmid": "28476836",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Surgical Treatment and Outcome of Patients with De Novo Lung Cancer After Liver Transplantation.",
"title_normalized": "surgical treatment and outcome of patients with de novo lung cancer after liver transplantation"
} | [
{
"companynumb": "JP-MYLANLABS-2017M1042252",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "We report effective treatment with nivolumab of a patient with recurrent primary central nervous system lymphoma (PCNSL) after multiple therapies. A 41-year-old woman with a right parietal PCNSL underwent treatment with high-dose methotrexate and radiotherapy. After recurrence in the left frontal lobe, the patient received several chemotherapies, including methotrexate and rituximab, and underwent surgery. The tumor was refractory to these treatments, and the patient then underwent intensity-modulated radiotherapy (IMRT). Multiple small, new recurrent tumors appeared in the right frontal lobe and the left frontoparietal region 2 months after IMRT. The patient received nivolumab 3 mg/kg with dendritic cell vaccination. Complete remission of the tumors was achieved after six cycles of nivolumab, and remission was maintained for 10 months after the initiation of nivolumab. Nivolumab could be a novel treatment for intractable recurrent PCNSL in the future.",
"affiliations": "Department of Neurosurgery, Osaka Medical College.;Department of Neurosurgery, Osaka Medical College.;Department of Neurosurgery, Osaka Medical College.;Department of Neurosurgery, Kitano Hospital, Tazuke Kofukai Medical Research Institute.;Department of Neurosurgery, Kitano Hospital, Tazuke Kofukai Medical Research Institute.;Saisei Mirai Medical Corporation.;Department of Neurosurgery, Osaka Medical College.;Department of Pathology, Osaka Medical College.;Department of Neurosurgery, Osaka Medical College.",
"authors": "Furuse|Motomasa|M|;Nonoguchi|Naosuke|N|;Omura|Naoki|N|;Shirahata|Mitsuaki|M|;Iwasaki|Koichi|K|;Inui|Toshio|T|;Kuroiwa|Toshihiko|T|;Kuwabara|Hiroko|H|;Miyatake|Shin-Ichi|SI|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000077594:Nivolumab",
"country": "Japan",
"delete": false,
"doi": "10.2176/nmc.cr.2016-0330",
"fulltext": "\n==== Front\nNeurol Med Chir (Tokyo)Neurol. Med. Chir. (Tokyo)NMCNeurologia medico-chirurgica0470-81051349-8029The Japan Neurosurgical Society 2833110110.2176/nmc.cr.2016-0330nmc-57-191Case ReportImmunotherapy of Nivolumab with Dendritic Cell Vaccination Is Effective against Intractable Recurrent Primary Central Nervous System Lymphoma: A Case Report FURUSE Motomasa 1NONOGUCHI Naosuke 1OMURA Naoki 1SHIRAHATA Mitsuaki 2IWASAKI Koichi 2INUI Toshio 3KUROIWA Toshihiko 1KUWABARA Hiroko 4MIYATAKE Shin-Ichi 11 Department of Neurosurgery, Osaka Medical College, Takatsuki, Osaka, Japan2 Department of Neurosurgery, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Osaka, Japan3 Saisei Mirai Medical Corporation, Moriguchi, Osaka, Japan4 Department of Pathology, Osaka Medical College, Takatsuki, Osaka, JapanAddress reprint requests to: Shin-Ichi Miyatake, MD, PhD, Department of Neurosurgery, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka 569-8686, Japan. e-mail: neu070@osaka-med.ac.jp4 2017 23 3 2017 57 4 191 197 \n22\n 12 \n2016\n \n02\n 2 \n2017\n © 2017 The Japan Neurosurgical Society2017This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/We report effective treatment with nivolumab of a patient with recurrent primary central nervous system lymphoma (PCNSL) after multiple therapies. A 41-year-old woman with a right parietal PCNSL underwent treatment with high-dose methotrexate and radiotherapy. After recurrence in the left frontal lobe, the patient received several chemotherapies, including methotrexate and rituximab, and underwent surgery. The tumor was refractory to these treatments, and the patient then underwent intensity-modulated radiotherapy (IMRT). Multiple small, new recurrent tumors appeared in the right frontal lobe and the left frontoparietal region 2 months after IMRT. The patient received nivolumab 3 mg/kg with dendritic cell vaccination. Complete remission of the tumors was achieved after six cycles of nivolumab, and remission was maintained for 10 months after the initiation of nivolumab. Nivolumab could be a novel treatment for intractable recurrent PCNSL in the future.\n\nimmunotherapynivolumabPCNSLrecurrence\n==== Body\nIntroduction\nPrimary central nervous system lymphoma (PCNSL) is a brain tumor sensitive to chemotherapy and radiotherapy. Methotrexate (MTX)-based chemotherapy is a first-line therapy for PCNSL. High-dose methotrexate (HD-MTX) followed by radiotherapy has high response rates.1,2) However, PCNSL always relapses after chemo-radiotherapy, and no treatment has had convincing beneficial effects on recurrent PCNSL. Median survival after recurrence is 14 months, even with salvage therapy.3) Recurrent PCNSL is one of the intractable brain tumors refractory to any treatment and still has a poor prognosis.\n\nImmunotherapy of cancer by programmed cell death-1 (PD-1) and PD-1 ligand (PD-L1) blockade has attracted attention and led to an expectation of a breakthrough cancer treatment. Nivolumab has already been approved by the Food and Drug Administration for melanoma, lung cancer, renal cell carcinoma, and Hodgkin’s lymphoma.4–9) The efficacy of nivolumab for central nervous system malignancy is unknown.\n\nWe observed that multiple recurrent tumors underwent complete remission in a patient with recurrent PCNSL after multiple treatments with nivolumab. Our patient also had dendritic cell vaccination while concurrently receiving nivolumab. We report this case here, with a discussion of the possibility of cancer immunotherapy for PCNSL.\n\nCase Report\nA 41-year-old woman with a right parietal tumor (Fig. 1A) underwent surgery with a diagnosis of PCNSL. The tumor recurred soon after the surgery, and the patient had two courses of HD-MTX therapy. The patient received whole-brain radiotherapy after HD-MTX therapy because the tumor did not respond to HD-MTX and progressed. The tumor had been completely remitted after radiotherapy for 2.5 years (Fig. 1B). The patient had a relapse of the tumor in the left frontal lobe without a local recurrence of the original tumor (Figs. 1C and 1C′) and received multiple sessions of chemotherapy with several combinations, including rituximab, cytarabine, and MTX with peripheral blood stem-cell transfusion, and cyclophosphamide-hydroxydaunorubicine-vincristine-prednisolone (CHOP) with MTX. The patient also had arterial infusion of carboplatin plus melphalan or carboplatin plus MTX in combination with intravenous infusion of rituximab. All of these chemotherapies failed to control the tumor, and the patient underwent surgery again followed by brentuximab. Although the tumor was grossly totally resected, it soon relapsed again (Fig. 1D). The patient then underwent intensity-modulated radiotherapy (IMRT) and the tumor went into remission. Two months later, multiple small, new tumors appeared in the right frontal lobe and the left frontoparietal region (Fig. 2A, white arrows). The patient started to receive nivolumab 3 mg/kg with and sometimes without dendritic cell vaccination. The patient underwent nivolumab at her own expense in the private practice clinic (Saisei Mirai Medical Corporation) with sufficient informed consent. The multiple small, new tumors were completely remitted after six cycles of nivolumab (Fig. 2B). After four more cycles, magnetic resonance images taken 7 months after IMRT showed a contrast-enhanced lesion adjacent to the left frontal horn of the lateral ventricle (Fig. 3A), and the patient showed a personality change. 11C-methionine positron emission tomography (PET) revealed low uptake of methionine in this lesion, which indicated radiation necrosis (Fig. 3B). A single dose of bevacizumab 5 mg/kg was administered for symptomatic radiation necrosis. Complete remission was still maintained 10 months after initiation of nivolumab with dendritic cell vaccination (Fig. 3C).\n\nDiscussion\nChemotherapy including MTX at a dose of 3 to 8 mg/m2 is recommended as first-line treatment for PCNSL.1,10–12) The CHOP regimen, with or without rituximab, which is one of the standard treatments for extracranial non-Hodgkin’s lymphoma, is not effective against PCNSL because it is difficult for these agents to penetrate the blood–brain barrier. PCNSL is a radio-sensitive tumor, and therefore radiation therapy plays an important role in its treatment. However, the tumor always relapses after radiation therapy, and after recurrence, there is no effective therapy for PCNSL. Rechallenge with HD-MTX is still effective against recurrent tumors in patients who responded to initial HD-MTX.13) In cases with relapse after radiation therapy, however, rechallenge with MTX after radiation therapy can carry a risk of leukoencephalopathy, which causes impairment of cognition because irradiation alters the distribution kinetics of MTX in the brain.14) Temozolomide is one of the anticancer drugs that is expected to be effective against PCNSL, and clinical trials have already been performed to test the efficacy of temozolomide for recurrent PCNSL.15,16)\n\nImmune checkpoint inhibitors are expected to be novel treatments for many cancers. Tumor cells express PD-L1 to bind PD-1 on T cells to escape the immune response. Therefore, PD-L1 should be the key molecule of this treatment strategy. It has been reported that PD-L1 expression on tumor cells is correlated with an objective response to nivolumab.17) We anticipated that the tumor cells in our patient should express PD-L1 abundantly. Figure 4 shows the results of immunohistochemistry (IHC) in this patient. IHC using anti-cluster of differentiation (CD)20 antibody showed strong positive staining, demonstrating the nature of this PCNSL as diffuse large B-cell lymphoma (DLBCL) (Fig. 4A″). Figure 4C shows that the strong immune staining of PD-L1 was confirmed in the trophoblastic membrane of human placenta as positive control, showing that this IHC assay worked well. On the other hand, PD-L1 was not expressed on tumor cells in the surgical specimen of our patient, but it was markedly expressed on macrophages, which were stained by CD 68 (data not shown) in the granulomatous tissue around the tumor (Figs. 4A′ and B′).\n\nAccording to published reports, PD-L1 expression on tumor cells and immune cells in tumor tissue may predict the response to anti-PD-1/PD-L1 immunotherapy.18) In metastatic bladder cancer, PD-L1 expression on immune cells in tumor tissue is the most predictive of the response to an anti-PD-L1 antibody.19) A meta-analysis in melanoma, lung, and genitourinary cancers showed that an objective response rate to nivolumab was 22.9% in tumors without PD-L1 expression on tumor cells.20) With regard to DLBCL, an objective response rate was 36%, although PD-L1 did not express on tumor cells in all patients from whom tissue sample was obtained for IHC analysis.21) However, PD-L1 expressed on nonmalignant immune cells within the tumor microenvironment in these patients. PD-L1 positive immune cells may be responsible for tumor response to nivolumab in PD-L1 negative tumors which respond to nivolumab. A possible hypothesis in our patient is that PD-L1 on tumor-associated macrophages binds to PD-1 on T cells to inactivate T cell–mediated immunity. Nivolumab may suppress this PD-L1–PD-1 interaction, and consequently T cells are activated, resulting in attacking tumor cells.\n\nDuring the treatment with nivolumab, the enhanced lesion appeared in the region located in the re-irradiated tumor in spite of maintaining complete remission in new lesions. We diagnosed this lesion as radiation necrosis on the basis of 11C-methionine PET, and low-dose bevacizumab was administered to treat the radiation necrosis, because this frontal enhanced lesion was symptomatic. We considered that amino acid PET was reliable to distinguish radiation necrosis from tumor recurrence, and low-dose bevacizumab was effective on radiation necrosis.22–24) Although we thought that the tumor was not recurred after initiation of nivolumab so far, it should be noted that a case report showed effectiveness of bevacizumab on recurrent PCNSL.25) Although we experienced only one effective case, nivolumab should be considered as alternative treatment strategy for recurrent PCNSL which is refractory to other treatments. Also vigorous study is necessary regarding PD-L1 and PD-1 expression on PCNSL.\n\nDendritic cell vaccination is a cancer immunotherapy that dendritic cells which are cultured and loaded with tumor antigen ex vivo activate T-cell to attack tumor cells by presenting tumor antigen. Dendritic cell vaccination has been already tested for some of cancers in clinical trials.26) The results of these trials were not conclusive, but encouraging further study. Treatment effect to combine nivolumab with dendritic cell vaccination is unknown. Inhibition of immune checkpoint by nivolumab and induction of tumor-specific effector T-cells by dendritic cell vaccination are theoretically reasonable combined cancer immunotherapy. A clinical trial of nivolumab with dendritic cell vaccines is now ongoing for recurrent brain tumors (AVERT trial, NCT02529072). It is to be hoped that clinical trials including AVERT trial will clarify probability of cancer immunotherapy for intractable brain tumors, especially in recurrent PCNSL.\n\nConclusion\nImmunotherapy of nivolumab with dendritic cell vaccination is expected to be a novel treatment for intractable recurrent PCNSL. Recurrent tumors were completely remitted after nivolumab treatment, although PD-L1 was expressed not on tumor cells but on tumor-associated macrophages in our patient. The correlation between IHC of PD-L1 and the response to nivolumab in PCNSL should be elucidated. The optimal dose and duration of nivolumab should also be clarified in further study, because nivolumab is very expensive, and continuation of a useless treatment puts a burden on patients and medical insurance. Dendritic cell vaccination theoretically reinforces effects of nivolumab on tumors and the synergistic effect of nivolumab and dendritic cell vaccination should also be elucidated.\n\nAcknowledgment\nWe thank Drs. Lakshmi Nayak and David Reardon of the Dana-Farber Cancer Institute, Harvard Medical School, the former for her excellent talk at the Asian Society of Neuro-Oncology 2016 in Sydney and the latter for fruitful discussion of the mechanism of the effectiveness of nivolumab for this case at Society of Neuro-Oncology 2016 in Scottsdale. This work was partly supported by a Grant-in-Aid for Scientific Research (C) (26462222) given to M.F. from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.\n\nConflicts of Interest Disclosure\n\nThe authors report no conflicts of interest concerning materials used in this case report.\n\nFig. 1 The patient had a right parietal mass at onset of PCNSL (A). The tumor was completely remitted after two cycles of high-dose methotrexate therapy and whole-brain radiotherapy (B). The tumor recurred in the left frontal lobe without local recurrence of the right parietal tumor 2.5 years after radiotherapy (C and C’). The tumor progressed in spite of multiple sessions of chemotherapy and surgical resection (D).\n\nFig. 2 The left frontal tumor responded to intensity-modulated radiotherapy, but multiple small, new tumors appeared in the right frontal lobe and the left frontoparietal region (white arrows) (A). The multiple small, new tumors were completely remitted after nivolumab and dendritic cell vaccination (B).\n\nFig. 3 A new enhancing lesion appeared in the left frontal lobe 7 months after intensity-modulated radiotherapy, but the multiple small, new tumors were still in remission (A). 11C-methionine-PET revealed low uptake of the tracer in this enhancing lesion (B). This lesion was diagnosed as radiation necrosis on the basis of PET findings. Complete remission was maintained 10 months after initiation of nivolumab and dendritic cell vaccination with a single dose of bevacizumab (C).\n\nFig. 4 Results of hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) of surgical specimen. A, A′, and A″ are ×40 magnification and show almost the identical photomicrograph field. H&E stain shows tumor cells with granulomatous tissue and infiltrating macrophages (A). Anti-PD-L1 IHC shows that macrophages in granulomatous tissue are positively stained (A′), and tumor cells that are stained by anti-CD 20 IHC (A″) are not stained by anti-PD-L1 IHC. B and B′ are higher-powered (×200) photomicrographs showing H&E staining and anti-PD-L1 IHC of the granulomatous field of A, A′, and A″. Oval tumor cells are not stained by anti-PD-L1 IHC (B′). IHC of human placenta shows that the trophoblastic membrane is stained as positive control for PD-L1 expression (C, ×20). Immunostaining was performed with a BOND-MAX autoimmunostainer (Leica Microsystems, Wetzlar, Germany). Deparaffinized and rehydrated sections were subjected to endogenous peroxidase blocking. After heating in antigen unmasking solution, the slides were incubated with PD-L1 (E1L3N, Cell Signaling Technology, Danvers, MA, USA) or with CD20 (L26, Dako, Santa Clara, CA, USA). Color development was performed with DAB, and the slides were counterstained with hematoxylin. Placental tissues were used as positive controls, and procedures without a primary antibody were used as negative controls.\n==== Refs\nReferences\n1) \nGlass J Gruber ML Cher L Hochberg FH : \nPreirradiation methotrexate chemotherapy of primary central nervous system lymphoma: Long-term outcome . \nJ Neurosurg \n81 : \n188 –\n195 , \n1994 \n8027800 \n2) \nHiraga S Arita N Ohnishi T Kohmura E Yamamoto K Oku Y Taki T Sato M Aozasa K Yoshimine T : \nRapid infusion of high-dose methotrexate resulting in enhanced penetration into cerebrospinal fluid and intensified tumor response in primary central nervous system lymphomas . \nJ Neurosurg \n91 : \n221 –\n230 , \n1999 \n10433310 \n3) \nReni M Ferreri AJ Villa E : \nSecond-line treatment for primary central nervous system lymphoma . \nBr J Cancer \n79 : \n530 –\n534 , \n1999 \n10027325 \n4) \nRobert C Long GV Brady B Dutriaux C Maio M Mortier L Hassel JC Rutkowski P McNeil C Kalinka-Warzocha E Savage KJ Hernberg MM Lebbe C Charles J Mihalcioiu C Chiarion-Sileni V Mauch C Cognetti F Arance A Schmidt H Schadendorf D Gogas H Lundgren-Eriksson L Horak C Sharkey B Waxman IM Atkinson V Ascierto PA : \nNivolumab in previously untreated melanoma without braf mutation . \nNew Engl J Med \n372 : \n320 –\n330 , \n2015 \n25399552 \n5) \nWeber JS D’Angelo SP Minor D Hodi FS Gutzmer R Neyns B Hoeller C Khushalani NI Miller WH JrLao CD Linette GP Thomas L Lorigan P Grossmann KF Hassel JC Maio M Sznol M Ascierto PA Mohr P Chmielowski B Bryce A Svane IM Grob JJ Krackhardt AM Horak C Lambert A Yang AS Larkin J : \nNivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-ctla-4 treatment (checkmate 037): a randomised, controlled, open-label, phase 3 trial . \nLancet Oncol \n16 : \n375 –\n384 , \n2015 \n25795410 \n6) \nBorghaei H Paz-Ares L Horn L Spigel DR Steins M Ready NE Chow LQ Vokes EE Felip E Holgado E Barlesi F Kohlhäufl M Arrieta O Burgio MA Fayette J Lena H Poddubskaya E Gerber DE Gettinger SN Rudin CM Rizvi N Crinò L Blumenschein GR JrAntonia SJ Dorange C Harbison CT Graf Finckenstein F Brahmer JR : \nNivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer . \nN Engl J Med \n373 : \n1627 –\n1639 , \n2015 \n26412456 \n7) \nBrahmer J Reckamp KL Baas P Crinò L Eberhardt WE Poddubskaya E Antonia S Pluzanski A Vokes EE Holgado E Waterhouse D Ready N Gainor J Aren Frontera O Havel L Steins M Garassino MC Aerts JG Domine M Paz-Ares L Reck M Baudelet C Harbison CT Lestini B Spigel DR : \nNivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer . \nNew Engl j Med \n373 : \n123 –\n135 , \n2015 \n26028407 \n8) \nMotzer RJ Escudier B McDermott DF George S Hammers HJ Srinivas S Tykodi SS Sosman JA Procopio G Plimack ER Castellano D Choueiri TK Gurney H Donskov F Bono P Wagstaff J Gauler TC Ueda T Tomita Y Schutz FA Kollmannsberger C Larkin J Ravaud A Simon JS Xu LA Waxman IM Sharma P : \nNivolumab versus everolimus in advanced renal-cell carcinoma . \nN Engl J Med \n373 : \n1803 –\n1813 , \n2015 \n26406148 \n9) \nAnsell SM Lesokhin AM Borrello I Halwani A Scott EC Gutierrez M Schuster SJ Millenson MM Cattry D Freeman GJ Rodig SJ Chapuy B Ligon AH Zhu L Grosso JF Kim SY Timmerman JM Shipp MA Armand P : \nPd-1 blockade with nivolumab in relapsed or refractory hodgkin’s lymphoma . \nNew Engl J Med \n372 : \n311 –\n319 , \n2015 \n25482239 \n10) \nBatchelor T Carson K O’Neill A Grossman SA Alavi J New P Hochberg F Priet R : \nTreatment of primary cns lymphoma with methotrexate and deferred radiotherapy: A report of nabtt 96-07 . \nJ Clinical Oncol \n21 : \n1044 –\n1049 , \n2003 \n12637469 \n11) \nReni M Ferreri AJ Guha-Thakurta N Blay JY Dell’Oro S Biron P Hochberg FH : \nClinical relevance of consolidation radiotherapy and other main therapeutic issues in primary central nervous system lymphomas treated with upfront high-dose methotrexate . \nInt J Radiat Oncol Biol Phys \n51 : \n419 –\n425 , \n2001 \n11567816 \n12) \nThiel E Korfel A Martus P Kanz L Griesinger F Rauch M Roth A Hertenstein B von Toll T Hundsberger T Mergenthaler HG Leithauser M Birnbaum T Fischer L Jahnke K Herrlinger U Plasswilm L Nägele T Pietsch T Bamberg M Weller M : \nHigh-dose methotrexate with or without whole brain radiotherapy for primary cns lymphoma (g-pcnsl-sg-1): A phase 3, randomised, non-inferiority trial . \nLancet Oncol \n11 : \n1036 –\n1047 , \n2010 \n20970380 \n13) \nPlotkin SR Betensky RA Hochberg FH Grossman SA Lesser GJ Nabors LB Chon B Batchelor TT : \nTreatment of relapsed central nervous system lymphoma with high-dose methotrexate . \nClin Cancer Res \n10 : \n5643 –\n5646 , \n2004 \n15355887 \n14) \nBleyer WA : \nNeurologic sequelae of methotrexate and ionizing radiation: A new classification . \nCancer Treat Rep \n65 Suppl 1 : \n89 –\n98 , \n1981 \n\n15) \nReni M Mason W Zaja F Perry J Franceschi E Bernardi D Dell’Oro S Stelitano C Candela M Abbadessa A Pace A Bordonaro R Latte G Villa E Ferreri AJ : 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(anti-pd-l1) treatment leads to clinical activity in metastatic bladder cancer . \nNature \n515 : \n558 –\n562 , \n2014 \n25428503 \n20) \nCarbognin L Pilotto S Milella M Vaccaro V Brunelli M Caliò A Cuppone F Sperduti I Giannarelli D Chilosi M Bronte V Scarpa A Bria E Tortora G : \nDifferential activity of nivolumab, pembrolizumab and MPDL3280A according to the tumor expression of programmed death-ligand-1 (PD-L1): Sensitivity analysis of trials in melanoma, lung and genitourinary cancers . \nPLoS One \n10 : \ne0130142 , \n2015 \n26086854 \n21) \nLesokhin AM Ansell SM Armand P Scott EC Halwani A Gutierrez M Millenson MM Cohen AD Schuster SJ Lebovic D Dhodapkar M Avigan D Chapuy B Ligon AH Freeman GJ Rodig SJ Cattry D Zhu L Grosso JF Bradley Garelik MB Shipp MA Borrello I Timmerman J : \nNivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study . \nJ Clin Oncol \n34 : \n2698 –\n704 , \n2016 \n27269947 \n22) \nFuruse M Kawabata S Kuroiwa T Miyatake S : \nRepeated treatments with bevacizumab for recurrent radiation necrosis in patients with malignant brain tumors: a report of 2 cases . \nJ Neurooncol \n102 : \n471 –\n475 , \n2011 \n20694573 \n23) \nFuruse M Nonoguchi N Kawabata S Yoritsune E Takahashi M Inomata T Kuroiwa T Miyatake S : \nBevacizumab treatment for symptomatic radiation necrosis diagnosed by amino acid pet . \nJpn J Clin Oncol \n43 : \n337 –\n341 , \n2013 \n23303838 \n24) \nFuruse M Nonoguchi N Kuroiwa T Miyamoto S Arakawa Y Shinoda J Miwa K Iuchi T Tsuboi K Houkin K Terasaka S Tabei Y Nakamura H Nagane M Sugiyama K Terasaki M Abe T Narita Y Saito N Mukasa A Ogasawara K Beppu T Kumabe T Nariai T Tsuyuguchi N Nakatani E Kurisu S Nakagawa Y Miyatake SI : \nA prospective, multicentre, single-arm clinical trial of bevacizumab for patients with surgically untreatable, symptomatic brain radiation necrosis . \nNeuro Oncol Pract \n3 : \n272 –\n280 , \n2016 \n\n25) \nNieto K Gordon LI Raizer J : \nBevacizumab for recurrent primary central nervous system lymphoma: A new treatment? \nNeuro Oncol \n17 : \n1648 –\n1649 , \n2015 \n26541631 \n26) \nPalucka K Banchereau J : \nCancer immunotherapy via dendritic cells . \nNat Rev Cancer \n12 : \n265 –\n277 , \n2012 \n22437871\n\n",
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"keywords": "PCNSL; immunotherapy; nivolumab; recurrence",
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"title": "Immunotherapy of Nivolumab with Dendritic Cell Vaccination Is Effective against Intractable Recurrent Primary Central Nervous System Lymphoma: A Case Report.",
"title_normalized": "immunotherapy of nivolumab with dendritic cell vaccination is effective against intractable recurrent primary central nervous system lymphoma a case report"
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"abstract": "Patients with Takayasu arteritis often present with reduced vision related either to the disease per se or due to complications of therapy. We report a patient with Takayasu arteritis who developed acute onset bilateral visual loss 6wks following percutaneous revascularization of occluded aortic arch branches. No ocular cause for the visual loss was evident. The reason for visual loss in this patient was an extraocular cause. Ocular and extraocular causes of visual loss in Takayasu arteritis are discussed.",
"affiliations": "Assistant Professor, Department of Ophthalmology, Christian Medical College , Vellore, India .;Professor and Head, Department of Cardiology Unit I, Christian Medical College , Vellore, India .;Professor, Department of Neurology, Christian Medical College , Vellore, India .;Associate Professor, Department of Medicine, Christian Medical College , Vellore, India .",
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"title": "Visual loss in Takayasu Arteritis - Look Beyond the Eye.",
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"abstract": "Alternative medical therapy with multiple intravenous colloidal silver infusions may cause severe illness, including profound copper deficiency-induced anemia and hepatic toxicity. No chelating agent for silver poisoning exists and effective therapy requires apheresis in combination with continuous administration of oral copper.",
"affiliations": "Department of Clinical Medicine Weill Cornell Medical College New York NY USA.;Houston Methodist Hospital Houston TX USA.;School of Public Health University of Colorado Boulder CO USA.",
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"doi": "10.1002/ccr3.2316",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.2316CCR32316Case ReportCase ReportsAnemia and leukopenia following intravenous colloidal silver infusions—Clinical and hematological features, unique peripheral blood film appearance and effective therapy with supplemental oral copper and apheresis NATELSON et al.Natelson Ethan A. https://orcid.org/0000-0002-1449-609X\n1\n\n2\n\n3\neanatelson@att.net Baker Kelty R. \n3\nPyatt David W. \n4\n\n5\n\n6\n\n1 \nDepartment of Clinical Medicine\nWeill Cornell Medical College\nNew York\nNY\nUSA\n\n2 \nDepartment of Academic Medicine\nHouston Methodist Hospital, Methodist Hospital Research Institute\nHouston\nTX\nUSA\n\n3 \nHouston Methodist Hospital\nHouston\nTX\nUSA\n\n4 \nSchool of Public Health\nUniversity of Colorado\nBoulder\nCO\nUSA\n\n5 \nSchool of Pharmacy\nUniversity of Colorado\nBoulder\nCO\nUSA\n\n6 \nSummit Technology, LLP\nWest Hartford\nCT\nUSA\n* Correspondence\n\nEthan A. Natelson, Department of Academic Medicine, Houston Methodist Hospital, Houston, TX, USA.\n\nEmail: eanatelson@att.net\n09 8 2019 9 2019 7 9 10.1002/ccr3.v7.91757 1762 06 4 2019 06 5 2019 20 6 2019 © 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nAlternative medical therapy with multiple intravenous colloidal silver infusions may cause severe illness, including profound copper deficiency‐induced anemia and hepatic toxicity. No chelating agent for silver poisoning exists and effective therapy requires apheresis in combination with continuous administration of oral copper.\n\napheresiscolloidal silvercopperineffective myelopoiesis source-schema-version-number2.0component-idccr32316cover-dateSeptember 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.9 mode:remove_FC converted:16.09.2019\n\n\nNatelson \nEA \n, \nBaker \nKR \n, \nPyatt \nDW \n. Anemia and leukopenia following intravenous colloidal silver infusions—Clinical and hematological features, unique peripheral blood film appearance and effective therapy with supplemental oral copper and apheresis . Clin Case Rep . 2019 ;7 :1757 –1762 . 10.1002/ccr3.2316\n==== Body\n1 INTRODUCTION\nThree patients received purported therapeutic medical treatment at a Wellness Center, including multiple intravenous infusions containing colloidal silver. We describe clinical consequences, laboratory features, and results of corrective therapy for ensuing and persistent anemia with the combination of oral copper sulfate administration and therapeutic apheresis in one of these patients.\n\nThe potential toxicities of colloidal silver‐containing preparations administered topically, or taken orally, are well‐known, but little published information is available concerning the adverse health effects of intravenously administered colloidal silver solutions. We report here, a group of three patients receiving alternative and purported therapeutic medical treatment at a Wellness Center, which included multiple intravenous colloidal silver infusions. We describe the clinical consequences and corrective therapy for the ensuing and persistent anemia with the combination of oral copper sulfate administration and therapeutic apheresis, in one of these patients. This outcome contrasts with the continuing anemia and disability in the other two patients, who declined apheresis.\n\nPharmaceutical preparations and bandages containing silver salts or colloidal silver have long been used topically in patients with burns and other wounds as a protection barrier against infection.1 However, silver‐containing compounds have never been proven as effective systemic therapy against any specific pathogens either by oral or parenteral administration.2, 3 A Federal Drug Administration (FDA) Advisory Expert Panel found no efficacy in humans for its systemic administration and silver as medication was long ago removed from its approved use in over the counter product publications.2 The excretion of absorbed oral silver is very poor—some may be lost through shedding intestinal cellular material and in the bile but only very small amounts appear in the urine.2, 3 However, there appears to be no significant excretory pathway for colloidal silver administered intravenously and a severe and unusual form of persistent anemia and some degree of neutropenia is a consequence.\n\nA dreaded complication of silver poisoning is argyria, a gray‐blue discoloration of the skin and present even in the sclera, and that is permanent.2, 4, 5 Other potential systemic complications associated with silver toxicity include neurological, hepatic, and renal aberrations that may cause disability or death.2, 6, 7 No chelating agents have yet proven useful in remitting silver toxicity, and this includes more recently introduced products such as dimercaptosuccinic acid (Succimer), useful in lead poisoning.8 The mechanism resulting in anemia consequent to intravenous silver infusion is, in large part, due to accelerated, persistent, and profound copper and perhaps zinc excretory losses promoted by the elevated serum silver levels.9, 10 Leukopenia and neutropenia may also be present but seem less of a clinically important issue than the anemia.\n\n2 CASE PRESENTATION\n2.1 Case 1\nA 30‐year‐old woman was referred to our hematology section because of a severe anemia. Several months earlier, she had sought medical attention at a Wellness Center for symptoms of fatigue and depression. She denied suffering weight loss, tick bites, skin rash, or fever. Her evaluation included numerous laboratory diagnostic studies including an IgG panel consisting of 10 separate markers targeting Lyme disease antigens along with a similar panel for IgM markers. All of these results were normal as was a Western blot assay for Lyme disease. A routine blood count showed a hemoglobin concentration of 14.4 g/dL, along with a total leukocyte count of 7.5 × 109/L and platelet count of 257 × 109/L. A differential cell count included 66.7% neutrophils, 21.8% lymphocytes, and 9.8% monocytes. Despite this extensive laboratory evaluation, she was informed that she was suffering from Lyme disease and required specialized therapy. This treatment consisted of 48 separate infusions, each containing hydrogen peroxide, ozone, and colloidal silver administered through a peripherally inserted central catheter (PIC line), over a 3‐month interval. About midway during this treatment period, another blood count indicated her hemoglobin concentration had fallen to 10.9 g/dL with a total leukocyte count of 3.1 × 109/L with 32% neutrophils, 39% lymphocytes, and 25% monocytes and a normal platelet count.\n\nTwo months after completing this treatment plan, she noticed progressive fatigue and ultimately sought care at an emergency center. Her hemoglobin concentration was 6 g/dL with a mean corpuscular volume (MCV) of 97 fL, a reduced white blood cell count of 1.7 × 109/L with neutropenia, and a normal platelet count. She received three units of packed red blood cells in treatment of the anemia and a single injection of Neupogen, 300 mcg, to improve her neutropenia. She underwent a bone marrow study several days later. Her blood count then showed a hemoglobin concentration of 8.7 g/dL, with a total leukocyte count of 1.5 × 109/L and platelet count of 318 × 109/L.\n\nWe obtained and reviewed the bone marrow slide material and agreed with the hematopathology report, which described a 60% cellular marrow with 1% blasts, 31% myelocytes/metamyelocytes, 15% bands and segmented neutrophils, 4% eosinophils, 19% erythroid cells, 9% monocytes, 13% lymphocytes, including hematogones, and 19% erythroid precursors with normoblastic maturation and no significant dysplasia. While hematogones were increased, there was no increase in myeloblasts. There was mild megakaryocytic hyperplasia. The myeloid to erythroid (M:E) cell ratio was 2.7. A flow cytometry cell differential showed 30.9% lymphocytes, 14% monocytes, and a total of 42.8% granulocytes and no increase in phenotypic blast forms. Iron stores were increased but ringed sideroblasts were not identified. There was no evident erythrophagocytosis by histiocytes. Cytogenetic studies gave normal results. No specific diagnosis was suggested, and a clinical hematology consultation was recommended.\n\nHer initial consultative blood count, obtained several weeks after the blood transfusion and bone marrow study, showed a hemoglobin concentration of 9.0 g/dL with a total leukocyte count of 2.3 × 109/L with 50% neutrophils. The MCV was 97 fL, and the platelet count was normal. Her peripheral blood film was extremely abnormal containing large numbers of tear drop erythrocytes (dacrocytes) of varying size and shape along with marked poikilocytosis and anisochromia (Figures 1 and 2). A few large, polychromatic erythrocytes contained Howell‐Jolly bodies (Figure 3). There was also a very small but definitive population of spherocytes, but no microangiopathic changes. Basophilic stippling was not noted, and circulating normoblasts were not present—mature neutrophil and platelet morphology were unremarkable. The serum ferritin value, normal on her pretreatment screening, was elevated at 500 ng/dL. The blood lead level was <2.0 mcg/dL (normal range, up to 4.9 mcg/dL). The serum copper concentration was <5 mcg/dL.\n\nFigure 1 Variation in erythrocyte shape, size and coloration (poikilocytosis and anisochromia) with spherocytes (arrows) and leukopenia\n\nFigure 2 Tear drop erythrocytes or dacrocytes (arrows)\n\nFigure 3 Polychromatophilic erythrocyte containing a Howell Jolly body (arrow)\n\nWe ultimately obtained her prior medical records and then first learned that she had received the specific colloidal silver preparation Argentyn 23, marketed for oral usage, in her infusions. This particular product contains 236 mg Ag/L. She received variable volume amounts of the Argentyn 23 solution with each infusion, from 20 mL to 180 mL, without explanation. Accordingly, her total dose of parenteral silver amounted to 883 mg.\n\nInitially, she received treatment for her continuing anemia and profound copper deficiency with 12 mg of copper sulfate daily in oral divided doses with meals. Her hemoglobin concentration improved slightly, and the leukopenia resolved over a 2‐month period but serum copper measurements remained below accurate quantitation levels. Her serum silver level also remained unchanged from its initial value, at 350 mcg/L. After a few additional months of observation, and realizing that there was to be no progressive fall in the markedly elevated silver level, or correction of the greatly reduced serum copper level, despite oral supplements, we began apheresis therapy. This process is accomplished at our blood center with automated equipment designed to exchange 1‐1.5 of the patient's total plasma volume with 5% albumin in normal saline, containing calcium gluconate and potassium chloride. After the first plasma exchange, the serum copper became accurately measurable at 21 mcg/L (normal range 80‐155 mcg/L), after the second exchange, it was 40 mcg/L, after the third exchange 50 mcg/L,and after the fourth exchange, it reached 79 mcg/L.\n\nHer hemoglobin concentration slowly rose to 13.4 g/dL, and her peripheral blood film became entirely normal in appearance. We had allowed a few weeks between each apheresis. Her serum silver level fell to 240 mcg/L after the first apheresis, to 200 mcg/L after the second, to 160 mcg/L after the third exchange, and to 130 mcg/L after the fourth exchange. At that point, we reduced her oral copper intake to 4 mg daily and decided to simply observe subsequent laboratory values and her clinical status. Her initially elevated serum ferritin value had fallen to 165 ng/mL. A psychiatrist successfully treated her depression with an oral medication, at low dosage, and she remains asymptomatic.\n\nWhile evaluating and discussing this patient with other hematologists, one of the authors (KRB) reported that she had recently been caring for two women, one who was quite ill and admitted to a nearby medical center hospital. Both had been treated in the same fashion as my patient, and at the same Wellness Center and for the same alleged diagnosis of Lyme disease. These patients will be described as Case 2 and Case 3.\n\n2.2 Case 2\nA 74‐year‐old woman with no past history of anemia sought medical attention in another city and received multiple antibiotics for 2 months as treatment for alleged Lyme disease. Returning to her home, she presented to the Wellness Center discussed in this report, continuing to describe fatigue. Her blood counts were normal at that time, and she had no history of prior blood transfusions. She then received multiple intravenous infusions containing hydrogen peroxide, ozone, and colloidal silver, the latter also in the form of Argentyn 23. Her total administered dose of parenteral colloidal silver was 623 mg. Three months later, she was found to have a hemoglobin concentration of 7.1 g/dL, with a total leukocyte count of 2.6 × 109/L and 40% neutrophils. The platelet count was 28.8 × 109/L. The uncorrected reticulocyte count was 1.1% (absolute reticulocyte count 0.663 cells/µL) with normal serum LDH and haptoglobin values. Her serum ferritin value was greatly elevated a 2063 ng/L, and the serum silver concentration was 220 mcg/L. Her initial serum copper level was < 5 mcg/L, and after several weeks of receiving oral copper supplements, rose only to 11 mcg/L. Her serum zinc concentration was not initially measured and following oral copper therapy was later found to be 127 mcg/dL (normal value 60‐130 mcg/dL). She received a total of eight units of blood over the next several weeks to maintain a satisfactory hemoglobin concentration. She also received a course of treatment with Succimer, without any effect on reducing her elevated serum silver level. She declined apheresis. Her leukopenia gradually resolved, with the final blood count available to us indicating a hemoglobin concentration of 10.6 g/dL, total leukocyte count of 5.1 × 109/L with 68% neutrophils, and a platelet count of 224 × 109/L. At that time, the markedly elevated serum ferritin value had fallen slightly to 1827 ng/L. She was advised to continue oral copper therapy but she declined further follow‐up.\n\n2.3 Case 3\nA 46‐year‐old woman sought medical attention at the same Wellness Center described for Case 1 and Case 2 and also with symptoms of chronic fatigue. Her physical examination was normal, and she had no past history of anemia or liver disease. Initial laboratory examination revealed a hemoglobin concentration of 13.3 g/dL (MCV 96 fL) with a total leukocyte count of 4.3 × 109/L and platelet count of 281 × 109/L. A differential white blood cell count was unremarkable, with 51% neutrophils. Additional chemistry values showed normal liver and renal function values. Serologic panels for multiple hepatic viral diseases gave normal results and serologic tests for Lyme disease and a Western blot study were also normal, as in Case 1.\n\nNevertheless, she was also informed that she had Lyme disease and received multiple intravenous infusions of hydrogen peroxide, ozone, and colloidal silver, in a similar fashion to our Case 1 and Case 2, but we were unable to obtain records of her total administered dose of colloidal silver. Three months later, her hemoglobin concentration had fallen to 7.8 gm/dL (MCV 109 fL) with a total leukocyte count of 3.4 × 109/L and 36% neutrophils. The platelet count was 420 × 109/L). The uncorrected reticulocyte count was 0.8% (absolute reticulocyte count 0.416 cells/µL) and serum erythropoietin value only mildly increased relative to the degree of anemia, at 68.7 IU (normal value, at a normal hemoglobin concentration, 3.7‐36 IU). She received multiple blood transfusions, but remained anemic and clinically became progressively very ill and was ultimately admitted to the hospital 2 months later, and there referred for hematology consultation. Her admission laboratory evaluation showed an elevated alkaline phosphatase value of 792 IU/L (normal range 44‐147 IU/L), and ALT and AST values of 416 U/L and 487 U/L, respectively (normal range 8‐40 U/L), and a total bilirubin concentration of 2.5 mg/dL. These transaminase levels continued to rise and peak at 1,200 and 670 U/L, respectively, with a total bilirubin of 4.5 mg/dL. All of these elevated laboratory values then gradually declined. Her serum silver level was 210 mcg/dL and initial copper level below accurate laboratory quantitation and reported as <5 mcg/dL Serum haptoglobin concentration was 109 mg/dL (normal range, 30‐300 mg/dL). Imaging studies indicated a slightly enlarged spleen at 13 cm in length. She required additional blood transfusions. Her admitting serum ferritin value, which was normal precolloidal silver infusion, was now 332 ng/dL, and it continued to rise and peak at 1278 ng/dL (normal range for women, 12‐150 ng/dL).\n\nShe received oral copper supplementation daily, as Case 1 and Case 2 did, once silver poisoning was documented, but her serum copper level rose only to 19 mcg/L after weeks of administration. She refused to consider apheresis. A liver biopsy revealed mild, patchy portal, and lobular inflammation with scattered apoptotic hepatocytes and thought consistent with drug toxicity effect. Her abnormal liver function ultimately abated over several weeks without any specific therapy, and her elevated platelet count returned to normal. Nevertheless, she remained with significant anemia at discharge, but declined continuing follow‐up by the hematologist.\n\n3 DISCUSSION\nThe hematological effects of intravenous colloidal silver infusions were studied by the Nobel Laureate, Dr George H. Whipple. In 1930‐1931, he infused multiple dogs with colloidal silver in a fashion similar to our three patients.9 Prior animal studies suggested to him that the causal mechanism for silver‐induced anemia might be induction of bone marrow aplasia, a model he was seeking in the study of human aplastic anemia. His dogs all ultimately died with marked anemia but with a hypercellular bone marrow appearance on repeat examinations. He thought the mechanism of the anemia had some association with hemolysis by the gross serum and urine appearance but he did not describe the peripheral blood film morphology. It is possible the dogs had manifest liver pathology, as our Case 3, causing the visual changes he observed in the plasma and urine, and not significant hemolysis.\n\nIn more current literature, that copper and zinc deficiency may both occur with silver poisoning has been commented upon.10 It is known that zinc and copper compete with each other for access to a common relatively weak excretion pathway and that excess oral zinc administration may cause copper deficiency anemia.11, 12, 13, 14, 15 It appears from our three patients, that infused colloidal silver has no significant excretion pathway, as the markedly elevated serum silver levels remained constant over many weeks. However, its presence likely facilitates persistent excess urinary losses of both copper and zinc, and particularly for copper, into both the bile and urine. Copper deficiency is known to produce significant anemia and leukopenia, even simulating myelodysplastic syndromes (MDS) by the abnormal peripheral blood and bone marrow cellular morphology; increased hematogones, which may be confused with blast forms, were noted in the bone marrow of our Case 1.15\n\n\nThe anemia of colloidal silver poisoning is presumably promoted by the resulting profound copper deficiency and attributed to ineffective myelopoiesis with a cellular marrow, as present in MDS and in our Case 1.13, 14, 15, 16 Ringed sideroblasts have also been noted in the bone marrow with copper deficiency‐induced anemia but were not present in our patient. She did manifest a small number of spherocytes in the peripheral blood but hemolysis did not appear to significantly contribute to the anemia. It may simply have been a consequence of the more elevated serum silver level relative to those measured in our other two cases.\n\nSevere copper deficiency is no longer an unusual diagnosis in the modern era, now occasionally occurring shortly following bariatric Roux‐en‐Y surgery with anemia and leukopenia as a consequence. Short‐term parenteral administration of zinc and copper salts have been used in this setting, as effective therapy.17 In our Case 1, it appeared that the massive blood silver level effectively accelerated excretion of virtually all of the initially administered oral copper. Providing excess oral copper, in this circumstance, may have retarded excessive loss of zinc, which competes with copper for excretion, and eliminated the need for supplemental zinc. We did not perform a zinc level prior to initiating oral copper therapy in this patient but later, prior to apheresis, it was 96 mcg/dL (normal value, 60‐120 mcg/dL). The serum zinc may initially have been low, but could have become normal consequent to the prolonged administration of excess oral copper. This would be unlike the bariatric surgery mediated mineral losses.\n\n4 CONCLUSION\nAs this report illustrates, the use of infused colloidal silver as a primary or adjunctive therapy to treat alleged Lyme disease or other systemic infections must be condemned as both ineffective and with predictable long‐term toxicity. Silver administered by the intravenous route is more toxic than that associated with oral preparations because of both higher dose and the apparent inability of the body to excrete this material, resulting in continuous prolonged and profound intravascular colloidal silver exposure. Copper and possibly zinc losses are accelerated by the presence of circulating colloidal silver, and reduction of particularly serum copper may cause severe anemia as a consequence. The resulting anemia creates an unusual peripheral blood erythrocyte morphologic pattern similar to that of isolated copper deficiency and simulating MDS. However, it may have a slight direct hemolytic component evident at the higher colloidal silver levels present in Case 1, presumably explaining the very small number of spherocytes, without apparent clinical significance. Serum ferritin values rapidly increase following colloidal silver poisoning and may represent an inflammatory component or acute phase stimulus.\n\nThe only effective therapy to significantly reduce the circulating colloidal silver load, is with apheresis. We found only a single patient previously so treated and reported in the medical literature.6 In that case, the greatly elevated serum silver level dropped substantially after a single exchange. However, the patient died with neurological complications of the silver toxicity before additional apheresis sessions could be accomplished.\n\nSerial apheresis is clearly useful therapy, as demonstrated with the outcome of Case 1, in contrast with the need for repeated transfusions and persistent anemia despite oral copper supplementation present in Case 2 and Case 3. This, even though their serum silver levels were significantly less than those measured in Case 1. Apheresis should be supplemented with constant oral copper administration in order to maintain a satisfactory hemoglobin concentration.\n\nModern apheresis with albumin rather than plasma substitution is a very safe procedure but the intravascular silver reduction increment lessens with each successive exchange. Nevertheless, it appears that the major reduction in circulating silver accomplished by apheresis eliminates need for supportive blood transfusions and may reduce the later appearance of argyrosis. The required dose of supplemental oral copper is also clearly reduced. However, the ultimate potential consequences of persistently elevated intravascular colloidal silver levels, such as argyria, or renal dysfunction, are uncertain and will require longer‐term observation of the patient group described here.\n\nWe reported full documentation for all three cases to the Texas Medical Board for review, and ultimately, the initial treating physician agreed to voluntarily surrender his Texas medical license in lieu of further disciplinary proceedings.\n\nCONFLICT OF INTEREST\nEach of the authors declare that there is no conflict of interest regarding the publication of this paper.\n\nAUTHOR CONTRIBUTIONS\nEAN: involved in hematology consulting and treating physician for the patient described as Case 1 and prepared the manuscript and photographs.KRB: involved in hematology consulting and treating physician for the patients described as Cases 2 and 3 and reviewed the manuscript.and DWP: helped, as a toxicologist, with literature research concerning chelation therapy and silver toxicity and calculations as to the silver content of the colloidal silver product, Argenten 23, discussed in the manuscript. He also reviewed the manuscript.\n==== Refs\nREFERENCES\n1 \n\nBrouillard \nC \n, \nBursztejn \nA‐C \n, \nLatarche \nC \n, et al. Silver absorption and toxicity evaluation of silver wound dressings in 40 patients with chronic wounds . Eur Acad Dermat Venereol . 2018 ;32 (12 ):2295 ‐2299 .\n2 \n\nFung \nMC \n, \nBowen \nDL \n. Silver products for medical indications: risk‐benefit assessment . Clin Toxicol . 1996 ;34 :119 ‐126 .\n3 \n\nLansdown \nA \n. A pharmacological and toxicological profile of silver as an antimicrobial agent in medical devices . Adv Pharmacol Sci . 2010 ;2010 :1 ‐16 .\n4 \n\nChhabra \nL \n, \nSareen \nP \n, \nTrivedi \nN \n. The silver man: a rare cosmetic complication of alternative medicine . Case Rep . 2013 ;2013 (jul08 2 ):bcr2013009728 ‐bcr2013009728 .\n5 \n\nChung \nI‐S \n, \nLee \nM‐Y \n, \nShin \nD‐H \n, \nJung \nH‐R \n. Three systemic argyria cases after ingestion of colloidal silver solution . Int J Dermatol . 2010 ;49 :1175 ‐1177 .20883406 \n6 \n\nMirsattari \nSM \n, \nHammond \nRR \n, \nSharpe \nMD \n, \nLeung \nFY \n, \nYoung \nGB \n. Myoclonic status epilepticus following repeated oral ingestion of colloidal silver . Neurology . 2004 ;62 :1408 ‐1410 .15111684 \n7 \n\nRezk \nT \n, \nPenton \nJ \n, \nStevenson \nA \n, et al. Pauci immune crescentic glomerulonephritis in a patient with T‐cell lymphoma and argyria . BMC Nephrol . 2016 ;17 (1 ):49 .27189346 \n8 \n\nSears \nM \n. Chelation: harnessing and enhancing heavy metal detoxification—a review . The Scientific World J . 2013 ;2013 :1 ‐13 .\n9 \n\nShouse \nSS \n, \nWhipple \nWH \n. Effects of the intravenous injection of colloidal silver upon the hematopoietic system in dogs . J Exp Med . 1931 ;53 :413 ‐420 .19869854 \n10 \n\nStepien \nKM \n, \nTaylor \nA \n. Colloidal silver ingestion with copper and caeruloplasmin deficiency . 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Acquired myelodysplasia (AMD) or myelodysplastic syndrome (MDS) ‐ clearing the fog . Adv Hematol . 2013 ;2013 :309637 .24194760 \n17 \n\nKumar \nP \n, \nHamza \nN \n, \nMadhok \nB \n, et al. Copper deficiency after gastric bypass for morbid obesity: a systematic review . Obes Surg . 2016 ;26 :1335 ‐1342 .27034062\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "7(9)",
"journal": "Clinical case reports",
"keywords": "apheresis; colloidal silver; copper; ineffective myelopoiesis",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "1757-1762",
"pmc": null,
"pmid": "31534743",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports",
"references": "15111684;1575212;17236184;17706281;19869854;20883406;21188244;22080848;22375039;23690738;23843406;24194760;27034062;27189346;29730878;29959467;8632503",
"title": "Anemia and leukopenia following intravenous colloidal silver infusions-Clinical and hematological features, unique peripheral blood film appearance and effective therapy with supplemental oral copper and apheresis.",
"title_normalized": "anemia and leukopenia following intravenous colloidal silver infusions clinical and hematological features unique peripheral blood film appearance and effective therapy with supplemental oral copper and apheresis"
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"abstract": "Breast cancer comprised at least 21.8% of the overall cancer among young adult (YA) women and became the leading cancer in this group in Japan, with 50% adolescent and YAs being diagnosed and 15-44-year-old women showing excellent 5-year survival. Surgical-chemoradiation therapy often results in excellent survivorship with an increased incidence of treatment-induced subfertility. Therefore, adding fertility preservation (FP) to the primary cancer treatment is necessary. Herein, we reported a series of cases of YA women with breast cancer who opted for FP, where their option was tailored accordingly. To date, the selection of oocytes, embryos and ovarian tissue is widely available as an FP treatment. PGT could reduce the risk of BRCA mutation transmission amongst BRCA carriers before pregnancy planning. Otherwise, gonadotropin-releasing hormone analog has no gonadoprotective effect and thus should not be considered as an FP option.",
"affiliations": "Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, Kawasaki, Japan.;Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, Kawasaki, Japan.;Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, Kawasaki, Japan.;Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, Kawasaki, Japan.;Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, Kawasaki, Japan.;Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, Kawasaki, Japan.;Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, Kawasaki, Japan.;Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, Kawasaki, Japan.;Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, Kawasaki, Japan.",
"authors": "Ahmad|Mohd Faizal|MF|;Sugishita|Yodo|Y|;Suzuki-Takahashi|Yuki|Y|;Sawada|Shino|S|;Iwahata|Hideyuki|H|;Shiraishi|Eriko|E|;Takae|Seido|S|;Horage-Okutsu|Yuki|Y|;Suzuki|Nao|N|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fmed.2021.670872",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.670872\nMedicine\nCase Report\nCase Report: Young Adults With Breast Cancer: A Case Series of Fertility Preservation Management and Literature Review\nAhmad Mohd Faizal 1 2\n\nSugishita Yodo 1 3\n\nSuzuki-Takahashi Yuki 1\nSawada Shino 1\nIwahata Hideyuki 1\n\nShiraishi Eriko 1 4\n\nTakae Seido 1\n\nHorage-Okutsu Yuki 1\nSuzuki Nao 1 *\n\n1Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, Kawasaki, Japan\n2Department of Obstetrics and Gynaecology, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia\n3Laboratory of Cancer and Reproductive Science, Department of Frontier Medicine, St. Marianna University, School of Medicine, Kawasaki, Japan\n4Department of Obstetrics and Gynecology, Jikei University School of Medicine, Tokyo, Japan\nEdited by: Carlos Calhaz-Jorge, Santa Maria Hospital, Portugal\n\nReviewed by: Giuliano Marchetti Bedoschi, University of São Paulo, Brazil; Nalini Mahajan, Independent Researcher, New Delhi, India\n\n*Correspondence: Nao Suzuki nao@marianna-u.ac.jp\nThis article was submitted to Obstetrics and Gynecology, a section of the journal Frontiers in Medicine\n\n06 8 2021\n2021\n8 67087222 2 2021\n13 7 2021\nCopyright © 2021 Ahmad, Sugishita, Suzuki-Takahashi, Sawada, Iwahata, Shiraishi, Takae, Horage-Okutsu and Suzuki.\n2021\nAhmad, Sugishita, Suzuki-Takahashi, Sawada, Iwahata, Shiraishi, Takae, Horage-Okutsu and Suzuki\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nBreast cancer comprised at least 21.8% of the overall cancer among young adult (YA) women and became the leading cancer in this group in Japan, with 50% adolescent and YAs being diagnosed and 15–44-year-old women showing excellent 5-year survival. Surgical-chemoradiation therapy often results in excellent survivorship with an increased incidence of treatment-induced subfertility. Therefore, adding fertility preservation (FP) to the primary cancer treatment is necessary. Herein, we reported a series of cases of YA women with breast cancer who opted for FP, where their option was tailored accordingly. To date, the selection of oocytes, embryos and ovarian tissue is widely available as an FP treatment. PGT could reduce the risk of BRCA mutation transmission amongst BRCA carriers before pregnancy planning. Otherwise, gonadotropin-releasing hormone analog has no gonadoprotective effect and thus should not be considered as an FP option.\n\nbreast cancer\ncryopreservation\nfertility preservation\noncofertility\nyoung adult\n==== Body\nIntroduction\n\nBreast cancer comprised at least 21.8% of the overall cancer among young adult (YA) women and became the leading cancer in this group in Japan, followed by cervical cancer at 12.8% and malignant germ cells and other gonadal tumors at 8.5% (1). Overall, 50% of breast cancer cases were among adolescent and YAs (AYA); in addition, the age group of 15–44 years old showed an excellent 5-year survival rate of almost 90% in localized cancer group, 80% in regional cancer group, and 35% in distant metastasis cancer group (2). The combination of surgical and chemoradiation therapy in managing breast cancer often results in excellent survivorship. However, it could also lead to a reduction in fecundity. Therefore, considering the increased incidence of chemotherapy-induced subfertility that leads to a devastating quality of life, adding fertility preservation (FP) to the primary cancer treatment is deemed essential in oncofertility services (3). A prompt strategy is paramount to evaluate FP's best option tailored to age, cancer stage age, and marital status. Herein, we reported a series of cases of YA women with breast cancer who opted for FP, where their option was tailored accordingly.\n\nCase Series\n\nOur first case is a 31-year-old single and nulliparous woman with newly diagnosed stage I of right breast cancer (T1N0M0). Her hormone receptors were found positive (ER+/PR+) with HERS2-ve and Ki67 < 10%. Therefore, she was planned for right mastectomy and sentinel axillary lymph nodes biopsy, followed by possible chemotherapy (Taxane-based group if the nodes were positive). She was also planned for tamoxifen (TAM) therapy for at least 10 years. Therefore, she was referred to us for FP with an interval of 10 weeks before operation intervention. Her level of anti-Mullerian hormone (AMH) was 4.51 ng/dL. Given that she was single with applicable timeframe, a choice of oocyte cryopreservation was deemed appropriate. She was keen to start controlled ovarian stimulation (COS) as soon as possible; thus, the random start (RS) protocol with an aromatase inhibitor (AI) was offered. She managed to cryopreserve 10 oocytes and is currently still ongoing second COS before embarking on surgery next month. Although the chemotherapy is not yet planned, she was referred for possible long-term endocrine therapy for 10 years. By the time of treatment completion, the AMH could decline due to aging. Given that she has a borderline AMH level, the prediction of a further decrease in AMH level made the FP essential in managing her condition. However, oocyte cryopreservation could help motivate compliance to the primary treatment disease as her fertility ability has been covered.\n\nOur second case is a 28-year-old married woman with preliminary diagnosis of left breast cancer upon tissue biopsy. Unfortunately, her lymph nodes tissue was found to be positive. Thus, she was categorized as T2N1M0. However, her hormonal subtype was ER/PR+. HERS2 was also positive and Ki67 > 20% (luminar B-like tumor). She was counseled for a left mastectomy with unilateral axillary lymph node clearance, followed by chemotherapy; anthracycline-based group or combination with taxane-based regime depending on the final histopathology examination and immunochemistry assessment of post-surgical specimen. She was also counseled regarding the possibility of anti-HER2 therapy for 1 year, followed by TAM for at least 5 years. Her current AMH level was 2.32 ng/dL. Therefore, she was counseled for FP treatment because the chemotherapeutic agent is gonadotoxic and long-term therapy because she is married. The option of embryo cryopreservation was an excellent choice. The interval before the primary cancer treatment was 6 weeks. Thus, adequate time was available for her FP. Fortunately, she was on her second day of menses; thus, conventional COS was initiated. To date, she had eight embryos cryopreserved (blastocyst stage) following two cycles of conventional COS. She is currently receiving chemotherapy and was planned for years for a cryopreservation update. She responded well with the chemotherapy (doxorubicin + cyclophosphamide), and she is currently on trastuzumab. Her latest AMH was 0.08 ng/dL. She experienced amenorrhea after 6 months of chemotherapy. Due to the FP strategy, she secured her chance for pregnancy in the future despite having a poor ovarian reserve due to her primary cancer treatment.\n\nOur third case is a 37-year-old single and nulliparous woman diagnosed with right breast cancer 6 years ago. She was referred to us previously for FP treatment. She was diagnosed as triple negative because all her hormonal receptors were negative. However, her BRCA status was unknown due to financial constraints for testing. Her AMH level was 3.18 ng/dL. The timeframe for stimulation was limited at that time as her chemotherapy was scheduled a week after the FP counseling. Thus, the ovarian tissue cryopreservation (OTC) opted to follow FP counseling. She underwent laparoscopic left oophorectomy for OTC in November 2013. We obtained 23 pieces of ovarian tissue (1 mm3 per piece) and 13 MII oocytes after in-vitro maturation; both were cryopreserved. To date, she completed her chemotherapy (doxorubicin + cyclophosphamide and olaparib), and she is currently in remission. Her latest AMH was 0.96 ng/dL. Given that she is still single, she had no plan to fertilize the oocytes and continue follow-up yearly to update her cryopreservation status.\n\nThe last case is a 33-year-old nulliparous married woman with grade III intraductal carcinoma of the right breast, with ER/PR+, HERS2+, and Ki67 > 20%. Her current AMH level was 2.54 ng/dL. She was diagnosed in February 2018, and she underwent right mastectomy with ipsilateral axillary lymph node clearance a month later. She was referred to us within 6 weeks before the initiation of chemotherapy. We offered embryo cryopreservation but were only able to pursue a single COS cycle. She managed to preserve three good-quality embryos at that time (blastocyst stage). She received four cycles of doxorubicin and trastuzumab for 1 year and completed 3 years of TAM. Given that she is now in remission, she is keen to embark on pregnancy, with clearance obtained from her breast oncologist. She was planned for frozen embryo transfer (FET), with natural cycles for at least 3 months following the last dose of TAM as the “wash-out” period. Tentatively, her FET was planned for September 2021. Although the period was regular, her AMH level 6 months ago was 0.07 ng/dL, confirming the chemotherapy's gonadotoxic effect on her ovarian reserve. Thus, FP was an appropriate choice in her case.\n\nAll these cases represented the current scenario of managing breast cancer among YA women, where FP is deemed essential to be incorporated into the primary disease management. The gonadotoxic effect of the chemo-regime in breast cancer is contemplating, and recommendations seem to be inconclusive. Therefore, a proactive strategy in adding FP as a wise strategy in managing young women with breast cancer is appropriate. The summary of the cases is tabulated in Table 1.\n\nTable 1 The summary of main characteristics and reproductive outcomes.\n\nCase\tBackground\tDiagnosis\tTreatment\tFP Indication\tFP Outcome\t\n1\t31, Single Nulliparous\tRight Breast Ca Stage I (T1N0M0)\nLuminar A Tumor\nER+/PR+\nHERS2-ve\nKi67 < 10%\nAMH 4.51 ng/dL\tChemotherapy: Possible – Taxane-based group\nSuppression Therapy: Tamoxifen- 10 years\tLong term endocrine therapy\nPossible of age related decrease ovarian reserve\tCompleted 1 COS-OC\nOn dual stimulation – On-going 2nd Cycle\n1st Cycle- 10 Oocytes Cryopreservation (OC)\t\n2\t28, Married, Nulliparous\tLeft Breast Ca Stage II (T2N1M0)\nLuminar B-Like Tumor\nER+/PR+\nHERS2 +ve\nKi67 > 20%\nAMH 2.32 ng/dL\tChemotherapy: Doxorubicin, Cyclophosphamide\nSuppression Therapy: Trastuzumab-1 year, Tamoxifen- 5 years\tGonadotoxicity of chemotherapy\nPossible of age related decrease ovarian reserve\tCompleted 2 COS-IVF\nEmbryo Cryopreservation (EC)- 8 Blastocyst\nAMH 0.08 ng/dL\t\n3\t37, Single, Nulliparous\tRight Breast Ca\nER–/PR\nHERS2 -ve (Triple Negative)\nAMH\n3.18 ng/dL\tChemotherapy: Doxorubicin, Cyclophosphamide with Olaparib\nSuppression Therapy: -\tGonadotoxicity of chemotherapy\nPossible of age related decrease ovarian reserve\tOvarian Tissue Cryopreservation (OTC) (left oophorectomy)+\nin-vitro Maturation (IVM)\n13 Oocytes Cryopreservation (OC)\n23 pieces of ovarian tissue\nAMH 0.96 ng/dL\t\n4\t33, Married, Nulliparous\tIntraductal carcinoma grade III (IDC)\nLuminar B-Like Tumor\nER+/PR+\nHERS2 +ve\nKi67 > 20%\nAMH\n2.54 ng/dL\tChemotherapy: Doxorubicin\nSuppression Therapy: Trastuzumab-1 year, Tamoxifen- 3 years\tGonadotoxicity of chemotherapy\nPossible of age related decrease ovarian reserve\tCompleted 1 COS-IVF\nEmbryo Cryopreservation (EC) - 3 Blastocyst\nAMH 0.07 ng/dL\t\n\nDiscussion\n\nAs known, at least 15–25% of breast cancer cases affected premenopausal women, with 7% below 40 years old, which is categorized as AYA group (3). This group usually has a poorer prognosis than the post-menopausal group. However, the surviving rate increased by up to 80–90% in locoregional type due to the efficient breast cancer treatment at present (2, 3). At least 60% of the overall breast cancer among the AYA group is stage II, and above with highly associated with hormonal receptor-positive and high-grade variant. Thus, they highly likely require cytotoxic chemotherapy with prolonged endocrine therapy, which leads to low fecundity (4). Therefore, the FP treatment among AYA group is paramount. The types of cryopreservation among breast cancer varies in accordance with women's preference, marital status, and the availability of the interval timeframe for FP treatment, as suggested in the FP for breast cancer referral workflow (Figure 1). Embryo cryopreservation is an established method worldwide (5). It is cost-effective and it reduces the interval of time for pregnancy because the embryo is ready to be transferred once pregnancy is desired. However, it is only permitted for women with a steady partner or those legally married, as elaborated in our second case. This treatment is the best choice among YA women as the majority had an established relationship in their life.\n\nFigure 1 The suggested referral work flow for oncofertility referral for breast cancer cases.\n\nOocyte cryopreservation is also recommended as the first line of treatment among single YA women, because it was no longer considered as experimental starting from 2013 (5, 6). However, the number of oocytes is a key to determine the prediction of successful pregnancy concerning age. Among YA women, at least 15 oocytes are required to predict a 50% chance of successful pregnancy (6). Therefore, repeat COS is needed to ensure that a justified number of oocytes could be cryopreserved prior to chemotherapy. Likewise, in our first case, the patient already managed to secure 10 oocytes and continued to collect more oocytes in a given timeframe to ensure good pregnancy outcome in the future. Impromptu initiation of COS and its safety among breast cancer had been overcome by the implementation of random start (RS) protocol with a combination of AI in supplementing conventional COS. The usage of AI is well-known to stabilize the estradiol level to reduce the risk of activating estrogen-driven cancer cell (7–10). Meanwhile, the RS protocol helps overcome the delay in starting COS in the follicular phase, thus reducing the waiting time for FP treatment (10, 11). Both of these measures have been proven as an effective strategy among cancer women without jeopardizing the numbers and quality of oocytes compared with conventional COS (8). Therefore, in our first case, we managed initiating the COS and RS-AI, and she successfully cryopreserved 10 oocytes. The subsequent cycles are still ongoing, with the aim of more oocytes to be cryopreserved.\n\nOTC is not considered as the first line for YA women with breast cancer. It is usually reserved for women with limited timeframe, because FP treatment is squeezed prior to early chemotherapy schedule or in between ongoing chemotherapy cycle, thus making the combination of oocyte and embryo cryopreservation impossible. To date, OTC is still considered as experimental (12–14). The selection of OTC candidates is currently based on Edinburg's criteria to ensure a good outcome (Table 2). Majority of the YA group who selected for FP treatment required cytotoxic chemotherapy, followed by long term hormonal suppression treatment, mainly TAM (1, 11, 12). By the time when ovarian tissue transplantation (OTT) is the aim, most of the women already had a low fertility potential due to the nature of the aging process. Fortunately, in women who received OTC, the possibility of harvesting immature oocytes simultaneously during the procedure could allow enhanced pregnancy outcome. The implementation of in-vitro maturation (IVM) made the maturation process possible, thus improving the FP outcome, because we managed to combine both oocytes and OTC (6, 14). This scenario was reflected in our third case, where the patient received OTC due to the limited timeframe and managed to secure 13 oocytes via IVM during the procedure.\n\nTable 2 The Edinburg criteria for ovarian tissue cryopreservation (1, 11, 12).\n\nCriteria's\t\nAge < 35 years old\t\nNo previous chemotherapy/ radiotherapy if age > 15 years at diagnosis but mild, non-gonadotoxic chemotherapy if < 15 years old is acceptable\t\nA realistic chance of surviving 5 years\t\nA high risk of premature ovarian insufficiency (> 50%)\t\nInform consent (parent where appropriate)\t\nNegative HIV, syphilis and hepatitis serology\t\nNon-pregnant and no existing children\t\n\nBy contrast, the implementation of gonadotropin-releasing hormone analog (GnRHa) as gonadal protection among women with breast cancer is still inconclusive (15). Most centers utilize it as a shield to reduce the direct effect of chemotherapy by creating a transient resting follicle environment. Theatrically, the resting follicles are more resistant to chemotherapeutic agents, thereby reducing the risk of ovarian damage. Surprisingly, most of the data concluded that the level of GnRHa suppression was not sufficient to protect the ovarian tissue from chemotherapeutic damage. Therefore, most of the international bodies do not recommend the usage of GnRHa as one of the FP strategies (15, 16). Currently, GnRHa is mainly used to create the transient amenorrhea period to reduce the risk of heavy menstrual bleeding while on treatment compared with FP treatment. However, GnRHa is reserved as an FP option in centers where the established FP options, such as embryo, oocyte, or ovarian cryopreservation, were not available. Therefore, GnRHa was not offered for any of our cases (11, 15, 16).\n\nConcerning germline mutation, at least 10% of young women with breast cancer were related to BRCA1 or BRCA2 gene. An increased risk of BC was seen in BRCA1 (20%) and BRCA2 (10%). Implementing these gene screenings has become an excellent strategy (17). However, they are still not widely available due to cost. Evidence did show that the BRCA-related BC ovarian reserve was lower than the non-BRCA BC (11, 18). Therefore, FP should be offered before primary cancer treatment. The choice of FP should be carefully discussed as OTC may have the risk of reintroducing ovarian cancer (OC) following OTT. The risk of OC is 40% for BRCA1 compared to that for BRCA2 at 15% (17). Therefore, a lengthy discussion should be offered before OTC. Furthermore, following OTC, BRCA mutation BC has a lower number of oocytes per ovarian tissue piece than non-BRCA BC, leading to lower pregnancy chance following OTT. Thus, oocyte and embryo cryopreservation is considered as a better option in terms of inadequate FP timeframe for stimulation. The use of COS-AI is also recommended to reduce the risk of breast tissue stimulation (7, 9). However, the risk of transferring to the offspring needs to be highlighted as an autosomal dominant (AD) link (17, 18). It could be carried in cryopreserved oocytes or embryos. Thus, pre-implantation genetic testing (PGT) should be offered before embryo transfer or the usage of oocytes to determine the status of BRCA mutation (18, 19). PGT could be a good FP strategy among BRCA BC women aiming for healthy offspring. The current limitation is the awareness and cost of testing that both lead to low uptake of FP among BRCA BC women. In our cases, none of the women was offered BRCA mutation screening due to cost, because it was not covered by insurance. As a proper FP strategy, BRCA mutation screening should be offered to young women with breast cancer to ensure good FP outcome.\n\nIn addition, most of the single women among breast cancer survivors in the YA group who received FP treatment have an increased possibility to remain single upon completion of the treatment (20). Therefore, the indefinite allowable duration of cryopreservation therapy and its effect on pregnancy outcome are still inconclusive. Previously published literature concluded that the duration of storage does not influence pregnancy outcome in cryopreserved material; thus, no timeframe was currently allocated for the duration of cryopreservation (21). The scenario is applicable to our first and third cases, as the cryopreservation will be renewed until they embark in a stable relationship and had a desire to conceive. Meanwhile, pregnancy in women with breast cancer was proven to be safe with no additional risk of recurrence with potentially more favorable prognosis compared with non-pregnant women with breast cancer (22, 23). However, the timing of pregnancy is essential. To date, no evidence that recommends a proper timeframe from the diagnosis to pregnancy could be found. Most of the centers depend on the molecular subtype, histological grade, and stage of cancer when anticipating the risk of recurrence following pregnancy. The first 2–3 years is mostly vital to ensure no pregnancy due to an increased risk of recurrence, particularly in estrogen receptor-positive cases. Some of the centers tend to defer up to 5 years, especially in luminal-type and in women with positive lymph nodes, to ensure no late relapse (24). Regarding the subtype of BC with FP outcome, triple-negative BC was reported to have decreased oocyte yield and pregnancy rates (19). Therefore, the urgency of FP should be highlighted to this group to ensure that an adequate number of oocytes or embryos could be cryopreserved before chemotherapy. Our triple-negative case opted for OTC due to limited time for stimulation. Fortunately, with the IVM, she was able to secure 13 MII oocytes. Thus, the combination of OTC and OC improved her future fertility outcome.\n\nIn our center, we practice a conjoint decision with breast oncologist in determining the overall patient status before allowing pregnancy. On the basis of standard rules, most of our cases are considered for conception at least after 24 months of endocrine therapy with no evidence of relapse. Currently, our center is included in the clinical trial for “Pregnancy Outcome and Safety of Interrupting Therapy for Women with Endocrine Responsive Breast Cancer” (The POSITIVE Trial, NCT02308085). This trial is recruiting women from the YA group with breast cancer who are willing to embark in pregnancy after receiving adjuvant endocrine therapy, either selective estrogen receptor modulator (SERM) alone or GnRHa + SERM or AI for ≥ 18 months but ≤ 30 months for early breast cancer (25). The study completed its first phase of recruitment and is now waiting for the analysis of the results. The estimated time for the completion of study recruitment is December 2028. Therefore, we allowed our fourth case to proceed with FET as she already finished the 2 years of TAM and deferred FET for at three 3 months following the last dose of TAM for “wash-out” period to ensure a good pregnancy outcome.\n\nConclusion\n\nManagement of breast cancer women in the YA group is complex, from the variant of molecular cancer subtype to the requirement of cytotoxic chemotherapy and desire for fertility. Therefore, a proper selection of cryopreservation type and targeted timeframe for pregnancy based on a joint decision from oncofertility specialist and breast oncologist is needed to facilitate the FP treatment. To date, the selection of oocytes, embryos, and ovarian tissue is widely available as an FP treatment. However, the risk of BRCA mutation transmission should be considered among BRCA BC women, and PGT should cooperate to ensure enhanced FP outcomes. GnRHa has no gonadoprotective effect and thus should not be considered as an FP option.\n\nData Availability Statement\n\nThe datasets presented in this article are not readily available because there are no data for this case series. Requests to access the datasets should be directed to nao@marianna-u.ac.jp.\n\nEthics Statement\n\nWritten informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nYS, MA, YS-T, and NS: conceptualization. YS, MA, YH-O, ST, SS, HI, ES, and YS-T: data curation. YS, MA, YH-O, YS-T, and ST: formal analysis. YS, MA, YH-O, YS-T, ST, and NS: methodology and project administration. YH-O, YS-T, ST, and NS: supervision. ES, MA, and YS-T: writing—original draft. YS, MA, YH-O, YS-T, ST, and NS: writing—review and editing. All authors have read and agreed to the published version of the manuscript.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nWe would like to thank all the staff in reproductive outpatient clinic and reproductive center who contributed to this study.\n==== Refs\nReferences\n\n1. Katanoda K Shibata A Matsuda T Hori M Nakata K Narita Y . Childhood, adolescent and young adult cancer incidence in Japan in 2009-2011. Jpn J Clin Oncol. 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Fertility preservation in BRCA mutation carriers—efficacy and safety issues: a review. Reprod Biol Endocrinol. (2020) 18 :11. 10.1186/s12958-019-0561-0 32070378\n19. Balayla J Tulandi T Buckett W Holzer H Steiner N Shrem G . Outcomes of ovarian stimulation and fertility preservation in breast cancer patients with different hormonal receptor profiles. J Assist Reprod Genet. (2020) 37 :913–21. 10.1007/s10815-020-01730-9 32144524\n20. Carreira H Williams R Müller M Harewood R Stanway S Bhaskaran K . Associations between breast cancer survivorship and adverse mental health outcomes: a systematic review. J Natl Cancer Inst. (2018) 110 :1311–27. 10.1093/jnci/djy177 30403799\n21. Aflatoonian N Pourmasumi S Aflatoonian A Eftekhar M . Duration of storage does not influence pregnancy outcome in cryopreserved human embryos. Iran J Reprod Med. (2013) 11 :843–6. 24639706\n22. Azim HA Jr Santoro L Pavlidis N Gelber S Kroman N . Safety of pregnancy following breast cancer diagnosis: a meta-analysis of 14 studies. Eur J Cancer. (2011) 47 :74–83. 10.1016/j.ejca.2010.09.007 20943370\n23. Pagani O Partridge A Korde L Badve S Bartlett J Albain K . Pregnancy after breast cancer: if you wish, ma'am. Breast Cancer Res Treat. (2011) 129 :309–17. 10.1007/s10549-011-1643-7 21698406\n24. Ives A Saunders C Bulsara M Semmens J . Pregnancy after breast cancer: population based study. BMJ. (2007) 334 :194. 10.1136/bmj.39035.667176.55 17158581\n25. Pregnancy Outcome and Safety of Interrupting Therapy for Women With Endocrine Responsive Breast Cancer (POSITIVE) (2014–2021). Available from: https://clinicaltrials.gov/ct2/show/NCT02308085 (accessed July 1, 2021).\n\n",
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"issn_linking": "2296-858X",
"issue": "8()",
"journal": "Frontiers in medicine",
"keywords": "breast cancer; cryopreservation; fertility preservation; oncofertility; young adult",
"medline_ta": "Front Med (Lausanne)",
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"pages": "670872",
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"pmid": "34422852",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "15894097;30875815;29259426;30723908;32070378;15811616;30607119;17158581;20943370;32419845;24639706;30377391;24707345;28541571;25729416;21698406;31190993;28874104;29620997;16651642;32144524;30403799;32046442",
"title": "Case Report: Young Adults With Breast Cancer: A Case Series of Fertility Preservation Management and Literature Review.",
"title_normalized": "case report young adults with breast cancer a case series of fertility preservation management and literature review"
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... |
{
"abstract": "Codeine has a spasmodic effect on sphincter of Oddi and is suspected to cause acute pancreatitis in patients with a history of cholecystectomy.\n\n\n\nTo assess the association between codeine use and acute pancreatitis in patients with a previous cholecystectomy.\n\n\n\nWe conducted a retrospective nested case-control study using the 2005-2015 MarketScan® Commercial Claims and Encounters Database. The cohort included patients aged 18-64; cohort entry began 365 days after cholecystectomy. Odds ratios (ORs) and 95% CIs for acute pancreatitis hospitalization were estimated comparing use of codeine with non-use of codeine. In a secondary analysis, use of codeine was compared with an active comparator: use of non-steroidal anti-inflammatory drugs (NSAIDs).\n\n\n\nOf the 664,083 patients included in the cohort, 1707 patients were hospitalized for acute pancreatitis (incidence 1.1 per 1000 person-years) and were matched to 17,063 controls. Compared with non-use of codeine, use of codeine was associated with an increased risk of acute pancreatitis (OR 2.67; 95% CI 1.63, 4.36), particularly elevated in the first 15 days of codeine use (OR 5.37; 95% CI 2.70, 10.68). Compared with use of NSAIDs, use of codeine was also associated with an increased risk of acute pancreatitis (OR 2.64; 95% CI 1.54, 4.52).\n\n\n\nCodeine is associated with an increased risk of acute pancreatitis in patients who have previously undergone cholecystectomy; greater clinician awareness of this association is needed.",
"affiliations": "Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, P.O. Box 100496, Gainesville, FL, USA. jhkim.ek@gmail.com.;REMEDY, Emergency Department, Royal Derby Hospital, Uttoxeter Road, Derby, DE22 3NE, UK.;REMEDY, Emergency Department, Royal Derby Hospital, Uttoxeter Road, Derby, DE22 3NE, UK.;Department of Biostatistics, College of Public Health and Health Professions, College of Medicine, University of Florida, P.O. Box 117450, Gainesville, FL, 32611, USA.;Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, P.O. Box 100496, Gainesville, FL, USA.",
"authors": "Kim|Juhyeun|J|0000-0001-6323-4785;Tabner|Andrew John|AJ|;Johnson|Graham David|GD|;Brumback|Babette A|BA|;Hartzema|Abraham|A|",
"chemical_list": "D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003061:Codeine",
"country": "United States",
"delete": false,
"doi": "10.1007/s10620-019-05803-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-2116",
"issue": "65(1)",
"journal": "Digestive diseases and sciences",
"keywords": "Acute pancreatitis; Cholecystectomy; Codeine; Sphincter of Oddi",
"medline_ta": "Dig Dis Sci",
"mesh_terms": "D000208:Acute Disease; D000067575:Administrative Claims, Healthcare; D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002763:Cholecystectomy; D003061:Codeine; D016208:Databases, Factual; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010195:Pancreatitis; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D055815:Young Adult",
"nlm_unique_id": "7902782",
"other_id": null,
"pages": "292-300",
"pmc": null,
"pmid": "31468265",
"pubdate": "2020-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "21673538;26978756;16518275;12136374;25983269;15334697;11489400;24331075;27435328;11095359;29430565;3729583;9598820;19857610;29536056;23628270;26019439;3197985;26085977;15460170;29499361;23138573;23395525;11922555;8884856;10891755;8644362;9557456;15946633;9414983;18577477;24198981;16803609;16293553;7678324;9700957;26157656",
"title": "Increased Risk of Acute Pancreatitis with Codeine Use in Patients with a History of Cholecystectomy.",
"title_normalized": "increased risk of acute pancreatitis with codeine use in patients with a history of cholecystectomy"
} | [
{
"companynumb": "US-JNJFOC-20200138069",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRAMADOL HYDROCHLORIDE"
},
"drugadditional": "3",... |
{
"abstract": "OBJECTIVE\nTo summarize the efficacy and examine the safety and tolerability of pregabalin in patients with central neuropathic pain due to spinal cord injury (SCI).\n\n\nMETHODS\nData were pooled from two 12 to 16 week, placebo-controlled trials of pregabalin in patients with neuropathic pain due to SCI. Pain diaries were used to rate pain from 0 = no pain to 10 = worst possible pain. Efficacy measures included: mean change in pain from baseline to endpoint; duration adjusted average change (DAAC) in pain; the percentage of patients with ≥30% or ≥50% reductions in pain score from baseline to endpoint; and Patient Global Impression of Change (PGIC) score at endpoint. Adverse events (AEs) were also compared between treatment groups.\n\n\nRESULTS\nIn total 174 patients received placebo and 182 received pregabalin. Mean change in pain from baseline to endpoint was improved in the pregabalin group compared with placebo (placebo-adjusted difference = -0.79; 95% CI = -1.15, -0.43; p < 0.001; baseline-observation-carried-forward). DAAC in pain was improved in patients receiving pregabalin compared with placebo (p < 0.001). The percentage of patients achieving ≥30% and ≥50% reductions in pain from baseline to endpoint was greater in the pregabalin arm compared with placebo (placebo: 30% = 22.5%, 50% = 11.6: pregabalin 30% = 35.6%, 50% = 22.4%) (all p < 0.01). PGIC scores at endpoint were significantly better in the pregabalin arm compared with placebo (p < 0.05). Treatment-related AEs, most commonly somnolence, dizziness, dry mouth, fatigue, edema, blurred vision, and constipation occurred more frequently in patients treated with pregabalin than placebo. The majority of AEs were mild to moderate in severity.\n\n\nCONCLUSIONS\nPregabalin reduced neuropathic pain due to SCI over a 12 to 16 week treatment period. Treatment-related AEs were mostly mild to moderate in severity and are consistent with the known safety profile of pregabalin. These findings should not be extrapolated to longer durations of treatment or other patient populations.",
"affiliations": "Pfizer Inc. , New York, NY , USA.",
"authors": "Parsons|Bruce|B|;Sanin|Luis|L|;Yang|Ruoyong|R|;Emir|Birol|B|;Juhn|Mark|M|",
"chemical_list": "D000700:Analgesics; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid",
"country": "England",
"delete": false,
"doi": "10.1185/03007995.2013.834815",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-7995",
"issue": "29(12)",
"journal": "Current medical research and opinion",
"keywords": null,
"medline_ta": "Curr Med Res Opin",
"mesh_terms": "D000328:Adult; D000700:Analgesics; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D009437:Neuralgia; D059408:Pain Management; D010147:Pain Measurement; D000069583:Pregabalin; D013119:Spinal Cord Injuries; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "0351014",
"other_id": null,
"pages": "1675-83",
"pmc": null,
"pmid": "23998397",
"pubdate": "2013-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy and safety of pregabalin in patients with spinal cord injury: a pooled analysis.",
"title_normalized": "efficacy and safety of pregabalin in patients with spinal cord injury a pooled analysis"
} | [
{
"companynumb": "US-PFIZER INC-2017552040",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREGABALIN"
},
"drugadditional": "3",
... |
{
"abstract": "A case is descibed of radiation recall dermatitis in a patient treated with adjuvant radiation therapy followed by capecitabine for triple negative breast cancer with residual disease after neoadjuvant chemotherapy.",
"affiliations": "Department of Therapeutic Radiology.;Department of Dermatology.;Department of Medical Oncology.;Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut. Electronic address: shari.damast@yale.edu.",
"authors": "Laird|James|J|;Leventhal|Jonathan|J|;Kanowitz|Jane|J|;Damast|Shari|S|",
"chemical_list": "D000069287:Capecitabine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.prro.2021.06.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1879-8500",
"issue": "11(6)",
"journal": "Practical radiation oncology",
"keywords": null,
"medline_ta": "Pract Radiat Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D000069287:Capecitabine; D017024:Chemotherapy, Adjuvant; D005260:Female; D006801:Humans; D020360:Neoadjuvant Therapy; D018365:Neoplasm, Residual; D011855:Radiodermatitis; D064726:Triple Negative Breast Neoplasms",
"nlm_unique_id": "101558279",
"other_id": null,
"pages": "448-452",
"pmc": null,
"pmid": "34157449",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Radiation Recall Dermatitis After Capecitabine in a Patient With Triple Negative Breast Cancer.",
"title_normalized": "radiation recall dermatitis after capecitabine in a patient with triple negative breast cancer"
} | [
{
"companynumb": "US-DRREDDYS-SPO/USA/21/0138029",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "... |
{
"abstract": "BACKGROUND\nMetopic suture synostosis leading to trigonocephaly is considered the second most frequent type of craniosynostosis. Besides esthetic results, we present 25 consecutive pediatric cases operated upon metopic suture synostosis with a focus on the child's motor, speech, and neurocognitive development.\n\n\nMETHODS\nTwenty-five children (aged 6 to 33 months; median 9.2 months) with trigonocephaly were operated upon between 2002 and 2012 with fronto-orbital advancement including frontal bone cranioplasty and fronto-orbital bandeau remodeling. Neurodevelopmental deficits were evaluated by a standardized questionnaire including gross motor function, manual coordination, speech, and cognitive function performed by independent pediatric/developmental neurologists before surgery and at 6 and 12 months of time interval postoperatively.\n\n\nRESULTS\nTwenty-one (84 %) boys and four (16 %) girls were included in this study. Mean follow-up period was 33 ± 28 months. Outcome analysis for esthetic results showed a high degree of satisfaction by the parents and treating physicians in 23 cases (92 %). Preoperative evaluation revealed neurodevelopmental deficits in 10 children (40 %; six mild, four moderate degree). Twelve children (48 %) were proven to have a normal preoperative neuropediatric development. Mild or moderate developmental restraints were no longer apparent in 6/13, improved but still apparent in 3/13, and stable in 4/13, 6 months after cranial vault reconstruction. At 12 months of follow-up, deficits were no longer present in 9/13 and improved in 4/13. Apart from this cohort, two children were diagnosed with a syndromic form, and one child had a fetal valproate syndrome. In these three children, neurodevelopmental deficits were more pronounced. Neurocognitive progress was obvious, but was comparably slower, and major deficits were still apparent at last follow-up. All children with proven mild/moderate/severe deficits received intensive physiotherapy, logopedic, or neurobehavioral support.\n\n\nCONCLUSIONS\nAs shown in a single-center observation, surgical correction of metopic suture synostosis not only refines esthetic appearance but also might improve neurodevelopmental outcome if deficits are apparent, even in syndromic forms of the deformity under additional physiotherapy, logopedic, or neurobehavioral support.",
"affiliations": "Department of Neurosurgery, Klinikum Großhadern, Ludwig-Maximilians-University Munich, Marchioninistrasse 15, 81377, Munich, Germany.",
"authors": "Kunz|Mathias|M|;Lehner|Markus|M|;Heger|Alfred|A|;Armbruster|Lena|L|;Weigand|Heike|H|;Mast|Gerson|G|;Peraud|Aurelia|A|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00381-013-2340-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0256-7040",
"issue": "30(6)",
"journal": "Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery",
"keywords": null,
"medline_ta": "Childs Nerv Syst",
"mesh_terms": "D002675:Child, Preschool; D003072:Cognition Disorders; D003398:Craniosynostoses; D002658:Developmental Disabilities; D005260:Female; D005624:Frontal Bone; D006801:Humans; D021621:Imaging, Three-Dimensional; D007223:Infant; D008297:Male; D011183:Postoperative Complications; D011597:Psychomotor Performance; D019651:Reconstructive Surgical Procedures; D012189:Retrospective Studies; D013060:Speech; D011795:Surveys and Questionnaires; D015898:Tomography Scanners, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "8503227",
"other_id": null,
"pages": "1075-82",
"pmc": null,
"pmid": "24337567",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article",
"references": "15185114;21724409;11151714;17328262;19569905;19326483;17186250;19164997;8695623;21233734;10654710;21187784;15871027;20888312;22246335;15861054;12042920;15714353;16770193;15864600;22872249;9734408;8911474;17569057;19357856;18216668;22373978",
"title": "Neurodevelopmental and esthetic results in children after surgical correction of metopic suture synostosis: a single institutional experience.",
"title_normalized": "neurodevelopmental and esthetic results in children after surgical correction of metopic suture synostosis a single institutional experience"
} | [
{
"companynumb": "DE-ABBVIE-14P-062-1256140-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VALPROATE SODIUM"
},
"drugadditional": nul... |
{
"abstract": "It is not yet entirely clear what is the relevance of skin symptoms and what clinical implications are related to their appearance in COVID-19 patients. We describe two cases of COVID-19-associated pneumonia, which presented skin manifestations in advanced stage of illness, when nasopharyngeal swabs became negative for SARS-CoV-2. The first case presented erythematous, maculopapular lesions; the second developed petechial, vesicular and blood-encrusted lesions on the limbs. Histopathology documented perivascular lymphocytic infiltrates, with prevalent CD4+ T-cells in both patients. The research of SARS-CoV-2 in tissues with real time RT-PCR was negative. Basal keratinocytes displayed C4d deposits in one case, who developed laboratory signs indicative of a procoagulative condition at the same time as the skin rash. Skin manifestations during SARS-CoV-2 infection seem to be clinically relevant and further studies are necessary to assess if they are linked to systemic complications, lack of viral clearance or cascades of immune responses induced by the virus, even in patients affected by mild pneumonia.",
"affiliations": "Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases \"L. Spallanzani\" IRCCS, Rome, Italy.;Dermatology Consultation Service, National Institute for Infectious Diseases \"L. Spallanzani\" IRCCS, Rome, Italy.;Pathology Unit, National Institute for Infectious Diseases \"L. Spallanzani\" IRCCS, Rome, Italy.;Virology Unit, National Institute for Infectious Diseases \"L. Spallanzani\" IRCCS, Rome, Italy.;Laboratory of Electron Microscopy, National Institute for Infectious Diseases \"L. Spallanzani\", IRCCS, Rome, Italy.;Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases \"L. Spallanzani\" IRCCS, Rome, Italy.;Laboratory of Electron Microscopy, National Institute for Infectious Diseases \"L. Spallanzani\", IRCCS, Rome, Italy.;Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases \"L. Spallanzani\" IRCCS, Rome, Italy.;Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases \"L. Spallanzani\" IRCCS, Rome, Italy.;Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases \"L. Spallanzani\" IRCCS, Rome, Italy.;Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases \"L. Spallanzani\" IRCCS, Rome, Italy.;Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases \"L. Spallanzani\" IRCCS, Rome, Italy.;Pathology Unit, National Institute for Infectious Diseases \"L. Spallanzani\" IRCCS, Rome, Italy.;Virology Unit, National Institute for Infectious Diseases \"L. Spallanzani\" IRCCS, Rome, Italy.;Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases \"L. Spallanzani\" IRCCS, Rome, Italy.",
"authors": "Mencarini|Paola|P|https://orcid.org/0000-0001-8928-8183;Scarabello|Alessandra|A|;Del Nonno|Franca|F|;Lalle|Eleonora|E|;Falasca|Laura|L|;Gualano|Gina|G|;Nardacci|Roberta|R|;Mosti|Silvia|S|;Musso|Maria|M|;Libertone|Raffaella|R|;Di Bari|Virginia|V|;Rosati|Silvia|S|;Colombo|Daniele|D|;Castilletti|Concetta|C|;Palmieri|Fabrizio|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/1346-8138.15714",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-2407",
"issue": "48(5)",
"journal": "The Journal of dermatology",
"keywords": "COVID-19; SARS-CoV-2 infection; inflammation markers; rash; skin biopsy",
"medline_ta": "J Dermatol",
"mesh_terms": "D000086382:COVID-19; D000086742:COVID-19 Testing; D004890:Erythema; D005076:Exanthema; D006801:Humans; D000086402:SARS-CoV-2",
"nlm_unique_id": "7600545",
"other_id": null,
"pages": "651-656",
"pmc": null,
"pmid": "33624293",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Dermatological manifestations during COVID-19 and histological picture: Description of two clinical cases.",
"title_normalized": "dermatological manifestations during covid 19 and histological picture description of two clinical cases"
} | [
{
"companynumb": "IT-TEVA-2021-IT-1931229",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Tyrosine kinase inhibitors (TKIs) are widely used for systemic chemotherapy of hepatocellular carcinoma (HCC). Arterial thromboembolism (ATE) has been reported to be an adverse event associated with TKI therapy, but its incidence is rare. Here, we report a case of an HCC patient who developed a thrombus in the superior mesenteric artery (SMA) while on TKI therapy. The patient was a 78-year-old Japanese man with hepatitis C virus-associated HCC with multiple nodules. Several sessions of transarterial chemoembolization therapy caused him to become refractory to the treatment. Sorafenib and regorafenib therapy had also been previously performed, but his disease continued to progress gradually. Therefore, we started lenvatinib therapy. When a contrast-enhanced computed tomography (CT) examination was performed 2 months later, we found a thrombus in the SMA. Retrospective analysis of the CT images revealed that the thrombus formed during the sorafenib-regorafenib sequential therapy and it developed rapidly, especially during the lenvatinib therapy. An HCC patient developed a thrombus in the SMA during TKI therapy. The incidence of ATE is rare in TKI treatment; however, long-term or sequential TKI therapy may increase the frequency of ATE. Further study is needed.",
"affiliations": "Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan. t-nawa@mc.pref.osaka.jp.;Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan.;Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan.;Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan.;Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan.;Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan.;Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan.;Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan.;Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan.;Department of Gastroenterology, Yao Municipal Hospital, 1-3-1 Ryugecho, Yao, Osaka, 581-0069, Japan.;Department of Onco-Cardiology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan.;Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan.",
"authors": "Nawa|Takatoshi|T|http://orcid.org/0000-0002-5604-5676;Katayama|Kazuhiro|K|;Kiyota|Ryosuke|R|;Imai|Toshihiro|T|;Abe|Yutaro|Y|;Hasegawa|Noriko|N|;Takada|Ryoji|R|;Fukutake|Nobuyasu|N|;Ikezawa|Kenji|K|;Sakakibara|Mitsuru|M|;Fujita|Masashi|M|;Ohkawa|Kazuyoshi|K|",
"chemical_list": "D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D011505:Protein-Tyrosine Kinases; C531958:lenvatinib",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-019-01021-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "13(2)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Arterial thromboembolism; Hepatocellular carcinoma; Lenvatinib; Sequential therapy; Tyrosine kinase inhibitor",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000368:Aged; D006528:Carcinoma, Hepatocellular; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D017538:Mesenteric Artery, Superior; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011804:Quinolines; D012189:Retrospective Studies; D013927:Thrombosis",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "247-251",
"pmc": null,
"pmid": "31317371",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18650514;20351323;21898496;28223329;25589937;30483103;25197551;25295214;30575325;21351269;29433850;19150949;29231094;27932229;29703600;29704513;20156114;25667293;23561917",
"title": "Development of a thrombus in the superior mesenteric artery associated with sequential therapy with tyrosine kinase inhibitors for hepatocellular carcinoma.",
"title_normalized": "development of a thrombus in the superior mesenteric artery associated with sequential therapy with tyrosine kinase inhibitors for hepatocellular carcinoma"
} | [
{
"companynumb": "JP-EISAI MEDICAL RESEARCH-EC-2018-043912",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LENVATINIB"
},
"drugadditional... |
{
"abstract": "Over the last few decades, cocaine and morphine (heroin) have been among the primary causes of deaths related to drug abuse. Cocaine is frequently altered by dilution, substitution, contamination, and adulteration. Trimethoprim has never been identified in the powders of cocaine, making this the first post-mortem case report in which the presence of this compound is described. The case reported here is that of a 46-year-old woman with a history of cocaine and morphine abuse who was found dead inside her bathroom. The police found the corpse next to a syringe, with a telephone card containing trace of cocaine on the sink. Toxicological analysis was performed, and drug levels were measured by means of gas chromatography/mass spectrometry. In addition to the presence of cocaine and smaller alkaloids, trimethoprim was also detected on the syringe and telephone card and in the woman's nasal mucosa. Trimethoprim analysis is very quick and easy and can be added to the routine analysis of drugs of abuse seized on the illicit market to obtain more information.",
"affiliations": "Institute of Public Health, Section of Legal Medicine, Università Cattolica del Sacro Cuore, Largo F. Vito, Rome, Italy nadiafucci@rm.unicatt.it.;Institute of Public Health, Section of Legal Medicine, Università Cattolica del Sacro Cuore, Largo F. Vito, Rome, Italy.",
"authors": "Fucci|Nadia|N|;Pascali|Vincenzo L|VL|",
"chemical_list": "D065687:Cytochrome P-450 CYP2C8 Inhibitors; D009020:Morphine; D014295:Trimethoprim; D003042:Cocaine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-7370",
"issue": "44(4)",
"journal": "Annals of clinical and laboratory science",
"keywords": "comparative analysis; illicit cocaine; trimethoprim",
"medline_ta": "Ann Clin Lab Sci",
"mesh_terms": "D003042:Cocaine; D019970:Cocaine-Related Disorders; D065687:Cytochrome P-450 CYP2C8 Inhibitors; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D009020:Morphine; D014295:Trimethoprim",
"nlm_unique_id": "0410247",
"other_id": null,
"pages": "499-501",
"pmc": null,
"pmid": "25361939",
"pubdate": "2014",
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"references": null,
"title": "Acute morphine and cocaine related death after trimethoprim-adultered cocaine abuse.",
"title_normalized": "acute morphine and cocaine related death after trimethoprim adultered cocaine abuse"
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"companynumb": "IT-ROXANE LABORATORIES, INC.-2015-RO-00051RO",
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"abstract": "Temporal lobe epilepsy is a rare but treatable cause of apnoea.",
"affiliations": "West Middlesex University Hospital, London TW7 6AF, UK.;National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.",
"authors": "Wu|Zhe|Z|;Rugg-Gunn|Fergus|F|",
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"country": "England",
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"doi": "10.1177/2054270414554246",
"fulltext": "\n==== Front\nJRSM OpenJRSM OpenSHRspshrJRSM Open2054-2704SAGE Publications Sage UK: London, England 10.1177/205427041455424610.1177_2054270414554246Case ReportsBreathing difficulty in a middle-aged woman – a dangerous cause? Wu Zhe 1Rugg-Gunn Fergus 21 West Middlesex University Hospital, London TW7 6AF, UK2 National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UKZhe Wu. Email: zjwu87900@yahoo.co.uk19 1 2015 1 2015 6 1 2054270414554246© The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav2015The Royal Society of MedicineThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page(http://www.uk.sagepub.com/aboutus/openaccess.htm).Lesson\nTemporal lobe epilepsy is a rare but treatable cause of apnoea.\n\ntemporal lobe epilepsyictal apnoea\n==== Body\nA previously fit and well 47-year-old teacher initially presented in 2007 with a two-year history of recurrent episodes characterised by a sensation of detachment followed by speech disturbance, lasting 60 s on each occasion. These were occurring on average every three months. She retained awareness, had no post-event confusion and no motor automatisms. A magnetic resonance imaging (MRI) brain scan and electroencephalography (EEG) were unremarkable.\n\nThe possibility of simple partial seizures was considered but the symptoms were thought atypical; there was a strong temporal relationship with increasing stress at work and the patient was concerned about starting potentially long-term anti-epileptic medication. The episodes settled spontaneously and she remained well until November 2008, when following a particularly stressful and busy week, she suffered an episode of involuntary nocturnal vigorous chest thrusting lasting 20 min, followed by apparent unresponsiveness and mild confusion for 10 min. A repeat EEG and MRI were again unremarkable.\n\nAfter reducing her workload, no further events occurred until October 2009 when she experienced an episode characterised by severe postural arching of her back followed by waking up gasping for breath. Identical episodes, arising only from sleep, occurred over the next few months. Home oximetry studies recorded desaturations of less than 60%. Formal spirometry was normal and she was extremely fit, running in excess of 25 miles per week. Her sleep study was unremarkable although no episodes occurred during the recording period. She was reviewed by the respiratory team, and a primary respiratory mechanism was thought to be unlikely.\n\nAfter repeated sleep studies and EEG recordings without capturing a clinical event, a five-day period of video EEG/ECG telemetry showed rare interictal epileptiform abnormalities over the left temporal lobe at night. Neither nocturnal attacks nor desaturations were recorded. In light of the EEG findings, the MRI was repeated and revealed a subtle area of cortical dysplasia around the left amygdala and adjacent cortex (Figure 1).\nFigure 1. MRI brain with arrow showing left cortical dysplasia.\n\n\n\nA presumed diagnosis of ictal apnoea was made and anti-epileptic medication was recommended. The patient developed significant side-effects, such as sedation, cognitive slowing and dizziness at low doses of a number of different medications, including levetiracetam, clobazam and lamotrigine, and she was concerned about the veracity of the diagnosis. Finally, another video EEG study captured two EEG events typical for left temporal lobe seizures with a 23-s period of apnoea preceding the second event (Figure 2). The dose of her anti-epileptic medication, lacosamide, was increased and her seizures improved subsequently.\nFigure 2. EEG showing a 23 second period of apnoea (red arrow) prior to epileptiform activity (blue arrow).\n\n\n\nHypoventilation during sleep can be due to obstructive or central causes. Although most cases are due to obstruction, a normal body habitus with no evidence of snoring should raise the suspicion of a central cause. Central sleep apnoea is characterised by the interruption of airflow and respiratory effort for at least 10 s on polysomnography.1 The most common causes are primary central apnoea, drug-related apnoea, Cheyne-Stokes breathing pattern often seen in heart failure and apnoea in stroke and neurodegenerative diseases.2\n\nIctal apnoea is a rare but treatable cause. The unusual seizure semiology during our patient’s nocturnal episodes is likely to be due to the additional effects of the apnoea/hypoxia. Ictal apnoea is important to recognise, as this is a candidate pathophysiological mechanism underlying sudden unexpected death in epilepsy (SUDEP). Alternative mechanisms include cardiac dysrhythmias and post-ictal generalised EEG suppression, ‘cerebral shutdown’. SUDEP is defined as sudden death that is not due to trauma, drowning, status epilepticus, a structural or toxicological cause.3 Sudden death is 20 times more likely in epileptics than the general population and increased frequency of generalised tonic clonic seizures is the major risk factor.3 However, nocturnal supervision confers some protection.4\n\nIn our case, the diagnosis was not straightforward. Typically, temporal lobe seizure semiology includes déjà and jamais vu, a rising epigastric sensation, olfactory or gustatory hallucinations, aphasia and automatisms.5 Impaired consciousness and amnesia during the event may occur. Our patient had speech disturbance but no other key features. Diagnosis was only made after repeated video EEG telemetry. This case reports the unusual presentation of ictal apnoea in temporal lobe epilepsy and illustrates the importance of persistence in investigating patients with undiagnosed intermittent symptoms. Importantly, clinicians should be aware that while correct diagnosis means treatment can be initiated, an incorrect verdict causes unwarranted stress and anxiety.\n\nDeclarations\nCompeting interests\nNone declared\n\nFunding\nFR-G is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.\n\nEthical approval\nWritten informed consent for publication was obtained from the patient.\n\nGuarantor\nFR-G\n\nContributorship\nBoth authors are equally responsible for the conception, drafting the article and revising it critically for important intellectual content and final approval of the article.\n\nAcknowledgements\nWe would like to thank the patient for her consent for publication.\n\nProvenance\nNot commissioned; peer-reviewed by Ricardo Oliveira-Souza.\n==== Refs\nReferences\n1 American Academy of Sleep Medicine. International classification of sleep disorders. 2nd ed. Diagnostic and coding manual. Westchester, IL: American Academy of Sleep Medicine, 2005, p.35–37 .\n2 Chowdhuri S Badr MS \nCentral sleep apnoea . Indian J Med Res \n2010 ; 131 : 150 –164 .20308740 \n3 Shorvon S Tomson T \nSudden unexpected death in epilepsy . Lancet \n2011 ; 378 : 2028 –2038 .21737136 \n4 Nashef L Garner S Sander JWAS Fish DR Shorvon SD \nCircumstances of death in sudden death in epilepsy: interviews of bereaved relatives . J Neurol Neurosurg Psychiatry \n1998 ; 64 : 349 –352 .9527147 \n5 Blair RD \nTemporal lobe epilepsy semiology . Epilepsy Res Treat \n2012 ; 2012 : 751510 –751510 .22957241\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2054-2704",
"issue": "6(1)",
"journal": "JRSM open",
"keywords": "ictal apnoea; temporal lobe epilepsy",
"medline_ta": "JRSM Open",
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"nlm_unique_id": "101625786",
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"pages": "2054270414554246",
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"pmid": "25852950",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports",
"references": "20308740;21737136;22957241;9527147",
"title": "Breathing difficulty in a middle-aged woman - a dangerous cause?",
"title_normalized": "breathing difficulty in a middle aged woman a dangerous cause"
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"abstract": "Parvovirus B19 (PVB19) is a DNA virus which causes clinically relevant infection in renal transplant recipients (RTR) leading to significant morbidity. Manifestations include erythropoietin resistant anemia, proteinuria, and glomerulosclerosis in the allograft. Severe infection may require administration of intravenous immunoglobulin, reduction in immunosuppression and transfusions. The major challenge in managing and preventing the infection in RTR involves the act of balancing the decreased level of immunosuppression and the risk of rejection. The objective of this article is to understand the importance of PVB19 infection and its outcome in RTR. We reviewed the medical records of three RTR with confirmed PVB19 infection and recorded patient information including demographics, clinical and laboratory data, management, and outcome. The average time of occurrence of PVB19 infection as transplant was 8.6 weeks and they presented with symptomatic anemia. Elevated creatinine values were noted in two of them. Following treatment, anemia improved and creatinine values returned to baseline. One of them developed an early relapse and had to be treated once again similarly. We emphasize the importance of maintaining a high index of suspicion for PVB19 infection in patients with anemia in the posttransplant phase, especially in patients on higher doses of immunosuppressants. Early and proper treatment can prevent worsening clinical condition and possible effects on the allograft.",
"affiliations": "Department of Transplant Program, North Shore University Hospital, Boulevard, Manhasset, New York.;Department of Transplant Program, North Shore University Hospital, Boulevard, Manhasset, New York.;Department of Transplant Program, North Shore University Hospital, Boulevard, Manhasset, New York.;Department of Transplant Program, North Shore University Hospital, Boulevard, Manhasset, New York.;Department of Transplant Program, North Shore University Hospital, Boulevard, Manhasset, New York.;Department of Transplant Program, North Shore University Hospital, Boulevard, Manhasset, New York.;Department of Anesthesiology, Brookdale University Hospital and Medical Center, Boulevard, Manhasset, New York.;Department of Transplant Program, North Shore University Hospital, Boulevard, Manhasset, New York.;Department of Nephrology, North Shore University Hospital, Boulevard, Manhasset, New York.;Department of Transplant Program, North Shore University Hospital, Boulevard, Manhasset, New York.;Department of Transplant Program, North Shore University Hospital, Boulevard, Manhasset, New York.;Department of Transplant Program, North Shore University Hospital, Boulevard, Manhasset, New York.;Department of Transplant Program, North Shore University Hospital, Boulevard, Manhasset, New York.",
"authors": "Krishnan|Prathik|P|;Ramadas|Poornima|P|;Rajendran|Prejith P|PP|;Madhavan|Parvathy|P|;Alex|Asha|A|;Jayaschandran|Vivek|V|;Humayun|Shaesta G|SG|;Ali|Nicole|N|;Sachdeva|Mala|M|;Flecha|Antonette|A|;Basu|Amit|A|;Bhaskaran|Madhu|M|;Molmenti|Ernesto P|EP|",
"chemical_list": null,
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"issn_linking": "1061-1711",
"issue": "24(2)",
"journal": "The International journal of angiology : official publication of the International College of Angiology, Inc",
"keywords": "allograft; anemia; immunosuppression; intravenous immunoglobulin; parvovirus B19; renal transplant",
"medline_ta": "Int J Angiol",
"mesh_terms": null,
"nlm_unique_id": "9504821",
"other_id": null,
"pages": "87-92",
"pmc": null,
"pmid": "26060378",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article",
"references": "17895931;19099488;23465012;10852625;12270996;17699510;20070674;18522549;16433780;7615755;11152317;8672044;22310606;12042652;11127313;3037373;15543575;10585325;12637086;12123207;11992590;16758416",
"title": "Effects of Parvovirus B19 Infection in Renal Transplant Recipients: A Retrospective Review of Three Cases.",
"title_normalized": "effects of parvovirus b19 infection in renal transplant recipients a retrospective review of three cases"
} | [
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
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"abstract": "Four preterm infants receiving long-term furosemide therapy were examined for hypercalciuria, hyperparathyroidism, renal calcification, and bone demineralization. All four infants had increased urinary calcium excretion. Three infants had high serum concentrations of parathyroid hormone, and in these three infants, bone mineral content was below the mean of \"osteopenic\" preterm infants of comparable gestational and postnatal age. In two of these infants, there was ultrasound evidence of renal calcification. In one infant, autopsy disclosed bone changes of hyperparathyroidism, gallstones, and calcification in the heart and kidney.",
"affiliations": null,
"authors": "Venkataraman|P S|PS|;Han|B K|BK|;Tsang|R C|RC|;Daugherty|C C|CC|",
"chemical_list": "D010281:Parathyroid Hormone; D005665:Furosemide; D002118:Calcium",
"country": "United States",
"delete": false,
"doi": "10.1001/archpedi.1983.02140380017006",
"fulltext": null,
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"issn_linking": "0002-922X",
"issue": "137(12)",
"journal": "American journal of diseases of children (1960)",
"keywords": null,
"medline_ta": "Am J Dis Child",
"mesh_terms": "D001847:Bone Diseases; D001842:Bone and Bones; D002118:Calcium; D005665:Furosemide; D006801:Humans; D006962:Hyperparathyroidism, Secondary; D007231:Infant, Newborn; D007235:Infant, Premature, Diseases; D007669:Kidney Calculi; D010281:Parathyroid Hormone; D012127:Respiratory Distress Syndrome, Newborn; D013997:Time Factors; D014463:Ultrasonography",
"nlm_unique_id": "0370471",
"other_id": null,
"pages": "1157-61",
"pmc": null,
"pmid": "6637931",
"pubdate": "1983-12",
"publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Secondary hyperparathyroidism and bone disease in infants receiving long-term furosemide therapy.",
"title_normalized": "secondary hyperparathyroidism and bone disease in infants receiving long term furosemide therapy"
} | [
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"companynumb": "US-PFIZER INC-2017543484",
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"activesubstancename": "CALCIUM"
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"abstract": "Ectopic kidney and inherent vascular abnormalities may result in renovascular hypertension. The case we report is peculiar as a left ectopic iliac kidney supplied by a superior and an inferior polar renal arteries was detected in a treatment-resistant hypertensive man. In conclusion, percutaneous renal artery denervation was successfully performed in the right renal artery and in both left accessory renal arteries, obtaining excellent blood pressure decrease at follow-up.",
"affiliations": "Centro Cardiologico \"Monzino\", IRCCS, Institute of Cardiology, University of Milan, Via Parea, 4, 20138, Milan, Italy. daniela.trabattoni@ccfm.it.;Centro Cardiologico \"Monzino\", IRCCS, Institute of Cardiology, University of Milan, Via Parea, 4, 20138, Milan, Italy.;Centro Cardiologico \"Monzino\", IRCCS, Institute of Cardiology, University of Milan, Via Parea, 4, 20138, Milan, Italy.;Centro Cardiologico \"Monzino\", IRCCS, Institute of Cardiology, University of Milan, Via Parea, 4, 20138, Milan, Italy.",
"authors": "Trabattoni|Daniela|D|;Teruzzi|Giovanni|G|;Cia|Alessia Dalla|AD|;Fabbiocchi|Franco|F|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s12928-016-0405-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1868-4297",
"issue": "32(3)",
"journal": "Cardiovascular intervention and therapeutics",
"keywords": "Ectopic kidney; Renal denervation; Resistant hypertension",
"medline_ta": "Cardiovasc Interv Ther",
"mesh_terms": "D000368:Aged; D003714:Denervation; D006801:Humans; D006977:Hypertension, Renal; D007668:Kidney; D008297:Male; D010388:Pelvis; D012077:Renal Artery; D014057:Tomography, X-Ray Computed; D017211:Treatment Failure",
"nlm_unique_id": "101522043",
"other_id": null,
"pages": "259-262",
"pmc": null,
"pmid": "27240463",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Renal denervation in a patient with unilateral ectopic kidney in the pelvis and refractory hypertension.",
"title_normalized": "renal denervation in a patient with unilateral ectopic kidney in the pelvis and refractory hypertension"
} | [
{
"companynumb": "IT-DSJP-DSE-2017-145837",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
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"activesubstancename": "RAMIPRIL"
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"abstract": "BACKGROUND\nPublished guidelines recommend baseline cardiac function testing before initiating anthracycline-based chemotherapy. These recommendations are based largely on consensus, and there is little information regarding how often testing leads to alterations in therapy or whether testing is able to predict subsequent cardiac toxicity.\n\n\nMETHODS\nWe performed a retrospective analysis of patients with Hodgkin lymphoma and non-Hodgkin lymphoma to determine whether there was a prechemotherapy evaluation of left ventricular function and whether findings from the evaluation led to alterations in therapy. Records also were reviewed to evaluate subsequent test results of cardiac function.\n\n\nRESULTS\nWe identified 309 patients with lymphoma between 2004 and 2012 with a planned anthracycline- or anthracenedione-based regimen. Of this total, 232 patients (75%) had a pretreatment cardiac evaluation. There were 201 patients (87%) in this group with no history of cardiac disease. Although 22 of these patients (11%) had abnormal echocardiograms, none had a change in therapy and no subsequent cases of cardiomyopathy were identified. Five of the remaining 179 patients with a normal cardiac evaluation developed a cardiomyopathy. Thirty-one patients had a history of cardiac disease, and only 4 patients had a change in therapy. There were 77 patients (25%) who did not have a prechemotherapy cardiac evaluation. No subsequent cases of cardiomyopathy were identified in this group.\n\n\nCONCLUSIONS\nPretreatment evaluation rarely leads to a change in management and is not helpful in predicting subsequent cardiomyopathy. Guidelines that recommend evaluation of left ventricular function in all patients before anthracycline-based chemotherapy should be reexamined.",
"affiliations": "Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.;Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.;Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.;Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.;Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.;Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.;Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.;Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.;Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.;Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE. Electronic address: pjbierma@unmc.edu.",
"authors": "Steuter|John|J|;Bociek|Robert|R|;Loberiza|Fausto|F|;Mathers|Daniel|D|;Armitage|James|J|;Vose|Julie|J|;Bast|Martin|M|;Saxena|Shikhar|S|;Porter|Thomas|T|;Bierman|Philip|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "15(1)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Anthracycline; Cardiomyopathy; Doxorubicin; Echocardiogram; Lymphoma",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D019468:Disease Management; D005260:Female; D006334:Heart Function Tests; D006801:Humans; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D016277:Ventricular Function, Left; D055815:Young Adult",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "29-34",
"pmc": null,
"pmid": "25074024",
"pubdate": "2015-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Utility of prechemotherapy evaluation of left ventricular function for patients with lymphoma.",
"title_normalized": "utility of prechemotherapy evaluation of left ventricular function for patients with lymphoma"
} | [
{
"companynumb": "US-JNJFOC-20141220594",
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"activesubstancename": "VINCRISTINE"
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"abstract": "Previous reports have suggested that non-Hodgkin's lymphoma (NHL) is more likely to develop in patients with Hodgkin lymphoma (HL) compared to the general population. These two can occur synchronously or metachronously. We report here on a case of nodular sclerosis classical HL and T cell NHL that occurred in a patient metachronously. Peripheral T cell lymphoma (PTCL) of the patient was found about 2 years after treatment of classical HL. When the patient was diagnosed with HL, biopsy revealed typical RS cells, presenting positive for CD30 and CD15 and negative for CD79a and CD3 in immunohistochemistry. And PCR analysis showed IgH gene rearrangement; however, T cell receptor gene rearrangement and Epstein-Barr virus (EBV) were not detected on PCR analysis. After 2 years of treatment of HL, colonoscopic biopsy and lymph node biopsy showed CD3 positive atypical cells intermixed with small reactive lymphoid cells and plasma cells, indicating T cell lymphoma. PCR analysis demonstrated T cell receptor gene rearrangement and did not detect EBV. Although it is rare, synchronous or metachronous HL and NHL may occur. Therefore, we may need to ensure pathological confirmation, especially in case of lymphoma that did not respond to chemotherapy.",
"affiliations": "Department of Pathology, Inje University Ilsan Paik Hospital, 170 Joohwa-ro, Ilsanseo-gu, Goyang 411-706, Republic of Korea.;Department of Internal Medicine, Inje University Ilsan Paik Hospital, 170 Joohwa-ro, Ilsanseo-gu, Goyang 411-706, Republic of Korea.",
"authors": "Chang|Sun Hee|SH|;Lee|Hye Ran|HR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2015/438385",
"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi Publishing Corporation 10.1155/2015/438385Case ReportPeripheral T Cell Non-Hodgkin's Lymphoma following Treatment of Hodgkin's Lymphoma Chang Sun Hee \n1\nLee Hye Ran \n2\n\n*\n1Department of Pathology, Inje University Ilsan Paik Hospital, 170 Joohwa-ro, Ilsanseo-gu, Goyang 411-706, Republic of Korea2Department of Internal Medicine, Inje University Ilsan Paik Hospital, 170 Joohwa-ro, Ilsanseo-gu, Goyang 411-706, Republic of Korea*Hye Ran Lee: leehr@paik.ac.krAcademic Editor: Nurdan Tacyildiz\n\n2015 13 1 2015 2015 43838515 11 2014 26 12 2014 26 12 2014 Copyright © 2015 S. H. Chang and H. R. Lee.2015This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Previous reports have suggested that non-Hodgkin's lymphoma (NHL) is more likely to develop in patients with Hodgkin lymphoma (HL) compared to the general population. These two can occur synchronously or metachronously. We report here on a case of nodular sclerosis classical HL and T cell NHL that occurred in a patient metachronously. Peripheral T cell lymphoma (PTCL) of the patient was found about 2 years after treatment of classical HL. When the patient was diagnosed with HL, biopsy revealed typical RS cells, presenting positive for CD30 and CD15 and negative for CD79a and CD3 in immunohistochemistry. And PCR analysis showed IgH gene rearrangement; however, T cell receptor gene rearrangement and Epstein-Barr virus (EBV) were not detected on PCR analysis. After 2 years of treatment of HL, colonoscopic biopsy and lymph node biopsy showed CD3 positive atypical cells intermixed with small reactive lymphoid cells and plasma cells, indicating T cell lymphoma. PCR analysis demonstrated T cell receptor gene rearrangement and did not detect EBV. Although it is rare, synchronous or metachronous HL and NHL may occur. Therefore, we may need to ensure pathological confirmation, especially in case of lymphoma that did not respond to chemotherapy.\n==== Body\n1. Introduction\nIt has been reported that the occurrence of Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL) in same patient is not rarer than expected [1]. A population based study found a greater than 3-fold increased incidence of NHL in patients previously given a diagnosis of HL [2]. A diffuse large B-cell lymphoma following previous nodular lymphocyte predominant HL can be seen the most common, but all types of NHL and HL have been observed, including T cell lymphoma (TCL) [3]. It can be developed synchronously and metachronously. Synchronous onset of HL and NHL at different anatomic sites or even both histologic manifestations present within the same tissue specimen referred to as composite lymphomas [1–3]. It is extremely rare and thought to be genetically identical with morphological differences due to different transformation events of common precursor cells [1]. Metachronously developed cases were considered to be attributed to complications of previous chemotherapy; however, they may be associated with immune system abnormalities [3]. Recent studies made progress to understand the cell of origin and clonality of RS cells. Studies showed that about 15% to 38% of RS cells expressed lymphoid antigens CD20 and 11% to 24% of these expressed CD3. Clonal immunoglobulin heavy chain gene rearrangements in RS cells were detected in 90–95% of HL cases. It was also revealed that 15% to 20% of RS cells expressing T cells antigens retain clonal TCR gene rearrangements [3–5].\n\nWe report a case of PTCL that seemed to develop metachronously in the patient with HL and review of literatures for histogenetic relationship between two lymphomas.\n\n2. The Case Report\nA 64-year-old female patient came to the hospital complaining of abrupt weight loss of 10 kg in 2 months. She became 40 kg from 50 kg. She also complained of abdominal pain and bloating that has been annoying her for several months. She has been taking medicines for hypertension and diabetes. Multiple lymph nodes were palpable on right and left supraclavicular areas, right cervical area, and both inguinal areas. The largest one was measured 2.5 cm × 1.5 cm on left supraclavicular area. She had no history of fever and sweating. A neck computed tomography (CT) was performed and showed multiple lymphadenopathies on both supraclavicular and right jugular chains. A chest CT also showed multiple enlarged lymph nodes in mediastinum with small amount of pericardial effusion. An abdominal pelvis CT (AP CT) revealed enhanced multiple enlarged lymph nodes in abdominal retroperitoneal space (Figure 1). Excisional biopsy was performed on left supraclavicular lymph node and revealed Hodgkin's lymphoma (HL), nodular sclerosis type (NS) (Figure 2(a)). The biopsy revealed typical Reed-Sternberg (RS) cells and their variants (usually mononuclear cells and occasional lacunar cells) (Figure 2(b)). RS cells were immunohistochemically positive for CD30 (Figure 2(c)) and CD15 and negative for CD79a and CD3. Surrounding T cells were normal morphologically. PCR analysis showed IgH gene rearrangement. T cell receptor gene rearrangement was not detected. Epstein-Barr virus (EBV) was not detected on PCR analysis. Bone marrow examination showed no involvement of lymphoma. The echocardiography was performed to reevaluate pericardial effusion. It revealed that the ejection fraction was 60% and pericardial effusion was too small to be drained. Therefore, she was diagnosed with classical HL of nodular sclerosis type, stage IIIB, or possibly stage IV/BE due to pericardial involvement. According to International Prognostic Score (IPS) for risk stratification, she had 1 point by age of 64 years. Chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD regimen) was administered. After 3 cycles of chemotherapy, a follow-up chest CT and an APCT were taken and showed partial response by RECIST criteria (Figure 3). However further chemotherapy was not given because she was intolerable to chemotherapy due to gastrointestinal (GI) symptoms including diarrhea and abdominal bloating. In order to find out the causes of GI symptoms, colonoscopy was performed and colonoscopic biopsy showed chronic nonspecific colitis with focal erosion on rectosigmoid colon. After 12 months of follow-up loss, CT showed slightly increased sizes of lymph nodes on neck, mediastinum, and retroperitoneal space (Figure 4). She was retreated again with 3 cycles of chemotherapy of ABVD regimen. Following APCT showed that size and numbers of multiple enlarged lymph nodes in retroperitoneal space and mesentery were decreased but persistently remained. It also showed diffuse edematous thickening of sigmoid colonic wall and rectal wall. Colonoscopic biopsy was reperformed and revealed malignant lymphoma of T cell phenotype with active ulcer along with necrosis on rectum and sigmoid colon, which was consistent with peripheral T cell lymphoma (TCL) involving rectum and sigmoid colon. In order to confirm peripheral TCL, enlarged right inguinal lymph node was excised for biopsy. Biopsy specimen of inguinal lymph node revealed effacement of nodal architecture by an atypical lymphoid infiltrate. The infiltrates consisted of medium to large sized lymphoid cells. The atypical cells showed hyperchromatic nuclei and discernible cytoplasm (Figure 2(d)). Some atypical cells had open chromatin and nuclear convolution, but nuclear pleomorphism was not evident. These atypical cells were intermixed with small reactive lymphoid cells and plasma cells. The atypical cells were positive for CD3, indicating T cell lymphoma. PCR analysis demonstrated T cell receptor gene rearrangement. EBV was not detected on PCR analysis. She received 3 cycles of chemotherapy with etoposide containing regimen. PTCL was regressed partially after 3 cycles of chemotherapy, but she refused to receive more chemotherapy. She died of disease progression 6 months later.\n\n3. Discussion\nThere are several explanations for the development of HL and subsequent TCL such as therapy induced, immunodeficiency related, and tumor biological relations [1, 3, 6]. TCL occurring about 2 years after chemotherapy of HL and showing more aggressive clinical courses might be considered to be treatment induced [3, 6, 7]. The persistent immune dysregulations are known to be associated with HL [8]. Brown et al. described a case of HL and anaplastic large cell lymphoma (ALCL) in which a faint T cell receptor (TCR) gene rearrangement was detected in the initial HL. It suggested that this rearrangement had arisen from an oligoclonal population of reactive T cells because the RS cells were positive for CD20 [3]. The initial and persistent oligoclonal T cell expansion might have permitted the emergence of the ALCL. Thus, the ALCL and possibly the HL developed as a result of a persistently abnormal immune microenvironment. The development of HL and B cell lymphoma would be explained by clonal progression of malignant B cells through mutational accumulation and progression into a more aggressive, higher grade B cell lymphoma, because neoplastic RS cells are a type of B lymphocytes in most cases [9]. The pathogenesis of cases of classic HL and TCL is more difficult to explain. HL is rarely of T cell lineage, probably fewer than 5% of all cases [4]. Two recent studies focused on RS cells that express aberrant T cell antigens and found that only 15% to 20% of these harbor clonal TCR gene rearrangements [10, 11]. Davis et al. reported a case in which lymphomatoid papulosis, HL, and cutaneous TCL, occurring during a period of 14 years, were derived from a single T cell clone, as determined by PCR [11]. Therefore, it seems likely that HL and TCL derive from the same precursor, similar to that of HL and B cell lymphoma. Sanchez et al. reported a case of composite HL and TCL associated with Epstein Barr virus infection and suggested the possibility of malignant transformation of a preexisting T cell population developed in response to a neoplastic EBV-positive RS cells [9]. Our patient was diagnosed with peripheral TCL 2 years after the diagnosis of HL. RS cells of our case revealed no TCR gene rearrangement and EBV on PCR. Therefore, the occurrence of TCL in this case is probably related to chemotherapy. However, we are not sure whether composite lymphoma existed when HL was diagnosed, because we obtained just only supraclavicular lymph node and confirmed HL. When she received chemotherapy for HL, she suffered from diarrhea and was diagnosed with chronic nonspecific colitis with focal erosion by colonoscopic biopsy. Colonoscopic biopsy that was performed 2 years after diagnosis of HL revealed TCL, also supporting sequential development of HL and TCL rather than composite lymphoma. With these results taken into account, the direct clonal relationship between HL and PTCL was observed in few reports. So, the majority of PTCL following treatment of HL could result from therapy induced immunodeficiency rather than from clonal progression.\n\nWe report a case of HL and T cell lymphoma developing in the same patient. Although it is rare, synchronous or metachronous HL and NHL can occur more often than we expect. Therefore, we may need to consider reconfirming tissue when lymphoma is not regressed enough by chemotherapy. And, the further study for pathogenesis will be required to understand the relationship of HL and NHL.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 (a) A chest CT shows multiple enlarged lymph nodes in mediastinum. (b) An AP CT reveals multiple enlarged lymph nodes in abdominal retroperitoneal space. (White arrows: enlarged lymph nodes.)\n\nFigure 2 (a) The lymph node shows nodules separated by broad bands of fibrosis. (b) Reed-Sternberg cells and their variants are in the nodules. (c) Reed-Sternberg cells are CD30 positive. (d) Atypical lymphoid cells have hyperchromatic nuclei with discernible cytoplasm.\n\nFigure 3 (a) A follow-up chest CT after 3 cycles of ABVD chemotherapy shows dramatic improvement of the lymphadenopathy in the mediastinum. (b) As compared with previous APCT, enlarged lymph nodes are decreased in number and size after 3 cycles of ABVD chemotherapy.\n\nFigure 4 A chest CT (a) and an AP CT (b) show increased sizes of lymph nodes on mediastinum and retroperitoneal space after 12 months of follow-up loss.\n==== Refs\n1 Amini R. M. Enblad G. Sundström C. Glimelius B. Patients suffering from both Hodgkin's disease and non-Hodgkin's lymphoma: a clinico-pathological and immuno-histochemical population-based study of 32 patients International Journal of Cancer 1997 71 4 510 516 9178801 \n2 Dong C. Hemminki K. Second primary neoplasms among 53 159 haematolymphoproliferative malignancy patients in Sweden, 1958–1996: a search for common mechanisms British Journal of Cancer 2001 85 7 997 1005 10.1038/sj.bjc.6691998 2-s2.0-0035964620 11592772 \n3 Brown J. R. Weng A. P. Freedman A. S. Hodgkin disease associated with T-Cell non-Hodgkin lymphomas: case reports and review of the literature The American Journal of Clinical Pathology 2004 121 5 701 708 10.1309/w1gw-43ht-793u-f86r 2-s2.0-2042526883 15151210 \n4 Küppers R. Molecular biology of Hodgkin's lymphoma Advances in Cancer Research 2002 84 277 312 10.1016/s0065-230x(02)84009-x 2-s2.0-0036189576 11883530 \n5 Muschen M. Re D. Brauninger A. Somatic mutations of the CD95 gene in Hodgkin and Reed-Sternberg cells Cancer Research 2000 60 20 5640 5643 2-s2.0-0034667371 11059754 \n6 Steinhoff M. Assaf C. Anagnostopoulos I. Geilen C. C. Stein H. Hummel M. Three coexisting lymphomas in one patient: genetically related or only a coincidence? The Journal of Clinical Pathology 2006 59 12 1312 1315 10.1136/jcp.2005.030825 2-s2.0-33846017634 17142574 \n7 Krikorian J. G. Burke J. S. Rosenberg S. A. Kaplan H. S. Occurrence of non-Hodgkin's lymphoma after therapy for Hodgkin's disease The New England Journal of Medicine 1979 300 9 452 458 10.1056/nejm197903013000902 2-s2.0-0018415536 366418 \n8 Fisher R. I. deVita V. T. Jr. Bostick F. Persistent immunologic abnormalities in long-term survivors of advanced Hodgkin's disease Annals of Internal Medicine 1980 92 5 595 599 10.7326/0003-4819-92-5-595 2-s2.0-0018868483 6992672 \n9 Sanchez S. Holmes H. Katabi N. Composite lymphocyte-rich Hodgkin lymphoma and peripheral T-cell lymphoma associated with Epstein-Barr virus: a case report and review of the literature Archives of Pathology and Laboratory Medicine 2006 130 1 107 112 2-s2.0-30444433604 16390224 \n10 Seitz V. Hummel M. Marafioti T. Anagnostopoulos I. Assaf C. Stein H. Detection of clonal T-cell receptor gamma-chain gene rearrangements in Reed-Sternberg cells of classic Hodgkin disease Blood 2000 95 10 3020 3024 2-s2.0-0034658050 10807764 \n11 Davis T. H. Morton C. C. Miller-Cassman R. Balk S. P. Kadin M. E. Hodgkin's disease, lymphomatoid papulosis, and cutaneous T-cell lymphoma derived from a common T-cell clone The New England Journal of Medicine 1992 326 17 1115 1122 10.1056/nejm199204233261704 2-s2.0-0026518130 1532439\n\n",
"fulltext_license": "CC BY",
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"issue": "2015()",
"journal": "Case reports in oncological medicine",
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"medline_ta": "Case Rep Oncol Med",
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"pages": "438385",
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"pmid": "25664194",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "366418;16390224;10807764;11059754;11592772;11883530;9178801;17142574;15151210;6992672;1532439",
"title": "Peripheral T Cell Non-Hodgkin's Lymphoma following Treatment of Hodgkin's Lymphoma.",
"title_normalized": "peripheral t cell non hodgkin s lymphoma following treatment of hodgkin s lymphoma"
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"abstract": "Purpose Treating small-cell lung cancer (SCLC) remains a therapeutic challenge. Experimental studies show that statins exert additive effects with agents, such as cisplatin, to impair tumor growth, and observational studies suggest that statins combined with anticancer therapies delay relapse and prolong life in several cancer types. To our knowledge, we report the first large, randomized, placebo-controlled, double-blind trial of a statin with standard-of-care for patients with cancer, specifically SCLC. Patients and Methods Patients with confirmed SCLC (limited or extensive disease) and performance status 0 to 3 were randomly assigned to receive daily pravastatin 40 mg or placebo, combined with up to six cycles of etoposide plus cisplatin or carboplatin every 3 weeks, until disease progression or intolerable toxicity. Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), response rate, and toxicity. Results Eight hundred forty-six patients from 91 United Kingdom hospitals were recruited. The median age of recruited patients was 64 years of age, 43% had limited disease, and 57% had extensive disease. There were 758 deaths and 787 PFS events. No benefit was found for pravastatin, either in all patients or in several subgroups. For pravastatin versus placebo, the 2-year OS rate was 13.2% (95% CI, 10.0 to 16.7) versus 14.1% (95% CI, 10.9 to 17.7), respectively, with a hazard ratio of 1.01 (95% CI, 0.88 to 1.16; P = .90. The median OS was 10.7 months v 10.6 months, respectively. The median PFS was 7.7 months v 7.3 months, respectively. The median OS (pravastatin v placebo) was 14.6 months in both groups for limited disease and 9.1 months versus 8.8 months, respectively, for extensive disease. Adverse events were similar between groups. Conclusion Pravastatin 40 mg combined with standard SCLC therapy, although safe, does not benefit patients. Our conclusions are the same as those found in all four much smaller, randomized, placebo-controlled trials specifically designed to evaluate statin therapy in patients with cancer.",
"affiliations": "Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.;Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.;Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.;Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.;Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.;Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.;Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.;Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.;Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.;Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.;Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.;Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.;Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.;Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.",
"authors": "Seckl|Michael J|MJ|;Ottensmeier|Christian H|CH|;Cullen|Michael|M|;Schmid|Peter|P|;Ngai|Yenting|Y|;Muthukumar|Dakshinamoorthy|D|;Thompson|Joyce|J|;Harden|Susan|S|;Middleton|Gary|G|;Fife|Kate M|KM|;Crosse|Barbara|B|;Taylor|Paul|P|;Nash|Stephen|S|;Hackshaw|Allan|A|",
"chemical_list": "D005047:Etoposide; D016190:Carboplatin; D017035:Pravastatin; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2016.69.7391",
"fulltext": "\n==== Front\nJ Clin OncolJ. Clin. OncoljcojcoJCOJournal of Clinical Oncology0732-183X1527-7755American Society of Clinical Oncology 2824096769739110.1200/JCO.2016.69.7391THOR5ChemotherapyTHOR6Combined ModalityORIGINAL REPORTSThoracic OncologyMulticenter, Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Pravastatin Added to First-Line Standard Chemotherapy in Small-Cell Lung Cancer (LUNGSTAR) Pravastatin and Chemotherapy in Small-Cell Lung CancerSeckl Michael J. Ottensmeier Christian H. Cullen Michael Schmid Peter Ngai Yenting Muthukumar Dakshinamoorthy Thompson Joyce Harden Susan Middleton Gary Fife Kate M. Crosse Barbara Taylor Paul Nash Stephen Hackshaw Allan Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.M.J.S. and A.H. contributed equally to this work.\n\nCorresponding author: Michael J. Seckl, MD, Department of Medical Oncology, Charing Cross Hospital Campus of Imperial College London, Fulham Palace Rd, London W6 8RF, United Kingdom; e-mail: m.seckl@imperial.ac.uk.10 5 2017 27 2 2017 27 2 2017 35 14 1506 1514 © 2017 by American Society of Clinical Oncology2017American Society of Clinical OncologyLicensed under the Creative Commons Attribution 4.0 License: http://creativecommons.org/licenses/by/4.0/Purpose\nTreating small-cell lung cancer (SCLC) remains a therapeutic challenge. Experimental studies show that statins exert additive effects with agents, such as cisplatin, to impair tumor growth, and observational studies suggest that statins combined with anticancer therapies delay relapse and prolong life in several cancer types. To our knowledge, we report the first large, randomized, placebo-controlled, double-blind trial of a statin with standard-of-care for patients with cancer, specifically SCLC.\n\nPatients and Methods\nPatients with confirmed SCLC (limited or extensive disease) and performance status 0 to 3 were randomly assigned to receive daily pravastatin 40 mg or placebo, combined with up to six cycles of etoposide plus cisplatin or carboplatin every 3 weeks, until disease progression or intolerable toxicity. Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), response rate, and toxicity.\n\nResults\nEight hundred forty-six patients from 91 United Kingdom hospitals were recruited. The median age of recruited patients was 64 years of age, 43% had limited disease, and 57% had extensive disease. There were 758 deaths and 787 PFS events. No benefit was found for pravastatin, either in all patients or in several subgroups. For pravastatin versus placebo, the 2-year OS rate was 13.2% (95% CI, 10.0 to 16.7) versus 14.1% (95% CI, 10.9 to 17.7), respectively, with a hazard ratio of 1.01 (95% CI, 0.88 to 1.16; P = .90. The median OS was 10.7 months v 10.6 months, respectively. The median PFS was 7.7 months v 7.3 months, respectively. The median OS (pravastatin v placebo) was 14.6 months in both groups for limited disease and 9.1 months versus 8.8 months, respectively, for extensive disease. Adverse events were similar between groups.\n\nConclusion\nPravastatin 40 mg combined with standard SCLC therapy, although safe, does not benefit patients. Our conclusions are the same as those found in all four much smaller, randomized, placebo-controlled trials specifically designed to evaluate statin therapy in patients with cancer.\n\n SJS Export v1\n==== Body\nINTRODUCTION\nSmall-cell lung cancer (SCLC) accounts for 15% to 20% of all new cases of lung cancer worldwide, with a low median survival of 12 to 14 months for patients with limited stage disease and 8 to 12 months for those with extensive stage disease. Although few therapeutic advances have been made over the past 40 years, there has been much progress in the understanding of the biologic processes, including the importance of, for example, TP53 and RB1 gene mutations, and the potential for targeted therapies—for example, poly (ADP-ribose) polymerase inhibitors and immunotherapeutics—of which several trials are ongoing.1\n\nStatins are an inexpensive and established therapy for cardiovascular disease prevention and treatment. Despite initial concerns that long-term use might increase the risk of developing cancer, large-scale meta-analyses of randomized trials have shown no excess cancer incidence or mortality2; however, evidence from experimental and preclinical studies has indicated that statins can inhibit tumor growth and induce apoptosis in several tumor types, including pancreatic carcinoma,3 mesothelioma,4 breast cancer,5 and SCLC cells.6 Mechanistically, mitogen-activated protein kinase and extracellular signal-regulated kinase upregulates antiapoptotic molecules in SCLC cells,7,8 and simvastatin can disrupt this process through impaired Ras superfamily signaling. This is achieved because statins block 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, thereby reducing cholesterol biosynthesis and impairing geranylation and farnesylation of Ras superfamily members.6 Statins could therefore act in an additive or synergistic fashion when combined with chemotherapy agents, such as paclitaxel,9 cisplatin,5,10 and doxorubicin.5 Experiments in H-69 human SCLC xenografts in nude mice showed impressive single-agent activity of orally administered statin.6 Our early studies implied that statins, such as simvastatin, would enhance the effects of single-agent or combination chemotherapy, including cisplatin and etoposide, triggering apoptosis and/or reverse chemoresistance.6 These effects were not confined to one platinum type because atorvastatin has subsequently been shown to enhance efficacy of carboplatin in non-SCLC cells in vitro and in vivo.11 Furthermore, before our trial, an unblinded randomized trial of pravastatin in patients with liver cancer reported a striking 9-month increase in overall survival (OS).12\n\nIt is worth considering the large body of evidence for statins in cancer prevention or treatment, which received significant interest during major conferences held in 2015 and 2016 (ASCO, ASCO-GI, and the San Antonio Breast Cancer Symposium). Using large prospective cohort or registry studies, all but one study was positive. The magnitude of the effects found by these studies, along with study size, show why they attracted attention: a 22% reduction in cancer deaths among 146,326 women,13 no effect on breast cancer incidence among 79,518 women,14 40% reduction in prostate deaths among 22,110 high-risk patients with prostate cancer,15 14% reduction in all-cause mortality in 2,142 patients with pancreatic cancer,16 18% reduction in recurrence and/or deaths in 8,010 patients with breast cancer,17 and 29% reduction in breast cancer mortality from a meta-analysis of 12 studies covering 87,951 patients with breast cancer.18 There have also been other large studies that have reported that statins, usually when still taken after diagnosis, can reduce recurrence or mortality in patients with esophageal,19 colorectal,20 and lung cancer,21 and all tumors combined,22 with further evidence from meta-analyses of all cancers,23 and prostate (postradiotherapy)24,25 and colorectal cancer.26 However, all studies were observational and none established a dose-response for statin efficacy.\n\nWe investigated statins for the treatment of SCLC because patients are treated with platinum and/or etoposide chemotherapy, used in the earlier experimental work, and the poor prognosis made it a good candidate for an inexpensive therapy even with a modest effect.\n\nPATIENTS AND METHODS\nEtoposide and Cisplatin or Carboplatin as First-Line Chemotherapy With or without Pravastatin in Treating Patients with Small-Cell Lung Cancer (LUNGSTAR) was a pragmatic, randomized (1:1), phase III, double-blind, placebo-controlled trial to investigate whether adding pravastatin to standard chemotherapy improves OS in patients with SCLC. Investigators are listed in Appendix Table A1 (online only). The trial had national ethics approval and was conducted according to the Declaration of Helsinki. All patients gave written informed consent.\n\nPatients\nPatients age ≥ 18 years were recruited from 91 United Kingdom National Cancer Research Network hospitals. Eligibility criteria included histologically or cytologically confirmed SCLC (limited or extensive disease), Eastern Cooperative Oncology Group performance status 0 to 3, life expectancy > 8 weeks, and adequate renal and bone marrow function. Patients were ineligible if they had mixed cell histology, prior chemoradiotherapy for the tumor, history of a malignant tumor, had used statins within the previous 12 months, or had been treated with fibrates within 4 weeks before random assignment. Patients were randomly assigned by research nurses after telephoning the University College London Cancer Trials Centre, using minimization stratified by disease status (limited v extensive) and Eastern Cooperative Oncology Group performance status (0 to 1 v 2 to 3).\n\nPravastatin or matching placebo (40 mg) were administered orally once per day from the start of chemotherapy for 2 years, unless disease progression or intolerable toxicity occurred. We used pravastatin because this seemed to be active in liver cancer12 and, unlike other statins, did not interact with cytochrome P450 family members, thereby reducing potential important drug interactions.27,28 All patients received standard treatment every 3 weeks for up to six cycles: etoposide (120 mg/m2 intravenously on day 1, then either the same on days 2 and 3 or 100 mg twice per day orally on days 2 and 3), with either cisplatin (60 mg/m2 intravenously on day 1) or carboplatin (on day 1: area under curve [AUC] 5 or 6 using EDTA, or the Cockcroft and Gault method, to assess glomerular filtration rate). Radiotherapy was administered per local practice. Patients with limited disease were recommended to have concurrent chemoradiotherapy, preferably with the second chemotherapy cycle, or sequential chemoradiotherapy to the chest (the protocol did not specify dose), with prophylactic cranial radiation offered to those who achieved a partial response or complete tumor response (CR). Patients with extensive disease and who achieved CR were offered thoracic radiotherapy—recommended 40 Gy in 15 fractions over 3 weeks to the mediastinum and 25 Gy in 10 fractions over 2 weeks to the brain. All researchers and patients were blinded to statin and placebo. Primary care physicians of randomly assigned patients were contacted and asked not to prescribe statins while their patient was enrolled in the trial—so we did not collect data on statin use outside of the study.\n\nAssessments\nClinical examinations, biochemical tests, and chest x-rays were performed at baseline, before each chemotherapy cycle, then every 2 months for the next year and every 3 months thereafter. Chest and abdomen computed tomography scans were performed at baseline, at the end of cycle 3, within 4 weeks of completing chemotherapy, and when clinically indicated thereafter. Brain scans were performed before random assignment, where indicated, to exclude patients with brain metastases who required immediate radiotherapy.\n\nStatistical Analysis\nThe primary end point was OS, measured from the date of random assignment until death from any cause. Surviving patients were censored on the date last known to be alive. Secondary end points were progression-free survival (PFS), tumor response assessed by the treating clinician (Response Evaluation Criteria in Solid Tumors [RECIST] v1.0) and toxicity (Common Terminology Criteria for Adverse Events v3.0). PFS was calculated from the date of random assignment to the date of first progression or death, whichever occurred first. OS and PFS were compared by using Cox proportional hazards regression models, adjusted for the randomization stratification factors, which were also preplanned subgroup analyses. Tablet adherence was assessed by a Wilcoxon test. The worst grade of adverse event for each patient and each toxicity type was used. All analyses were by intention-to-treat, except for adverse events, which were reported only for patients who took at least one dose of statin or placebo.\n\nThe trial was designed to detect an improvement in median OS with hazard ratio (HR) of 0.82 from an expected median in controls of 12 months, which corresponds to a difference in 2-year OS rates of 10% versus 15%. This required 842 patients (792 deaths) with 80% power and 5% two-sided significance.\n\nRESULTS\nEight hundred forty-six patients were recruited between February 19, 2007 and January 3, 2012 (Fig 1). Of 1,537 patients who were screened, where screening logs were available, 338 (22%) patients were ineligible because they were recent or current statin users. Three randomly assigned patients who were later found to be ineligible were included in the analyses (intention-to-treat), because they had already started trial drug, which stopped within 6 months. Baseline characteristics were well balanced (Table 1). Median follow-up was 39.6 months.\n\nFig 1. CONSORT diagram. Discontinued intervention includes patients who stopped statin and/or placebo early as a result of disease progression, toxicity, or patient and/or clinical decision.\n\nTable 1. Baseline Patient Characteristics\n\nAdherence\nThe median length of time on study drug was 8.6 months (pravastatin) and 7.8 months (placebo). Among 725 patients who started treatment and with available data on number of tablets dispensed and returned, the median number of tablets reportedly taken was 210 (pravastatin) and 181 (placebo; P = .38). Similarly, there was little difference found in the number of tablets returned (median, 38 and 36, respectively).\n\nThe amount of chemotherapy administered was similar between the two groups (P = .19); in each treatment arm, 57% received six cycles (Appendix Table A2, online only). There was little difference in the reasons for stopping chemotherapy early (Appendix Table A3, online only). The mean number of chemotherapy cycles was similar between patients with extensive disease (4.8) and limited disease (4.9).\n\nAppendix Table A4 (online only) summarizes the types of additional treatments administered to patients after they finished chemotherapy, which were well balanced between the statin and placebo arms, and within patients with extensive and limited disease.\n\nEfficacy\nThere were 758 deaths. Six hundred ninety-seven (92%) were a result of SCLC, including six deaths that were considered to be related to chemotherapy in the pravastatin group and none in the placebo group; eight deaths were attributed to a combination of cancer and treatment in the pravastatin arm and six in the placebo arm.\n\nOS was similar between treatment groups (Fig 2), with medians of 10.7 months and 10.6 months for pravastatin and placebo, respectively, (unadjusted HR, 1.01 [95% CI, 0.88 to 1.16; P = .90] and adjusted for the stratification factors [1.02; 95% CI, 0.89 to 1.18; P = .76]). The corresponding 2-year OS rates were 14.1% (95% CI, 10.9 to 17.7) and 13.2% (95% CI, 10.0 to 16.7), respectively.\n\nFig 2. (A) Overall survival (OS) and (b) progression-free survival (PFS). The number of events in the pravastatin versus placebo groups were 381 versus 377 deaths, and 395 versus 392 PFS events, respectively. HR, hazard ratio.\n\nThere were 787 PFS events. Median PFS was 7.7 months (pravastatin) versus 7.3 months (placebo), with unadjusted HR of 0.98 (95% CI, 0.85 to 1.13; P = .81), and adjusted HR of 1.01 (95% CI, 0.88 to 1.17; P = .86). The corresponding 1-year PFS rates were 25.3% and 24.2%, respectively; the 2-year PFS rates were 7.5% (95% CI, 5.2 to 10.3) and 7.2% (95% CI, 4.9 to 10.0), respectively.\n\nPravastatin also had no effect as a function of disease extent (Fig 3). Median OS was 14.6 months (pravastatin) versus 14.6 months (placebo) for limited stage disease, and 9.1 months versus 8.8 months for extensive stage (interaction P = .53). Furthermore, no subgroup effects were observed for performance status, age, sex, type of platinum therapy administered, pleural effusion, or presence of affected lymph nodes (Appendix Fig A1, online only). Allowing for a slight imbalance between the two arms for type of platinum treatment (Table 1) made little difference to the results (HR, 1.04; 95% CI, 0.90 to 1.19; P = .63).\n\nFig 3. Overall survival (OS) in patients with (A) limited stage and (B) extensive stage disease. HR, hazard ratio.\n\nTumor response was similar between trial groups with 29 (69.0%) of 422 patients on pravastatin and 293 (69.1%) of 424 patients on placebo achieving a partial or complete (best) overall response; there was little difference in response rates for limited and extensive stage disease (Appendix Table A5, online only).\n\nThe number of patients who received thoracic radiotherapy was similar between trial groups with 202 (47.9%) patients in the pravastatin arm and 210 (49.5%) in the placebo arm, with a corresponding median total dose of 39 Gy (range, 3 to 66) and 40 Gy (range, 2 to 66), respectively. Furthermore, 203 (48.1%) patients in the pravastatin arm and 207 (48.8%) patients in the placebo arm received prophylactic cranial brain irradiation, with corresponding median total dose of 25 Gy (range, 2 to 40) and 25 Gy (range, 2 to 56), respectively.\n\nAdverse Events\nTable 2 shows that the distribution of grade 3 to 5 adverse events was similar between the pravastatin and placebo arms with 333 (81.2%) of 410 patients versus 333 (81.4%) of 409 patients, respectively (P = .94). The most common grade 3 to 5 adverse event was neutropenia, which affected 184 (44.9%) of patients in the pravastatin arm and 176 (43.0%) of patients in the placebo arm. Myalgia or myositis of any grade—recognized toxicities of statins—occurred in 74 patients in the pravastatin arm and 77 patients in the placebo arm; the majority of these were grade 1 or 2, with three patients who received pravastatin experiencing grade 3 and 4 (three grade 3, one grade 4) compared with three patients who received placebo (all grade 3). GI bleeding (grade 1) was experienced by three patients in the statin group, in addition to two (grade 2) and one (grade 3) events. GI bleeding (grade 1) was experienced by two patients in the placebo group in addition to two (grade 2) events.\n\nTable 2. Worst Grade of Adverse Events for Each Patient (grade ≥ 3)\n\nDISCUSSION\nTo our knowledge, LUNGSTAR, by far, is the largest randomized trial of statin therapy in patients with cancer reported to date. Use of placebo avoids an important bias present in observational studies. Although pravastatin was safe, with high adherence—patients tended to continue until disease progression—it did not improve outcomes in patients with SCLC, nor in those with limited stage or extensive stage disease.\n\nWhen LUNGSTAR was developed in 2005, preclinical evidence was sufficient, though not considered overwhelming by some; however, rather than perform further experimental and/or preclinical studies, followed by phase II, then phase III trials, the investigators and funder (Cancer Research UK) decided to launch a definitive large study sooner rather than later, given the growing evidence in this field at the time. The independent data monitoring committee reviewed efficacy during the trial. In April 2010, when 25% of the target number of deaths was observed, conditional power (CP) for OS was 66%—CP is the chance of obtaining the target HR of 0.82 if the trial continued to the end, given the data thus far. In February 2011, with 655 patients recruited and 41% of events, CP was 11% for OS, but 30% for PFS, which was not considered low enough to stop the study early, even though it was a secondary end point. Additional important reasons for finishing accrual were to have a large study size with convincing results, whether positive or negative, particularly given the accumulating positive observational studies, and to ensure sufficient patient numbers for limited disease and extensive disease in case pravastatin was effective for one and not the other.\n\nVarious possibilities might explain our findings, including dose, type of statin, or that our mechanistic understanding was too simplistic. When our study was established, the maximum pravastatin dose was 40 mg, which seemed to be effective in a randomized cancer trial12; however, this dose might be too low and the current 80 mg maximal dose could have achieved efficacy. Alternatively, hydrophilic statins, such as pravastatin, may not be as effective as lipophilic agents, such as simvastatin; some studies have suggested clearer benefits for simvastatin in lung cancer,21 with a lack of benefit for pravastatin in cancer prevention or cancer death observed in a trial of patients with coronary heart disease.29 However, there is insufficient evidence to reliably conclude whether any one type of statin is better than another, and biologic plausibility for a difference is lacking.22 Of interest, more recent evidence in glioma cells has suggested that statins may fail to work in certain cancer cells because of a phosphatidylinositol 3-kinase–mediated pathway connected to LDL receptors.30,31 It is unclear whether this might impact the responsiveness to statins of other cancers. Another study limitation is that blood lipid levels were not measured as part of routine biochemistry for managing patients with SCLC, which would have unblinded the trial, and we did not secure funds to measure cholesterol and other relevant markers from stored samples; therefore, we are unable to correlate these or other factors, such as HMG-CoA reductase levels, in tumor biopsies with outcomes at present.\n\nWe compared patient outcomes in LUNGSTAR with others. Our observed median OS (10.7 months) is similar to that observed in another United Kingdom trial of SCLC (comparing thalidomide with placebo, but little difference was found), which had a similar mix (approximately one half) of limited stage and extensive stage disease (median 10.5 months).32 However, survival for limited stage patients (median 14.6 months LUNGSTAR, 12.1 months in the thalidomide trial), is less than observed in a recent radiotherapy trial (median OS, 25 to 30 months),33 probably because it enrolled patients from several countries, where more radiotherapy has been given than in the United Kingdom in previous years.\n\nWe conducted a systematic literature review to identify all randomized trials that were specifically designed to evaluate lipid-lowering therapies among patients with cancer using MEDLINE (1966 to March 2016), and the keywords ‘lipid’, ‘cholesterol’, ‘statin’ (and specific names), and ‘tumor/tumor’, ‘cancer’, ‘carcinoma’, ‘adenocarcinoma’ and ‘random.’ There were only 10 trials12,34-42 (9 of statins), which are summarized in Table 3. LUNGSTAR is three times larger than any other randomized trial, the next largest having enrolled 283 patients. The 9-month OS improvement for pravastatin in the earlier trial by Kawata et al12 was probably the result of a lack of blinding and small study size (n = 83). Of importance, there are now five published double-blind studies of statins in patients with cancer, including ours (SCLC, gastric, pancreas, colorectal, and precancerous melanoma lesions), of which one used pravastatin, one lovastatin, and three simvastatin, and none showing statins of various types to be effective.36-39\n\nTable 3. Prospective Randomized Clinical Trials of Anticancer Therapy With or Without Statin or Lipid-Lowering Therapy Among Patients With Cancer1\n\nWe also found a single-arm, phase II trial and a nonrandomized, unblinded trial in patients with lung cancer. One was for previously untreated extensive-disease– SCLC (n = 61) in which simvastatin plus irinotecan and etoposide produced a 1-year OS rate of 39.3% (target 45%); median OS and PFS were 11.0 months and 6.1 months, respectively, which was similar to current treatments.43 The other trial included patients with stage III and IV cancer with non-SCLC, whose tumors were KRAS-mutant and epidermal growth factor receptor wild-type, reported better outcomes for 12 patients treated with a tyrosine kinase inhibitor plus either simvastatin or atorvastatin compared with 55 who received tyrosine kinase inhibitor alone. In that study the PFS was 2.0 months versus 1.0 month (P = .025), and OS 14.0 months versus 5.4 months (P = .13); however, it was not reported why those patients received a statin, hence there could be important confounders not allowed for.44\n\nMost prior studies that have reported benefits for statins were observational, with inherent design problems, including confounding and bias.45 Time-related biases are particularly concerning.46 Immortal time bias occurs when there is a length of time between the start of follow-up and a subsequent start of statin therapy, which is counted in the total follow-up time for a participant—but during which the participant is actually unexposed—and, thus, it seems that this participant has survived longer than a control (nonstatin user). Jeon et al47 show how this bias can spuriously create an association by using studies of patients with liver cancer in which the OS HR for statin use versus nonuse was 0.84 (P = .047) before and 0.98 (P = .82) after allowance for this bias. Randomized controlled trials, such as LUNGSTAR, avoid these issues.\n\nPreclinical studies continue to report positive effects for statins in lung cancer cell lines with regard to reduced proliferation,48,49 reduced migration,50 increased apoptosis,49 and reduced tumor growth.50 There are also several ongoing trials of statins in various cancers (eg, ClinicalTrials.gov: NCT02360618, NCT01980823, NCT01038154, NCT02161822, NCT02483871, NCT02569645, and NCT02029573). Given the findings from our trial and the other published, double-blind, randomized controlled trials, independent data monitoring committees of studies that are still recruiting or in follow-up should examine interim analyses of clinical end points and stop early if there is sufficient evidence for futility, thus saving resources. Trials of statins in patients with cancer, which require an unexposed control group, will become more difficult to conduct because the usual age group of patients with cancer (middle and old age) already take them, as seen in LUNGSTAR, in which 22% of screened patients were ineligible because they were recent or current statin users.\n\nIn summary, we found no value for pravastatin when combined with standard platinum chemotherapy in patients with SCLC. Ongoing and future trials of statins used for either cancer prevention or treatment should monitor clinical efficacy, and for planned studies of patients with cancer, investigators should ensure preclinical evidence is sufficient enough to warrant large-scale randomized studies.\n\nSupported by Cancer Research UK (Grants No. C1312/A5335 and C1312/A12462).\n\nPresented at the World Conference on Lung Cancer, Sydney, Australia, October 27-30, 2013.\n\nISRCTN number: ISRCTN56306957.\n\nClinical trial information: NCT00433498.\n\nSee accompanying Editorial on page 1497\n\nACKNOWLEDGMENT\nWe are grateful to all the patients who agreed to participate in this study. We thank all participating sites and site staff, the Cancer Research UK and University College London Cancer Trials Centre for managing and coordinating the trial. We also acknowledge the support of the National Cancer Research Network.\n\nAUTHOR CONTRIBUTIONS\nConception and design: Michael J. Seckl, Christian H. Ottensmeier, Michael Cullen, Peter Schmid, Allan Hackshaw\n\nProvision of study materials or patients: Christian H. Ottensmeier, Kate M. Fife\n\nCollection and assembly of data: Michael J. Seckl, Christian H. Ottensmeier, Michael Cullen, Peter Schmid, Yenting Ngai, Dakshinamoorthy Muthukumar, Joyce Thompson, Susan Harden, Gary Middleton, Kate M. Fife, Barbara Crosse, Paul Taylor\n\nData analysis and interpretation: Michael J. Seckl, Michael Cullen, Peter Schmid, Stephen Nash, Allan Hackshaw\n\nManuscript writing: All authors\n\nFinal approval of manuscript: All authors\n\nAccountable for all aspects of the work: All authors\n\nAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST\nMulticenter, Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Pravastatin Added to First-Line Standard Chemotherapy in Small-Cell Lung Cancer (LUNGSTAR)\nThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.\n\nMichael J. Seckl\nExpert Testimony: Actavis\n\nTravel, Accommodations, Expenses: Bristol-Myers Squibb\n\nChristian H. Ottensmeier\nNo relationship to disclose\n\nMichael Cullen\nNo relationship to disclose\n\nPeter Schmid\nHonoraria: Roche (I), Pfizer, AstraZeneca\n\nConsulting or Advisory Role: Novartis, Merck, Bayer, Boehringer Ingelheim, AstraZeneca, Pfizer\n\nResearch Funding: AstraZeneca (Inst), Genentech (Inst), Medivation (Inst), OncoGenex (Inst), Astellas Pharma (Inst)\n\nYenting Ngai\nNo relationship to disclose\n\nDakshinamoorthy Muthukumar\nNo relationship to disclose\n\nJoyce Thompson\nConsulting or Advisory Role: Novartis\n\nSusan Harden\nNo relationship to disclose\n\nGary Middleton\nStock or Other Ownership: Phosimmune\n\nHonoraria: MSD Oncology, Bristol-Myers Squibb UK\n\nConsulting or Advisory Role: MSD Oncology, Bristol-Myers Squibb UK, AstraZeneca, Eli Lilly\n\nResearch Funding: Kael gEMVAX\n\nTravel, Accommodations, Expenses: MSD Oncology\n\nKate M. Fife\nNo relationship to disclose\n\nBarbara Crosse\nNo relationship to disclose\n\nPaul Taylor\nHonoraria: Amgen\n\nTravel, Accommodations, Expenses: Pierre Fabre\n\nStephen Nash\nNo relationship to disclose\n\nAllan Hackshaw\nStock or Other Ownership: Thermo Fisher Scientific, Illumina\n\nHonoraria: Roche, Boehinger Ingelheim, Merck Serono\n\nConsulting or Advisory Role: Roche\n\nResearch Funding: Roche, Boehringer Ingelheim, Eli Lilly (Inst)\n\nAppendix\nFig A1. Forest plot showing subgroup analyses (overall survival). ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio.\n\nTable A1. Recruiting Centers and Principal Investigators\n\nTable A2. Compliance to Chemotherapy\n\nTable A3. Reasons for Stopping Chemotherapy Before Four Cycles\n\nTable A4. Additional Treatments Given to Patients After Finishing Initial Chemotherapy or After Progression\n\nTable A5. Best Overall Tumor Response (all patients)\n==== Refs\nREFERENCES\n1. 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Garwood ER Kumar AS Baehner FL et al Fluvastatin reduces proliferation and increases apoptosis in women with high grade breast cancer Breast Cancer Res Treat 119 137 144 2010 19728082 \n36. Kim ST Kang JH Lee J et al Simvastatin plus capecitabine-cisplatin versus placebo plus capecitabine-cisplatin in patients with previously untreated advanced gastric cancer: A double-blind randomised phase 3 study Eur J Cancer 50 2822 2830 2014 25218337 \n37. Hong JY Nam EM Lee J et al Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients Cancer Chemother Pharmacol 73 125 130 2014 24162380 \n38. Linden KG Leachman SA Zager JS et al A randomized, double-blind, placebo-controlled phase II clinical trial of lovastatin for various endpoints of melanoma pathobiology Cancer Prev Res (Phila) 7 496 504 2014 24614012 \n39. Lim SH Kim TW Hong YS et al A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer Br J Cancer 113 1421 1426 2015 26505681 \n40. Konings IR van der Gaast A van der Wijk LJ et al The addition of pravastatin to chemotherapy in advanced gastric carcinoma: A randomised phase II trial Eur J Cancer 46 3200 3204 2010 20727735 \n41. Han JY Lee SH Yoo NJ et al A randomized phase II study of gefitinib plus simvastatin versus gefitinib alone in previously treated patients with advanced non-small cell lung cancer Clin Cancer Res 17 1553 1560 2011 21411446 \n42. Limburg PJ Mahoney MR Ziegler KL et al Randomized phase II trial of sulindac, atorvastatin, and prebiotic dietary fiber for colorectal cancer chemoprevention Cancer Prev Res (Phila) 4 259 269 2011 21209397 \n43. Han JY Lim KY Yu SY et al A phase 2 study of irinotecan, cisplatin, and simvastatin for untreated extensive-disease small cell lung cancer Cancer 117 2178 2185 2011 21523731 \n44. Fiala O Pesek M Finek J et al Statins augment efficacy of EGFR-TKIs in patients with advanced-stage non-small cell lung cancer harbouring KRAS mutation Tumour Biol 36 5801 5805 2015 25702091 \n45. Hoffmeister M Jansen L Rudolph A et al Statin use and survival after colorectal cancer: The importance of comprehensive confounder adjustment J Natl Cancer Inst 107 djv045 2015 25770147 \n46. Lévesque LE Hanley JA Kezouh A et al Problem of immortal time bias in cohort studies: Example using statins for preventing progression of diabetes BMJ 340 b5087 2010 20228141 \n47. Jeon CY Goodman MT Cook-Wiens G et al Statin use and survival with early-stage hepatocellular carcinoma Cancer Epidemiol Biomarkers Prev 25 686 692 2016 26908429 \n48. Li Y Fu J Yuan X et al Simvastatin inhibits the proliferation of A549 lung cancer cells through oxidative stress and up-regulation of SOD2 Pharmazie 69 610 614 2014 25158572 \n49. Yu X Pan Y Ma H et al Simvastatin inhibits proliferation and induces apoptosis in human lung cancer cells Oncol Res 20 351 357 2013 23924855 \n50. Liu H Wang Z Li Y et al Simvastatin prevents proliferation and bone metastases of lung adenocarcinoma in vitro and in vivo Neoplasma 60 240 246 2013 23373992\n\n",
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"abstract": "Focal status epilepticus in POLG-related mitochondrial disease is highly refractory to pharmacological agents, including general anesthesia. We report the challenges in managing a previously healthy teenager who presented with de novo epilepsia partialis continua and metabolic stroke resulting from the homozygous p.Ala467Thr POLG mutation, the most common pathogenic variant identified in the Caucasian population. We applied transcranial direct current stimulation (tDCS; 2 mA; 20 min) daily as an adjunctive therapy because her focal seizures failed to respond to five antiepileptic drugs at maximal doses. The electrical and clinical seizures stopped after 3 days of tDCS. The second course of tDCS was administered for 14 days when the focal seizures re-emerged a month later. The patient tolerated the procedure well. Following 4 months of hospitalization and prolonged community rehabilitation, our patient has now returned to full-time education with support, and there is no report of cognitive deficit. We have demonstrated the safety and efficacy of tDCS in treating refractory focal motor seizures caused by mitochondrial disease.",
"affiliations": "Wellcome Centre for Mitochondrial Research Institute of Neuroscience Newcastle University Newcastle United Kingdom.;Department of Paediatric Neurology Royal Victoria Infirmary Newcastle upon Tyne United Kingdom.;Department of Clinical Neurophysiology Royal Victoria Infirmary Newcastle United Kingdom.;Department of Paediatric Neurology Royal Victoria Infirmary Newcastle upon Tyne United Kingdom.;Department of Paediatric Neurology Royal Victoria Infirmary Newcastle upon Tyne United Kingdom.;Department of Paediatrics City Hospitals Sunderland NHS Foundation Trust Sunderland United Kingdom.;Wellcome Centre for Mitochondrial Research Institute of Neuroscience Newcastle University Newcastle United Kingdom.;Wellcome Centre for Mitochondrial Research Institute of Neuroscience Newcastle University Newcastle United Kingdom.;Wellcome Centre for Mitochondrial Research Institute of Neuroscience Newcastle University Newcastle United Kingdom.;Wellcome Centre for Mitochondrial Research Institute of Neuroscience Newcastle University Newcastle United Kingdom.;Department of Clinical Neurophysiology Royal Victoria Infirmary Newcastle United Kingdom.",
"authors": "Ng|Yi Shiau|YS|;van Ruiten|Henriette|H|;Lai|H Ming|HM|;Scott|Rebecca|R|;Ramesh|Venkateswaran|V|;Horridge|Karen|K|;Taylor|Robert W|RW|;Turnbull|Doug M|DM|;Gorman|Gráinne S|GS|;McFarland|Robert|R|;Baker|Mark R|MR|",
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"fulltext": "\n==== Front\nEpilepsia OpenEpilepsia Open10.1002/(ISSN)2470-9239EPI4Epilepsia Open2470-9239John Wiley and Sons Inc. Hoboken 2958899510.1002/epi4.12094EPI412094Short Research ArticleShort Research ArticlesThe adjunctive application of transcranial direct current stimulation in the management of de novo refractory epilepsia partialis continua in adolescent‐onset POLG‐related mitochondrial disease Y. S. Ng et al.Ng Yi Shiau \n1\n*van Ruiten Henriette \n2\nLai H. Ming \n3\nScott Rebecca \n2\nRamesh Venkateswaran \n2\nHorridge Karen \n4\nTaylor Robert W. \n1\nTurnbull Doug M. \n1\nGorman Gráinne S. \n1\nMcFarland Robert \n1\n\n2\nBaker Mark R. m.r.baker@ncl.ac.uk \n3\n\n5\n\n1 \nWellcome Centre for Mitochondrial Research\nInstitute of Neuroscience\nNewcastle University\nNewcastle\nUnited Kingdom\n\n2 \nDepartment of Paediatric Neurology\nRoyal Victoria Infirmary\nNewcastle upon Tyne\nUnited Kingdom\n\n3 \nDepartment of Clinical Neurophysiology\nRoyal Victoria Infirmary\nNewcastle\nUnited Kingdom\n\n4 \nDepartment of Paediatrics\nCity Hospitals Sunderland NHS Foundation Trust\nSunderland\nUnited Kingdom\n\n5 \nInstitute of Neuroscience\nNewcastle University\nNewcastle upon Tyne\nUnited Kingdom\n* Address correspondence to Mark R. Baker, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom. E‐mail: m.r.baker@ncl.ac.uk11 1 2018 3 2018 3 1 10.1002/epi4.2018.3.issue-1103 108 20 11 2017 © 2017 The Authors. Epilepsia Open published by Wiley Periodicals Inc. on behalf of International League Against Epilepsy.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.Summary\nFocal status epilepticus in POLG‐related mitochondrial disease is highly refractory to pharmacological agents, including general anesthesia. We report the challenges in managing a previously healthy teenager who presented with de novo epilepsia partialis continua and metabolic stroke resulting from the homozygous p.Ala467Thr POLG mutation, the most common pathogenic variant identified in the Caucasian population. We applied transcranial direct current stimulation (tDCS; 2 mA; 20 min) daily as an adjunctive therapy because her focal seizures failed to respond to five antiepileptic drugs at maximal doses. The electrical and clinical seizures stopped after 3 days of tDCS. The second course of tDCS was administered for 14 days when the focal seizures re‐emerged a month later. The patient tolerated the procedure well. Following 4 months of hospitalization and prolonged community rehabilitation, our patient has now returned to full‐time education with support, and there is no report of cognitive deficit. We have demonstrated the safety and efficacy of tDCS in treating refractory focal motor seizures caused by mitochondrial disease.\n\nFocal seizuresMitochondrial diseaseNeurostimulationRefractory status epilepticusWellcome Centre for Mitochondrial Research203105Medical Research Council (MRC) Centre for Translational Research in Neuromuscular DiseaseNewcastle University Centre for Ageing and VitalityMitochondrial Disease Patient Cohort (UK)G0800674Lily FoundationUK NIHR Biomedical Research Centre for Ageing and Age‐Related Disease award to the Newcastle upon Tyne Foundation Hospitals NHS TrustUK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and ChildrenUK MRCNIHR source-schema-version-number2.0component-idepi412094cover-dateMarch 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.4 mode:remove_FC converted:03.06.2019\n==== Body\nThe clinical manifestations of mitochondrial disease are heterogeneous,1 and seizures affect approximately a quarter of adult patients.2 Refractory seizures have been long recognized as one presenting feature of Alpers‐Huttenlocher syndrome (AHS) in early childhood caused by pathogenic variants in the POLG gene. More recently, juvenile‐onset de novo status epilepticus with or without hepatic failure has been increasingly reported as a POLG‐related mitochondrial disorder.3, 4 Mixed seizure types, including generalized convulsive seizures, epilepsia partialis continua (EPC), myoclonus, and occipital seizures, are frequently observed.5 To date, there remains no effective treatment for POLG‐related epileptic encephalopathy. New therapeutic approaches are desperately needed, given the carrier frequency of common POLG mutations is prevalent (0.5–1% in the white European population) and high disease burden and mortality observed in those in whom disease presents with intractable epilepsy (median interval between disease onset and death was 1 year).5\n\n\nWe have directly managed two cases of juvenile‐onset POLG disease from our region over the last 8 years. The first case was a 17‐year‐old girl who died in the intensive care unit despite maximal medical intervention in refractory status epilepticus (for details see Data S1 and Figure S1). Here we describe details of the second case, in whom, despite a near fatal course, seizures stopped after applying a noninvasive brain stimulation technique known as transcranial direct current stimulation (tDCS).\n\nCase report\nA right‐handed 15‐year‐old girl who was previously fit and well, presented with a prolonged generalized tonic‐clonic seizure that required intubation and sedation in June 2015. Extubation was performed 48 h later, and jerking of her left arm spreading periodically to involve the rest of her body was noted. Metabolic, structural, infective, and autoimmune causes of seizures were excluded with normal routine laboratory studies, MRI head, lumbar puncture, negative anti‐NMDAR and anti‐VGKC antibodies, and MRI pelvis. She was commenced on oral phenytoin and levetiracetam and discharged home after several days of admission. A month later, she represented with five generalized tonic‐clonic seizures, preceded by a 2‐day history of headache, positive visual phenomena (colored circles), unsteadiness, and hypersomnolence. Seizures were inadequately controlled with a combination of phenytoin, levetiracetam, sodium valproate, and pulses of methylprednisolone, and treatment was escalated to general anesthesia. Following extubation, the generalized seizures ceased, but she remained encephalopathic and had frequent focal motor seizures affecting the left arm. Electroencephalography (EEG) confirmed electrical EPC arising from the right occipital region. Sodium valproate was stopped as mitochondrial disease was suspected at this stage. Her liver function was normal.\n\nThe patient was transferred to the regional neurology unit. She developed a new epileptic focus affecting the right arm after transfer, and the MRI brain showed stroke‐like lesions (Figs. 1A–F). Direct sequencing of the POLG gene (GenBank Accession number NM_002693.2) identified a pathogenic homozygous c.1399G>A, p.(Ala467Thr) variant. Despite a cocktail of antiepileptic drugs (AEDs), including lacosamide, perampanel, phenobarbitone, phenytoin, levetiracetam, and diazepam, EPC did not abate. The patient was admitted to the pediatric intensive care unit where the head was cooled and thiopentone administered until a burst‐suppression pattern was achieved on EEG. Following the withdrawal of thiopentone, recovery of consciousness took 11 days. She was free of overt clinical seizures for several days but had ongoing electrographic focal status epilepticus and significant encephalopathy. Debilitating EPC reemerged, affecting the right arm, leg, and paraspinal muscles, and frequent myoclonic jerks (including abdominal muscles) developed two weeks later. Further EEG studies continued to detect epileptic discharges arising from the posterior quadrant of the right hemisphere that spread over to the left side at times; there was no apparent EEG correlate with right upper and lower limb clonic movements. These reemergent seizures were refractory to AED therapy. Repeat administration of thiopentone was not considered owing to the side effects of prolonged recovery and risk of cardiorespiratory depression.\n\nFigure 1 Axial view of MRI head. FLAIR‐sequence (A–C) shows hyperintense lesions involving the right occipital lobe, right thalamus, and bilateral parietal lobes. DWI sequence (D–F) shows restricted diffusion in the bilateral occipital lobes, right thalamus, and left parietal lobe (red arrows) with increased ADC map (not shown), suggestive of vasogenic edema.\n\nConcern over the patient's deteriorating health urged us to consider cathodal tDCS as an adjunctive treatment.\n\nMethods for transcranial direct current stimulation\nThe clinical application of tDCS was approved as an emergency compassionate therapeutic intervention by the Newcastle upon Tyne Hospitals NHS Foundation Trust (NuTH) New Interventional Procedure Committee (NIPC) on a named patient basis. We obtained written consent from the patient's parents.\n\nThe location for the cathode was determined on the basis of the stroke‐like lesions identified on the serial MRI head (Figs. 1A,D) and the electrode locations on the pre‐tDCS EEG at which phase‐reversal of the epileptiform discharges occurred (see Fig. 2A). In the case described, the location approximated to T6, and therefore the cathode was placed over the right occipito‐tempero‐parietal region (centered on P4/T6; see Fig. 2B). The anode was applied to the left forehead (on a point approximating FP1). FP1 was chosen primarily as the location for the anode because it was contralateral and sufficiently anterior to the area of cortical edema (and the epileptogenic focus), thus reducing the possibility of causing an increase in seizure activity. The long axis of both electrodes was oriented in a coronal plane. tDCS was delivered by a battery‐powered (9V battery; IEC 6LR61) constant current stimulator (custom‐built by the Medical Physics Department, Newcastle upon Tyne Hospitals) through a pair of 5 × 7 cm conductive rubber electrodes covered in saline‐soaked sponges (neuroConn, Ilmenau, Germany).\n\nFigure 2 Electrophysiology. Pretreatment EEG (A) showing continuous seizure activity over the right parieto‐tempero‐occipital region. Diagram (schematic representation of international 10–20 system) indicating approximate locations of the cathode (blue) and anode (red) used for DC stimulation (B). Graphical representation of the effect of tDCS on the patient's seizures in a single session (C). The total number of myoclonic jerks was counted for each 15‐s epoch of video‐EEG and the mean seizure count for four consecutive epochs calculated (jerks/minute) and plotted (error bars are standard deviations). The solid bar indicates when tDCS (2 mA; 20 minutes) was applied. The data in (C) are further summarized in (D). In the bar graph, each bar plots the mean seizure frequency (jerks/second) before, during, and after tDCS (error bars represent 1 standard deviation from the mean). Bonferroni corrected t tests confirmed the significant effect of tDCS on seizure activity during tDCS. Posttreatment EEG (E), which confirmed that the seizure activity had ceased but some degree of encephalopathy continued. Note the change of EEG montage.\n\nTo maximize the therapeutic effects of direct current stimulation, a stimulus intensity of 2 mA was administered for 20 min. To comply with the guidance of the NuTH NIPC, the stimulation parameters chosen (2 mA and 20 min) were deemed to be the maximum safe parameters used in children based on published literature.6\n\n\nResults\nThe frequency of seizures was reduced significantly during tDCS but returned to previous levels after tDCS (see Figs. 2C,D). However, after 3 days of treatment, the clinical seizures stopped altogether with the termination of ictal discharges on the EEG (Fig. 2E). A month later, the patient developed irregular twitching of abdominal muscles and lower limbs, which her EEG captured as a clear buildup of rhythmical sharp activity over the posterior quadrant of the right hemisphere. We applied a 14‐day course of tDCS using the same protocol. She reported no side effects other than a mild tingling or burning sensation under the electrodes during the stimulation. Her AED treatments were not adjusted during the period of tDCS treatment.\n\nThe patient was discharged home after a total of 4 months of hospitalization, and she received a prolonged period of intense physical rehabilitation in the community. At the most recent clinic review (12 months after discharge from the hospital), she had returned to her studies with additional educational support at school. She reports an unsteady gait but can walk unaided. She has intermittent, brief sensory seizures affecting the right side. Her AED regime includes levetiracetam 1,750 mg twice daily, phenobarbitone 90 mg twice daily, and perampanel 8 mg once daily. Clinical examination showed subtle myoclonic jerks, poor visual acuity bilaterally, restricted upgaze, astereognosis on the right, areflexia, and an ataxic gait.\n\nDiscussion\nOur patient's clinical presentation and neuroimaging changes are consistent with stroke‐like episodes driven by protracted seizures. The clinical management of acute symptomatic seizures proved extremely challenging, despite administration of multiple AEDs and general anesthetic agents, including thiopentone. However, we have demonstrated that the adjunctive use of tDCS successfully terminated the debilitating seizures. To our knowledge, this is the first successful application of tDCS in the refractory focal epilepsy caused by recessive POLG mutations.5\n\n\nTranscranial direct current stimulation is a noninvasive subthreshold method of modulating cortical excitability using weak currents. First applied to the treatment of psychiatric disorders,7 there is now increasing interest in its potential therapeutic application to a range of neurological disorders, including focal epilepsy.8 The effects of tDCS on cortical excitability and the persistence of these effects are dependent on the current density applied (i.e., current intensity and electrode size), the polarity of the stimulus (cortical excitability is reduced by cathodal stimulation and increased by anodal stimulation), and the duration of DC stimulation.9 Although the clinical behavior of seizures observed in the context of mitochondrial diseases would suggest very different underlying mechanisms of epileptogenesis compared with other acquired or genetically determined epileptic syndromes, mitochondrial energy failure in neurones and glia is likely to be an important contributor. Cathodal tDCS will, as in all seizure disorders, reduce the probability of sodium and calcium channel opening and thus the probability of action potential generation (and seizure propagation) and, via long‐term depression (LTD), reduce the connectivity in epileptic networks.\n\nOther putative mechanisms of action of tDCS include depression of NMDA‐receptor‐mediated synaptic signals, reduction of presynaptic inputs via postsynaptic hyperpolarization, and alterations in NMDA receptor efficacy and transmembrane protein migration.10, 11 However, it should also reduce the energetic demands on mitochondria by indirect effects on spiking activity and possibly by direct effects on glia12 and intracellular bioenergetics.13, 14, 15 To date, several studies involving patients with refractory focal epilepsy have provided some compelling evidence for the efficacy of tDCS in reducing the frequency of clinical seizures.8, 16, 17 The technique of tDCS is emerging as a promising noninvasive, nonpharmacological, adjunctive treatment for refractory epilepsy owing to its low risk profile,8 low cost, and ease of use compared to other surgical neurostimulation techniques such as deep brain stimulation and vagus nerve stimulation.\n\nIn summary, we report that tDCS was an effective adjunctive therapy in a teenager who presented with refractory POLG‐related focal motor status epilepticus. Given the high prevalence of epilepsy in patients with mitochondrial disease,2 we suggest that the application of tDCS in mitochondrial epilepsy warrants further evaluation in prospective clinical studies.\n\nAuthor contribution\nConception and design of the study: Y.S.N., R.M., and M.R.B. Acquisition of data: All authors. Analysis and interpretation of data: Y.S.N., H.V.R., M.L., V.R., R.W.T., D.M.T., G.S.G., R.M., and M.R.B. Drafting the manuscript or figures: Y.S.N., H.V.R., R.M., and M.R.B. Critical review and revision: All authors.\n\nDisclosure\nNothing to report. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.\n\nSupporting information\n\nFigure S1. Neuroimaging and electrophysiology.\n\nClick here for additional data file.\n\n \nData S1. Supplementary data.\n\nClick here for additional data file.\n\n Acknowledgments\nY.S.N. holds a NIHR clinical lectureship and was the recipient of an MRC Centre for Neuromuscular Disease Clinical PhD studentship. This work is supported by the Wellcome Centre for Mitochondrial Research (203105), the Medical Research Council (MRC) Centre for Translational Research in Neuromuscular Disease, Newcastle University Centre for Ageing and Vitality (supported by the Biotechnology and Biological Sciences Research Council and MRC), Mitochondrial Disease Patient Cohort (UK) (G0800674), the Lily Foundation, the UK NIHR Biomedical Research Centre for Ageing and Age‐Related Disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust, and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children. M.R.B. is employed by the NHS, and research in his laboratory is funded by the UK MRC and NIHR. We would like to thank the laboratory staff of the NHS Highly Specialised Mitochondrial laboratory in Newcastle for molecular diagnostic studies.\n\n\nYi Shiau Ng is a NIHR clinical lecturer in neurology with an interest in mitochondrial disorders.\n==== Refs\nReferences\n1 \n\nGorman \nGS \n, \nChinnery \nPF \n, \nDiMauro \nS \n, et al. Mitochondrial diseases . Nat Rev Dis Primers \n2016 ;2 :16080 .27775730 \n2 \n\nWhittaker \nRG \n, \nDevine \nHE \n, \nGorman \nGS \n, et al. Epilepsy in adults with mitochondrial disease: a cohort study . Ann Neurol \n2015 ;78 :949 –957 .26381753 \n3 \n\nUusimaa \nJ \n, \nHinttala \nR \n, \nRantala \nH \n, et al. Homozygous W748S mutation in the POLG1 gene in patients with juvenile‐onset Alpers syndrome and status epilepticus . Epilepsia \n2008 ;49 :1038 –1045 .18294203 \n4 \n\nVisser \nNA \n, \nBraun \nKP \n, \nvan den Bergh \nWM \n, et al. Juvenile‐onset Alpers syndrome: interpreting MRI findings . 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Dynamic changes of NADH fluorescence images and NADH content during spreading depression in the cerebral cortex of gerbils . Brain Res \n2000 ;872 :294 –300 .10924711 \n14 \n\nHolandino \nC \n, \nTeixeira \nCA \n, \nde Oliveira \nFA \n, et al. Direct electric current treatment modifies mitochondrial function and lipid body content in the A549 cancer cell line . Bioelectrochemistry \n2016 ;111 :83 –92 .27243447 \n15 \n\nArdolino \nG \n, \nBossi \nB \n, \nBarbieri \nS \n, et al. Non‐synaptic mechanisms underlie the after‐effects of cathodal transcutaneous direct current stimulation of the human brain . J Physiol \n2005 ;568 :653 –663 .16037080 \n16 \n\nAssenza \nG \n, \nCampana \nC \n, \nAssenza \nF \n, et al. Cathodal transcranial direct current stimulation reduces seizure frequency in adults with drug‐resistant temporal lobe epilepsy: a sham controlled study . 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"title": "The adjunctive application of transcranial direct current stimulation in the management of de novo refractory epilepsia partialis continua in adolescent-onset POLG-related mitochondrial disease.",
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"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PHENOBARBITAL"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThis study was designed to identify factors associated with persistent delirium in an older medical intensive care unit (ICU) population.\n\n\nMETHODS\nThis is a prospective cohort study of 309 consecutive medical ICU patients 60 years or older. Persistent delirium was defined as delirium occurring in the ICU and continuing upon discharge to the ward. The Confusion Assessment Method was used to assess for delirium. Patient demographics, severity of illness, and medication data were collected. Univariate and multivariate analysis were used to assess factors associated with persistent delirium.\n\n\nRESULTS\nOf 309 consecutive admissions to the ICU, 173 patients had ICU delirium, survived the ICU stay, and provided ward data. One-hundred patients (58%) had persistent delirium. In a multivariable logistic regression model, factors significantly associated with persistent delirium included age more than 75 years (odds ratio [OR], 2.52; 95% confidence interval [CI], 1.23-5.16), opioid (morphine equivalent) dose greater than 54 mg/d (OR, 2.90; 95% CI, 1.15-7.28), and haloperidol (OR, 2.88; 95% CI, 1.38-6.02); change in code status to \"do not resuscitate\" (OR, 2.62; 95% CI 0.95-7.35) and dementia (OR, 1.93; 95% CI 0.95-3.93) had less precise associations.\n\n\nCONCLUSIONS\nAge, use of opioids, and haloperidol were associated with persistent delirium. Further research is needed regarding the use of haloperidol and opioids on persistent delirium.",
"affiliations": "Department of Internal Medicine, Pulmonary and Critical Care Section, and the Program on Aging, Yale University School of Medicine, New Haven, CT 06520-8057, USA. margaret.pisani@yale.edu",
"authors": "Pisani|Margaret A|MA|;Murphy|Terrence E|TE|;Araujo|Katy L B|KL|;Van Ness|Peter H|PH|",
"chemical_list": "D000701:Analgesics, Opioid; D011619:Psychotropic Drugs; D006220:Haloperidol",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jcrc.2010.02.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-9441",
"issue": "25(3)",
"journal": "Journal of critical care",
"keywords": null,
"medline_ta": "J Crit Care",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000701:Analgesics, Opioid; D000704:Analysis of Variance; D003422:Critical Care; D003693:Delirium; D003704:Dementia; D006220:Haloperidol; D006801:Humans; D007362:Intensive Care Units; D008875:Middle Aged; D010343:Patient Admission; D011446:Prospective Studies; D011619:Psychotropic Drugs; D012307:Risk Factors; D012720:Severity of Illness Index",
"nlm_unique_id": "8610642",
"other_id": null,
"pages": "540.e1-7",
"pmc": null,
"pmid": "20413252",
"pubdate": "2010-09",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "2240918;12560416;12752846;12752832;17931586;11730446;10798458;11445689;16540616;15673358;10456379;17102966;17469164;16919169;15071384;14707567;16103670;16394685;11430542;9539601;8208879;11797025;15082703;3558716;16551316;2740664;17698685;12075033",
"title": "Factors associated with persistent delirium after intensive care unit admission in an older medical patient population.",
"title_normalized": "factors associated with persistent delirium after intensive care unit admission in an older medical patient population"
} | [
{
"companynumb": "US-JNJFOC-20150609060",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nAlthough anti-tumor necrosis factor (TNF) therapy is the treatment of choice for perianal fistulizing Crohn's disease (CD), the efficacy and safety of anti-TNF therapy in enterocutaneous fistula (ECF) remains unclear.\n\n\nMETHODS\nBetween January 2008 and December 2009, we retrospectively reviewed the outcomes of all CD patients with ECF (excluding perianal fistula) treated with anti-TNF therapy followed up in Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif (GETAID) centers. ECF closure and tolerance of anti-TNF therapy were studied using univariate and multivariate analyses.\n\n\nRESULTS\nForty-eight patients (twenty-six women; median age 34.6 (interquartile range=25.0-45.5) years) were included in this study. The median follow-up period was 3.0 (2.0-6.6) years. The fistula was located in the small bowel (n=38), duodenum (n=1), and colon (n=9). The fistula has been developed in ileocolonic anastomosis in 17 (35%) cases. Sixteen patients (33%) had complex fistulas with multiple tracts and eleven patients (23%) had a high ECF output (if wearing an ostomy bag). Complete ECF closure was achieved in 16 (33%) patients, of whom eight relapsed during the follow-up period. In multivariate analysis, complete ECF closure was associated with the absence of multiple ECF tracts and associated stenosis. An abdominal abscess developed in 15 (31%) patients. ECF resection was needed in 26 (54%) patients. One patient died after surgery owing to abdominal sepsis.\n\n\nCONCLUSIONS\nIn CD patients with ECF, anti-TNF therapy may be effective in up to one-third of patients, especially in the absence of stenosis and complex fistula. A careful selection of patients is mandatory to prevent treatment failure and improves the safety.",
"affiliations": "1] Department of Gastroenterology, Henri Mondor Hospital, UPEC, Creteil, France [2] These authors contributed equally to this work.;1] Department of Gastroenterology, IBD and Nutrition Support, Beaujon Hospital, University Paris 7 Denis Diderot, Clichy, France [2] These authors contributed equally to this work.;Department of Gastroenterology, Saint-Antoine Hospital, University Paris 6 Pierre and Marie Curie, Paris, France.;Department of Gastroenterology, Saint-Louis Hospital, University Paris 7 Denis Diderot, Paris, France.;Department of Gastroenterology, Henri Mondor Hospital, UPEC, Creteil, France.;Department of Gastroenterology, Gent Hospital, University of Gent, Gent, Belgium.;Department of Gastroenterology, Haut-Leveque Hospital, University of Bordeaux 2, Pessac, France.;Department of Gastroenterology, Claude Huriez Hospital, University of Lille 2, Lille, France.;Department of Gastroenterology, Cochin Hospital, University Paris 5 Descartes, Paris, France.;Department of Gastroenterology, Cote de Nacre Hospital, University of Caen, Caen, France.;Department of Gastroenterology, Rangueil University Hospital, University of Toulouse, Toulouse, France.;Department of Gastroenterology, Montpellier University Hospital, University of Montpellier, Montpellier, France.;Department of Gastroenterology, Edouard Herriot Hospital, University Lyon 1 Claude Bernard, Lyon, France.;Department of Gastroenterology, Saint-Antoine Hospital, University Paris 6 Pierre and Marie Curie, Paris, France.;Department of Gastroenterology, Saint-Louis Hospital, University Paris 7 Denis Diderot, Paris, France.;Department of Gastroenterology, Henri Mondor Hospital, UPEC, Creteil, France.",
"authors": "Amiot|Aurelien|A|;Setakhr|Vida|V|;Seksik|Philippe|P|;Allez|Mathieu|M|;Treton|Xavier|X|;De Vos|Martine|M|;Laharie|David|D|;Colombel|Jean-Frederic|JF|;Abitbol|Vered|V|;Reimund|Jean Marie|JM|;Moreau|Jacques|J|;Veyrac|Michel|M|;Flourié|Bernard|B|;Cosnes|Jacques|J|;Lemann|Marc|M|;Bouhnik|Yoram|Y|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab",
"country": "United States",
"delete": false,
"doi": "10.1038/ajg.2014.183",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9270",
"issue": "109(9)",
"journal": "The American journal of gastroenterology",
"keywords": null,
"medline_ta": "Am J Gastroenterol",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000714:Anastomosis, Surgical; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003106:Colon; D003108:Colonic Diseases; D003424:Crohn Disease; D017577:Cutaneous Fistula; D004378:Duodenal Diseases; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007082:Ileum; D000069285:Infliximab; D007412:Intestinal Fistula; D007421:Intestine, Small; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult",
"nlm_unique_id": "0421030",
"other_id": null,
"pages": "1443-9",
"pmc": null,
"pmid": "25091063",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Long-term outcome of enterocutaneous fistula in patients with Crohn's disease treated with anti-TNF therapy: a cohort study from the GETAID.",
"title_normalized": "long term outcome of enterocutaneous fistula in patients with crohn s disease treated with anti tnf therapy a cohort study from the getaid"
} | [
{
"companynumb": "FR-JNJFOC-20141102915",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
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"drugadditional": null,
... |
{
"abstract": "Undifferentiated pleomorphic sarcoma (UPS) was previously known as malignant fibrous histiocytoma (MFH). This sarcoma occurs preferentially in the extremities and retroperitoneal space; primary pulmonary UPS/MFH is rare. We report a 52-year-old woman referred to our hospital with dyspnea and severe cough. Chest computed tomography (CT) revealed a pulmonary mass in the left upper lobe and pleural effusion. Cytology of the effusion showed no malignancy; however, the tumor increased rapidly in size, and the patient's respiratory symptoms worsened. The tumor occupied almost all of the left upper lobe and involved the adjacent pericardium. She underwent left upper lobectomy with pericardial resection and reconstruction. Postoperative pathology of the resected specimen showed undifferentiated pulmonary sarcoma, pT4N0M1a stage IV A, and genetic analyses revealed the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation. The patient's dyspnea recurred 1 month postoperatively, and CT showed marked pleural effusion. An 18F-fluorodeoxyglucose positron emission tomography demonstrated abnormal diffuse accumulation of 18F-fluorodeoxyglucose in the left pleural cavity. We initiated five cycles of chemotherapy with doxorubicin and ifosfamide, and the patient has been well without recurrence for 24 months after multidisciplinary treatment with surgery followed by systemic combination chemotherapy. We successfully treated our patient with primary pulmonary UPS/MFH using a multidisciplinary approach, even though this sarcoma carries a poor prognosis and is insensitive to both chemotherapy and radiotherapy.",
"affiliations": "Department of Thoracic Surgery, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu, Japan.;Department of Musculoskeletal Oncology and Metabolic Bone Disease Research, Fukushima Medical University School of Medicine, Fukushima, Japan.;Department of Surgery, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu, Japan.;Department of Surgery, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu, Japan.;Department of Surgery, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu, Japan.;Department of Surgery, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu, Japan.;Department of Thoracic Surgery, Kanazawa Medical University School of Medicine, Kanazawa, Japan.;Department of Clinical Pathology, Kanazawa Medical University School of Medicine, Kanazawa, Japan.;Department of Pathology, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu, Japan.;Department of Chest Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.",
"authors": "Higuchi|Mitsunori|M|;Yamada|Hitoshi|H|;Machino|Kakeru|K|;Oshibe|Ikuro|I|;Soeta|Nobutoshi|N|;Saito|Takuro|T|;Uramoto|Hidetaka|H|;Yamada|Sohsuke|S|;Hojo|Hiroshi|H|;Suzuki|Hiroyuki|H|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000506897",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575 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\n10.1159/000506897\ncro-0013-0385\nCase Report\nSuccessful Multidisciplinary Treatment for Aggressive Primary Pulmonary Undifferentiated Pleomorphic Sarcoma\nHiguchi Mitsunori a* Yamada Hitoshi b Machino Kakeru c Oshibe Ikuro c Soeta Nobutoshi c Saito Takuro c Uramoto Hidetaka d Yamada Sohsuke e Hojo Hiroshi f Suzuki Hiroyuki g aDepartment of Thoracic Surgery, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu, Japan\nbDepartment of Musculoskeletal Oncology and Metabolic Bone Disease Research, Fukushima Medical University School of Medicine, Fukushima, Japan\ncDepartment of Surgery, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu, Japan\ndDepartment of Thoracic Surgery, Kanazawa Medical University School of Medicine, Kanazawa, Japan\neDepartment of Clinical Pathology, Kanazawa Medical University School of Medicine, Kanazawa, Japan\nfDepartment of Pathology, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu, Japan\ngDepartment of Chest Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan\n*Mitsunori Higuchi, MD, PhD, Department of Thoracic Surgery, Aizu Medical Center, Fukushima Medical University, 21-2 Maeda, Tanisawa, Kawahigashi, Aizuwakamatsu 969-3492 (Japan), higuchi@fmu.ac.jp\nJan-Apr 2020 \n9 4 2020 \n9 4 2020 \n13 1 385 391\n27 2 2020 2 3 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This 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.Undifferentiated pleomorphic sarcoma (UPS) was previously known as malignant fibrous histiocytoma (MFH). This sarcoma occurs preferentially in the extremities and retroperitoneal space; primary pulmonary UPS/MFH is rare. We report a 52-year-old woman referred to our hospital with dyspnea and severe cough. Chest computed tomography (CT) revealed a pulmonary mass in the left upper lobe and pleural effusion. Cytology of the effusion showed no malignancy; however, the tumor increased rapidly in size, and the patient's respiratory symptoms worsened. The tumor occupied almost all of the left upper lobe and involved the adjacent pericardium. She underwent left upper lobectomy with pericardial resection and reconstruction. Postoperative pathology of the resected specimen showed undifferentiated pulmonary sarcoma, pT4N0M1a stage IV A, and genetic analyses revealed the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation. The patient's dyspnea recurred 1 month postoperatively, and CT showed marked pleural effusion. An 18F-fluorodeoxyglucose positron emission tomography demonstrated abnormal diffuse accumulation of 18F-fluorodeoxyglucose in the left pleural cavity. We initiated five cycles of chemotherapy with doxorubicin and ifosfamide, and the patient has been well without recurrence for 24 months after multidisciplinary treatment with surgery followed by systemic combination chemotherapy. We successfully treated our patient with primary pulmonary UPS/MFH using a multidisciplinary approach, even though this sarcoma carries a poor prognosis and is insensitive to both chemotherapy and radiotherapy.\n\nKeywords\nUndifferentiated pulmonary sarcomaMalignant fibrous histiocytomaMultidisciplinary treatmentLong-term complete response\n==== Body\nIntroduction\nUndifferentiated pleomorphic sarcoma (UPS) was previously known as malignant fibrous histiocytoma (MFH), which was first reported by O'Brien et al. in 1964 [1]. MFH did not fit any of the recognized sarcoma categories by the end of the 1980s; however, MFH subsequently became to be the single largest category of sarcoma [2]. In 2013, MFH was declassified as a formal diagnostic entity and renamed “undifferentiated pleomorphic sarcoma” by the World Health Organization. UPS/MFH occurs in the extremities in 16% and retroperitoneum in 68% of patients [2]. Primary pulmonary UPS/MFH is uncommon and highly malignant, and there are no optimal or consensus treatment strategies. We experienced a patient with primary pulmonary UPS who achieved long-term complete response with surgery followed by chemotherapy. We also performed next-generation DNA sequencing of the UPS/MFH tissue from this patient.\n\nCase Presentation\nA 52-year-old woman was referred to our hospital because of dyspnea and severe cough. Chest computed tomography at her first visit revealed a pulmonary mass in the left upper lobe with pleural effusion (Fig. 1a). Cytology of the effusion showed no malignancy; however, only 1 month after her visit, the tumor had increased rapidly in size (Fig. 1b) and her respiratory symptoms had worsened. At that time, the tumor occupied almost all of the left upper lobe and involved the adjacent pericardium. She underwent left upper lobectomy with pericardial resection and reconstruction. We confirmed localized pleural dissemination during surgery, which was proven pathologically. The resected specimen measured 15 cm (maximum size), and postoperative pathology of the specimen showed a diffuse proliferation of admixed spindle-shaped and circular, highly atypical cells, arranged in a characteristic storiform growth pattern (Fig. 2a). Immunohistochemical staining revealed that tumor cells were positive for vimentin (Fig. 2b) and negative for epithelial markers. According to these findings, she was diagnosed as having UPS, pT4N0M1a stage IV A. Genetic analyses by next-generation DNA sequencing revealed a positive v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation (G12D) at codon 12; programmed death ligand 1 (PD-L1) expression was less than 1%. One month postoperatively, repeat computed tomography revealed marked pleural effusion, and the patient again experienced dyspnea. Postoperative 18F-fluorodeoxyglucose positron emission tomography demonstrated abnormal and diffuse accumulation of 18F-fluorodeoxyglucose in the left pleural cavity (Fig. 1c). We initiated five cycles of chemotherapy with doxorubicin and ifosfamide, which induced grade 3 myelosuppression and febrile neutropenia, as adverse events. The patient has been well without recurrence for 24 months after multidisciplinary treatment with surgery followed by systemic combination chemotherapy (Fig. 1d).\n\nDiscussion\nUPS/MFH is an aggressive soft tissue sarcoma originating from mesenchymal cells. UPS/MFH accounts for 5–10% of sarcomas in adults older than 40 years of age [3]; however, the sarcoma accounts for only 0.04–0.2% of pulmonary tumors [4]. The symptoms of primary pulmonary UPS/MFH are chest pain, dyspnea, cough, hemoptysis, and weight loss. Our patient also suffered from dyspnea and severe cough. Histologically, tumors are composed of a storiform arrangement of highly pleomorphic and spindle-shaped cells. UPS/MFH shows no specific immunohistochemical findings that enable more specific subclassification [5], and cells stain positive only for vimentin, in most patients, as in our patient. Qorbani et al. [6] reported a brief review of literature on primary pulmonary UPS/MFH of 85 patients who had been reported in the English literature since 1979. We added two reports [7, 8] and our patient to this previous report. 54 out of 88 patients included the complete data of age, gender, location of the tumor, tumor size, treatments, lymph node status, survival time and prognosis. Then we summarized and analyzed the data of primary pulmonary UPS/MFH of 54 patients. These patients' characteristics are shown in Table 1. Survival probabilities were estimated using the Kaplan-Meier method. A p value of <0.05 was considered statistically significant. Statistical analysis was conducted with SPSS version 21.0 (IBM Corp., Armonk, NY, USA). 33 out of 54 patients were male and 21 were female. The patient age ranged from 12 to 86 years with a mean age of 56.1 years. The locations of tumor were right side in 28 patients, left side in 25 patients, and both sides in one patient. The tumor size ranged from 1.7 to 25 cm with average size of 7.3 cm. Lymph node metastases were positive in 12 patients and negative in 42 patients. 48 out of 54 patients received any surgical treatments including lobectomy in 35 patients, pneumonectomy in 8 patients, and other resection in 5 patients. The 2-year, 5-year, and 10-year overall survival rates were 46.4, 40.2, and 34.5%, respectively (Fig. 3a). The 5-year overall survival rates in no lymph node metastatic group and lymph node metastatic group were 48.7 and 16.7%, respectively, with a significant difference (p = 0.006) (Fig. 3b). According to these data, nodal status might contribute to the prognosis of primary pulmonary UPS/MFH as well as lung cancer. The effective treatment for UPS/MFH is complete resection and appropriate surgical procedure is lobectomy.\n\nFew reports have evaluated the effectiveness of chemotherapy, including combination chemotherapy with cyclophosphamide, vincristine, adriamycin, and dacarbazine [9]. Edmonson et al. [10] reported that combination chemotherapy using doxorubicin and ifosfamide improved the response rate and progression-free survival. However, consensus regarding standard treatment for primary pulmonary UPS/MFH has not been established. Although chemotherapy for UPS/MFH is in generally not a promising treatment modality, our patient achieved long-term complete response in accordance with Edmonson's report [10]. This case is encouraging regarding patients with UPS/MFH; however, we will continue to follow our patient, closely. Doxorubicin and ifosfamide treatment may be more likely to cause myelosuppression [10] compared with doxorubicin alone, and our patient suffered grade 3 myelosuppression and subsequent febrile neutropenia. Physicians must collect and evaluate data describing both the effectiveness and adverse events of multidisciplinary treatment for this rare entity.\n\nIn non-small cell lung cancer, major advances have been made in treatment with the advent of immune-checkpoint inhibitors such as nivolumab (anti-programmed cell death 1 [PD-1] antibody), pembrolizumab (anti-PD-1 antibody), durvalumab (anti-PD-L1 antibody), atezolizumab (anti-PD-L1 antibody), and ipilimumab (anti-cytotoxic T lymphocyte antigen 4 antibody). In patients with advanced bone and soft tissue sarcomas, pembrolizumab showed promising activity in the SARC028 trial [11]. In this trial, responses to pembrolizumab were seen even in the absence of PD-L1 expression; however, the authors stated that the role of PD-L1 expression in soft-tissue sarcoma remains unclear. Based on this trial, a novel phase II study is now ongoing that is evaluating single-agent anti-PD-1 antibody and combination anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) and anti-PD-1 therapy for surgically resectable UPS/MFH and dedifferentiated liposarcoma [12]. We expect these immunotherapies will be promising treatment modalities for UPS/MFH in the near future; however, a specific biomarker is needed to predict the effectiveness and prognosis of immune checkpoint inhibitors in this rare sarcoma.\n\nUPS/MFH is reported to have genetic mutations, which are responsible for primary pulmonary UPS/MFH formation and progression. Li et al. [13] reported that the mutation frequency of the tuberous sclerosis complex 2 gene was 15.64%, and this gene activates the mammalian target of rapamycin (mTOR) pathway. Li et al. [5] reported a case of concurrent KRAS mutation and phosphatidylinositol 3-kinase p110 subunit alpha (PIK3CA) mutation [8]. Serrano et al. [14] also reported that the RAS/mitogen activated protein kinase (RAS/MAPK) and phosphatidylinositol 3-kinase (PI3K)/mTOR pathways were activated in the majority of patients with UPS/MFH. KRAS is a proto-oncogene located at 12p12.1, and a frequently altered gene, with mutations occurring in 17–25% of all cancers [5]. Constitutive activation of growth factor signaling pathways is responsible for the maintenance of aggressiveness and tumor phenotype, and among the pathways, the RAS/MAPK and PI3K/mTOR pathways commonly drive oncogenic stimuli in soft tissue sarcomas [15]. Serrano et al. [14] reported that RAS/MAPK was activated in the majority of patients with UPS, and that this pathway contributed to the aggressive behavior of UPS/MFH. Considering these findings, our patient's medical status was dire, both before and after surgery. The clinical investigation of novel agents targeting the RAS/MAPK pathway in UPS/MFH as well as in other malignancies, is urgently needed.\n\nConclusions\nOur patient with primary pulmonary UPS/MFH achieved long-term complete response following multidisciplinary treatment even though this sarcoma carries a poor prognosis and is insensitive to both chemotherapy and radiotherapy.\n\nStatement of Ethics\nThe need for ethical approval was waived for this case report. Written consent was obtained from the patient to undergo the procedures described in this report. Written consent was obtained from the patient for the publication of this case report and accompanying images.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nAuthor Contributions\nM.H. collected and assembled the data, and drafted the article. H.Y., K.M., I.O., N.S., T.S., H.U., S.Y., and H.H. assisted with data collection. H.S. helped draft the article and finally approved the article. All authors read and approved the final manuscript.\n\nAcknowledgements\nThe authors thank Mr Takashi Sato, Ms Miho Sagawa, and Ms Michie Kojimahara from the Department of Pathology, Aizu Medical Center, Fukushima Medical University for their excellent technical work and support, and Dr Jane Charbonneau, DVM, from Edanz Group (www.edanzediting.com/ac) for editing a draft of the manuscript.\n\nFig. 1 Chest computed tomographic images showing a pulmonary mass in the left upper lobe with pleural effusion at the patient's first visit (a). This tumor grew rapidly to occupy the entire left upper lobe 1 month after the patient's first visit (b). Postoperative 18F-fluorodeoxyglucose positron emission tomographic images showing abnormal and diffuse accumulation of 18F-fluorodeoxyglucose in the left pleural cavity (c), which disappeared after five cycles of chemotherapy (d).\n\nFig. 2 Histopathological findings showing an admixture of spindle-shaped and circular cells, arranged in a storiform pattern (hematoxylin and eosin, ×100) (a). Immunohistochemical staining revealed cells positive for vimentin (×100) (b).\n\nFig. 3 The 2-year, 5-year, and 10-year overall survival (OS) rates were 46.4%, 40.2%, and 34.5%, respectively (a). The 5-year OS rates in no lymph node metastatic group (solid line) and lymph node metastatic group (dotted line) were 48.7 and 16.7%, respectively, with a significant difference (p = 0.006) (b).\n\nTable 1 Patients' characteristics (n = 54)\n\nCharacteristics\t\t\nAge, years\t56.1±15.6\t\nSex\t\t\n Male\t33 (61.1%)\t\n Female\t21 (38.9%)\t\nSide\t\t\n Right\t28 (51.9%)\t\n Left\t25 (46.3%)\t\n Both\t1 (1.8%)\t\nTumor size, cm\t7.2±4.1\t\nTreatment\t\t\n Surgery alone\t37 (58.5%)\t\n Surgery and chemotherapy\t3 (5.6%)\t\n Surgery and radiotherapy\t6 (11.1%)\t\n Surgery, chemotherapy, and radiotherapy\t2 (3.7%)\t\n Chemotherapy alone\t1 (1.8%)\t\n Radiotherapy alone\t2 (3.7%)\t\n No treatment\t3 (5.6%)\t\nNodal status\t\t\n Positive\t12 (22.2%)\t\n Negative\t42 (77.8%)\t\nPrognosis\t\t\n Dead\t28 (51.9%)\t\n Alive\t26 (48.1%)\n==== Refs\nReferences\n1 O'Brien JE Stout AP Malignant fibrous xanthomas Cancer 1964 17 1445 55 14223761 \n2 Weiss SW Enzinger FM Malignant fibrous histiocytoma: an analysis of 200 cases Cancer 1978 41 (6) 2250 66 207408 \n3 Fletcher CD The evolving classification of soft tissue tumours − an update based on the new 2013 WHO classification Histopathology 2014 64 (1) 2 11 24164390 \n4 Maitani F Fujimori S Hayashi Y Hasegawa A Iwazaki M A case of juvenile primary pulmonary malignant fibrous histiocytoma Tokai J Exp Clin Med 2010 35 (4) 130 2 21319042 \n5 Li B Li L Li X Wang Y Xie Y Liu C Undifferentiated pleomorphic sarcoma with co-existence of KRAS/PIK3CA mutations Int J Clin Exp Pathol 2015 8 (7) 8563 7 26339434 \n6 Qorbani A Nelson SD Primary pulmonary undifferentiated pleomorphic sarcoma (PPUPS) Autops Case Rep 2019 Jul-Sep 9 (3) e2019110 31528627 \n7 Pleština S Librenjak N Marušić A Batelja Vuletić L Janevski Z Jakopović M An extremely rare primary sarcoma of the lung with peritoneal and small bowel metastases: a case report World J Surg Oncol 2019 17 147 31426804 \n8 Coşgun T Tezel Y Akyıl M Kolbaş İ Şen A Tezel Ç Primary pulmonary malignant fibrous histiocytoma Turk Thorac J 2017 18 54 6 29404161 \n9 Leite C Goodwin JW Sinkovics JG Baker LH Benjamen R Chemotherapy of malignant fibrous histiocytoma: a Southwest Oncology Group report Cancer 1977 40 (5) 2010 4 200332 \n10 Edmonson JH Ryan LM Blum RH Brooks JS Shiraki M Frytak S Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas J Clin Oncol 1993 11 (7) 1269 75 8315424 \n11 Tawbi HA Burgess M Bolejack V Van Tine BA Schuetze SM Hu J Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial Lancet Oncol 2017 18 1493 501 28988646 \n12 Keung EZ Lazar AJ Torres KE Wang WL Cormier JN Ashleigh Guadagnolo B Phase II study of neoadjuvant checkpoint blockade in patients with surgically resectable undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma BMC Cancer 2018 18 (1) 913 30249211 \n13 Li X Liu R Shi T Dong S Ren F Yang F Primary pulmonary malignant fibrous histiocytoma: case report and literature review J Thorac Dis 2017 9 (8) E702 8 28932590 \n14 Serrano C Romagosa C Hernández-Losa J Simonetti S Valverde C Moliné T RAS/MAPK pathway hyperactivation determines poor prognosis in undifferentiated pleomorphic sarcomas Cancer 2016 122 (1) 99 107 26479291 \n15 Dodd RD Mito JK Eward WC Chitalia R Sachdeva M Ma Y NF1 deletion generates multiple subtypes of soft-tissue sarcoma that respond to MEK inhibition Mol Cancer Ther 2013 12 (9) 1906 17 23858101\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "13(1)",
"journal": "Case reports in oncology",
"keywords": "Long-term complete response; Malignant fibrous histiocytoma; Multidisciplinary treatment; Undifferentiated pulmonary sarcoma",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "385-391",
"pmc": null,
"pmid": "32355494",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "26479291;24164390;28988646;28932590;30249211;31528627;31426804;21319042;200332;207408;23858101;8315424;29404161;14223761;26339434",
"title": "Successful Multidisciplinary Treatment for Aggressive Primary Pulmonary Undifferentiated Pleomorphic Sarcoma.",
"title_normalized": "successful multidisciplinary treatment for aggressive primary pulmonary undifferentiated pleomorphic sarcoma"
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"companynumb": "JP-BAXTER-2020BAX010324",
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"abstract": "Duodenal ulcers are most often caused by Helicobacter pylori (HP) infection, followed by nonsteroidal anti-inflammatory drugs and hypoperfusion. Posttransplant lymphoproliferative disorder (PTLD) occurs in about 1-6.3% of patients with a heart transplant under immunosuppression therapy. Up to 25% of cases of PTLD have gastrointestinal involvement. Due to a wide spectrum of clinical symptoms and pathological entities, the diagnosis can be challenging. We report the case of a 55-year-old man 12 years after receiving a heart transplant being treated with immunosuppressive agents (tacrolimus) who presented with recurrent bleeding from peptic duodeni. Immunohistochemistry revealed a rare Epstein-Barr-virus-associated polymorphic PTLD. Rarely, PTLD can manifest only with isolated lesions of the duodenal bulb. The course was progressive, going from an incidental finding requiring transfusion anemia to a perforation within 1 month. Repeated endoscopic interventions were unsuccessful. After a surgical intervention the patient died in the course of multiple organ failure. Retrospectively, a reduction of immunosuppression in polymorphic PTLD would have been a treatment option.",
"affiliations": "Gastroenterologie, Marien-Hospital Euskirchen, Gottfried-Disse-Str. 40, 53879, Euskirchen, Deutschland. yilin.vogel@marien-hospital.com.;Innere Medizin, Eifelklinik St. Brigida, Simmerath, Deutschland.;Kardiologie, Marien-Hospital Euskirchen, Euskirchen, Deutschland.;Institut für Pathologie Bonn-Duisdorf, Bonn, Deutschland.",
"authors": "Vogel|Y|Y|;Wolff|I|I|;Zobel|C|C|;Hildenbrand|R|R|",
"chemical_list": "D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00108-018-0492-4",
"fulltext": null,
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"issn_linking": "0020-9554",
"issue": "60(3)",
"journal": "Der Internist",
"keywords": "Bleeding, gastrointestinal; Epstein-Barr virus; Immunosuppression; Lymphoproliferative disorders, posttransplant, polymorphic; Tacrolimus",
"medline_ta": "Internist (Berl)",
"mesh_terms": "D004381:Duodenal Ulcer; D020031:Epstein-Barr Virus Infections; D017809:Fatal Outcome; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016559:Tacrolimus; D016896:Treatment Outcome",
"nlm_unique_id": "0264620",
"other_id": null,
"pages": "298-303",
"pmc": null,
"pmid": "30242430",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19451438;19280542;22618860;18465033;26019475;22410851;17509986;22820701;14974943",
"title": "Recurrent bleeding of a duodenal ulcer in a 55-year-old man after heart transplantation.",
"title_normalized": "recurrent bleeding of a duodenal ulcer in a 55 year old man after heart transplantation"
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"abstract": "Hyperbaric oxygen therapy (HBOT) has been shown to be effective in the treatment of diabetic ulcers, air embolism, carbon monoxide poisoning and gas gangrene with minimal adverse effects. Very few cases of HBOT causing acute pulmonary edema (PE) has been described; with a study on dogs suggesting that a complication of this therapy could be PE. We describe the case of an 80-year-old man with a history of stable systolic heart failure and diabetes mellitus presenting with acute PE following treatment with HBOT for diabetic foot.",
"affiliations": "Department of Medicine , Maimonides Medical Center , Brooklyn, NY , USA.;Department of Pulmonary/Critical Care , Maimonides Medical Center , Brooklyn, NY , USA.;Department of Cardiology , Maimonides Medical Center , Brooklyn, NY , USA.;Department of Cardiology , Maimonides Medical Center , Brooklyn, NY , USA.;Department of Cardiology , Maimonides Medical Center , Brooklyn, NY , USA.",
"authors": "Obiagwu|Chukwudi|C|;Paul|Vishesh|V|;Chadha|Sameer|S|;Hollander|Gerald|G|;Shani|Jacob|J|",
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"doi": "10.1093/omcr/omv002",
"fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcromcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omv002omv0022002200Case ReportsAcute pulmonary edema secondary to hyperbaric oxygen therapy Obiagwu Chukwudi 1*Paul Vishesh 2Chadha Sameer 3Hollander Gerald 3Shani Jacob 31 Department of Medicine, Maimonides Medical Center, Brooklyn, NY, USA2 Department of Pulmonary/Critical Care, Maimonides Medical Center, Brooklyn, NY, USA3 Department of Cardiology, Maimonides Medical Center, Brooklyn, NY, USA* Correspondence address. 4802 10th Avenue, Brooklyn, NY 11219, USA. Tel: +1-347-249-9880; Fax: +1-718-283-8498; E-mail: chudiobiagwu@yahoo.com2 2015 04 2 2015 2015 2 183 184 1 12 2014 2 1 2015 7 1 2015 © The Author 2015. Published by Oxford University Press.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comHyperbaric oxygen therapy (HBOT) has been shown to be effective in the treatment of diabetic ulcers, air embolism, carbon monoxide poisoning and gas gangrene with minimal adverse effects. Very few cases of HBOT causing acute pulmonary edema (PE) has been described; with a study on dogs suggesting that a complication of this therapy could be PE. We describe the case of an 80-year-old man with a history of stable systolic heart failure and diabetes mellitus presenting with acute PE following treatment with HBOT for diabetic foot.\n==== Body\nINTRODUCTION\nHyperbaric oxygen therapy (HBOT) has been shown to be effective in the treatment of diabetic ulcers, air embolism, carbon monoxide poisoning, and gas gangrene [1]. It is usually well tolerated with very few side effects. A study on dogs suggested that a rare complication of HBOT is pulmonary edema (PE) with an estimated incidence of 1 per 1000 [2]. In divers who received recompression treatment for dysbarism, the incidence of pulmonary toxicity was 5 per 100 recompressions [3]. We describe a case of acute PE precipitated by HBOT.\n\nCASE REPORT\nAn 80-year-old male with ischemic cardiomyopathy (ejection fraction 25%), noninsulin-dependent diabetes mellitus (NIDDM) and peripheral vascular disease (PVD) was admitted because of sudden onset of dyspnea. He was getting hyperbaric oxygen treatment for a non-healing plantar ulcer at our outpatient clinic. He was not on antibiotic therapy at the time as wound was not infected. His pre- HBOT heart rate (HR) was 80 beats/min, respiratory rate (RR) was 15 breaths/min and blood pressure (BP) was 134/80 mmHg. After 60 min of breathing 100% oxygen at 2.4 atms, he developed rapidly worsening dyspnea. He was brought to the hospital on 100% oxygen via non-rebreather mask. Physical examination revealed HR 110 beats/min, RR 30 breaths/min, BP 138/74 mmHg, and was significant for diffuse inspiratory and expiratory crackles. Owing to worsening respiratory distress and decline in cognition, he required emergent intubation and mechanical ventilation. Arterial blood gas values were as follows: pH 7.27; PaCO2 58 mmHg; PaO2 117 mmHg; and arterial oxygen saturation was 0.85. EKG did not show any ischemic changes. Cardiac biomarkers were negative, but his BNP was significantly elevated at 1568 pg/ml. There were pink frothy secretions in the endotracheal tube and chest radiography showed bilateral alveolar and perivascular infiltrates (Fig. 1). Diagnosis of acute respiratory failure secondary to PE was made, and he was admitted to the cardiac ICU. He received intravenous diuretics, and was successfully extubated 3 days later (Fig. 2).\nFigure 1: Chest X-ray after emergent intubation on presentation.\n\n\nFigure 2: Chest X-ray on Day 3 after extubation.\n\n\n\nDISCUSSION\nHBOT has been shown to improve the rate of healing of diabetic foot ulcers. Suggested mechanisms include improved wound tissue hypoxia, enhanced perfusion and down-regulation of inflammatory cytokines [4]. Some side effects of HBOT that are described include otic barotrauma, visual changes and possible CNS oxygen toxicity. Very few cases of PE due to HBOT have been described. Weaver et al. [5] described three cases in 2001—all of them had pre-existing cardiac disease, and two of them were diabetic. An increased risk of PE in persons with low cardiac ejection fractions has been reported [6]; however, details of this study are not available.\n\nProposed mechanisms for this include HBO-induced hyperoxia leading to increased peripheral vasoconstriction and thus cardiac afterload, increased oxidative myocardial stress, decreased LV compliance by oxygen radical-mediated reduction in nitric oxide, right and left ventricular imbalance and increased pulmonary capillary permeability [2]. HBOT has also been shown to increase N-terminal pro-B-type natriuretic peptide (NT pro-BNP) levels in diabetics by a mean of 100 pg/ml and causing considerable ventricular wall stress [7]. Any of these can precipitate acute PE in a patient with pre-existing heart disease or a diabetic, but further research is necessary.\n\nTreatment remains primarily supportive with diuretics, supplemental oxygen and occasionally ventilatory support.\n\nOur patient had several comorbidities including ischemic cardiomyopathy, NIDDM and PVD, but he was functional and had no overt manifestation of heart failure prior to HBOT. However, his overall hypoxic predisposition might have served as a risk factor for acute PE.\n\nCONCLUSION\nAcute PE seems to be a rare but serious side effect of HBOT in patients with pre-existing heart disease. Thus caution should be observed in treating patients with prior heart disease and low LVEF with hyperbaric oxygen.\n==== Refs\nREFERENCES\n1 Goldman RJ Hyperbaric oxygen therapy for wound healing and limb salvage: a systematic review PM R 2009 1 471 89 19627935 \n2 Abel FL McNamee JE Cone DL Clarke D Tao J Effects of hyperbaric oxygen on ventricular performance, pulmonary blood volume, and systemic and pulmonary vascular resistance Undersea Hyperb Med 2000 27 67 73 11011796 \n3 Smerz R Incidence of oxygen toxicity during the treatment of dysbarism Undersea Hyperb Med 2004 31 199 202 15485081 \n4 Whalen RE Saltzman HA Holloway DH Jr Mcintosh HD Sieker HO Brown IW Jr Cardiovascular and blood gas responses to hyperbaric oxygenation Am J Cardiol 1965 15 638 46 14285147 \n5 Weaver LK Churchill S Pulmonary edema associated with hyperbaric oxygen therapy Chest 2001 120 1407 9 11591590 \n6 Riddick MF Kindwall EP Whelan HT Sternal wound infections, dehiscence, and sternal osteomyelitis: the role of hyperbaric oxygen therapy Hyperbaric Medicine Practice 1999 2nd edn Flagstaff, AZ Best Publishing 617 40 \n7 Yildiz S Uzun G Uz O Ipcioglu OM Kardesoglu E Ozcan O N-terminal pro-B-type natriuretic peptide levels increases after hyperbaric oxygen therapy in diabetic patients Clin Invest Med 2008 31 E231 E235 18980711\n\n",
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"issue": "2015(2)",
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"keywords": null,
"medline_ta": "Oxf Med Case Reports",
"mesh_terms": null,
"nlm_unique_id": "101642070",
"other_id": null,
"pages": "183-4",
"pmc": null,
"pmid": "25988073",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports",
"references": "11591590;15485081;19627935;18980711;14285147;11011796",
"title": "Acute pulmonary edema secondary to hyperbaric oxygen therapy.",
"title_normalized": "acute pulmonary edema secondary to hyperbaric oxygen therapy"
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"companynumb": "US-AIR PRODUCTS AND CHEMICALS, INC. -1043788",
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"abstract": "Large cell neuroendocrine carcinoma (LCNEC) of the lung with epidermal growth factor receptor (EGFR) mutation is rare, and few cases have been treated with EGFR tyrosine kinase inhibitors (TKIs). We report the treatment of combined LCNEC with adenocarcinoma harboring an EGFR mutation with EGFR-TKIs and bevacizumab. Our patient was a 70-year-old asymptomatic woman who underwent surgical resection of the lung for combined LCNEC with adenocarcinoma harboring an activating EGFR mutation 11 months previously. Magnetic resonance imaging (MRI) and positron emission tomography revealed metastatic lesions in the brain and lung. The patient was diagnosed with recurrence of combined LCNEC with adenocarcinoma. The brain lesion was irradiated, followed by administration of afatinib. Eight months after irradiation, brain MRI revealed ringed enhancement and perilesional edema after radiotherapy without new metastatic lesions. We switched treatment to erlotinib and bevacizumab, resulting in maintenance of stable disease for 10 months. Overall, the disease was controlled for 18 months with EGFR-TKIs and bevacizumab. Combination treatment with EGFR-TKIs and bevacizumab could be a treatment option for LCNEC of the lung harboring EGFR mutations, especially with brain metastasis.",
"affiliations": "Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan.;Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan.;Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan.;Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan.;Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan.;Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan.;Department of Diagnostic Pathology, Fukushima Medical University, Fukushima, Japan.;Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan.",
"authors": "Muto|Satoshi|S|;Ozaki|Yuki|Y|;Okabe|Naoyuki|N|;Matsumura|Yuki|Y|;Hasegawa|Takeo|T|;Shio|Yutaka|Y|;Hashimoto|Yuko|Y|;Suzuki|Hiroyuki|H|",
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"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575 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\n10.1159/000511112\ncro-0013-1387\nCase Report\nSuccessful Treatment of Combined Large Cell Neuroendocrine Carcinoma Harboring an EGFR Mutation with EGFR-TKIs plus Bevacizumab: A Case Report\nMuto Satoshi a* Ozaki Yuki a Okabe Naoyuki a Matsumura Yuki a Hasegawa Takeo a Shio Yutaka a Hashimoto Yuko b Suzuki Hiroyuki a aDepartment of Chest Surgery, Fukushima Medical University, Fukushima, Japan\nbDepartment of Diagnostic Pathology, Fukushima Medical University, Fukushima, Japan\n*Satoshi Muto, Department of Chest Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-8062 (Japan), smutoo@fmu.ac.jp\nSep-Dec 2020 \n30 11 2020 \n30 11 2020 \n13 3 1387 1392\n24 8 2020 24 8 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This 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.Large cell neuroendocrine carcinoma (LCNEC) of the lung with epidermal growth factor receptor (EGFR) mutation is rare, and few cases have been treated with EGFR tyrosine kinase inhibitors (TKIs). We report the treatment of combined LCNEC with adenocarcinoma harboring an EGFR mutation with EGFR-TKIs and bevacizumab. Our patient was a 70-year-old asymptomatic woman who underwent surgical resection of the lung for combined LCNEC with adenocarcinoma harboring an activating EGFR mutation 11 months previously. Magnetic resonance imaging (MRI) and positron emission tomography revealed metastatic lesions in the brain and lung. The patient was diagnosed with recurrence of combined LCNEC with adenocarcinoma. The brain lesion was irradiated, followed by administration of afatinib. Eight months after irradiation, brain MRI revealed ringed enhancement and perilesional edema after radiotherapy without new metastatic lesions. We switched treatment to erlotinib and bevacizumab, resulting in maintenance of stable disease for 10 months. Overall, the disease was controlled for 18 months with EGFR-TKIs and bevacizumab. Combination treatment with EGFR-TKIs and bevacizumab could be a treatment option for LCNEC of the lung harboring EGFR mutations, especially with brain metastasis.\n\nKeywords\nLarge cell neuroendocrine carcinomaEpidermal growth factor receptor mutationTyrosine kinase inhibitorsBevacizumab\n==== Body\nIntroduction\nTyrosine kinase inhibitors (TKIs) are now the first choice for treatment of non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) gene mutations. Recently, the efficacy of combination treatment of erlotinib with bevacizumab for NSCLC harboring EGFR mutations has been reported. Erlotinib and bevacizumab combination therapy improves progression-free survival to a greater extent than erlotinib monotherapy in patients with NSCLC harboring EGFR mutations [1, 2].\n\nHowever, EGFR mutations have also been identified in large cell neuroendocrine carcinoma (LCNEC) of the lung [3, 4, 5]. LCNEC is a rare tumor of the lung, accounting for 3% of lung cancer cases, and is a type of neuroendocrine tumor. LCNEC resembles small cell lung cancer (SCLC) with features such as high-grade malignancy, poor prognosis, and high incidence in males and smokers. Both LCNEC and SCLC show neuroendocrine markers in immunohistochemistry. LCNEC is distinguished from SCLC by several morphological criteria including large cell size and abundant cytoplasm. Etoposide and platinum-based regimens are often selected for advanced LCNEC. LCNEC harboring EGFR mutations is extremely rare, and to our knowledge, only 2 cases of LCNEC treated with an EGFR-TKI have been reported to date, both of which were treated with gefitinib and showed a good response. Here we report a case of combined LCNEC with adenocarcinoma harboring an EGFR mutation treated with EGFR-TKIs and bevacizumab.\n\nCase Presentation\nA 70-year-old woman with no history of neoplastic disease presented with an abnormality identified by chest X-ray. Chest computed tomography (CT) scanning revealed a lung tumor in the left lower lobe. Tumor tissue obtained by transbronchial lung biopsy was diagnosed as LCNEC. Chromogranin A was positive in more than 50% of the tumor, and CD56 was weakly positive (Fig. 1). Thyroid transcription factor 1 and cytokeratin 7 were positively expressed and cytokeratin 20 was partially positive. An activating EGFR mutation (exon 19, E746–A750 deletion) was detected by the PCR-INVADER method. Positron emission tomography scanning and brain magnetic resonance imaging (MRI) did not show distant metastasis. Surgical resection was performed. The patient's lung cancer had various histological features including rosette formation, necrotic tissue, and adenocarcinoma with an acinar and solid architecture. The pathological diagnosis was combined LCNEC with adenocarcinoma, and the pathological stage was T1cN1M0 stage IIB. Cisplatin and vinorelbine as adjuvant chemotherapy were administered only once after surgery because of several adverse events.\n\nEleven months later, the lung cancer recurred as a brain metastasis in her left parietal lobe (Fig. 2a) alongside a small lung metastasis. After stereotactic irradiation of this brain lesion, afatinib (20 mg/day) was administered as the first-line treatment, and stable disease was maintained for 6 months (Fig. 2b). The patient had grade 2 rash acneiform and paronychia during this period. Eight months later, paralysis of the right lower limb manifested. Brain MRI revealed ringed enhancement and perilesional edema after radiotherapy without new metastatic lesions (Fig. 2c). New lesions were not identified by positron emission tomography scan. The treatment was then switched to erlotinib (150 mg/day) and bevacizumab (15 mg/kg q3w). The paralysis rapidly improved, and stable disease was maintained for 6 months (Fig. 2d). During this time, she had grade 2 paronychia, rash acneiform, anorexia, and hypertension. Erlotinib was decreased to 100 mg/day at first, then 50 mg/day. The lung metastatic lesion remained stable during the afatinib, erlotinib, and bevacizumab treatment period. After 10 months of treatment with erlotinib and bevacizumab, metastatic lesions in the brain and lung began to grow (Fig. 2e, f). EGFRT790M mutation was not found in serum biopsy.\n\nDiscussion\nLCNEC of the lung is a rare tumor, and there are no established standard treatment strategies. Cases of advanced or recurrent LCNEC are often treated as SCLC [6]. It was reported that LCNECs have a similar genomic profile to SCLC, including TP53 mutations and genetic alterations in the PI3K/AKT/mTOR pathway, and EGFR mutation was detected in only one of 78 LCNEC samples [7]. There are few reports that describe EGFR-TKI treatment of EGFR-mutated LCNECs [4, 8]. Gefitinib was selected in both of these previous reports and resulted in a good response. In our case, we first conducted radiotherapy because of brain metastasis and subsequently administered afatinib. After progression of the disease, we undertook treatment with erlotinib and bevacizumab because of brain edema around the metastatic lesions.\n\nVascular endothelial growth factor produced in the perinecrotic area is thought to be a major cause of both angiogenesis and perilesional edema after radiation therapy to metastatic lesions of the brain [9]. The efficacy and safety of bevacizumab treatment for brain metastasis of NSCLC are well known [10, 11, 12], while efficacy of bevacizumab combined with EGFR-TKIs for EGFR-mutated NSCLC with brain metastasis has also been reported [13, 14]. Furthermore, Mairinger et al. [15] reported that angiogenesis was also activated to some extent in LCNECs. Thus, the addition of bevacizumab to treatment regimens for LCNECs is thought be one of the reasons for the long-term effectiveness of this treatment strategy.\n\nA limitation of our study is that we could not perform biopsies of the recurrent lesions. Because our patient had combined LCNEC with adenocarcinoma, recurrent lesions might have consisted of adenocarcinoma components. Despite this limitation, this is the first report showing the activity of EGFR-TKIs and bevacizumab in LCNEC harboring an EGFR mutation. EGFR-TKIs and bevacizumab could be a treatment option for LCNECs harboring EGFR mutations, especially with brain metastasis.\n\nStatement of Ethics\nWritten informed consent was obtained from the patient for the publication of this case report.\n\nConflict of Interest Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nThe authors have no funding sources in regard to this case report.\n\nAuthor Contributions\nConceptualization: Satoshi Muto and Hiroyuki Suzuki. Investigation: Satoshi Muto. Resources: Yuki Ozaki, Naoyuki Okabe, Yuki Matsumura, Takeo Hasegawa, and Yutaka Shio. Supervision: Hiroyuki Suzuki. Validation: Yuko Hashimoto. Writing − original draft: Satoshi Muto. Writing − review and editing: Satoshi Muto and Hiroyuki Suzuki.\n\nAcknowledgements\nWe thank H. Nikki March, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.\n\nFig. 1 Histological features. Chromogranin A was positive (a) and CD56 was weakly positive (b) in the tumor tissue obtained by transbronchial biopsy.\n\nFig. 2 Gadolinium-enhanced magnetic resonance imaging and positron emission tomography. Stereotactic irradiation followed by afatinib controlled brain metastasis (a) for 6 months (b). Ringed enhancement appeared 8 months later (c). Erlotinib and bevacizumab improved the perilesional edema, and stable disease was maintained for 6 months (d). Metastatic lesions in the brain (e) and lung (f) began to grow 10 months later.\n==== Refs\nReferences\n1 Seto T Kato T Nishio M Goto K Atagi S Hosomi Y Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study Lancet Oncol 2014 10 15 (11) 1236 44 25175099 \n2 Saito H Fukuhara T Furuya N Watanabe K Sugawara S Iwasawa S Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial Lancet Oncol 2019 5 20 (5) 625 35 30975627 \n3 Iyoda A Travis WD Sarkaria IS Jiang SX Amano H Sato Y Expression profiling and identification of potential molecular targets for therapy in pulmonary large-cell neuroendocrine carcinoma Exp Ther Med 2011 Nov-Dec 2 (6) 1041 5 22977617 \n4 De Pas TM Giovannini M Manzotti M Trifirò G Toffalorio F Catania C Large-cell neuroendocrine carcinoma of the lung harboring EGFR mutation and responding to gefitinib J Clin Oncol 2011 12 29 (34) e819 22 22042963 \n5 Sakai Y Yamasaki T Kusakabe Y Kasai D Kotani Y Nishimura Y Large-cell neuroendocrine carcinoma of lung with epidermal growth factor receptor (EGFR) gene mutation and co-expression of adenocarcinoma markers: a case report and review of the literature Multidiscip Respir Med 2013 7 8 (1) 47 23866929 \n6 Fasano M Della Corte CM Papaccio F Ciardiello F Morgillo F Pulmonary large-cell neuroendocrine carcinoma: from epidemiology to therapy J Thorac Oncol 2015 8 10 (8) 1133 41 26039012 \n7 Miyoshi T Umemura S Matsumura Y Mimaki S Tada S Makinoshima H Genomic profiling of large-cell neuroendocrine carcinoma of the lung Clin Cancer Res 2017 2 23 (3) 757 65 27507618 \n8 Aroldi F Bertocchi P Meriggi F Abeni C Ogliosi C Rota L Tyrosine kinase inhibitors in EGFR-mutated large-cell neuroendocrine carcinoma of the lung? A case report Case Rep Oncol 2014 3 7 (2) 478 83 25202262 \n9 Nonoguchi N Miyatake S Fukumoto M Furuse M Hiramatsu R Kawabata S The distribution of vascular endothelial growth factor-producing cells in clinical radiation necrosis of the brain: pathological consideration of their potential roles J Neurooncol 2011 6 105 (2) 423 31 21688077 \n10 Socinski MA Langer CJ Huang JE Kolb MM Compton P Wang L Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases J Clin Oncol 2009 11 27 (31) 5255 61 19738122 \n11 De Braganca KC Janjigian YY Azzoli CG Kris MG Pietanza MC Nolan CP Efficacy and safety of bevacizumab in active brain metastases from non-small cell lung cancer J Neurooncol 2010 12 100 (3) 443 7 20440540 \n12 Besse B Le Moulec S Mazières J Senellart H Barlesi F Chouaid C Bevacizumab in patients with nonsquamous non-small cell lung cancer and asymptomatic, untreated brain metastases (BRAIN): a nonrandomized, phase II study Clin Cancer Res 2015 4 21 (8) 1896 903 25614446 \n13 Chikaishi Y Kanayama M Taira A Nabe Y Shinohara S Kuwata T Effect of erlotinib plus bevacizumab on brain metastases in patients with non-small cell lung cancer Ann Transl Med 2018 10 6 (20) 401 30498728 \n14 Jiang T Zhang Y Li X Zhao C Chen X Su C EGFR-TKIs plus bevacizumab demonstrated survival benefit than EGFR-TKIs alone in patients with EGFR-mutant NSCLC and multiple brain metastases Eur J Cancer 2019 11 121 98 108 31569068 \n15 Mairinger FD Walter RF Werner R Christoph DC Ting S Vollbrecht C Activation of angiogenesis differs strongly between pulmonary carcinoids and neuroendocrine carinomas and is crucial for carcinoid tumourgenesis J Cancer 2014 5 5 (6) 465 71 24959299\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "13(3)",
"journal": "Case reports in oncology",
"keywords": "Bevacizumab; Epidermal growth factor receptor mutation; Large cell neuroendocrine carcinoma; Tyrosine kinase inhibitors",
"medline_ta": "Case Rep Oncol",
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"nlm_unique_id": "101517601",
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"title": "Successful Treatment of Combined Large Cell Neuroendocrine Carcinoma Harboring an EGFR Mutation with EGFR-TKIs plus Bevacizumab: A Case Report.",
"title_normalized": "successful treatment of combined large cell neuroendocrine carcinoma harboring an egfr mutation with egfr tkis plus bevacizumab a case report"
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"abstract": "Acid-base disturbances are common occurrence in hospitalized patients with life threatening complications. 5-oxoproline has been increasingly recognized as cause of high anion gap metabolic acidosis (AGMA) in association with chronic acetaminophen use. However, laboratory workup for it are not widely available. We report case of 56-year-old female with severe AGMA not attributable to ketoacidosis, lactic acidosis or toxic ingestion. History was significant for chronic acetaminophen use, and laboratory workup negative for all frequent causes of AGMA. Given history and clinical presentation, our suspicion for 5-oxoproline toxicity was high. Our patient required emergent hemodialysis and subsequently improved clinically. With an increasing awareness of the uncommon causes of high AGMA, tests should be more readily available to detect their presence. Physicians should be more vigilant of underdiagnosed causes of AGMA if the presentation and laboratory values do not reflect a common cause, as definitive treatment may vary based on the offending agent.",
"affiliations": "Department of Internal Medicine, Albert Einstein Medical Center, 5501 Old York Road, Suite 363, Philadelphia, PA, USA.;Department of Internal Medicine, Albert Einstein Medical Center, 5501 Old York Road, Suite 363, Philadelphia, PA, USA.;Department of Internal Medicine, Albert Einstein Medical Center, 5501 Old York Road, Suite 363, Philadelphia, PA, USA.;Department of Internal Medicine, Albert Einstein Medical Center, 5501 Old York Road, Suite 363, Philadelphia, PA, USA.;Department of Internal Medicine, Albert Einstein Medical Center, 5501 Old York Road, Suite 363, Philadelphia, PA, USA.",
"authors": "Agrawal|Akanksha|A|;Kishlyansky|Marina|M|;Biso|Sylvia|S|;Patnaik|Soumya|S|;Punjabi|Chitra|C|",
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"fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omx054omx054Case ReportCommon, yet elusive: a case of severe anion gap acidosis Agrawal Akanksha 1Kishlyansky Marina 1Biso Sylvia 1Patnaik Soumya 1Punjabi Chitra 1\n1 \nDepartment of Internal Medicine, Albert Einstein Medical Center, 5501 Old York Road, Suite 363, Philadelphia, PA, USA* Correspondence address. Department of Internal Medicine, Albert Einstein Medical Center, 5501 Old York Road, Suite 363, Philadelphia, PA 19118, USA. Tel: +1-973-874-3640; Fax: +1-215-456-7375; E-mail: Akanksha21agr@gmail.com9 2017 04 9 2017 04 9 2017 2017 9 omx05415 5 2017 14 7 2017 © The Author 2017. Published by Oxford University Press.2017This 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\nAcid–base disturbances are common occurrence in hospitalized patients with life threatening complications. 5-oxoproline has been increasingly recognized as cause of high anion gap metabolic acidosis (AGMA) in association with chronic acetaminophen use. However, laboratory workup for it are not widely available. We report case of 56-year-old female with severe AGMA not attributable to ketoacidosis, lactic acidosis or toxic ingestion. History was significant for chronic acetaminophen use, and laboratory workup negative for all frequent causes of AGMA. Given history and clinical presentation, our suspicion for 5-oxoproline toxicity was high. Our patient required emergent hemodialysis and subsequently improved clinically. With an increasing awareness of the uncommon causes of high AGMA, tests should be more readily available to detect their presence. Physicians should be more vigilant of underdiagnosed causes of AGMA if the presentation and laboratory values do not reflect a common cause, as definitive treatment may vary based on the offending agent.\n\nanion gapmetabolic acidosisoxyproline\n==== Body\nINTRODUCTION\nHigh anion gap metabolic acidosis (AGMA) is a frequently observed acid–base disturbance seen in hospitalized patients. Common causes include diabetic, alcoholic and starvation ketoacidosis, lactic acidosis, renal failure or ingestion of salicylate, methanol, ethylene glycol and propylene glycol. There have been a few case reports in the recent years describing accumulation of organic acids such as pyroglutamic acid (5-oxoproline) in the setting of chronic acetaminophen use or d-lactate in a patient with short gut syndrome as the culprit for AGMA. We report a case of 56-year-old female with high AGMA of unknown etiology.\n\nCASE VIGNETTE\nA 56-year-old African–American female with a history of chronic back pain presented to the emergency department with epigastric pain and nausea for 2 days. Her vitals were stable on presentation and examination was unremarkable, but her laboratory workup revealed severe AGMA with a gap of 35 mmol/l, bicarbonate of 5 mmol/l and pH of 7.00.\n\nOn further questioning, she admitted to being a social drinker, but her last drink was 2 glasses of gin 2 days prior to arrival. She denied any toxic substance ingestion, including anti-freeze, wood alcohol or aspirin, and only admitted to chronic use of acetaminophen, ~1.5 g/day. Her glucose, ketone and l-lactic acid level were normal. Acetaminophen, salicylate and ethanol levels were undetectable. Her kidney function was preserved with creatinine 1 mg/dl and blood urea nitrogen 13 mg/dl. She had an osmolar gap of 22 mOsm/kg. Her ethylene glycol, methanol and propylene glycol levels were undetectable.\n\nShe received intravenous fluids and bicarbonate infusion in the emergency department with no significant improvement in her acidosis. After discussion with nephrologist, the patient received emergent hemodialysis for the profound acidemia. Subsequent laboratory workup after hemodialysis showed normal venous pH of 7.37, anion gap of 22 mmol/l and bicarbonate level of 14 mmol/l. Since the common causes were ruled out, the foremost differential was pyroglutamic acid toxicity in the setting of chronic acetaminophen use. Unfortunately, urine testing for pyroglutamic acid and d-lactic acid were not available in the hospital laboratory. The patient was advised to refrain from chronic acetaminophen use and was discharged home in 3 days and advised follow-up within a week.\n\nDISCUSSION\nMetabolic acidosis is a commonly observed acid–base disturbance in hospitalized patients. While old mnemonics like ‘MUDPILES’ are popular, with the additional newly identified causes, Mehta et al. [1] described a new mnemonic of the 21st century: GOLD MARK to enumerate the causes of high AGMA. It includes glycols (ethylene and propylene), oxoproline, l-Lactate, d-Lactate, methanol, aspirin, renal failure and ketoacidosis.\n\nFirst described in 1989, 5-oxoproline has been increasingly recognized as a cause of high AGMA. The propensity to develop this toxicity following acetaminophen exposure might be genetically determined, and there appears to be a propensity in women [2, 3]. 5-oxoproline is a product of the gamma-glutamyl cycle; a lack of glutathione leads to accumulation of glutamylcysteine and its conversion to 5-oxoproline through an alternate pathway [4]. There is some albeit weak evidence supporting the role of N-acetyl cysteine in treating 5-oxoprolinemia; Fenves et al. [3] support its supplementation to increase glutathione synthesis. Definitive treatment, however, depends on recognizing its presence and cessation of acetaminophen intake.\n\nAnother under recognized cause of AGMA is d-lactic acidosis, which occurs in patients with malabsorption after short bowel syndrome or bariatric surgery [5] as a product of bacterial carbohydrate metabolism. The commonly measured lactic acid in laboratory usually only reflects the l-lactic acid.\n\nOur patient was admitted with high AGMA, with the common causes ruled out. With the history of chronic acetaminophen use, our suspicion for 5-oxoproline toxicity was high. Due to non-availability of the test in hospital laboratory, we were unable to prove the etiology of the metabolic acidosis in our patient.\n\nCONCLUSION\nHigh AGMA is usually associated with known common conditions such as diabetic, alcoholic, starvation ketoacidosis and lactic acidosis, though rarely it may be secondary to accumulation of urine organic acids such as pyroglutamic acid or d-lactic acid. With an increasing awareness of the uncommon causes of high AGMA, tests should be more readily available to detect their presence. Also a clinician should be suspicious for these underdiagnosed causes if the presentation and laboratory values do not reflect a common cause.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n==== Refs\nREFERENCES\n1 \nMehta AN , Emmett JB , Emmett M \nGOLD MARK: an anion gap mnemonic for the 21st century . Lancet 2008 ;372 :892 .18790311 \n2 \nLiss DB , Paden MS , Schwarz ES , Mullins ME \nWhat is the clinical significance of 5-oxoproline (pyroglutamic acid) in high anion gap metabolic acidosis following paracetamol (acetaminophen) exposure? Clin Toxicol (Phila) 2013 ;51 :817 –27 .24111553 \n3 \nFenves AZ , Kirkpatrick HM III, Patel W , Sweetman L , Emmett M \nIncreased anion gap metabolic acidosis as a result of 5-oxoproline (pyroglutamic acid): a role of acetaminophen . Clin J Am Soc Nephrol 2006 ;1 :441 –7 .17699243 \n4 \nNjalsson R \nGlutathione synthetase deficiency . Cell Mol Life Sci 2005 ;62 :1938 –45 .15990954 \n5 \nFabian E , Kramer L , Siebert F , Hogenauer C , Raggam RB , Wenzl H , Krejs GJ \nD-lactic acidosis- case report and review of the literature . Z Gastroenterol 2017 ;55 :75 –82 .27723911\n\n",
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"title": "Common, yet elusive: a case of severe anion gap acidosis.",
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"abstract": "OBJECTIVE\nGastrointestinal stromal tumours are the most frequently occurring sarcoma of the gastrointestinal tract. Current treatment involves complete resection although the surgical or pathological margin required remains unclear. In this study we aimed to examine the risk of local and distant recurrence following laparoscopic resection.\n\n\nMETHODS\nFrom a prospective tumour database, we identified and risk stratified primary non-metastatic tumours treated by laparoscopic resection from 2002-2012. Local technique involves allowing a 1 cm margin for resection. We then identified all cases of tumour recurrence and tumour related death in order to calculate overall survival, freedom from GIST recurrence and disease-specific survival respectively.\n\n\nRESULTS\n90 patients were identified with a median follow-up of 3.9 years (range 1 week to 12.3 years). Five-year freedom from GIST recurrence and disease-specific survival rates in the high-risk group stood at 0.63 and 0.90. In the moderate-risk group these figures stood at 0.61 and 0.80 respectively. The low- and very-low-risk groups had a 10-year recurrence-free survival of 100% with no incidences of tumour-related recurrence. There were no local recurrences seen in any group at up to 10 years.\n\n\nCONCLUSIONS\nThe low recurrence rate suggests that these tumours can safely be treated laparoscopically with an R0 resection using a macroscopic surgical margin of 10 mm. Disease-specific survival was high. This may reflect earlier detection and the use of adjuvant imatinib.",
"affiliations": "Norwich Medical School, Norfolk and Norwich University Hospital, Norwich, UK.",
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"title": "Long-term outcomes and recurrence patterns in upper gastrointestinal tract gastrointestinal stromal tumours (GISTs) treated by minimally invasive surgery.",
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"abstract": "A 78-year-old man was referred from his primary care clinic to the emergency department due to bluish discolouration of his lips and decreased oxygen saturation on pulse oximetry. The patient was asymptomatic. Physical exam was normal except for lip cyanosis. A CT pulmonary angiogram was negative for pulmonary embolism. Arterial blood gas (ABG) analysis with co-oximetry showed low oxyhaemoglobin, normal partial pressure of oxygen and methaemoglobinaemia, but an unexplained 'gap' in total haemoglobin saturation. This gap was felt to be due to sulfhaemoglobinaemia. After a thorough review of his medications, ferrous sulfate was stopped which resulted in resolution in patient's cyanosis and normalisation of his ABG after 7 weeks.",
"affiliations": "Internal Medicine, University of Missouri Kansas City School of Medicine, Kansas City, Missouri, USA.;Internal Medicine, University of Missouri Kansas City School of Medicine, Kansas City, Missouri, USA.;Pulmonary/Critical Care Department, University of Missouri Kansas City School of Medicine, Kansas City, Missouri, USA.;Internal Medicine, University of Missouri Kansas City School of Medicine, Kansas City, Missouri, USA.;Internal Medicine, University of Missouri Kansas City School of Medicine, Kansas City, Missouri, USA.",
"authors": "Derbas|Laith|L|;Warsame|Mohamed|M|;Omar|Mohannad Abu|MA|;Zafar|Yousaf|Y|;Howell|Gregory|G|",
"chemical_list": "D005296:Ferrous Compounds; C020748:ferrous sulfate",
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"keywords": "adult intensive care; drugs and medicines; emergency medicine; haematology (drugs and medicines); poisoning",
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"mesh_terms": "D000368:Aged; D001784:Blood Gas Analysis; D003490:Cyanosis; D003937:Diagnosis, Differential; D004638:Emergency Treatment; D005296:Ferrous Compounds; D006801:Humans; D008297:Male; D008708:Methemoglobinemia; D010092:Oximetry",
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"title": "Sulfhaemoglobinaemia caused by ferrous sulfate.",
"title_normalized": "sulfhaemoglobinaemia caused by ferrous sulfate"
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"abstract": "Chronic constipation is a common condition which may result in fecal impaction. A 13-year-old male with chronic constipation and encopresis presented with fecal impaction for three weeks. The impaction caused abdominal pain, distension, encopresis, and decreased oral intake. He was found in severe distress with non-pitting edema of his feet and ankles along with perineal edema. The pedal edema worsened after receiving a fluid bolus, so concern arose for venous compression or a thrombus. A Duplex Ultrasound demonstrated changes in the venous waveforms of the bilateral external iliac and common femoral veins without thrombosis. Manual disimpaction and polyethylene glycol 3350 with electrolytes resolved the pedal and perineal edema. Four months later, he had soft bowel movements without recurrence of the edema. A repeat Duplex Ultrasound was normal. We present a child in whom severe fecal impaction caused pelvic venous compression resulting in bilateral pedal and perineal edema.",
"affiliations": "Department of Pediatrics, Penn State Milton S Hershey Medical Center , PA, USA.;Department of Vascular Surgery, Penn State Milton S Hershey Medical Center , PA, USA.;Division of Pediatric Gastroenterology, Penn State Milton S Hershey Medical Center , PA, USA.;Department of Radiology, Penn State Milton S Hershey Medical Center , PA, USA.;Department of Surgery, Penn State Milton S Hershey Medical Center , PA, USA.;Department of Surgery, Penn State Milton S Hershey Medical Center , PA, USA.",
"authors": "Naramore|Sara|S|;Aziz|Faisal|F|;Alexander|Chandran Paul|CP|;Methratta|Sosamma|S|;Cilley|Robert|R|;Rocourt|Dorothy|D|",
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"fulltext": "\n==== Front\nPediatr RepPediatr RepPRPediatric Reports2036-749X2036-7503PAGEPress Publications, Pavia, Italy 10.4081/pr.2015.5999Case ReportFecal Impaction Causing Pelvic Venous Compression and Edema Naramore Sara 1Aziz Faisal 2Alexander Chandran Paul 3Methratta Sosamma 4Cilley Robert 5Rocourt Dorothy 51 Department of Pediatrics, Penn State Milton S Hershey Medical Center, PA, USA2 Department of Vascular Surgery, Penn State Milton S Hershey Medical Center, PA, USA3 Division of Pediatric Gastroenterology, Penn State Milton S Hershey Medical Center, PA, USA4 Department of Radiology, Penn State Milton S Hershey Medical Center, PA, USA5 Department of Surgery, Penn State Milton S Hershey Medical Center, PA, USADivision of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Penn State Milton S Hershey Medical Center, Mail Code H085, 500 University Drive, Hershey, PA 17033, USA. +1.717.531.1043 - +1.717.531.0653. calexander@hmc.psu.eduContributions: SN reviewed the existing literature, drafted the initial manuscript, approved the final manuscript; FA reported the findings on the Doppler Ultrasound, reviewed and revised the manuscript, approved the final manuscript; CPA supervised the patient care, reviewed and revised the manuscript, approved the final manuscript; SM, reported the findings on the abdominal radiograph, reviewed and revised the manuscript, approved the final manuscript; RC supervised the fecal disimpaction procedure, reviewed and revised the manuscript, and approved the final manuscript; DR assisted with the fecal disimpaction, reviewed and revised the manuscript, and approved the final manuscript.\n\nConflict of interest: the authors declare no conflict of interest.\n\n28 9 2015 28 9 2015 7 3 599908 5 2015 17 7 2015 21 7 2015 ©Copyright S. Naramore et al.2015Licensee PAGEPress, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Chronic constipation is a common condition which may result in fecal impaction. A 13-year-old male with chronic constipation and encopresis presented with fecal impaction for three weeks. The impaction caused abdominal pain, distension, encopresis, and decreased oral intake. He was found in severe distress with non-pitting edema of his feet and ankles along with perineal edema. The pedal edema worsened after receiving a fluid bolus, so concern arose for venous compression or a thrombus. A Duplex Ultrasound demonstrated changes in the venous waveforms of the bilateral external iliac and common femoral veins without thrombosis. Manual disimpaction and polyethylene glycol 3350 with electrolytes resolved the pedal and perineal edema. Four months later, he had soft bowel movements without recurrence of the edema. A repeat Duplex Ultrasound was normal. We present a child in whom severe fecal impaction caused pelvic venous compression resulting in bilateral pedal and perineal edema.\n\nKey words\nPedal edemaduplex ultrasoundpolyethylene glycol 3350 with electrolytesconstipationfecal impaction\n==== Body\nIntroduction\nChildhood constipation is a common complaint leading to about 3% of visits to a general pediatrician and about 25% of visits to a pediatric gastroenterologist.1 The worldwide prevalence of functional constipation in children varies between 0.7-29.6% and costs the United States alone approximately 3.9 billion Dollars per year in health care costs. In over 90% of patients with constipation, the diagnosis of functional constipation is given as no organic etiology is found. Full resolution is difficult, and follow-up is necessary as 50% of children will continue to have difficulty with constipation five years after treatment. Fecal impaction occurs in approximately a third of these children and needs to be managed promptly before serious complications occur.2 We report a unique case in which a child with severe fecal impaction developed bilateral lower limb edema with erythema due to pelvic venous compression. The edema resolved after disimpaction and a thorough bowel cleanout.\n\nCase Report\nA thirteen-year-old Caucasian male presented to the Penn State Hershey Emergency Department (PA, USA) with severe fecal impaction for three weeks. He had an episode of encopresis at school while taking 8.5 g of polyethylene glycol 3350 per day infrequently – his pediatrician had prescribed 17 g by mouth once daily on a regular basis, but the encopresis experienced on this dose caused significant embarrassment to the patient resulting in noncompliance. Two days prior to admission, he developed severe abdominal pain with cramping, vomiting, decreased oral intake, and diminished urine output. He also complained of pallor, diaphoresis, insomnia, and restlessness. He was treated with magnesium citrate 10 ounces orally and a saline enema at an outside hospital without relief and eventual worsening of his symptoms. He had a significant history of chronic functional constipation beginning at the age of two years consisting of large, hard, painful stools that led to a pattern of withholding for upwards of eight days. He struggled to become toilet trained and was seen in our Pediatric Gastroenterology clinic for a first visit at three years of age. He had passed meconium shortly after birth, and his medical history only included a repair of a penile hypospadias. His diet contained less than sixteen ounces of milk per day, and he was growing well with weight and height in the 85th percentile and 50th percentile, respectively. A rectal examination demonstrated normal sphincter tone and a posterior shelf. Daily oral mineral oil was prescribed; however, he was lost to follow-up thereafter. He was seen by his pediatrician for annual health visits since 10 years of age and concerns of constipation with encopresis were addressed appropriately – including regular daily osmotic laxative therapy, letters to school teachers to facilitate the patient’s use of the restroom as needed, and high fiber diet. His parents reportedly attempted to manage his constipation with intermittent doses of oral mineral oil, senna, naturopathic therapy, and glycerin or bisacodyl suppositories as needed primarily to manage acute distress as they were wary of long term dependence on medications. With increasing age, the patient was given more responsibility for adhering to his therapy. To his parents, he appeared to be in control of his constipation for the most part, till onset of the current illness. His diet was predominantly low fiber with very limited intake of vegetables or fruits.\n\nUpon arrival to our hospital, he was in constant, severe discomfort and restless, but preferentially lying on his sides. His temperature was 36.4°C, heart rate 116 beats per minute, and blood pressure 126/93 mmHg. His weight was 68 kg (93rd percentile) and height was 168 cm (76th percentile). He had dry mucosal membranes and skin. His abdomen was moderately distended, firm to palpation with diffuse tenderness, and had palpable hard fecal masses in the suprapubic area and bilateral lower quadrants. He had mild bilateral non-pitting pedal edema. Perianal inspection revealed oozing, liquid brown stool with no skin tags. A digital rectal examination revealed a large, hard ball of stool impacted in the distal rectum. Inguinal lymphadenopathy and scrotal edema were absent. An abdominal radiograph demonstrated a large stool burden causing rectal dilation of 10 cm with distention of the sigmoid colon extending upwards to the level of the umbilicus (Figure 1). Laboratory testing revealed the following results which were all within normal limits: sodium 140 mmol/L, potassium 4.1 mmol/L, chloride 100 mmol/L, bicarbonate 24 mmol/L, blood urea nitrogen 11 mg/dL, creatinine 0.61 mg/dL, and glucose 91 mg/dL. His complete blood cell count, thyroid function studies, tissue transglutaminase IgA and total IgA were normal. He was given a parenteral normal saline bolus for rehydration. Within thirty minutes of the fluid bolus, he developed worsening pedal edema and overlying erythema spreading upwards from his feet to his knees. Due to a concern for deep venous thrombosis, a Duplex Ultrasound was performed; it did not reveal a thrombus, but showed changes in the waveforms in his common femoral and external iliac veins bilaterally, indicating pelvic venous compression (Figure 2A,B). D-dimer and coagulation studies were obtained and were within normal limits. The pediatric surgeons performed a manual disimpaction under general anesthesia due to his worsening clinical status. A three-digit rectal examination encountered perineal edema and a large fecal impaction, which was manually removed with abdominal compression and transanal disruption. Nine liters of crystalloid solution were given in serial irrigations and resulted in multiple stool masses being removed. Over the next three days, his bowel was sufficiently cleaned out with sixteen liters of polyethylene glycol 3350 with electrolytes infused via a nasogastric tube. A repeat abdominal radiograph confirmed a significant reduction in the stool burden and decompression of his entire colon. His pedal and perineal edema resolved, and he was discharged on maintenance polyethylene glycol 3350 solution 17 gm twice daily and Bisacodyl 10 mg tablet once daily.\n\nOne week later he had a barium enema which showed a posterior rectal shelf along with a change in caliber of the distal rectum with spiculations. These findings created concern for decreased colonic motility. Four months after discharge, he continued to have soft daily bowel movements with compliance to maintenance laxative therapy. The pedal and perineal edema had resolved. He had a good appetite and denied abdominal discomfort. Serial clinical examinations at two follow up visits did not reveal recurrence of palpable mass per abdomen. An abdominal radiograph one month later demonstrated minimal residual stool, and a repeat Doppler ultrasound showed normal venous waveforms (Figure 2C,D). Hence, imaging studies for evaluating other causes of extrinsic venous compression were not pursued. Further investigation of the etiology of the constipation, including a rectal biopsy and anorectal and colonic manometry, were deferred at this time due to the resolution of the constipation. Subsequent annual visits to his pediatrician’s office found him to be adhering to a higher fiber diet, daily laxative as prescribed, with no reported difficulty in stooling and steady growth. His weight had gone up to 70.5 kg at 14 years of age and to 81.4 kg at 15 years of age.\n\nDiscussion\nAccording to the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition [North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN)] guidelines, constipation is defined as difficulty with defecation for two weeks or more and causes significant distress to the patient.1 The Rome III Criteria state the child will have two or fewer defecations per week, at least one episode of fecal incontinence per week, painful or hard bowel movements, and a large fecal mass in the rectum. The highest prevalence occurs during preschool years when the child is beginning to develop voluntary control over stooling.\n\nThe etiology of chronic functional constipation is usually multifactorial and can include prior episodes of painful stooling, the introduction of toilet training, and a diet low in fiber. Additional risk factors include a positive family history, a sedentary lifestyle, and psychological factors, such as emotional stress at home or at school.3 It is important to address all contributing issues in order to ensure adequate resolution of the constipation.\n\nThe fear of difficult or painful defecation may lead to fecal withholding. This retention begins a cycle of persistent large, hard stools which produce rectal dilation and eventual loss of rectal sensation. With time, fecal incontinence and encopresis develop, and the child loses the normal sensation to defecate.2 Children may also present with abdominal pain, vomiting, anorexia, and weight loss.3 These symptoms cause a significant amount of psychosocial stress, physical morbidity, and impaired quality of life for the child.2\n\nLess commonly, fecal impaction secondary to chronic constipation has been associated with various serious clinical presentations, such as stercoral ulcers of the rectosigmoid with perforation, bleeding, peritonitis, and bacteremia.4 Other serious complications can include intussusception caused from an intramural fecolith, acquired megarectum and megacolon, rectovaginal fistula, appendicitis, and appendiceal colic.5,6 The large stool burden can cause compression of other organs resulting in sciatica, hydronephrosis, malfunction of a peritoneal dialysis catheter, urinary retention, and urinary tract infections.7-11\n\nIn our patient, the prolonged fecal impaction with massive colonic fecal loading led to increased intra-abdominal pressure causing pelvic deep venous compression with resultant bilateral pedal edema. The impedance of venous return caused an increase in capillary hydrostatic pressure in the lower extremities which forced fluid into the interstitial spaces.12 The venous stasis placed him at risk for a pelvic vein thrombosis and embolism. Hence, the intra-abdominal pressure needed to be relieved quickly in order to prevent further morbidity.\n\nConclusions\nTherefore it is important to treat constipation in children appropriately before complications arise. In the majority of cases, it can be managed in an outpatient setting with oral laxatives, adequate hydration, and a balanced diet. Fecal impaction develops in about a third of children and requires aggressive treatment with oral laxatives and rectal therapy.2 Thus, physicians should provide timely management, education especially about initial worsening of encopresis with laxatives and of the need to persist with medical therapy till establishment of regular toileting habits and resolution of soiling episodes, psycho-social support and more frequent follow-up in order to ensure a good long-term outcome.\n\nFigure 1. Abdominal radiograph showing fecal impaction.\n\nFigure 2. A) Color duplex showing evidence of flow inside the left external iliac artery (red) and left external iliac vein (blue). Absence of respiratory variations in venous waveforms suggests a proximal obstruction; B) Absence of respiratory variations in venous wave-form of the left femoral vein suggests a proximal obstruction. C) Color duplex after fecal disimpaction with normal venous waveforms in left external iliac vein and D) inferior vena cava.\n==== Refs\nReferences\n1. Pashankar DS \nChildhood constipation: evaluation and management . Clin Colon Rectal Surg \n2005 ;18 :120 -7 .20011352 \n2. Mugie SM Di Lorenzo C Benninga MA \nConstipation in childhood . Nat Rev Gastroenterol Hepatol \n2011 ;8 :502 -11 .21808283 \n3. Rajindrajith S Devanarayana NM \nConstipation in children: novel insight into epidemiology, pathophysiolocgy, and management . J Neurogastroenterol Motil \n2011 ;17 :35 -47 .21369490 \n4. Halawi HM Maasri KA Mourad FH Barada KA \nFaecal impaction: in-hospital complications and their predictors in a retrospective study on 130 patients . Colorectal Dis \n2012 ;14 :231 -6 .21848667 \n5. Buchta RM \nIntussusception in a 14-year-old boy secondary to an intramural fecalith . Am J Dis Child \n1978 ;132 :1140 -1 .717323 \n6. Singh JP Mariadason JG \nRole of the faecolith in modern-day appendicitis . Ann R Coll Surg Engl \n2013 ;95 :48 -51 .23317728 \n7. Djeddi D Vanrenterghem A Hamriti A. \nAn unusual case of hydronephrosis in a child . Arch Pediatr \n2011 ;18 :193 -4 ;215-6.21074389 \n8. Frischhut B Ogon M Trobos S Judmaier W. \nSciatica as a manifestation of idiopathic megacolon: a previously undescribed causal relationship . J Pediatr \n1998 ; 133 :449 .9738732 \n9. Rowan-Legg A \nManaging functional constipation in children . Paediatr Child Health \n2011 ;16 :661 -5 .23204909 \n10. Stonehill WH Smith DP Noe HN \nRadiographically documented fecal impaction causing peritoneal dialysis catheter malfunction . J Urol \n1995 ;153 :445 -6 .7815615 \n11. Ruoss KA O’Sullivan R. \nChronic constipation causing obstructive uropathy in an adolescent male . Pediatr Emerg Care \n2008 ;24 :462 -3 .18633305 \n12. Jacobs MK McCance KL Stewart ML \nLeg volume changes with EPIC and posturing in dependent pregnancy edema . Nurs Res \n1986 ;35 :86 -9 .3633511\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2036-749X",
"issue": "7(3)",
"journal": "Pediatric reports",
"keywords": "Pedal edema; constipation; duplex ultrasound; fecal impaction; polyethylene glycol 3350 with electrolytes",
"medline_ta": "Pediatr Rep",
"mesh_terms": null,
"nlm_unique_id": "101551542",
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"pages": "5999",
"pmc": null,
"pmid": "26500749",
"pubdate": "2015-09-28",
"publication_types": "D002363:Case Reports",
"references": "21848667;9738732;21808283;23204909;21369490;20011352;18633305;23317728;21074389;3633511;7815615;717323",
"title": "Fecal Impaction Causing Pelvic Venous Compression and Edema.",
"title_normalized": "fecal impaction causing pelvic venous compression and edema"
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"abstract": "The treatment efficacy of immune checkpoint inhibitor (ICI) and clinical outcomes in patients with non-small cell lung cancer (NSCLC) who develop severe grade checkpoint inhibitor pneumonitis (CIP) are unclear. Here, we report on the treatment efficacy of ICI and prognosis in NSCLC patients with severe grade CIP.\n\n\n\nIn this retrospective cohort study, CIP severity, CIP-related mortality, and ICI efficacy in 71 patients with advanced NSCLC treated with ICIs were evaluated. Data was obtained from the patients' medical charts.\n\n\n\nAll grade and severe grade CIP were observed in 22 and 11 patients, respectively. The CIP-related mortality rate was 22.7% (N = 5). An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of ≥2 and pre-existing interstitial lung disease (ILD) were significantly associated with the development of severe grade CIP (P = 0.001 and P = 0.035, respectively). The median progression-free survival (PFS) and overall survival (OS) were significantly shorter in patients with severe grade CIP than in those without severe grade CIP (PFS 1.0 month, 95% confidence interval [CI] 0.5-2.0 vs. 3.5 months, 95% CI 2.0-5.0 months, P = 0.003; OS 3.0 months, 95% CI 0.5-13 vs. 12.7 months, 95% CI 8.0-21.0 months, P = 0.011).\n\n\n\nCIP is a serious complication with a poor prognosis associated with high mortality. The efficacy of ICI is significantly worse in patients with severe grade CIP than in those without severe grade CIP. Whether ICIs should be administered to patients with CIP risk factors, such as an ECOG PS score of ≥2 or pre-existing ILD, should be carefully assessed.",
"affiliations": "Department of Respiratory Medicine, Japanese Red Cross Medical Center, Tokyo, Japan.;Department of Respiratory Medicine, Japanese Red Cross Medical Center, Tokyo, Japan.;Department of Respiratory Medicine, Japanese Red Cross Medical Center, Tokyo, Japan.;Department of Respiratory Medicine, Japanese Red Cross Medical Center, Tokyo, Japan.;Department of Respiratory Medicine, Japanese Red Cross Medical Center, Tokyo, Japan.;Department of Respiratory Medicine, Japanese Red Cross Medical Center, Tokyo, Japan.;Department of Respiratory Medicine, Japanese Red Cross Medical Center, Tokyo, Japan.;Department of Respiratory Medicine, Japanese Red Cross Medical Center, Tokyo, Japan.;Department of Respiratory Medicine, Japanese Red Cross Medical Center, Tokyo, Japan.;Department of Medical Oncology, Japanese Red Cross Medical Center, Tokyo, Japan.;Department of Medical Oncology, Japanese Red Cross Medical Center, Tokyo, Japan.",
"authors": "Tone|Mari|M|0000-0002-8230-0757;Izumo|Takehiro|T|;Awano|Nobuyasu|N|;Kuse|Naoyuki|N|;Inomata|Minoru|M|;Jo|Tatsunori|T|;Yoshimura|Hanako|H|;Minami|Jonsu|J|;Takada|Kohei|K|;Miyamoto|Shingo|S|;Kunitoh|Hideo|H|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D014408:Biomarkers, Tumor",
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"doi": "10.1111/1759-7714.13187",
"fulltext": "\n==== Front\nThorac CancerThorac Cancer10.1111/(ISSN)1759-7714TCAThoracic Cancer1759-77061759-7714John Wiley & Sons Australia, Ltd Melbourne 10.1111/1759-7714.13187TCA13187Original ArticleOriginal ArticlesHigh mortality and poor treatment efficacy of immune checkpoint inhibitors in patients with severe grade checkpoint inhibitor pneumonitis in non‐small cell lung cancer Poor prognosis in patients with CIPM. Tone et al.Tone Mari https://orcid.org/0000-0002-8230-0757\n1\nIzumo Takehiro \n1\nizumo_takehiro@med.jrc.or.jp Awano Nobuyasu \n1\nKuse Naoyuki \n1\nInomata Minoru \n1\nJo Tatsunori \n1\nYoshimura Hanako \n1\nMinami Jonsu \n1\nTakada Kohei \n1\nMiyamoto Shingo \n2\nKunitoh Hideo \n2\n\n1 \nDepartment of Respiratory Medicine\nJapanese Red Cross Medical Center\nTokyo\nJapan\n\n2 \nDepartment of Medical Oncology\nJapanese Red Cross Medical Center\nTokyo\nJapan\n* Correspondence\n\nTakehiro Izumo, Department of Respiratory Medicine, Japanese Red Cross Medical Center, 4‐1‐22 Hiroo, Shibuya, Tokyo 150‐8935, Japan.\n\nTel: +81 3 3400 1311\n\nFax: +81 3 3409 1604\n\nEmail: izumo_takehiro@med.jrc.or.jp\n03 9 2019 10 2019 10 10 10.1111/tca.v10.102006 2012 15 7 2019 15 8 2019 15 8 2019 © 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, LtdThis 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.Background\nThe treatment efficacy of immune checkpoint inhibitor (ICI) and clinical outcomes in patients with non‐small cell lung cancer (NSCLC) who develop severe grade checkpoint inhibitor pneumonitis (CIP) are unclear. Here, we report on the treatment efficacy of ICI and prognosis in NSCLC patients with severe grade CIP.\n\nMethods\nIn this retrospective cohort study, CIP severity, CIP‐related mortality, and ICI efficacy in 71 patients with advanced NSCLC treated with ICIs were evaluated. Data was obtained from the patients’ medical charts.\n\nResults\nAll grade and severe grade CIP were observed in 22 and 11 patients, respectively. The CIP‐related mortality rate was 22.7% (N = 5). An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of ≥2 and pre‐existing interstitial lung disease (ILD) were significantly associated with the development of severe grade CIP (P = 0.001 and P = 0.035, respectively). The median progression‐free survival (PFS) and overall survival (OS) were significantly shorter in patients with severe grade CIP than in those without severe grade CIP (PFS 1.0 month, 95% confidence interval [CI] 0.5–2.0 vs. 3.5 months, 95% CI 2.0–5.0 months, P = 0.003; OS 3.0 months, 95% CI 0.5–13 vs. 12.7 months, 95% CI 8.0–21.0 months, P = 0.011).\n\nConclusion\nCIP is a serious complication with a poor prognosis associated with high mortality. The efficacy of ICI is significantly worse in patients with severe grade CIP than in those without severe grade CIP. Whether ICIs should be administered to patients with CIP risk factors, such as an ECOG PS score of ≥2 or pre‐existing ILD, should be carefully assessed.\n\nImmune checkpoint inhibitorinterstitial lung diseasenon‐small cell lung cancer source-schema-version-number2.0component-idtca13187cover-dateOctober 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.9 mode:remove_FC converted:02.10.2019\n==== Body\nKey points\nSignificant findings of the study\nCIP‐related morbidity was 22.7%. Median PFS and OS were significantly worse in patients with severe‐grade CIP (PFS 1.0 vs. 3.5 months, P = 0.030; OS 3.0 vs. 12.7 months, P = 0.011).\n\nWhat this study adds\nCIP should be recognized as a poor prognostic predictor unlike other irAEs. ICI administration to patients with CIP risk factors, such as an ECOG PS score of ≥2 or pre‐existing ILD, should be carefully assessed.\n\nIntroduction\nThe application of immune checkpoint inhibitors (ICIs) has greatly expanded and the efficacy of ICIs is clinically useful in various diseases, including lung cancer.1, 2, 3, 4, 5 Because the combination therapy of ICIs and cytotoxic agents can be used in non‐small cell lung cancer (NSCLC) as a first‐line treatment, the chance of receiving ICI treatment has increased, particularly in patients with NSCLC.6, 7, 8, 9\n\n\nThe development of immune‐related adverse events (irAEs) should be considered in patients treated with ICIs.10, 11 However, the majority of irAEs are not associated with an increased risk of death. Checkpoint inhibitor pneumonitis (CIP) is one irAE that can lead to death, particularly in patients with NSCLC.12 Large scale clinical trials reported 1%–5% as the morbidity rate of CIP in patients with NSCLC,13, 14, 15, 16, 17 whereas high morbidity rates ranging from 13.2% to 19.0% have been reported in studies in real‐world settings.18, 19 This is because the real‐world clinical studies included patients who were older, in poor general condition, or with pre‐existing interstitial lung diseases (ILDs). Additionally, previous studies have reported pre‐existing ILD and the absence of extrathoracic metastases as risk factors for CIP.12, 18\n\n\nThe development of irAEs, including CIP, is considered a good predictive factor for the efficacy of ICI treatment.20 However, patients with severe grade CIP often experience poor outcomes following ICI treatment in clinical practice. To our knowledge, to date, no study has evaluated the treatment efficacy of ICI treatment and prognosis in patients with NSCLC experiencing severe grade CIP. Here, we report on the treatment efficacy of ICI and clinical outcomes in NSCLC patients with severe grade CIP.\n\nMethods\nPatient selection and data collection\nThis retrospective cohort study included patients with stage IV, unresectable stage III, or postoperative recurrent NSCLC treated with any ICI except durvalumab at the Japanese Red Cross Medical Center between January 2016 and January 2019. Data were collected from the medical charts. For patients treated with ICIs more than once, data related to the first ICI administration were included in the current study.\n\nThe assessment and treatment of irAEs, including CIP, that occurred during the observation period in response to ICIs was based on the American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines.21 The attending physicians diagnosed CIP clinically. When patients had clinical symptoms of cough or dyspnea and computed tomography (CT) findings of ground‐glass opacity or consolidation, several examinations were performed, such as sputum cultures, echocardiography and laboratory tests (procalcitonin, glucan endo‐1,3‐beta‐D‐glucosidase, and brain natriuretic peptide, etc) in order to exclude pulmonary infections and pulmonary edema. In addition, CIP diagnosis was occasionally made if there had been a poor response to antibiotic treatment. The efficacy of ICIs was evaluated based on overall response rate (ORR), progression‐free survival (PFS), and overall survival (OS). Response to ICI treatment was assessed by the attending physician based on the Response Evaluation Criteria in Solid Tumors version 1. PFS was defined as the time interval from ICI treatment initiation to the date of disease progression (PD) or death from any cause.\n\nThis study mainly focused on patients with severe grade CIP (grade 3 or worse) in response to ICIs. Patients were divided into groups “with severe grade CIP” and “without severe grade CIP” to evaluate the baseline characteristics, severity and mortality associated with CIP, and efficacy of ICI (ORR, PFS, and OS in both groups).\n\nEthical considerations\nThis retrospective study was approved by the Institutional Review Board of the Japanese Red Cross Medical Center (No. 983) and registered with the University Hospital Medical Information Network (UMIN 000037184). Due to the retrospective study design and based on the Japanese ethical guidelines for clinical research, the requirement for informed consent was waived in the current study.\n\nStatistical analysis\nTo evaluate factors associated with lung injury due to ICI therapy, Fisher's exact test was used for categorical data and the Mann‐Whitney U test for numerical data. ORRs to ICIs were compared using the chi‐square test. The PFS and OS curves were generated by the Kaplan‐Meier method and compared using the log‐rank test. Because CIP is a time‐varying covariate, we performed a one‐month landmark analysis for PFS and OS to account for immortal time bias. Patients who were progression‐free or alive at one month after the initiation of ICI administration were only included in the one‐month landmark analysis for PFS or OS, respectively. A one month cutoff was identified because the median onset of severe grade CIP was one month in our study. We defined the initiation of ICI administration as time 0. Furthermore, we performed univariate analysis of PFS and OS using Cox proportional hazard regression. The descriptive statistics presented in the current study included means, frequencies, and percentages. All reported P‐values were two‐sided, and P‐values of <0.05 were considered statistically significant. All statistical analyzes were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (the R Foundation for Statistical Computing, Vienna, Austria).\n\nResults\nBaseline patient characteristics\nA total of 73 patients were treated with ICIs for advanced NSCLC at the study institution during the study period. Of the 73 patients, two who received durvalumab as maintenance therapy after chemoradiotherapy were excluded; therefore, the remaining 71 patients were included in the final analysis. The baseline characteristics of the study cohort at the time of ICI treatment are summarized in Table 1. Among the ICIs, pembrolizumab, nivolumab, and atezolizumab were administered in 21, 40, and 10 patients, respectively. There was a median of one treatment line (range 0–4) of chemotherapy preceding the ICI treatment, and 15 patients received pembrolizumab as first‐line therapy. After receiving the ICI treatment, 22 and 11 patients developed all grade and severe grade CIP, respectively. Thus, 11 patients were categorized as “with severe grade CIP” group, whereas the remaining 60 patients were categorized as “without severe grade CIP” group.\n\nTable 1 Baseline characteristics of patients at the time of ICI therapy\n\nVariables\tTotal (N = 71)\tWith severe grade CIP (N = 11)\tWithout severe grade CIP (N = 60)\t\nP‐value\t\nAge, years\t69 (44–84)\t65 (44–80)\t69 (44–84)\t0.45\t\nMale/Female\t54 (76.1) /17 (23.9)\t7 (63.6)/4 (36.4)\t47 (78.3)/13 (21.7)\t0.29\t\nECOG PS 0–1/2–3\t54 (76.1) /17 (23.9)\n\t5 (45.5)/6 (54.5)\t49 (81.7)/11 (18.3)\t0.010\t\nNon‐sq/sq./unknown\n\t54 (76.1) /16 (22.5)/1 (1.4)\n\t8 (72.7)/3 (27.3)/0 (0)\t46 (76.7)/13 (21.6)/1 (1.7)\t0.85\t\nPD‐L1 expression\t\t\t\t0.82\t\n0%\t4 (5.6)\t0(0)\t4 (6.7)\t\t\n1%–49%\t11 (15.6)\t2 (18.2)\t9 (15.0)\t\t\n50%–100%\t28 (39.4)\t5 (45.5)\t23 (38.3)\t\t\nUnknown\t28 (39.4)\t4 (36.3)\t24 (40.0)\t\t\nBrinkman Index\t720 (0–2400)\t600 (0–166)\t735 (0–2400)\t0.38\t\nKL‐6 (U/mL)\t415 (72–33 040)\t384 (223–1583)\t415 (72–33 040)\t0.73\t\nSP‐D (ng/mL)\t64.2 (7.2–435)\t35.9 (17.2–435)\t66.8 (7.2–299)\t0.64\t\nICI\t\t\t\t0.82\t\nPembrolizumab\t21 (29.6)\t5 (45.5)\t16 (26.7)\t\t\nNivolumab\t40 (56.3)\t5 (45.5)\t35 (58.3)\t\t\nAtezolizumab\t10 (14.1)\t1 (9.0)\t9 (15.0)\t\t\nPre‐ICI treatment lines\t1 (0–4)\t1 (0–4)\t1 (0–4)\t0.62\t\nComplicated with radiation pneumonitis\t11 (15.5)\t0 (0)\t11 (18.3)\t0.12\t\nComplicated with other IPs†\n\t7 (9.9)\t3 (27.3)\t4 (6.7)\t0.035\t\n† \nOther IPs included rheumatic lung disease (N = 2) and idiopathic interstitial pneumonitis (N = 5).\n\nData are presented as median (range) or N (%).\n\nCIP, checkpoint inhibitor pneumonitis; ECOG PS, Eastern Cooperative Oncology Group Performance Status; ICI, immune checkpoint inhibitor; IP, interstitial pneumonia; KL‐6, sialylated carbohydrate antigen Krebs von den Lungen‐6; PD‐L1, programmed death‐ligand 1; SP‐D, surfactant protein‐D; sq., squamous cell carcinoma.\n\nThe Eastern Cooperative Oncology Group (ECOG) performance status (PS) score was significantly worse in “with severe grade CIP” group than that in the “without severe grade CIP” group (P = 0.001). There were no significant differences in tissue type, programmed death‐ligand 1 expression, levels of sialylated carbohydrate antigen Krebs von den Lungen‐6 and surfactant protein‐D, ICI type, or treatment line preceding the ICI therapy between the two groups.\n\nRadiation pneumonitis developed in 11 patients before the ICI therapy and seven patients had other ILDs (rheumatic lung disease, N = 2; idiopathic interstitial pneumonitis [IIP], N = 5) at the time of ICI therapy. The CT pattern was probable usual interstitial pneumonitis in all five patients with IIP. The patients in “severe grade CIP” group were more frequently complicated with a pre‐existing ILD except radiation pneumonitis than “without severe grade CIP” group (27.3% vs. 6.7%, P = 0.035), although there was no significant difference in morbidity due to radiation pneumonitis between the two groups (0% vs. 18.3%, P = 0.12).\n\nSeverity of CIP and other irAEs in response to ICI therapy\nOf the 22 patients who experienced all grade CIP, 11 developed grade 3 or worse CIP in response to ICI therapy. All patients with severe grade CIP received steroid treatment for CIP according to the ASCO Clinical Practice Guidelines; seven patients received steroid pulse therapy.\n\nFive patients died due to CIP after their chest imaging results worsened despite receiving steroid treatment for CIP. The mortality rate due to all grade CIP was 22.7%. The ECOG PS score was ≥2 in all five patients who died due to CIP, and three of the five patients had pre‐existing ILD (rheumatic lung disease and IIP). Of the five patients who died due to CIP, four patients experienced CIP during the first course of ICI therapy. None of the patients with radiation pneumonitis experienced grade 3 or worse CIP (Table 1). While CT pattern of CIP was organizing pneumonia pattern in 19 of 22 patients with all grade CIP (Fig 1a), the remaining three patients who were included in “severe grade CIP” group exhibited acute lung injury pattern (Fig 1b).\n\nFigure 1 Computed tomography (CT) images of representative cases with severe grade checkpoint inhibitor pneumonitis. (a) Organizing pneumonia pattern. CT shows focal consolidations with surrounding ground‐glass opacities in right middle lobe. (b) Acute lung injury pattern. CT shows widespread ground‐glass opacities and consolidations in bilateral lungs.\n\nThe irAEs other than CIP occurred in seven patients. Specifically, endocrine disorders (4), enterocolitis (2), hemophagocytic syndrome (1), and skin disorder (1) occurred with one patient experiencing two irAEs.\n\nICI treatment efficacy and salvage chemotherapy after ICI\nICIs were administered for a median of four (range, 1–71) courses. The median number of ICI treatment courses was significantly lower in “with severe grade CIP” group than that in “without severe grade CIP” group (1 (range, 1–71) vs. 4 [range, 1–52] courses, P = 0.01).\n\nThe ORR to ICI tended to be lower in patients with all grade CIP than in those without CIP (18.2% vs. 37.5%) as well as in those with severe grade CIP than in those without severe grade CIP (9.1% vs. 35.6%; Table 2). Conversely, the ORR to ICI was significantly higher in patients who experienced irAEs excluding CIP than in those who did not have irAEs excluding CIP (85.7% vs. 25.4%, P < 0.001).\n\nTable 2 Efficacy of ICI\n\nVariables(N = 71)\tWith severe grade CIP (N = 11)\tWithout severe grade CIP (N = 60)\t\nP‐value\t\nBest treatment effect of ICI\t\t\t0.47\t\nCR\t0 (0)\t1 (1.7)\t\t\nPR\t1 (9.1)\t20 (33.3)\t\t\nSD\t3 (27.3)\t14 (23.3)\t\t\nPD\t7 (63.6)\t24 (40.0)\t\t\nNot comparable†\n\t0 (0)\t1 (1.7)\t\t\nORR\t9.1%\t35.6%\t0.20\t\nDCR\t36.4%\t59.3%\t0.34\t\n† \nOne patient had no target‐lesion which could be assessed based on the Response Evaluation Criteria in Solid Tumors version 1.\n\nData are presented as N (%).\n\nCIP, checkpoint inhibitor pneumonitis; CR, complete response; DCR, disease control rate; ICI, immune checkpoint inhibitor; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease.\n\nThe median PFS in patients with and without all grade CIP was 2.0 (95% confidence interval [CI] 1.0–5.0) and 3.0 (2.0–5.0) months, respectively. There was no significance difference in PFS between the two groups (P = 0.66). Similarly, the median OS was not significantly different between the patients with and without all grade CIP (6.0 [95% CI 2.0–17.0] vs. 10.0 [7.0–15.0] months, P = 0.59). However, PFS and OS medians were significantly shorter in “with severe grade CIP” group than that in “without severe grade CIP” group (PFS, 1.0 [95% CI 0.5–2.0] vs. 3.5 [2.0–5.0] months, P = 0.003; OS, 3.0 [95% CI 0.5–13] vs. 12.7 [8.0–21.0] months, P = 0.011; Fig 2a,b). In addition, a one‐month landmark analysis confirmed that the median PFS was significantly different between the patients with and without severe grade CIP (2.0 [95% CI 2.0 ‐ not reached [NR]] vs. 6.0 [4.0–12.0] months, P = 0.04, N = 48). A one‐month landmark analysis showed a trend toward better median OS in the patients with severe grade CIP (6.0 [95% CI 2.0–18.0] months vs. 13.0 [12.0–21.0] months, P = 0.11, N = 65; Fig 3a,b). In the patients with other irAEs except CIP, the median PFS and OS were 19.0 (95% CI 2.0–NR) and 21.0 months (2.0–NR) months, respectively. Among the patients with mild‐grade CIP, the ORR to ICI was 27.3% and the median PFS and OS were 5 (95% CI 1–NR) and NR (95% CI 3.0–NR) months, respectively. Univariate analysis confirmed that complication with severe grade CIP and ECOG PS score of ≥2 was significantly associated with poor PFS and OS (Table 3).\n\nFigure 2 Kaplan‐Meier curves for (a) progression‐free‐survival (PFS) and (b) overall survival (OS) in patients with or without severe grade checkpoint inhibitor pneumonitis. () Without severe‐grade CIP and () with severe‐grade CIP.\n\nFigure 3 Kaplan‐Meier curves with one‐month landmark analysis for (a) progression‐free‐survival (PFS) and (b) overall survival (OS) in patients with or without severe grade checkpoint inhibitor pneumonitis. () Without severe‐grade CIP and () with severe‐grade CIP.\n\nTable 3 Cox proportional hazard regression analysis of progression‐free survival and overall survival\n\n\tPFS\tOS\t\nUnivarate hazard ratio(95% CI)\t\nP‐value\tUnivarate hazard ratio (95% CI)\t\nP‐value\t\nSex\t0.62 (0.34–1.10)\t0.10\t0.92 (0.47–1.78)\t0.80\t\nECOG PS (0–1 vs. ≥2)\t2.57 (2.40–8.79)\t0.002\t4.59 (2.40–8.79)\t<0.001\t\nHistology\t1.15 (0.63–2.11)\t0.65\t1.05 (0.52–2.12)\t0.89\t\nIPs at baseline†\n\t1.11 (0.44–2.79)\t0.82\t2.45 (0.95–6.34)\t0.065\t\nRadiation pneumonitis at baseline\t0.65 (0.29–1.44)\t0.28\t0.57 (0.23–1.45)\t0.24\t\nWith CIP\t0.91 (0.47–1.76)\t0.78\t0.89 (0.46–1.72)\t0.72\t\nWith severe grade CIP\t2.38 (1.30–4.65)\t0.011\t2.35 (1.17–4.76)\t0.017\t\nWith other irAEs\t0.36 (0.13–1.01)\t0.052\t0.30 (0.07–1.24)\t0.097\t\n† \nOther IPs included rheumatic lung disease (N = 2) and idiopathic interstitial pneumonitis (N = 5).\n\nCI, confidence interval; CIP, checkpoint inhibitor pneumonitis; ECOG PS, Eastern Cooperative Oncology Group Performance Status; IP, interstitial pneumonia; irAE, immune‐related adverse events; OS, overall survival; PFS, progression‐free survival.\n\nICI administration was discontinued in all patients in “with severe grade CIP” group, and only one of the patients could receive salvage chemotherapy after ICI. In “without severe grade CIP” group, salvage chemotherapy after ICI therapy was administered in 23 of 50 patients who discontinued the ICI therapy. The proportion of patients receiving salvage chemotherapy after ICI was significantly different between the two groups (9.1% and 38.3% in “with severe grade CIP” and “without severe grade CIP” groups, respectively; P = 0.024).\n\nDiscussion\nThe current retrospective cohort study, including 71 patients with advanced NSCLC who received ICI therapy, revealed the severity and high mortality of CIP in response to ICI therapy. Furthermore, we found that the median PFS and OS were significantly worse in patients with severe grade CIP than those without severe grade CIP.\n\nOur analyses revealed that 50.0% of all grade CIP cases were grade 3 or worse and that the severe grade CIP morbidity rate was 15.5% in the entire study cohort. Importantly, the CIP‐related mortality rate was 22.7% in the current study. The CIP morbidity rates were 1%–5% and 13.2%–19.0% in large scale clinical trials13, 14, 15, 16, 17 and studies in real‐world settings,18, 19 respectively. Similarly, the reported severe grade CIP incidence rates were 1%–3% and 3.4%–4.2% in large scale clinical trials13, 14, 15, 16, 17 and real‐world clinical studies,18, 19 respectively. Furthermore, although mortality related to CIP was not observed in large scale clinical trials,13, 14, 15, 16, 17 the CIP‐related mortality rate ranged from 12.8% to 18.2% in real‐world clinical studies.18, 19 Patients who are elderly, in poor clinical condition, or with pre‐existing ILDs are usually excluded from large scale clinical trials. However, many patients with these conditions are considered for ICI therapy in real‐world settings. In the current study, the incidence rate of severe grade CIP was significantly higher in the patients with worse ECOG PS scores and pre‐existing ILDs, except radiation pneumonitis compared with the other patients. Poor clinical condition and pre‐existing IIP, or rheumatic lung disease may be risk factors for the development and severity of CIP. Moreover, ECOG PS scores in all patients who died due to CIP were two or worse, and 60% of those patients had pre‐existing ILDs (rheumatic lung disease and IIP). These results suggest that these two factors may also be associated with high CIP‐related mortality and ICI therapy should be avoided in patients who have these factors. Additionally, salvage chemotherapy after ICIs could not be administered to most patients with severe grade CIP because their ECOG PS scores worsened after the development of CIP, and salvage chemotherapy could lead to CIP relapse. The fact that most patients with severe grade CIP cannot receive salvage chemotherapy after ICIs may also be a risk factor for their poor prognosis.\n\nThe treatment efficacy of ICIs in patients with severe grade CIP was worse than that those without severe grade CIP in the current study. The ORR to ICI tended to be lower and the median PFS and OS were significantly worse in the patients with severe grade CIP than in those without severe grade CIP. In addition, a one‐month landmark analysis and univariate analysis of PFS and OS supported these results. A previous study reported that the development of irAEs was a good predictor of survival outcomes in patients with NSCLC treated with nivolumab.21 The authors also showed that CIP was a good predictor of survival outcomes in patients with NSCLC. Another study showed that the ORR to nivolumab was higher in patients with pre‐existing ILD than in those without pre‐existing ILD22; however, the results of the present study contradicted the findings of the previous one. The difference between this and previous studies was to classify patients with CIP according to severity. Our results suggest that severe grade CIP as a complication of ICI therapy was a predictor of poor treatment efficacy of ICIs. We should recognize that poor prognosis is predicted based on the development of severe grade CIP, whereas good prognosis is predicted based on the development of other irAEs, except CIP.\n\nThe limitations of this study include the small sample size. Additionally, this was a retrospective study performed at a single institution including a heterogenous cohort of patients treated with various ICIs, and those who were administered ICIs as first‐ or later‐line treatment. Comparison of the patient characteristics in the present study with those of the previous ones suggests a significant difference in race. All patients in the present study were Japanese, and treatment‐related pneumonitis has been reported to be common in Japanese patients with lung cancer.23, 24 A large scale prospective cohort study should be conducted to further elucidate the prognosis of CIP in patients with NSCLC.\n\nIn conclusion, CIP is a serious complication with a poor prognosis in patients with NSCLC undergoing ICI therapy because pneumonitis‐related death has been observed. Moreover, the efficacy of ICI treatment was significantly worse in patients with severe grade CIP than those without severe grade CIP. These results clearly illustrate that whether ICIs should be administered to patients with CIP risk factors such as an ECOG PS score of ≥2 and pre‐existing ILD must be carefully assessed.\n\nDisclosure\nThe authors declare they have no conflict of interest.\n\nAcknowledgments\nThe authors would like to thank Enago (www.enago.jp) for the English language review.\n==== Refs\nReferences\n1 \n\nAssi \nHI \n, \nKamphorst \nAO \n, \nMoukalled \nNM \n, \nRamalingam \nSS \n. Immune checkpoint inhibitors in advanced non‐small cell lung cancer . Cancer \n2018 ; 124 : 248 –61 .29211297 \n2 \n\nPasquali \nS \n, \nChiarion‐Sileni \nV \n, \nRossi \nCR \n, \nMocellin \nS \n. Immune checkpoint inhibitors and targeted therapies for metastatic melanoma: A network meta‐analysis . Cancer Treat Rev \n2017 ; 54 : 34 –42 .28189914 \n3 \n\nAtkins \nMB \n, \nClark \nJI \n, \nQuinn \nDI \n. Immune checkpoint inhibitors in advanced renal cell carcinoma: Experience to date and future directions . Ann Oncol \n2017 ; 28 : 1484 –94 .28383639 \n4 \n\nWang \nY \n, \nWu \nL \n, \nTian \nC \n, \nZhang \nY \n. PD‐1‐PD‐L1 immune‐checkpoint blockade in malignant lymphomas . Ann Hematol \n2018 ; 97 : 229 –37 .29128997 \n5 \n\nKu \nGY \n. The current status of immunotherapies in esophagogastric cancer . Hematol Oncol Clin North Am \n2019 ; 33 : 323 –38 .30833003 \n6 \n\nGandhi \nL \n, \nRodríguez‐Abreu \nD \n, \nGadgeel \nS \n\net al\nPembrolizumab plus chemotherapy in metastatic non‐small‐cell lung cancer . N Engl J Med \n2018 ; 378 : 2078 –92 .29658856 \n7 \n\nPaz‐Ares \nL \n, \nLuft \nA \n, \nVicente \nD \n\net al\nPembrolizumab plus chemotherapy for squamous non‐small‐cell lung cancer . N Engl J Med \n2018 ; 379 : 2040 –51 .30280635 \n8 \n\nSocinski \nMA \n, \nJotte \nRM \n, \nCappuzzo \nF \n\net al\nAtezolizumab for first‐line treatment of metastatic nonsquamous NSCLC . N Engl J Med \n2018 ; 378 : 2288 –301 .29863955 \n9 \n\nWest \nH \n, \nMcCleod \nM \n, \nHussein \nM \n\net al\nAtezolizumab in combination with carboplatin plus nab‐paclitaxel chemotherapy compared with chemotherapy alone as first‐line treatment for metastatic non‐squamous non‐small‐cell lung cancer (IMpower130): A multicentre, randomised, open‐label, phase 3 trial . Lancet Oncol \n2019 ; 20 : 924 –37 . 10.1016/S1470-2045(19)30167-6 .31122901 \n10 \n\nFriedman \nCF \n, \nProverbs‐Singh \nTA \n, \nPostow \nMA \n. Treatment of the immune‐related adverse effects of immune checkpoint inhibitors: A review . JAMA Oncol \n2016 ; 2 : 1346 –53 .27367787 \n11 \n\nEl Osta \nB \n, \nHu \nF \n, \nSadek \nR \n, \nChintalapally \nR \n, \nTang \nSC \n. Not all immune‐checkpoint inhibitors are created equal: Meta‐analysis and systematic review of immune‐related adverse events in cancer trials . Crit Rev Oncol Hematol \n2017 ; 119 : 1 –12 .29065979 \n12 \n\nSuresh \nK \n, \nPsoter \nKJ \n, \nVoong \nKR \n\net al\nImpact of checkpoint inhibitor pneumonitis on survival in NSCLC patients receiving immune checkpoint immunotherapy . J Thorac Oncol \n2019 ; 14 : 494 –502 .30503891 \n13 \n\nRizvi \nNA \n, \nMazières \nJ \n, \nPlanchard \nD \n\net al\nActivity and safety of nivolumab, an anti‐PD‐1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non‐small‐cell lung cancer (CheckMate 063): A phase 2, single‐arm trial . Lancet Oncol \n2015 ; 16 : 257 –65 .25704439 \n14 \n\nBorghaei \nH \n, \nPaz‐Ares \nL \n, \nHorn \nL \n\net al\nNivolumab versus docetaxel in advanced nonsquamous non–small‐cell lung cancer . N Engl J Med \n2015 ; 373 : 1627 –39 .26412456 \n15 \n\nBrahmer \nJ \n, \nReckamp \nKL \n, \nBaas \nP \n\net al\nNivolumab versus docetaxel in advanced squamous‐cell non–small‐cell lung cancer . N Engl J Med \n2015 ; 373 : 123 –35 .26028407 \n16 \n\nGaron \nEB \n, \nRizvi \nNA \n, \nHui \nR \n\net al\nPembrolizumab for the treatment of non–small‐cell lung cancer . N Engl J Med \n2015 ; 372 : 2018 –28 .25891174 \n17 \n\nRittmeyer \nA \n, \nBarlesi \nF \n, \nWaterkamp \nD \n\net al\nAtezolizumab versus docetaxel in patients with previously treated non‐small‐cell lung cancer (OAK): A phase 3, open‐label, multicentre randomised controlled trial . Lancet \n2017 ; 389 : 255 –65 .27979383 \n18 \n\nSuresh \nK \n, \nVoong \nKR \n, \nShankar \nB \n\net al\nPneumonitis in non‐small cell lung cancer patients receiving immune checkpoint immunotherapy: Incidence and risk factors . J Thorac Oncol \n2018 ; 13 : 1930 –9 .30267842 \n19 \n\nCho \nJY \n, \nKim \nJ \n, \nLee \nJS \n\net al\nCharacteristics, incidence, and risk factors of immune checkpoint inhibitor‐related pneumonitis in patients with non‐small cell lung cancer . Lung Cancer \n2018 ; 125 : 150 –6 .30429014 \n20 \n\nBrahmer \nJR \n, \nLacchetti \nC \n, \nSchneider \nBJ \n\net al\nManagement of immune‐related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline . J Clin Oncol \n2018 ; 36 : 1714 –68 .29442540 \n21 \n\nRicciuti \nB \n, \nGenova \nC \n, \nDe Giglio \nA \n\net al\nImpact of immune‐related adverse events on survival in patients with advanced non‐small cell lung cancer treated with nivolumab: Long‐term outcomes from a multi‐institutional analysis . J Cancer Res Clin Oncol \n2019 ; 145 : 479 –85 .30506406 \n22 \n\nKanai \nO \n, \nKim \nYH \n, \nDemura \nY \n\net al\nEfficacy and safety of nivolumab in non‐small cell lung cancer with preexisting interstitial lung disease . Thorac Cancer \n2018 ; 9 : 847 –55 .29782069 \n23 \n\nKudoh \nS \n, \nKato \nH \n, \nNishiwaki \nY \n\net al\nInterstitial lung disease in Japanese patients with lung cancer: A cohort and nested case‐control study . Am J Respir Crit Care Med \n2008 ; 177 : 1348 –57 .18337594 \n24 \n\nTakeda \nM \n, \nOkamoto \nI \n, \nNakagawa \nK \n. Pooled safety analysis of EGFR‐TKI treatment for EGFR mutation‐positive non‐small cell lung cancer . Lung Cancer \n2015 ; 88 : 74 –9 .25704957\n\n",
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"issue": "10(10)",
"journal": "Thoracic cancer",
"keywords": "Immune checkpoint inhibitor; interstitial lung disease; non-small cell lung cancer",
"medline_ta": "Thorac Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011014:Pneumonia; D011379:Prognosis; D016016:Proportional Hazards Models; D012720:Severity of Illness Index; D014057:Tomography, X-Ray Computed",
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"pages": "2006-2012",
"pmc": null,
"pmid": "31482678",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": "29863955;27367787;30429014;30280635;29442540;29211297;27979383;25891174;29128997;30506406;26412456;30267842;28383639;18337594;25704957;30833003;29658856;29782069;31122901;29065979;26028407;25704439;28189914;30503891",
"title": "High mortality and poor treatment efficacy of immune checkpoint inhibitors in patients with severe grade checkpoint inhibitor pneumonitis in non-small cell lung cancer.",
"title_normalized": "high mortality and poor treatment efficacy of immune checkpoint inhibitors in patients with severe grade checkpoint inhibitor pneumonitis in non small cell lung cancer"
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"abstract": "OBJECTIVE\nThere is an unmet need in Japan for more optimal lipid-lowering therapy (LLT) for patients with homozygous familial hypercholesterolemia (HoFH) who respond inadequately to available drug therapies and/or apheresis, to achieve goals of low-density lipoprotein cholesterol (LDL-C) reduction by 50% or to ＜100 mg/dL.\n\n\nMETHODS\nIn this study, Japanese patients with HoFH on stable LLT and diet were treated with lomitapide, initiated at 5 mg/day and escalated to maximum tolerated dose (up to 60 mg/day) over 14 weeks. The primary efficacy endpoint was mean percentage change from baseline to Week 26 in LDL-C. Secondary endpoints included changes in other lipid parameters and safety throughout the 56-week study (including follow-up).\n\n\nRESULTS\nNine patients entered the efficacy phase of the study and, of these, eight completed 56 weeks. Mean LDL-C was reduced by 42% (p＜0.0001) at 26 weeks, from 199 mg/dL (95% CI: 149-250) at baseline to 118 mg/dL (95% CI: 70-166). A 50% reduction in LDL-C and LDL-C ＜100 mg/dL was achieved by five and six of nine patients, respectively, at 26 weeks. After 56 weeks, LDL-C was reduced by 38% (p=0.0032) from baseline. Significant reductions in non-HDL-C, VLDL-C, triglycerides, and apolipoprotein B were also reported at Week 26. There were no new safety signals and, similar to previous studies, gastrointestinal adverse events were the most common adverse events.\n\n\nCONCLUSIONS\nLomitapide, added to ongoing treatment with other LLTs, was effective in rapidly and significantly reducing the levels of LDL-C and other atherogenic apolipoprotein B-containing lipoproteins in adult Japanese patients with HoFH.",
"affiliations": "National Cerebral and Cardiovascular Research Center.",
"authors": "Harada-Shiba|Mariko|M|;Ikewaki|Katsunori|K|;Nohara|Atsushi|A|;Otsubo|Yoshihiko|Y|;Yanagi|Koji|K|;Yoshida|Masayuki|M|;Chang|Qing|Q|;Foulds|Pamela|P|",
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"doi": "10.5551/jat.38216",
"fulltext": "\n==== Front\nJ Atheroscler ThrombJ. Atheroscler. ThrombjatjatJournal of Atherosclerosis and Thrombosis1340-34781880-3873Japan Atherosclerosis Society 2815430510.5551/jat.38216Original ArticleEfficacy and Safety of Lomitapide in Japanese Patients with Homozygous Familial Hypercholesterolemia Harada-Shiba Mariko 1Ikewaki Katsunori 2Nohara Atsushi 3Otsubo Yoshihiko 4Yanagi Koji 5Yoshida Masayuki 6Chang Qing 7Foulds Pamela 71 National Cerebral and Cardiovascular Research Center, Osaka, Japan2 National Defense Medical College, Saitama, Japan3 Kanazawa University Graduate School of Medical Sciences, Ishikawa, Japan4 Shin-Koga Clinic, Medical Group Tenjin-kai, Fukuoka, Japan5 Kenporen Osaka Central Hospital, Osaka, Japan6 Tokyo Medical and Dental University, Tokyo, Japan7 Aegerion Pharmaceuticals, Inc., Cambridge, MA, USAAddress for correspondence: Mariko Harada-Shiba, National Cerebral and Cardiovascular Research Center, 5-7-1 Fujishirodai, Suita, Osaka, 565-8565, Japan Email: mshiba@ncvc.go.jp1 4 2017 24 4 402 411 24 9 2016 4 12 2016 2017 Japan Atherosclerosis Society2017This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.http://creativecommons.org/licenses/by-nc-sa/3.0/Aim: There is an unmet need in Japan for more optimal lipid-lowering therapy (LLT) for patients with homozygous familial hypercholesterolemia (HoFH) who respond inadequately to available drug therapies and/or apheresis, to achieve goals of low-density lipoprotein cholesterol (LDL-C) reduction by 50% or to < 100 mg/dL.\n\nMethods: In this study, Japanese patients with HoFH on stable LLT and diet were treated with lomitapide, initiated at 5 mg/day and escalated to maximum tolerated dose (up to 60 mg/day) over 14 weeks. The primary efficacy endpoint was mean percentage change from baseline to Week 26 in LDL-C. Secondary endpoints included changes in other lipid parameters and safety throughout the 56-week study (including follow-up).\n\nResults: Nine patients entered the efficacy phase of the study and, of these, eight completed 56 weeks. Mean LDL-C was reduced by 42% (p < 0.0001) at 26 weeks, from 199 mg/dL (95% CI: 149–250) at baseline to 118 mg/dL (95% CI: 70–166). A 50% reduction in LDL-C and LDL-C < 100 mg/dL was achieved by five and six of nine patients, respectively, at 26 weeks. After 56 weeks, LDL-C was reduced by 38% (p = 0.0032) from baseline. Significant reductions in non-HDL-C, VLDL-C, triglycerides, and apolipoprotein B were also reported at Week 26. There were no new safety signals and, similar to previous studies, gastrointestinal adverse events were the most common adverse events.\n\nConclusion: Lomitapide, added to ongoing treatment with other LLTs, was effective in rapidly and significantly reducing the levels of LDL-C and other atherogenic apolipoprotein B-containing lipoproteins in adult Japanese patients with HoFH.\n\nHomozygous familial hypercholesterolemiaLomitapideHypercholesterolemiaLDL-C\n==== Body\nSee editorial vol. 24: 390–392\n\nIntroduction\nHomozygous familial hypercholesterolemia (HoFH) is a rare, autosomal dominant genetic disorder characterized by substantially elevated low-density lipoprotein cholesterol (LDL-C) levels. In untreated patients, total plasma cholesterol and LDL-C levels are generally ≥ 500 mg/dL.1) and markedly premature atherosclerotic cardiovascular disease (ASCVD) occurs.2–4). If left untreated, most patients will develop atherosclerosis before the age of 20 years and generally do not survive past the age of 30 years.1). The primary goal of therapy is the prevention of ASCVD including coronary artery disease by controlling hypercholesterolemia. The European Atherosclerotic Society has defined the current LDL-C target for adults with HoFH as < 100 mg/dL, or < 70 mg/dL in the presence of clinical ASCVD.1). The American Heart Association recommends similar goals with the caveat that these targets may be difficult to achieve, therefore maximal LDL-C reduction that can be well tolerated is a pragmatic target.5). The Japan Atherosclerosis Society recommends that treatment for adults with HoFH should aim for LDL-C < 100 mg/dL; however, because this target may be challenging, they have suggested a secondary target of a 50% reduction in pretreatment levels of LDL-C.6). Individuals unable to achieve these LDL-C target levels may remain at high risk for ASCVD.1, 7). A recent review of familial hypercholesterolemia in Asia found that awareness of the disease, and its diagnostic criteria, varied between countries; concluding that more resources are required to raise awareness, improve care, and increase research in Asian populations.8). Ongoing observational studies will help elucidate geographic/epidemiological differences that may impact optimal management of HoFH, including screening, in different regions.9, 10).\n\nHoFH is commonly caused by loss of function mutations in the gene encoding the LDL-receptor (LDLR).3), but can also be caused by mutations in several other genes resulting in impairment of the LDLR pathway.11–13). Consequently, treatments with statins and PCSK9 inhibitors, which rely on upregulating hepatic LDLR, have reduced effects in most patients with HoFH, whose LDLRs are absent or defective. Since patients with HoFH usually do not achieve the recommended LDL-C target by using these treatments, adjunctive lipoprotein apheresis is also recommended. Apheresis can transiently reduce LDL-C by more than 50%.17, 18). However, the rapid re-accumulation of circulating LDL-C requires that apheresis be repeated frequently, every 1–2 weeks, and means that LDL-C targets are unlikely to be maintained. Even with regular lipoprotein apheresis, many patients with HoFH still develop coronary artery disease and/or aortic valve stenosis.19). More effective treatments for HoFH are required to prevent atherosclerosis in these patients.\n\nLomitapide (Juxtapid [AEGR-733], Aegerion Pharmaceuticals Inc., Cambridge, MA, USA; Lojuxta, Aegerion Pharmaceuticals Ltd, Uxbridge, UK) is an inhibitor of the microsomal triglyceride transfer protein that transfers triglycerides within the liver onto apolipoprotein B during the assembly of very-low-density lipoproteins (VLDLs), which are the precursors of circulating LDLs.20, 21). Lomitapide is indicated as an adjunctive therapy for adults with HoFH in a number of countries, including the USA, Canada, countries in the EU, Taiwan, and Korea.21–23).\n\nAim\nIn Japan, there is an unmet need for more optimal lipid-lowering therapy (LLT) for patients with HoFH who respond inadequately to available drug therapies and/or apheresis. The primary aim of this study was to evaluate, in Japanese adult patients with HoFH, the efficacy of lomitapide in reducing LDL-C in combination with other LLTs. Secondary aims were to evaluate the safety and tolerability of lomitapide and to evaluate changes in other lipid parameters, hepatic fat, and xanthomas.\n\nMethods\nStudy Design\nIn this phase 3, single-arm, open-label study, adult patients with HoFH added lomitapide to their maximally tolerated, stable, LLT. After initial screening, including informed consent (during Weeks −12 to −6), the study progressed in three phases (Fig. 1): −6–0 weeks, pre-treatment run-in during which both diet and other LLTs were stabilized; 0–26 weeks, dose-escalation and efficacy measures; and > 26–56 weeks, safety measures. At the conclusion of this trial, patients had the option of continuing in a long-term extension trial.\n\nFig. 1. Study design\n\nLLT, lipid-lowering therapy; MTD, maximum tolerated dose.\n\nDuring the run-in phase, the diet stabilization target required patients to obtain < 20% of food energy as fat and to take daily supplements of vitamin E (400 IU) and fatty acids (≥ 200 mg linoleic acid, 210 mg alpha-linolenic acid, 110 mg eicosapentaenoic acid, and 80 mg docosahexaenoic acid). Supplements of vitamin E, which is largely transported by LDL-C, were given in anticipation of LDL-C reductions. The stabilization target for other LLTs (including lipoprotein apheresis or plasmapheresis if applicable) was the maximum tolerated dose (MTD). The run-in phase started with a screening visit between ȡ12 weeks and −6 weeks. Adherence to the diet stabilization target was assessed by reviewing patients' self-completed dietary records (supplied by the sponsor along with detailed instructions) at Week −2 ± 1 and at all subsequent study visits.\n\nDuring the efficacy phase, oral lomitapide was initiated at 5 mg/day and escalated to each patient's MTD (up to a maximum of 60 mg/day). This dose is supported by previously reported pharmacokinetic results in Japanese patients.24). MTD was defined as the highest dose during Weeks 0–26 that did not result in unacceptable adverse events (AEs), including elevated liver function tests (LFTs). Patients attended study visits at Weeks 0, 2, 6, 10, 14, 18, 22, and 26. The last permitted dose increase was at Week 22.\n\nIn the safety phase, lomitapide was continued at the patient's MTD for an additional 30 weeks. Lomitapide dose could be decreased if dose modification rules were applied, and subsequent re-escalation was allowed up to the MTD that was determined during the efficacy phase. Adjustments to background LLTs were also allowed at the investigator's discretion. In addition to the study visits during the efficacy phase, patients were assessed at Weeks 31, 36, 41, 46, 51, and 56.\n\nThe study was conducted in accordance with the International Council for Harmonisation (ICH) Guidance for Industry E6, Guideline for Good Clinical Practice, which is consistent with the ethical principles that have their origins in the Declaration of Helsinki. The protocol and patient informed consent form were reviewed and approved by an Institutional Review Board and/or Independent Ethics Committee covering each participating facility before the study began.\n\nPatients\nPatients were recruited from six centers in Japan. Japanese men and women ≥ 18 years of age were eligible if diagnosed with functional HoFH. Diagnosis had to be based on at least one of the following criteria: documented functional mutation(s) in two LDL receptor alleles or alleles known to affect LDL receptor functionality; skin fibroblast or lymphocyte LDL receptor activity < 20% normal; fasting LDL-C ≥ 300 mg/dL on maximally tolerated LLT, and both parents having documented untreated total cholesterol (TC) > 250 mg/dL; or untreated TC ≥ 500 mg/dL and triglycerides < 300 mg/dL, and both parents having documented untreated TC > 250 mg/dL.\n\nPatients were excluded if they had uncontrolled hypertension, history of chronic renal insufficiency, or significant liver disease. Patients who required use of potentially hepatotoxic medications, especially those that could induce microvesicular or macrovesicular steatosis, were also excluded, as were patients who required use of strong or moderate CYP3A4 inhibitors or simvastatin > 10 mg/day, and patients who were unable to limit their alcohol consumption to no more than one alcoholic drink per day.\n\nOutcomes\nThe primary efficacy endpoint was the mean percentage change from baseline to Week 26 in directly measured LDL-C at the MTD of lomitapide. Key secondary efficacy endpoints were the mean percentage change in other lipid parameters: TC; non-high-density lipoprotein cholesterol (non-HDL-C); VLDL cholesterol (VLDL-C); triglycerides; apolipoprotein B; lipoprotein(a); HDL-C; and apolipoprotein A1. TC, LDL-C, HDL-C, and triglycerides were measured enzymatically; non-HDL-C and VLDL-C were calculated. Lipoprotein(a) and apolipoprotein B were measured by immunonephelometry. Apolipoprotein A1 was measured by Latex Agglutination. All lipid parameters were assessed at each efficacy phase visit and at Weeks 36, 46, and 56 during the safety phase. Lipid panels were obtained following a fasting period (except for water and medications) of at least 12 hours and at a consistent time point immediately prior to lipoprotein apheresis, when relevant. The timing of blood draws relative to lipoprotein apheresis was critical because the procedure causes a sharp drop in LDL-C followed by a more gradual rebound, thus consistency ensured that measures were always made at the same point on the rebound curve. A further secondary endpoint was xanthoma frequency and severity (monitored at regular clinical visits).\n\nLong-term safety and tolerability of lomitapide was evaluated by changes in laboratory parameters, electrocardiogram results, vital signs, physical examinations, and weight. Hepatic fat percentage was assessed at baseline, Week 26, and Week 56 using magnetic resonance imaging (MRI) scans, or computed tomography/ultrasound scans if MRI was contraindicated. Scans were processed by a central reader, VirtualScopics (Rochester, NY). Because the clinical relevance of change in hepatic fat is not clearly understood and there is minimal understanding of what constitutes an unhealthy level of hepatic fat, liver safety was primarily monitored by LFTs. AEs were classified according to their severity and their relationship to the study drug. LFTs were performed at all visits during both the efficacy and safety phases: tests were for alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin. Other laboratory assessments, physical examination, electrocardiogram, and vital sign measurements were performed at all visits during the efficacy phase and at Weeks 36, 46, and 56 during the safety phase. Blood and urine samples were centrally analyzed by PPD.® Central Labs at their locations in Singapore, Highland Heights (KY, USA), and Zaventem, Belgium.\n\nStatistical Analysis\nFor all efficacy endpoints, baseline values were taken to be the mean of data from the run-in compliance (Week −2 ± 1) visit and the Week 0 visit. Differences between baseline and Week 26 were analyzed using a mixed-model repeated measures analysis of variance, with factors for dose group (final escalated dose at Week 26), baseline LDL-C, and week of lipid assessment. The variance–covariance structure was data driven and was assessed during the data analysis. The differences between baseline and Week 26 were also analyzed using paired t-tests. In anticipation of patients with missing data, an imputation method was planned for evaluating LDL-C at Week 26; here, last observation carried forward meant that the last non-missing result prior to Week 26 was to be used if data were missing at Week 26.\n\nResults\nSubjects\nNine patients were screened and enrolled in the run-in phase, all were subsequently entered into the efficacy phase. All patients had documented LDLR defects consistent with a diagnosis of HoFH: four LDLR true homozygotes, two LDLR compound heterozygotes, and three LDLR/PCSK-9 double heterozygotes. All patients were on concomitant LLT, including six on lipoprotein apheresis. Baseline demographic and concomitant LLT data are shown in Table 1. A total of eight patients completed the 0–26-week efficacy phase, one patient discontinued at 22 weeks owing to an AE of LFT (persistent elevations of AST and ALT). Eight patients continued lomitapide during the 26–56-week safety phase and all nine patients were included in the 56-week safety analysis.\n\nTable 1. Baseline patient characteristics and concomitant lipid-lowering treatment/medications\nPatient #\tAge, years\tGender, M/F\tBMI, kg/m2\tHepatic fat, %\tLDL-C, mg/dL*\tConcomitant LLT/apheresis\t\n1\t40\tF\t19.2\t0.1\t199\tRosuvastatin, ezetimibe, lipoprotein apheresis\t\n2\t46\tM\t30.6\t1.5\t183\tRosuvastatin, ezetimibe, colestilan\t\n3\t33\tM\t24.5\t15.7\t331\tEthyl eicosapentaenoic acid, lipoprotein apheresis\t\n4\t52\tF\t18.8\t0.2\t259\tEzetimibe, ethyl eicosapentaenoic acid, lipoprotein apheresis\t\n5\t43\tM\t19.6\t0.6\t200\tAtorvastatin, ezetimibe, lipoprotein apheresis\t\n6\t35\tF\t18.5\t3.4\t221\tAtorvastatin, ezetimibe, probucol, lipoprotein apheresis\t\n7\t75\tM\t23.8\t4.5\t121\tAtorvastatin\t\n8\t63\tF\t19.0\t0.3\t134\tAtorvastatin, ezetimibe\t\n9\t66\tM\t25.3\t2.5\t147\tRosuvastatin, ezetimibe, colestilan, lipoprotein apheresis\t\n* Baseline LDL-C is the mean of the run-in visit at -2 weeks and the baseline visit at Week 0.\n\nBMI, body mass index; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy\n\nDose Escalation and Efficacy\nMost patients (5/9) progressed to an MTD of 20 mg lomitapide. Of the remaining three patients who completed the efficacy phase, the MTDs were 5 mg, 10 mg, and 40 mg lomitapide.\n\nThere was a highly significant reduction in LDL-C from baseline to Week 26 (Fig. 2, Table 2). Mean LDL-C reduced by 42% from 199 mg/dL (95% CI: 149–250) at baseline to 118 mg/dL (95% CI: 70–166) at Week 26. A decrease in mean LDL-C (19%) occurred as early as the first 2 weeks on treatment, with continued reduction occurring steadily over time thereafter (Fig. 3). The reduction in LDL-C was significant across patients with and without apheresis (Fig. 2). At Week 26, a ≥ 50% reduction in LDL-C from baseline was achieved by five out of nine patients which was maintained through to Week 56. During the efficacy phase, six of the nine patients achieved the target LDL-C level of < 100 mg/dL recommended for patients with HoFH; of these six patients, three achieved levels < 70 mg/dL by Week 26 and an additional patient achieved this by Week 56.\n\nFig. 2. Waterfall plot of individual patient response and dose at primary endpoint (26 weeks)\n\nA, patient receiving apheresis. LDL-C, low-density lipoprotein cholesterol\n\nTable 2. Primary and secondary efficacy endpoints\nLipid parameters*\tBaseline, mg/dL\tWeek 26,† mg/dL (n = 9)\tChange from baseline, %\tP-value\tWeek 56, mg/dL (n = 8)\tChange from baseline, %\tP-value\t\nLDL-C (primary endpoint)\t199 (66)\t118 (62)\t−42 (−56, −28)\t0.0001\t115 (56)\t−38 (−58, −17)\t0.003\t\nTotal cholesterol\t279 (80)\t190 (66)\t−32 (−42, −22)\t< 0.0001\t190 (62)\t−(−41, −10)\t0.006\t\nNon-HDL-C\t228 (78)\t140 (71)\t−40 (−53, −28)\t< 0.0001\t138 (63)\t−35 (−53, −16)\t0.003\t\nVLDL-C\t25 (13)\t15 (10)\t−42 (−52, −32)\t< 0.0001\t12 (5)\t−45 (−55, −35)\t< 0.0001\t\nTriglycerides‡\t104 (61–273)\t57 (36–203)\t−46 (−54, −21)\t< 0.0001\t54 (31–111)\t−42 (−60, −24)\t< 0.0001\t\nApolipoprotein B\t148 (40)\t85 (45)\t−45 (−59, −32)\t< 0.0001\t83 (42)\t−41 (−60, −23)\t0.001\t\nLipoprotein(a)§\t59 (21–325)\t49 (21–179)\t−19 (−45, 22)\tNS\t40 (14–180)\t−33 (−61, 9)\t0.014\t\nHDL-C\t50 (10)\t50 (12)\t1 (−15, 17)\tNS\t53 (11)\t6 (−11, 22)\tNS\t\nApolipoprotein A1\t135 (12)\t127 (20)\t−5 (−17, 7)\tNS\t131 (18)\t−3 (−13, 7)\tNS\t\n* Data are presented as mean (standard deviation) and mean percent change (Δ) from baseline (95% CI) except triglycerides and lipoprotein(a) that are presented as median (range) and median percent change (range)\n\n† Last observation carried forward; includes one patient who stopped lomitapide at Week 22\n\n‡ The mean (95% CI) percent changes from baseline in triglycerides for Weeks 26 and 56 were −42 (−51, −32) and −44 (−55, −34), respectively (both p < 0.001)\n\n§ Lipoprotein(a) levels are reported as nmol/L. The mean (95% CI) percent changes from baseline in lipoprotein(a) for Weeks 26 and 56 were −14 (−31, 3) and −27 (−47, −8), respectively (both not significant).\n\nCI, confidence internal; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NS, not significant; SD, standard deviation; VLDL-C, very-low-density lipoprotein cholesterol\n\nFig. 3. Percentage change in LDL-C during treatment (full analysis set)\n\nLDL-C, low-density lipoprotein cholesterol; LOCF, last observation carried forward\n\nDuring the safety phase from Week 26 through to Week 56, when patients were permitted to modify their background LLTs, including apheresis, there was a slight increase towards baseline in LDL-C levels between Weeks 26 and 36 with a plateau thereafter (Fig. 3). Note that the mean dose of lomitapide administered during the safety phase decreased slightly from 21.9 mg at Week 26 to 18.1 mg at Week 56. At the end of the safety phase, after 56 weeks of treatment, the mean percent change from baseline in LDL-C was clinically meaningful and statistically significant at 38% (p = 0.0032).\n\nThree of the six patients (50%) receiving apheresis were able to increase the interval between apheresis treatments during the safety phase and maintain low LDL-C levels through to Week 56. Patient #1, who was on apheresis once per week at baseline, switched to a mostly once every 2 weeks schedule. Patient #4 increased the interval between apheresis treatments from 2 weeks at baseline to 3 weeks. Patient #5 had weekly apheresis at baseline but steadily increased the interval between treatments, reaching a monthly interval by the end of the safety phase.\n\nSecondary endpoints included highly significant, clinically meaningful reductions in key lipid parameters: TC, non-HDL-C, VLDL-C, triglycerides, and apolipoprotein B (Table 2). The reduction in secondary lipid parameters at Week 26 was maintained through Week 56 (Table 2). At Week 26 there were smaller, non-significant, decreases in apolipoprotein A1 and lipoprotein(a), and there was no change in HDL-C (Table 2). By Week 56 the median reduction in lipoprotein(a) had improved to 27% (p = 0.0135).\n\nTwo patients showed improvement or resolution in xanthomas by Week 56. One patient (patient #2) with xanthomas on the knees, buttocks, Achilles tendon, heel, and toe at baseline was assessed by the investigator as having an improvement in xanthomas at Weeks 10, 22, and 46, and xanthomas on the knees and medial canthus were considered resolved for one patient (patient #5) at Week 56.\n\nDietary Compliance\nDuring the efficacy phase, mean percentage energy from dietary fat was 19%, which was below the study requirement of < 20%. Most patients were compliant with the fat intake at most study visits. Mean percentage energy from fat over the entire efficacy phase was > 25% for only one patient (patient #3, 30%), who was noncompliant with the recommended < 20% fat at most assessments. Mean values of vitamin E, which was given as a dietary supplement, were above normal limits at baseline then decreased during treatment with lomitapide, remaining within normal limits. The dietary supplementation with fatty acid complex kept fatty acid levels within normal limits, although mean decreases from baseline were observed during treatment with lomitapide.\n\nSafety and Tolerability\nDuring the dose-escalation phase, all patients experienced at least one treatment-emergent AE (Table 3), which were ameliorated by dose reduction/interruption for all but one patient (patient #3), who discontinued lomitapide treatment at Week 22 as the result of persistent LFT elevations. During the safety phase, seven of the eight patients experienced at least one treatment-emergent AE (Table 3). Gastrointestinal symptoms were the most common AEs and were reported in eight of the nine patients. There was one serious AE during the safety phase (chest pain) which was considered unrelated to study treatment. There were no deaths during the study.\n\nTable 3. Summary of treatment-emergent AEs\n\tDose of lomitapide at AE onset\t\t\nNumber of patients, n (%)\t5 mg\t10 mg\t20 mg\t40 mg\t60 mg\tAll patients\t\nEfficacy phase\t\n\t\nPatients who received the dose, n\t9\t9\t7\t4\t1\t9\t\n Adverse events\t6 (66.7)\t6 (66.7)\t6 (85.7)\t4 (100.0)\t1 (100.0)\t9 (100.0)\t\n Drug-related AEs\t5 (55.6)\t5 (55.6)\t5 (71.4)\t3 (75.0)\t1 (100.0)\t9 (100.0)\t\n Severe AEs\t1 (11.1)\t1 (11.1)\t1 (14.3)\t1 (25.0)\t0\t3 (33.3)*\t\n Serious AEs\t0\t0\t0\t0\t0\t0\t\n AEs leading to study discontinuation\t1 (11.1)†\t0\t0\t0\t0\t1 (11.1)†\t\n Dose held or reduced due to an AE\t2 (22.2)\t1 (11.1)\t4 (57.1)\t3 (75.0)\t1 (100.0)\t8 (88.9)\t\n\t\nSafety phase\t\n\t\nPatients who received the dose, n\t2\t2\t5\t1\t0\t8\t\n Adverse events\t2 (100.0)\t2 (100.0)\t5 (100.0)\t0\t0\t7 (87.5)\t\n Drug-related AEs\t1 (50.0)\t1 (50.0)\t4 (80.0)\t0\t0\t6 (75.0)\t\n Severe AEs\t0\t0\t0\t0\t0\t0\t\n Serious AEs\t0\t0\t1 (20.0)\t0\t0\t1 (12.5)\t\n AEs leading to study discontinuation\t0\t0\t0\t0\t0\t0\t\n Dose held or reduced due to an AE\t1 (50.0)\t1 (50.0)\t1 (20.0)\t0\t0\t3 (37.5)\t\n* Included abnormal liver function test (two patients) and diarrhea (one patient)\n\n† Elevated transaminases.\n\nAE, adverse event\n\nLiver Safety and Hepatic Fat\nTreatment-emergent ALT and AST elevations to ≥ 3 × ULN were found in three of the nine patients. In two of these patients (patients #2 and #7), maximum ALT reached ≥ 3 × ULN while AST remained < 3 × ULN. In both cases, transaminase elevations were effectively managed by reduction in the lomitapide dose or temporary dose interruption with both patients completing the study through Week 56. In the third patient (patient #3), ALT levels reached ≥ 5 × ULN with AST ≥ 3 × ULN, and the patient discontinued lomitapide due to these LFT elevations. The patient had transaminases within normal ranges at Week 2, and the dose of lomitapide was increased to 10 mg. Subsequently, on Day 43, the patient developed elevated ALT (168 U/L: 4.2 × ULN) and AST (84 U/L: 2.0 × ULN). The AE was considered moderate and probably related to the study drug, thus the dose of lomitapide was reduced to 5 mg at Day 50; after elevated transaminases persisted, the dose of lomitapide was interrupted 7 days later. Maximal elevations in ALT (267 U/L: 6.7×ULN) and AST (128 U/L: 3×ULN) were noted at Week 9. Treatment with 5 mg lomitapide resumed at Week 18 (Day 127) when the patient's ALT level had improved to 92 U/L (2.3 × ULN) and their AST level had returned to within normal limits (40 U/L). The patient again experienced elevations in ALT, and treatment with lomitapide was discontinued at Week 22 (Day 155); the patient had subsequent peak elevations in ALT of 268 U/L (6.7 × ULN) and in AST of 130 U/L (3.0 × ULN). At the 26-week visit (Day 183), the patient's ALT and AST levels were 197 U/L (4.9×ULN) and 90 U/L (2.1 × ULN), respectively.\n\nBilirubin levels were within the normal range at all time points during the treatment period for all patients with ALT and/or AST elevations ≥ 3 × ULN; mean levels of total bilirubin and alkaline phosphatase decreased from baseline to Week 26/last observation carried forward, with mean changes of −2.3 µmol/L and −2.3 U/L, respectively. There were no reported cases of Hy's law. There were no clinically meaningful changes in hematology/coagulation parameters from baseline to Week 56.\n\nMean (range) percent hepatic fat, based on imaging data, increased from 3.2% (0.1–15.7%) at baseline to 15.6% (2.1–38.8%, last observation carried forward) at Week 26 (n = 9) and 12.7% (3.6–40.2%) at Week 56 (n = 8). In five patients, measures of hepatic fat remained ≤ 10% at Weeks 26 and 56. One patient (patient #6) had hepatic fat levels between 10% and 20% at both time points. The remaining three patients (patients #2, #3, and #7), all of whom had elevations in AST and/or ALT ≥ 3 × ULN, had hepatic fat levels of > 20%. In three patients who completed the study and discontinued treatment at study conclusion (patients #6, #7, and #8), hepatic fat assessments were conducted 4 weeks after discontinuation of lomitapide; all patients showed a rapid return toward baseline hepatic fat levels.\n\nDiscussion\nCurrent LLTs for patients with HoFH do not enable all patients to reach target goals for LDL-C. The limited efficacy of statins and the transient nature of apheresis leave many patients at a high risk of developing atherosclerosis, with many developing coronary artery disease and/or aortic valve stenosis.19). Despite the development of various LLTs in recent decades, there remains a need for improved treatments for patients with HoFH. The current study demonstrated that adding lomitapide to existing LLTs (including apheresis) reduced LDL-C levels by 42% in patients with HoFH, which was similar to the result of the prior phase 3 study in non-Japanese patients.21). This reduction was sufficient to bring LDL-C levels to < 100 mg/dL for six of the nine patients, and to < 70 mg/dL for four of those six patients at least once during the study. Although it is not possible to predict the clinical consequences of these reductions with certainty, it has been reported that even sub-optimal reductions of circulating LDL-C reduces mortality in patients with HoFH.25). It should be noted that, currently, no morbidity or mortality outcome data exist for lomitapide.\n\nThis study showed that treatment with lomitapide enabled three of the six patients receiving apheresis at baseline to decrease the frequency of treatments and still maintain low LDL-C levels: this is comparable to the results of the prior phase 3 trial, in which six out of 13 patients successfully reduced or eliminated apheresis.26). In addition to LDL-C reductions, there were also substantial, highly significant, mean reductions in key secondary lipid parameters, including TC (32%), triglycerides (42%), non-HDL-C (40%), apolipoprotein B (45%), and VLDL-C (42%). These reductions in lipid parameters were maintained during the safety phase to 56 weeks. In addition, two patients had improvements in xanthoma over the 56 weeks of study, which was an encouraging result.\n\nBecause lomitapide acts in the liver, preventing the transport of lipids, hepatic AEs are directly associated with its mechanism of action; hepatic fat accumulation and LFT anomalies were considered carefully. Changes in transaminases and hepatic fat were variable across the nine patients. ALT levels ≥ 3 × ULN were seen in three patients; however, these were not associated with elevated bilirubin or alkaline phosphatase, and they resolved with dose reduction in two of the three cases. There were no indications for Hy's law, and bilirubin levels declined during treatment and did not go outside the normal limits. Mean hepatic fat percentage increased between baseline and Week 26, but it did not increase further between Weeks 26 and 56. In most cases (5/9) hepatic fat levels remained below 10%. Three patients had hepatic fat levels > 20%; these were the same patients who experienced treatment-emergent increases in ALT. In previous studies of lomitapide, the greatest elevations in transaminases and liver fat were observed in patients who reported consuming larger quantities of alcohol than were permitted in the protocol, which may have predisposed them to greater increases in these parameters.21, 27). In the current study, there was no report of protocol deviation with respect to alcohol and there were no other obvious factors that might have predisposed any patients to greater increases in hepatic fat. Consistent with results from a previous phase 2 study.27), measures of hepatic fat returned to baseline levels within 4 weeks after discontinuation of lomitapide in three patients who discontinued drug after completing the study. Although lomitapide-associated increases in hepatic fat appear to be stable and reversible, the long-term clinical implications remain unknown and warrant further investigation.\n\nOverall, the efficacy and safety of 26 weeks of lomitapide in Japanese patients were consistent with results in the global phase 3 study and with studies of lomitapide in other patient popluations.17, 22–24). The results of the current study were also in line with the real-world results reported from a global observational registry prospectively assessing the long-term safety and effectiveness of lomitapide in real-life clinical practice (the LOWER study).28). There were some demographic differences between the current study and the prior global phase 3 study.21): mean baseline age was around 50 years in the present study versus around 30 years in the prior study; three of the nine patients in the present study had double heterozygous mutations (containing PCSK9 gain of function mutation) versus none of the 29 patients in the prior study; and baseline LDL-C was lower in the present study (199 mg/dL) versus the prior study (336 mg/dL).21). It is possible that differences in these baseline parameters outline different HoFH patient profiles in Japanese versus Caucasian populations. A recent study of four patients with HoFH found that differences in the MTP gene were associated with a strong or weak response to lomitapide.29).\n\nThere were no new safety signals and, similar to previous studies, gastrointestinal AEs were the most common AEs. In the current study, there were no further reports of gastrointestinal AEs following dose reductions or interruptions in five patients.\n\nConclusion\nIn conclusion, lomitapide, added to ongoing treatment with other LLTs, was effective in rapidly and significantly reducing the levels of LDL-C and other atherogenic apolipoprotein B-containing lipoproteins in adult Japanese patients with HoFH. Six patients achieved LDL-C < 100 mg/dL at least once over the course of the study, and half of the patients receiving apheresis were able to increase the interval between apheresis treatments and maintain low LDL-C levels.\n\nAcknowledgments\nThe authors would like to thank all patients, their families, and the investigators who participated in this trial. Medical writing support for the development of this manuscript was provided by Esther Race of Choice Healthcare Solutions, and was funded by Aegerion Pharmaceuticals, Inc.\n\nConflicts of Interest\nThe authors report the following disclosures: M. Harada-Shiba has received honoraria from Astellas, Kaneka Medics, Kowa, MSD, and Pfizer, and clinical research funding from Kaneka Medics; A. Nohara has received clinical research funding from Aegerion Pharmaceuticals, Astellas Pharma, Keiai-Kai Medical, Kowa, MSD, Sanofi, Shionogi, and Synageva Biopharma; M. Yoshida has received honoraria from Daiichi Sankyo, Mitsubishi Tanabe Pharma, and MSD, and scholarship grants from: Astellas, AstraZeneca, Kowa, Nippon Boehringer Ingelheim, and Takeda Pharmaceutical; P. Foulds and Q. Chang own equity in, and are employees of, Aegerion Pharmaceuticals; K. Ikewaki, Y. Otsubo, and K. Yanagi have no disclosures to report.\n==== Refs\nReferences\n1) \nCuchel M Bruckert E Ginsberg HN Raal FJ Santos RD Hegele RA Kuivenhoven JA Nordestgaard BG Descamps OS Steinhagen-Thiessen E Tybjaerg-Hansen A Watts GF Averna M Boileau C Boren J Catapano AL Defesche JC Hovingh GK Humphries SE Kovanen PT Masana L Pajukanta P Parhofer KG Ray KK Stalenhoef AF Stroes E Taskinen MR Wiegman A Wiklund O Chapman MJ : Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society . Eur Heart J , 2014 ; 35 : 2146 -2157 25053660 \n2) \nBeigel R Beigel Y : Homozygous familial hypercholesterolemia: long term clinical course and plasma exchange therapy for two individual patients and review of the literature . 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Am J Cardiol , 2008 ; 102 : 1438 -1443 19026292 \n5) \nGidding SS Ann Champagne M de Ferranti SD Defesche J Ito MK Knowles JW McCrindle B Raal F Rader D Santos RD Lopes-Virella M Watts GF Wierzbicki AS on behalf of the American Heart Association Atherosclerosis, Hypertension, and Obesity in the Young Committee of the Council on Cardiovascular Disease in the Young, Council on Cardiovascular and Stroke Nursing, Council on Functional Genomics and Translational Biology, and Council on Lifestyle and Cardiometabolic Health : The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association . Circulation , 2015 ; 132 : 2167 -2192 26510694 \n6) \nTeramoto T Sasaki J Ishibashi S Birou S Daida H Dohi S Egusa G Hiro T Hirobe K Iida M Kihara S Kinoshita M Maruyama C Ohta T Okamura T Yamashita S Yokode M Yokote K Harada-Shiba M Arai H Bujo H Nohara A Ohta T Oikawa S Okada T Wakatsuki A : Familial hypercholesterolemia . J Atheroscler Thromb , 2014 ; 21 : 6 -10 24335046 \n7) \nHarada-Shiba M Arai H Oikawa S Ohta T Okada T Okamura T Nohara A Bujo H Yokote K Wakatsuki A Ishibashi S Yamashita S : Guidelines for the management of familial hypercholesterolemia . J Atheroscler Thromb , 2012 ; 19 : 1043 -1060 23095242 \n8) \nZhou M Zhao D : Familial hypercholesterolemia in Asian populations . Journal of atherosclerosis and thrombosis , 2016 ; 23 : 539 -549 27075771 \n9) \nWatts GF Ding PY George P Hagger MS Hu M Lin J Khoo KL Marais AD Miida T Nawawi HM Pang J Park JE Gonzalez-Santos LB Su TC Truong TH Santos RD Soran H Yamashita S Tomlinson B : Translational research for improving the care of familial hypercholesterolemia: the “ten countries study” and beyond . J Atheroscler Thromb , 2016 ; 23 : 891 -900 27384016 \n10) \nPang J Lansberg PJ Watts GF : International developments in the care of familial hypercholesterolemia: where now and where to next . J Atheroscler Thromb , 2016 ; 23 : 505 -519 26903443 \n11) \nHegele RA : Monogenic dyslipidemias: window on determinants of plasma lipoprotein metabolism . Am J Hum Genet , 2001 ; 69 : 1161 -1177 11704922 \n12) \nMarais AD : Familial hypercholesterolaemia . Clin Biochem Rev , 2004 ; 25 : 49 -68 18516203 \n13) \nHarada-Shiba M Takagi A Miyamoto Y Tsushima M Ikeda Y Yokoyama S Yamamoto A : Clinical features and genetic analysis of autosomal recessive hypercholesterolemia . J Clin Endocrinol Metab , 2003 ; 88 : 2541 -2547 12788851 \n14) \nGagne C Gaudet D Bruckert E Ezetimibe Study Group : Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia . Circulation , 2002 ; 105 : 2469 -2475 12034651 \n15) \nYamamoto A Harada-Shiba M Endo M Kusakabe N Tanioka T Kato H Shoji T : The effect of ezetimibe on serum lipids and lipoproteins in patients with homozygous familial hypercholesterolemia undergoing LDL-apheresis therapy . Atherosclerosis , 2006 ; 186 : 126 -131 16043185 \n16) \nRaal FJ Honarpour N Blom DJ Hovingh GK Xu F Scott R Wasserman SM Stein EA TESLA Investigators : Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial . Lancet , 2015 ; 385 : 341 -350 25282520 \n17) \nThompson GR : LDL apheresis . Atherosclerosis , 2003 ; 167 : 1 -13 12618263 \n18) \nVella A Pineda AA O'Brien T : Low-density lipoprotein apheresis for the treatment of refractory hyperlipidemia . Mayo Clin Proc , 2001 ; 76 : 1039 -1046 11605688 \n19) \nMakino H Harada-Shiba M : Long-term effect of low-density lipoprotein apheresis in patients with homozygous familial hypercholesterolemia . Ther Apher Dial , 2003 ; 7 : 397 -401 12887721 \n20) \nWetterau JR Lin MC Jamil H : Microsomal triglyceride transfer protein . Biochim Biophys Acta , 1997 ; 1345 : 136 -150 9106493 \n21) \nCuchel M Meagher EA du Toit Theron H Blom DJ Marais AD Hegele RA Averna MR Sirtori CR Shah PK Gaudet D Stefanutti C Vigna GB Du Plessis AM Propert KJ Sasiela WJ Bloedon LT Rader DJ : Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study . Lancet , 2013 ; 381 : 40 -46 23122768 \n22) \nLOJUXTA: (lomitapide) summary of product characteristics \nAegerion Pharmaceuticals Ltd , 2015 ; 4 \n23) \nJUXTAPID: (lomitapide) prescribing information \nAegerion Pharmaceuticals , Cambridge, MA , 2014 ; 8 \n24) \nTaubel J Sumeray M Lorch U McLean A : Pharmacokinetics and pharmacodynamics of lomitapide in Japanese subjects . J Atheroscler Thromb , 2016 ; 23 : 606 -620 26686567 \n25) \nRaal FJ Pilcher GJ Panz VR van Deventer HE Brice BC Blom DJ Marais AD : Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy . Circulation , 2011 ; 124 : 2202 -2207 21986285 \n26) \nStefanutti C Blom DJ Averna MR Meagher EA Theron H Marais AD Hegele RA Sirtori CR Shah PK Gaudet D Vigna GB Sachais BS Di Giacomo S du Plessis AM Bloedon LT Balser J Rader DJ Cuchel M for Phase 3 HoFH Lomitapide Study Investigators : The lipid-lowering effects of lomitapide are unaffected by adjunctive apheresis in patients with homozygous familial hypercholesterolaemia - a post-hoc analysis of a Phase 3, single-arm, open-label trial . Atherosclerosis , 2015 ; 240 : 408 -414 25897792 \n27) \nCuchel M Bloedon LT Szapary PO Kolansky DM Wolfe ML Sarkis A Millar JS Ikewaki K Siegelman ES Gregg RE Rader DJ : Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia . The N Engl J Med , 2007 ; 356 : 148 -156 17215532 \n28) \nBlom DJ Kastelein JJ Larrey D Makris L Phillips H Bloeden L Underberg J : Lomitapide Observational Worldwide Evaluation Registry (LOWER): one-year data . American Heart Association Scientific Sessions , 2015 ; Abstract 2075 \n29) \nKolovou GD Kolovou V Papadopoulou A Watts GF : MTP gene variants and response to lomitapide in patients with homozygous familial hypercholesterolemia . J Atheroscler Thromb , 2016 ; 23 : 878 -883 27170061\n\n",
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"issue": "24(4)",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents; D001562:Benzimidazoles; D005260:Female; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II; D007564:Japan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D012449:Safety",
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"references": "23095242;26686567;23122768;12618263;12887721;25897792;12034651;25282520;26510694;27170061;19026292;1301956;27075771;21986285;25053660;24335046;17215532;27384016;16043185;26903443;11605688;18516203;11704922;9106493;19902516;12788851",
"title": "Efficacy and Safety of Lomitapide in Japanese Patients with Homozygous Familial Hypercholesterolemia.",
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"abstract": "Acetaminophen (APAP) overdose (APAPo) is predominant in the NIH Pediatric Acute Liver Failure (PALF) Study. We assayed multiple inflammatory mediators in serial serum samples from 13 PALF survivors with APAPo + N-acetylcysteine (NAC, the frontline therapy for APAPo), 8 non-APAPo + NAC, 40 non-APAPo non-NAC, and 12 non-survivors. High Mobility Group Box 1 (HMGB1) was a dominant mediator in dynamic inflammation networks in all sub-groups, associated with a threshold network complexity event at d1-2 following enrollment that was exceeded in non-survivors vs. survivors. We thus hypothesized that differential HMGB1 network connectivity after day 2 is related to the putative threshold event in non-survivors. DyNA showed that HMGB1 is most connected in non-survivors on day 2-3, while no connections were observed in APAPo + NAC and non-APAPo + NAC survivors. Inflammatory dynamic networks, and in particular HMGB1 connectivity, were associated with the use of NAC in the context of APAPo. To recapitulate hepatocyte (HC) damage in vitro, primary C57BL/6 HC and HC-specific HMGB1-null HC were treated with APAP + NAC. Network phenotypes of survivors were recapitulated in C57BL/6 mouse HC and were greatly altered in HMGB1-null HC. HC HMGB1 may thus coordinate a pro-inflammatory program in PALF non-survivors (which is antagonized by NAC), while driving an anti-inflammatory/repair program in survivors.",
"affiliations": "Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA.;Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA.;Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA.;Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, 60611, USA.;Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.;Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA.;Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA.;Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA.;Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15213, USA.;Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA. vodovotzy@upmc.edu.",
"authors": "Zamora|Ruben|R|;Barclay|Derek|D|;Yin|Jinling|J|;Alonso|Estella M|EM|;Leonis|Mike A|MA|;Mi|Qi|Q|;Billiar|Timothy R|TR|;Simmons|Richard L|RL|;Squires|Robert H|RH|;Vodovotz|Yoram|Y|http://orcid.org/0000-0002-4389-8768",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D015415:Biomarkers; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C582808:HMGB1 protein, mouse; D000082:Acetaminophen",
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"fulltext": "\n==== Front\nSci RepSci RepScientific Reports2045-2322Nature Publishing Group UK London 4256410.1038/s41598-019-42564-5ArticleHMGB1 is a Central Driver of Dynamic Pro-inflammatory Networks in Pediatric Acute Liver Failure induced by Acetaminophen Zamora Ruben 12Barclay Derek 1Yin Jinling 1Alonso Estella M. 3Leonis Mike A. 4Mi Qi 1Billiar Timothy R. 12Simmons Richard L. 1Squires Robert H. 5http://orcid.org/0000-0002-4389-8768Vodovotz Yoram vodovotzy@upmc.edu 121 0000 0004 1936 9000grid.21925.3dDepartment of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 USA 2 grid.470891.3Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15219 USA 3 0000 0004 0388 2248grid.413808.6Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611 USA 4 0000000106344187grid.265892.2Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233 USA 5 0000 0004 1936 9000grid.21925.3dDepartment of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15213 USA 12 4 2019 12 4 2019 2019 9 59714 12 2018 27 3 2019 © The Author(s) 2019Open 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/.Acetaminophen (APAP) overdose (APAPo) is predominant in the NIH Pediatric Acute Liver Failure (PALF) Study. We assayed multiple inflammatory mediators in serial serum samples from 13 PALF survivors with APAPo + N-acetylcysteine (NAC, the frontline therapy for APAPo), 8 non-APAPo + NAC, 40 non-APAPo non-NAC, and 12 non-survivors. High Mobility Group Box 1 (HMGB1) was a dominant mediator in dynamic inflammation networks in all sub-groups, associated with a threshold network complexity event at d1–2 following enrollment that was exceeded in non-survivors vs. survivors. We thus hypothesized that differential HMGB1 network connectivity after day 2 is related to the putative threshold event in non-survivors. DyNA showed that HMGB1 is most connected in non-survivors on day 2–3, while no connections were observed in APAPo + NAC and non-APAPo + NAC survivors. Inflammatory dynamic networks, and in particular HMGB1 connectivity, were associated with the use of NAC in the context of APAPo. To recapitulate hepatocyte (HC) damage in vitro, primary C57BL/6 HC and HC-specific HMGB1-null HC were treated with APAP + NAC. Network phenotypes of survivors were recapitulated in C57BL/6 mouse HC and were greatly altered in HMGB1-null HC. HC HMGB1 may thus coordinate a pro-inflammatory program in PALF non-survivors (which is antagonized by NAC), while driving an anti-inflammatory/repair program in survivors.\n\nhttps://doi.org/10.13039/100000062U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)UO1 DK072146UO1 DK072146UO1 DK072146UO1 DK072146UO1 DK072146UO1 DK072146UO1 DK072146UO1 DK072146UO1 DK072146UO1 DK072146Zamora Ruben Barclay Derek Yin Jinling Alonso Estella M. Leonis Mike A. Mi Qi Billiar Timothy R. Simmons Richard L. Squires Robert H. Vodovotz Yoram issue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nPediatric Acute Liver Failure (PALF) is a life-threatening clinical syndrome with poor outcomes and where one-half of patients die or receive liver transplantation (LTx)1. The etiology of PALF and its different clinical manifestations are very complex and still poorly understood. The precise onset of disease is rarely identified, with an exception being acute ingestions (e.g., mushrooms, acetaminophen)1. PALF has a dynamic and multifactorial clinical trajectory, and the outcomes vary among children with seemingly similar etiology, disease severity, and treatment; thus, additional factors are likely involved to explain these variations. Such factors likely include a complex interaction among the inflammatory milieu, end-organ damage, immune activation, potential for liver regeneration, and interventions.\n\nAcetaminophen (APAP) toxicity, commonly due to APAP overdose (APAPo) is the most common identifiable cause of Acute Liver Failure (ALF) in both children2 and adults3. Liver injury due to APAP toxicity occurs when inherent mechanisms to detoxify APAP – including conjugation with glutathione – are overwhelmed, resulting in the formation of reactive oxygen species that form destructive adducts with vital intracellular proteins. N-acetyl cysteine (NAC) serves to replete glutathione stores and is the established treatment for acute APAP toxicity. However, while NAC is a clinically accepted treatment of acute liver injury due to APAP toxicity, a potential mechanism to support its use in non-APAP ALF has not been established4.\n\nHigh-mobility group box-1 (HMGB1) is an evolutionarily conserved, chromatin-binding protein expressed in virtually all types of cells5. Cells that are undergoing necrosis passively release HMGB1 into the extracellular space, where HMGB1 works as a damage-associated molecular pattern (DAMP) molecule. HMGB1 is also a potential mediator of APAP-induced hepatotoxicity, and anti-HMGB1 antibodies and knocking out HMGB1 in the liver can reduce hepatic inflammation and liver injury in mouse models of APAP toxicity6.\n\nWe hypothesized that differential HMGB1 network connectivity is related to a putative threshold event that differentiate PALF patients. In addition, we also hypothesized that key inflammatory mediators and networks suggested from our computational analyses may differentiate patient etiologies and suggest novel therapeutic opportunities for PALF. To address these hypotheses, a panel of relevant serum mediators, including HMGB1, were measured in PALF participants. We focused on HMGB1 as a proximal mediator of interest because of its known role as a driver of inflammation in models of APAP-induced liver injury7. As an extension of our previous work8,9, Translational Systems Biology modeling methodology developed for biologically complex and dynamic conditions10,11 was applied to correlate biomarkers with clinical outcomes as well as identify potential therapeutic targets in PALF. Recapitulation of these findings using an in vitro model of isolated HC exposed to APAP ± NAC was used to create a bedside-to-bench translational platform for further investigation.\n\nResults\nTime-courses of inflammatory mediators in PALF survivors vs. non-survivors\nTo assess the response and time-dependent changes in inflammatory mediators across the PALF non-survivors and three survivor sub-groups (APAPo + NAC, non-APAPo + NAC, and non-APAPo non-NAC) (Fig. 1), we assayed a number of mediators that represent most of the major inflammatory and immune pathways. All inflammatory mediators varied over time in a complex fashion. Furthermore, all mediators except IL-10, MIP-1β, and HMGB1, differed significantly over time as a function of patient sub-group (Suppl. Fig. 1). This analysis suggested that the standard statistical analysis of mediators, singly or as a group, may be of limited use for characterizing and predicting patient outcomes, because of potentially more complex, non-linear, and non-intuitive interactions among inflammatory mediators. Thus, we next utilized computational analyses to study the PALF patient sub-groups.Figure 1 Flow chart of recruitment and PALF study participation. From a large cohort of 1,144 participants in the PALF study, an initial Convenience Sample was identified consisting of 371 participants with serum samples collected per protocol for analysis of immune and inflammatory markers. Participants were further selected (n = 101) if they had at least three daily samples with at least 100 µl of serum available. Following exclusion of 28 participants who received a LTx, selection criteria were met by 73 participants and clinical outcomes at 21 days following enrollment were assigned as indicated.\n\n\n\nDynamic Bayesian Network (DBN) analysis suggests a central role for HMGB1 in PALF\nWe next hypothesized that computational analysis would point us to the central inflammatory mediators and pathways associated with specific PALF patient sub-groups. Similar to our previous studies in PALF8,9, we utilized DBN inference to determine such network structures that could be discerned from the time courses of circulating inflammatory mediators in PALF participants. Central nodes were identified by seeking mediators that exhibited self-feedback. Though the data were segregated by outcome group prior to being subjected to DBN inference, the algorithm did not make assumptions about the connectivity of the network in any of the outcome sub-groups. Results of this analysis for each of the PALF sub-groups (as defined above) are shown in Fig. 2. First, similar to what we previously observed in non-survivors9, DBN inference suggested a primary network driven by a core motif consisting of HMGB1, which drives its own expression, in all patient sub-groups. However, certain differences were noted. In non-survivors, HMGB1 was the only mediator with an inferred positive self-feedback loop. In contrast, in the survivor sub-groups we observed, in addition to HMGB1, a cross-interaction consisting of MIG in APAPo + NAC, non-APAPo + NAC, and non-APAPo non-NAC, and IP-10 in non-APAPo non-NAC, each of which regulates its own expression.Figure 2 Dynamic Bayesian Network (DBN) analysis of circulating inflammatory mediators in PALF patients. Circulating inflammatory mediators in serum samples from PALF spontaneous survivors were segregated into three sub-groups (APAPo + NAC [n = 13 patients], non-APAPo + NAC [n = 8 patients], and non-APAPo non-NAC [n = 40 patients]) and non-survivors (n = 12 patients). DBN inference was performed as described in Materials and Methods. Inflammatory mediators are shown as nodes, and the arrows connecting them suggest an influence of one mediator on the one(s) to which it is connected. The arrows do not distinguish positive from negative influences of one mediator on another. Semi-circular arrows suggest either positive or negative feedback of a given mediator on itself. The thickness of each edge denotes the relative algorithmic confidence in a given interaction between nodes.\n\n\n\nDynamic Network Analysis (DyNA) of circulating inflammatory mediators shows differential trajectories that differentiate PALF patient sub-groups and suggests key network complexity thresholds\nPreviously, we showed that PALF non-survivors had more robust dynamic networks of inflammation than those of survivors, in line with the concept of pathology driven by self-sustaining inflammation9. Accordingly, we next hypothesized that employing the same methodology would further differentiate among the three sub-groups of PALF survivors. DyNA9,12,13 was used to discern and compare the interconnections among inflammatory mediators in the three survivor sub-groups vs. non-survivors over defined ranges of time (a detailed DyNA output template is shown in Suppl. Fig. 2 for reference). In support of our hypothesis, DyNA suggested a different dynamic network connectivity in each of the patient sub-groups (Fig. 3). Comparison of these networks by total number of connections in each sub-group showed that all survivors had fewer connections (APAPo + NAC [651], non-APAPo + NAC [677], non-APAPo non-NAC [369]) as compared to non-survivors [869] (Fig. 3A). Furthermore, analysis of the network complexity suggested the presence of two threshold network complexity events: the first one at d1–2 following enrollment, and a latter one around d4–5 (Fig. 3B). Prior to the d1–2 threshold, the presence of similar complexity scores suggests similar dynamic inflammatory responses among the patient sub-groups. However, after the first hypothesized threshold, network complexity was clearly higher in non-survivors but not in the other patient sub-groups. After d4–5, the complexity trajectories of all sub-groups, except that of non-APAPo non-NAC patients, again became nearly undistinguishable from each other (Fig. 3B). The non-APAPo/non-NAC group of survivors exhibited the fewest network connections when initially entered into the study, and the fewest overall, with the least change over time. In this group, the complexity of the mediator interactions never rose above a threshold level of 5 at any time period, and these patients were coincidentally not administered NAC by the care team.Figure 3 Dynamic Network Analysis (DyNA) of circulating inflammatory mediators in PALF patients. Circulating inflammatory mediators in serum samples from PALF spontaneous survivors were segregated into three sub-groups (APAPo + NAC [n = 13 patients], non-APAPo + NAC [n = 8 patients], and non-APAPo non-NAC [n = 40 patients]) and non-survivors (n = 12 patients). DyNA (stringency level = 0.7) was performed during each of the following seven time frames: d0-d1, d1–2, d2–3, d3–4, d4–5, d5–6, d6–7 as described in Materials and Methods. Panel A shows an overview of all the networks and mediator connections over all time intervals (the closed red circles represent mediators with at least one connection to another mediator, while open yellow circles represent mediators that had no connections to other mediators). Panel B shows the network complexity for the PALF sub-groups calculated as described in Materials and Methods.\n\n\n\nBased on our previous report9, as well as the implication of HMGB1 in the pathobiology of APAP toxicity in prior studies by others14, we hypothesized that the putative threshold events described above (Fig. 3B) are related to the differential HMGB1 connectivity in the different patient sub-groups. We therefore analyzed the DyNA networks associated solely with HMGB1. This analysis of connectivity in the HMGB1-focused DyNA showed that HMGB1 is most connected on d2–3 (connecting to IL-6, IL-8, and IP-10) in non-survivors, and has no connections at d3–4 and beyond (Fig. 4). In contrast, HMGB1 had no connections in the APAPo + NAC sub-group at d1–5. Furthermore, DyNA revealed a similar, relatively low number of HMGB1 connections in both the non-APAPo + NAC and non-APAPo non-NAC sub-groups at d0-d4 (Fig. 4). Interestingly, HMGB1 acquired additional connections between d5–7, but only in the APAPo + NAC and non-APAPo + NAC sub-groups. We note that comparison of the time-dependent changes in inflammatory mediators between PALF non-survivors with (n = 4 patients) and without NAC treatment (n = 8 patients) found no statistically significant difference in 26/27 of the inflammatory mediators assessed (data not shown), suggesting that the distinct and robust inflammatory networks in non-survivors are not dependent on the administration of NAC.Figure 4 HMGB1 connectivity to other inflammatory mediators depends on the use of NAC in the context of APAPo in PALF. Circulating inflammatory mediators were assessed in serum samples from PALF spontaneous survivors (APAPo + NAC [n = 13 patients], non-APAPo + NAC [n = 8 patients], and non-APAPo non-NAC [n = 40 patients]) and non-survivors (n = 12 patients). DyNA was performed as described in Fig. 3. Figure panels highlight the significant connections of HMGB1, extracted from the dynamic patterns and overall network connectivity shown in Fig. 3A.\n\n\n\nDynamic Network Analysis (DyNA) of inflammatory mediators in primary mouse hepatocytes confirms the central role for HMGB1 in the response to APAP toxicity\nThe effect of APAP in isolated cells has been studied widely and concentrations that range from 5 to 40 mM have been used to study APAP-mediated toxicity in vitro15. Given the central inflammatory role for HMGB1, we thought to compare the response to a toxic dose of APAP (10 mM) for 1 h alone or followed by 1 mM NAC added at 1, 3, 6 and 24 h following APAP in isolated mouse HC from C57BL/6 (wild-type) vs. HC-specific HMGB1-null mice (HC-HMGB1−/−). The time-courses of the 22 inflammatory mediators analyzed by Two-Way ANOVA showed different trajectories and revealed multiple inflammatory mediators that changed significantly (Suppl. Fig. 3). We next thought to compare the dynamic patterns of inflammatory mediators in isolated HC from C57BL/6 and HC-HMGB1−/− mice under the four experimental conditions (untreated Control, APAP, NAC, APAP + NAC) using DyNA as described above. This analysis showed a much more complex network pattern and higher total number of network connections in C57BL/6 HC (Fig. 5A) as compared to HC-HMGB1−/− cells (Fig. 5B). Interestingly, we also observed a difference in the number of negative mediator connections (mediators that change in an anti-correlated fashion in a given time-interval) depending on the use of NAC (APAP vs. APAP + NAC) and mouse strain: while in C57BL/6 HC the presence of negative connections increased from 4.2% (9/216 in APAP) to 25.9% (38/147 in APAP + NAC) (Fig. 5A), in HC-HMGB1−/− the number of negative connections remained essentially unchanged (6% vs. 7.5% in APAP [4/67/] and APAP + NAC [8/106], respectively) (Fig. 5B). Furthermore, the quantification of network complexity revealed a striking difference in the response of HC to APAP from the two mouse strains. There was no difference in control (Fig. 6A), NAC alone (Fig. 6C), or APAP + NAC-treated cells (Fig. 6D). However, APAP-treated C57BL/6 HC exhibited a much more complex dynamic networks than HC-HMGB1−/− cells (Fig. 6B), suggesting that HMGB1 plays a central role in orchestrating the inflammatory response to APAP.Figure 5 Dynamic Network Analysis (DyNA) of inflammatory mediators released by mouse HC from C57BL/6 and HC-HMGB1−/− mice. Freshly isolated HC from C57BL/6 or HC-HMGB1−/− mice were treated with 10 mM APAP alone (C57BL/6: n = 3, HC-HMGB1−/−: n = 5 mice) or for 1 h followed by 1 mM NAC (C57BL/6: n = 9, HC-HMGB1−/−: n = 6 mice) administered at 1–24 h following APAP (APAP + NAC) (C57BL/6: n = 3, HC-HMGB1−/−: n = 3 mice). Non-treated HC harvested at the same time points served as controls (C57BL/6: n = 12, HC-HMGB1−/−: n = 11 mice). Inflammatory mediators in supernatants were measured and analyzed using DyNA as described in Materials and Methods. An overview of all networks together with the number of network connections for each experimental condition (Control, APAP, NAC, and APAP + NAC) is shown in Panels A (C57BL/6 HC) and B (HC-HMGB1−/− HC). Black and red arrows represent positive and negative connections, respectively.\n\nFigure 6 Inflammatory network complexity of mediators released by HC from C57BL/6 and HC-HMGB1−/− mice suggests a central, coordinating role for HMGB1. Freshly isolated HC from C57BL/6 or HMGB1−/− mice were incubated with 10 mM APAP alone or for 1 h followed by 1 mM NAC administered at 1–24 h following APAP as described in Fig. 5. Non-treated HC harvested at the time points served as controls. Inflammatory mediators in supernatants were measured and analyzed using DyNA as described in Materials and Methods. Comparison of inflammatory network complexity in C57BL/6 vs. HC-HMGB1−/− HC in each experimental group is shown in Panel A (Control), Panel B (APAP), Panel C (NAC), and Panel D (APAP + NAC).\n\n\n\nDiscussion\nPediatric Acute Liver Failure is a rare but life-threatening clinical syndrome whose onset is not completely understood1. Despite recent advances in diagnosis and management, specific diagnostic and therapeutic targets and tools to predict spontaneous survival/death or to inform liver transplantation decisions in PALF are still not available. The present study sought to define central regulatory mechanisms associated with APAP-induced inflammation in PALF. We have reported previously that computational and data-driven analysis of principal inflammatory drivers and dynamic inflammatory networks could discriminate among sub-groups of PALF patients9. As an extension of these previous studies8,9, we hypothesized that novel insights into inflammatory responses in APAPo + NAC, non-APAPo + NAC, and non-APAPo non-NAC could be defined and differentiated from that of PALF non-survivors using multiplex assays of inflammatory mediators and data-driven analysis. The key insights from the present study are (1) the identification of a putative temporal threshold of inflammatory network connectivity; (2) the demonstration of a central role for HMGB1 in nucleating systemic inflammatory responses in PALF; and (3) a demonstration of the translational potential of combining in vitro, in silico, and clinical studies.\n\nNumerous studies, both in vitro and in vivo, have been directed to investigate the role of HC in the context of Acute Liver Failure (ALF), but to a lesser extent in PALF. Of particular interest to our present work are those experimental and clinical studies related to APAP overdose, the leading cause of ALF in most industrialized countries16. Those studies include the involvement of critical signaling pathways (e.g. APAP-mediated induction of receptor-interacting protein (RIP) signaling as a critical switch for hepatocellular necrosis17); the identification of proteins as potential biomarkers of liver injury (e.g. high levels of sFas and hepatocyte growth factor (HGF) in APAP-related ALF18; associations between levels of given proteins (e.g of M-30 antigen and CPS1) with clinical outcomes18,19; and increased levels of HMGB1 in both adult ALF20 and PALF8,9. We now suggest that the network coordination of HMGB1 is a key aspect of HC biology in the context PALF-associated inflammation.\n\nA recent study from the PALF Study Group has shown that children with undetermined diagnosis have lower spontaneous survival and higher rates of transplantation and death than other diagnostic groups, suggesting that reducing systemic inflammation would also limit neuroinflammation and improve survival significantly21. We have previously shown that PALF non-survivors had more robust dynamic networks of inflammation than those of survivors9, in line with the concept of pathology driven by self-sustaining inflammation in other disease states22. Dynamic Network Analysis9,12,13 highlighted the dynamic differences in the interconnections among inflammatory mediators in the three survivor sub-groups vs. non-survivors, and in particular the different network connectivity and total number of connections in each of the patient sub-groups (NS > APAPo + NAC, non-APAPo + NAC, non-APAPo non-NAC). This analysis, in line with our previous report9 and other studies implicating HMGB1 in the pathobiology of APAP toxicity14, also suggested the presence of two threshold network complexity events that seemed to be related to the differential HMGB1 connectivity in the different patient sub-groups.\n\nThe current approach to the management of APAP toxicity continues to be limited by imprecise and time-constrained risk assessments and late-stage markers of liver injury. Our present results suggest that the connectivity of HMGB1 may be a potential novel biomarker or drug target for PALF. Our results suggest that HMGB1 inflammatory connectivity, is affected significantly by the differential use of NAC in the context of APAP overdose. N-acetylcysteine has been the most effective therapy against APAP-induced liver injury in both adults3,23 and children2,24. This treatment is effective in patients with acute APAP-induced ALF, but its use for treating patients with liver injury caused by chronic APAP exposure warrants further investigation2. For example, a retrospective study of pediatric non-APAP-induced ALF showed that NAC was associated with a shorter length of hospital stay, higher incidence of native liver recovery without transplantation, and better survival after transplantation25. In contrast, the use of NAC failed to improve 1-year transplant-free survival in children with non-APAP ALF, highlighting the importance of conducting prospective pediatric drug trials, regardless of results in adults4.\n\nA practical and ethical consideration that complicates predictive biomarker research in this area is the clinical need to deliver antidote treatment within 10 h of APAP overdose26. In adult liver injury, inclusion of HMGB1 in a biomarker panel has been suggested to improve the speed of clinical decision-making, both in the treatment of acute liver injury and patient-individualized treatment strategies27. Our analysis suggests that the patients who were coincidentally not administered NAC by the care team (non-APAPo non-NAC group) exhibited both the fewest overall inflammatory network connections and the fewest connections when entered initially into the study. Interestingly, HMGB1 appeared to reemerge on day 5–7 in the APAPo + NAC and non-APAPo + NAC cohorts. HMGB1 has been shown to promote wound healing and endogenous stem cell differentiation28. Thus, HMGB1 may play a role not only in the initiation and propagation of the inflammatory response, but also in hepatocellular regeneration following liver injury.\n\nUnraveling the association of HMGB1 network connectivity is difficult in the clinical setting. Accordingly, we reasoned that the putative role of HMGB1 in coordinating the hepatic inflammatory response in PALF patients could be recapitulated in vitro. Ordinarily, extrapolating directly from in vitro studies to the clinical setting would be difficult if not impossible. However, the use of advanced computational tools demonstrated a qualitative agreement at the network level between mouse HC exposed to APAP + NAC in vitro vs. APAPo + NAC patients. Thus, we tested the hypothesis that a reduction or elimination of HMGB1 in HC in vitro would block the APAP-induced evolution of dynamic networks of inflammation. In support of this hypothesis, we found a much more complex network pattern and higher total number of network connections in C57BL/6 HC as compared to HC-HMGB1−/− cells, suggesting that indeed HMGB1 plays a central role in orchestrating the inflammatory response to APAP. This analysis was performed in the absence of adjacent immune cells that would be present in vivo, and therefore likely underestimates the full magnitude and complexity of the HMGB1-driven inflammatory response induced be HMGB1 following APAP toxicity. HMGB1 is a ubiquitous nuclear protein present in almost all cell types with both intracellular functions in the nucleus and extracellular functions as a DAMP29. In the context of liver injury, neutralizing HMGB1was protective against APAP-induced inflammation in mice6. Interestingly, in our experiments the levels of HMGB1 were significantly reduced in APAP-treated HC-HMGB1−/− cells, yet some form of HMGB1 or HMGB1 reactive molecule was detected in the supernatants of those cultures. This may be due to differential processing of HMGB1, or to a small contamination with non-HC cells in our primary cultures. Hyperacetylation of HMGB1 shifts its equilibrium from a predominant nuclear location toward a cytosolic and subsequent extracellular presence29. In addition, it has been demonstrated that the extracellular activity of HMGB1 as inflammatory mediator is closely related to the redox state of its three key cysteine residues30,31. Under strong oxidizing conditions such as those seen with APAP exposure in vitro, the oxidation of some or all of the cysteine residues could lead to loss of biological activity of HMGB130. Future studies will need to address the potential role of these HMGB1 modifications in coordinating networks of inflammation. Nonetheless, in our system the overall effect of APAP is likely not due to the presence of a pro-inflammatory form of HMGB1, as evidenced by the distinct and low network complexity in HC-HMGB1−/− cells as compared to wild-type cells.\n\nSimilar to our previous PALF studies8,9, there are some unavoidable limitations to the present work. First, we are unable to determine the onset for the systemic inflammation in PALF patients as the exact onset date for PALF cannot be determined. Equally important is that fact we only analyzed 8 days of samples, so changes in dynamic networks either before or after this time period remain unidentified; future studies will address this issue. The same applies to samples from participants with short, mild events or severe, rapid progression to death or transplantation that were excluded from this analysis given the analytical requirement for at least three available blood samples. We also note the relatively small number of patients and age heterogeneity in the non-survivors group. Finally, we acknowledge the difficulties in both measuring all the potential inflammatory mediators involved in (and relevant to) PALF and translating these complex analyses and hypotheses into a diagnostic test that could be used to assess outcome.\n\nIn conclusion, our results suggest that the inflammatory dynamic networks, and in particular HMGB1 connectivity, are dependent on (or reflect) the use of NAC in the context of APAP toxicity in PALF patients. In isolated HC, high APAP dose led to a much more complex dynamic networks in C57BL/6 HC than in cells from HMGB1−/− animals, suggesting that HMGB1 plays a central role in orchestrating the inflammatory response to APAP. In a broader context, our findings extend previous observations and suggest that analysis of dynamic networks of inflammation may be used to differentiate patient etiologies, which, when combined with appropriate in vitro studies, may lead to novel therapeutic opportunities for PALF. Specifically, PALF patients with high HMGB1 levels and high levels of inflammatory mediators early could be considered for therapies that target HMGB1, as they are at the greatest risk for death.\n\nMethods\nSelection of PALF patients and study design\nThis is a multi-center study conducted through the Pediatric Acute Liver Failure Consortia (PALF; National Institutes of Health/National Institutes of Diabetes, Digestive, and Kidney Disease: 5U01 DK072146). The study was performed in accordance with the relevant guidelines and regulations and was approved by the Institutional Review Boards from all participating institutions (listed in the Acknowledgments), with written informed consent from parents and/or legal guardians and Certificate of Confidentiality provided by NIH. Entry criteria for the study included children less than 18 years of age with (1) no known evidence of chronic liver disease, (2) biochemical evidence of acute liver injury, and (3) hepatic-based coagulopathy (not corrected with parenteral vitamin K) defined as a prothrombin time (PT) ≥ 15 seconds or international normalized ratio (INR) ≥ 1.5 in the presence of clinical hepatic encephalopathy (HE), or a PT ≥ 20 seconds or INR ≥ 2.0 regardless of the presence or absence of HE. After enrollment, demographic and clinical data were recorded daily for up to seven days with a single daily serum sample for research scheduled to be collected on the calendar day of enrollment (d0) or with the first morning blood draw following enrollment and daily for up to seven days (d1–d7), or until death, LTx, or discharge from hospital. Serum samples were promptly frozen at −80 °C at the enrollment site and later batch-shipped to the research bio-repository for long-term storage. At the time of this analysis, PALF study enrollment included 1,144 participants and the selection criteria for the analysis is shown in Fig. 1. Participants were selected if they had at least three daily samples with at least 100 µl of serum available. Selection criteria were met by 73 participants and clinical outcomes at twenty-one days following enrollment were assigned as follows: survival without LTx (spontaneous survivors, n = 61 patients) or death without LTx (non-survivors, n = 12 patients). Those receiving LTx prior to 21 days following enrollment were excluded. Otherwise, our cohort would have been a mixed cohort of participants who would have lived or would have died within 21 days had LTx not interrupted the clinical course. In the APAPo cohort, all received NAC and were survivors. We note that given the clinical nature of PALF, the interval between time of ingestion, recognition/acknowledgement of ingestion, admission to hospital, and enrollment cannot be expected to be uniform for all APAP PALF participants. In a previous study32, we reported that among 58 PALF cases with acute APAP toxicity, participants were enrolled between 1 to 6 days following ingestion with 93% enrolled within <4 days. Examining PALF survivors who did and did not receive NAC may provide insight into the impact of NAC in non-APAP PALF. In our previous study, we examined the cohort of spontaneous survivors as a whole9. For this new analysis, survivors were divided into three sub-groups including participants in a placebo-controlled clinical trial of NAC4: APAPo plus NAC, non-APAPo plus NAC, and non-APAPo non-NAC (Table 1). PALF non-survivors were a heterogeneous group that included 4 patients who received NAC and served to characterize differences in their inflammatory network from the three sub-groups of survivors. Serum samples from participants meeting all criteria were shipped from the NIH biorepository to the Surgery Research Laboratory at the University of Pittsburgh for Luminex™ analysis (see below). A comprehensive table with detailed demographic and clinical data in both survivors and non-survivors can be found in a previous publication from our group9.Table 1 Age distribution for PALF Study Patients.\n\nOutcome\tPatient Sub-group\tNo. of patients\tAge (mean)\tAge (median)\tQ1–Q3\t\nsurvivors\tAPAPo + NAC\t13\t15.2\t16.1\t15.3–17.7\t\nnon-APAPo + NAC\t8\t11.8\t13.1\t9.0–15.6\t\nnon-APAPo non-NAC\t40\t5.5\t3.1\t1.1–9.7\t\nAll survivors\t61\t8.4\t6.7\t1.5–15.3\t\nnon-survivors\t—\t12\t3.4\t0.1\t0.0–5.3\t\n\n\nMouse hepatocyte isolation and culture\nAll experiments involving animals were performed in accordance with relevant NIH guidelines and regulations and were approved by the Animal Care and Use Committee of the University of Pittsburgh. Primary mouse hepatocytes (HC) were harvested from male wild-type C57BL/6 mice (purchased from Charles River Laboratories, Wilmington, MA) and hepatocyte-specific HMGB1-null mice (HC-HMGB1−/−, generated on a C57BL/6 genetic background33) and plated as previously described13. Briefly, after overnight incubation, the medium was removed and cell monolayers (200,000 cells/well) were further incubated with fresh media containing 5% heat-inactivated calf serum and 10 mM Acetaminophen (APAP) alone or for 1 h followed by 1 mM N-acetylcysteine (NAC) administered at multiple time-points from 1 to 24 h following APAP (APAP + NAC) (n = 3 independent experiments performed in triplicate or as otherwise indicated in the Figure Legends). At the end of each experiment, the cell supernatants were stored at −20 °C until further analysis (see below). APAP was purchased from Sigma-Aldrich (St Louis, MO) and dilutions were made using a 250 mM stock solution prepared in ethanol. NAC was purchased from Sigma-Aldrich (St Louis, MO) and dilutions were made in cell culture media. Non-treated HC and HC treated with NAC alone for the times indicated served as control.\n\nAssays of inflammatory mediators\nWe measured a number of cytokines and chemokines that serve as biomarkers for the complex inflammatory response using the Luminex™ 100 IS system (Luminex™, Austin, TX) and the Human 25-plex® Luminex™ and MilliplexTM Mouse Cytokine/Chemokine Panel I beadsets (Millipore, Billerica, MA). These antibody bead kits include:\n\nHuman (25 mediators): Eotaxin, Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), Interferon (IFN)-α2, IFN-γ, Interleukin (IL)-1β, IL-1 Receptor Antagonist (IL-1RA), IL-2, Soluble IL-2 Receptor α chain (sIL-2Rα), IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p40, IL-12p70, IL-13, IL-15, IL-17A, IFN-γ-inducible Protein of 10 kDa (IP-10; CXCL10), Monocyte Chemotactic Protein-1 (MCP-1; CCL2), Monokine Induced by γ-Interferon (MIG; CXCL9), Macrophage Inflammatory Protein (MIP)-1α, MIP-1β, and Tumor Necrosis Factor (TNF)-α).\n\nMouse (20 mediators): GM-CSF, IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-13, IL-17, IP-10/CXCL10, Keratinocyte-derived Cytokine (KC/CXCL1), MCP-1/CCL2, MIG/CXCL9, MIP-1α/CCL3, TNF-α, and Vascular Endothelial Growth Factor (VEGF).\n\nIn addition, all samples were assayed for HMGB1 using a commercially available ELISA (Shino-Test, Kanagawa, Japan). We found that the cell culture media supplemented with calf serum used in our study contained significant amounts of HMGB1 or HMGB1-like protein as detected by the ELISA kit. Therefore, the concentrations of HMGB1 released by mouse HC were corrected before the computational analyses and are shown in Suppl. Fig. 3. The nitric oxide (NO) reaction products NO2− + NO3− were assayed using the nitrate reductase method (Cayman Chemical, Ann Arbor, MI). All mediator data were measured in pg/ml except for NO2− + NO3− measured in µM. The time courses of the inflammatory mediators were then plotted, shown as box plots representing the 25th and 75th percentiles with a line at the median and error bars defining the 10th and 90th percentile in PALF patients, and as mean ± SEM in mouse HC experiments.\n\nStatistical and data-driven computational analysis\nTwo-Way Analysis of Variance (ANOVA) followed by the Holm-Sidak post-hoc test was used to analyze the response and time-dependent changes in inflammatory mediators across PALF sub-groups and in the mouse HC experiments using SigmaPlot (Systat Software, San Jose, CA) as indicated.\n\nDynamic Bayesian Network (DBN) inference was carried out in order to define the most likely single network structure that best characterizes the dynamic interactions among systemic inflammatory mediators across all time points and, in the process, suggesting likely feedback structures that define central nodes. The networks may suggest possible mechanisms by which the progression of the inflammatory response differs within a given patient sub-group. Characterization of central nodes serves to suggest possible control points for a given dynamic process. In this analysis, time courses of unprocessed inflammatory mediator measurements from each patient were used as input for a DBN inference algorithm, implemented in MATLAB® as described previously for gene array data34 and modified by our group for the study of systemic acute inflammation8,9,35.\n\nDynamic Network Analysis (DyNA) was carried out to define, in a granular fashion, the central inflammatory network nodes as a function of both time and PALF patient sub-group, and experimental condition in vitro. Using inflammatory mediator measurements of at least three time-points for each patient, networks were created over seven consecutive time periods (d0-d1, d1–2, d2–3, d3–4, d4–5, d5–6, d6–7) using MATLAB® software8,9,13. Connections, defined as the number of trajectories of serum inflammatory mediators that move in parallel, were created if the Pearson correlation coefficient between any two nodes (inflammatory mediators) at the same time-interval was greater or equal to a threshold of 0.7 (a correlation value commonly used to characterize trajectories that move in parallel either up or down). The network complexity for each time-interval was calculated using the following formula: Sum (N1 + N2 + … + Nn)/n-1, where N represents the number of connections for each mediator and n is the total number of mediators analyzed. The total number of network connections represents the sum of the number of connections across all time-intervals for all patients in a given sub-group. The same methodology was applied to create networks using inflammatory mediator measurements over three consecutive time periods (1–3 h, 3–6 h, 6–24 h) from mouse HC as described.\n\nSupplementary information\n\nSuppl. Info\n\n \nLuminex data\n\n \n\n\nPublisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nSupplementary information accompanies this paper at 10.1038/s41598-019-42564-5.\n\nAcknowledgements\nThis work was supported by a Multi-Center Group to Study Acute Liver Failure in Children (NIH/NIDDK grant UO1 DK072146). We thank the collaborative effort of the following current and former principal and co-investigators of the Pediatric Acute Liver Failure Study (by site): University of Pittsburgh: Robert H. Squires MD, Benjamin L. Shneider MD; Cincinnati Children’s Hospital: John Bucuvalas MD and Mike Leonis MD PhD; Lurie Children’s Hospital of Chicago (Chicago): Estella Alonso MD; University of Texas Southwestern: Norberto Rodriguez-Baez MD; Seattle Children’s Hospital: Karen Murray MD and Simon Horslen MB ChB; Children’s Hospital Colorado (Aurora): Michael R. Narkewicz MD; St Louis Children’s Hospital: David Rudnick MD PhD and Ross W. Shepherd MD; University of California at San Francisco: Philip Rosenthal MD; Hospital for Sick Children (Canada): Vicky Ng MD; Riley Hospital for Children (Indianapolis): Girish Subbarao MD; Emory University: Rene Romero MD; Children’s Hospital of Philadelphia: Elizabeth Rand MD and Kathy Loomes MD; Kings College-London (England): Anil Dhawan MD; Birmingham Children’s Hospital (England): Dominic Dell Olio MD and Deirdre A. Kelly MD; Texas Children’s Hospital: Saul Karpen MD PhD, Mt. Sinai Medical Center: Nanda Kerkar MD; University of Michigan: M. James Lopez MD PhD; Children’s Hospital Medical Center (Boston): Scott Elisofon MD and Maureen Jonas MD; Johns Hopkins University: Kathleen Schwarz MD; Columbia University: Steven Lobritto MD. We would also like to thank Regina M. Hardison, Tamara Lee Haller, and Steven H. Belle from the Data Coordinating Center at the University of Pittsburgh and the dedicated research coordinators at each site.\n\nAuthor Contributions\nR.Z., R.H.S. and Y.V. contributed to study design, data analysis, funding and manuscript writing. D.B. and J.Y. D.B. performed the sample processing and Luminex analyses. Q.M. contributed to computational analyses. E.M.A. and M.A.L. contributed to the discussion of the clinical data. T.R.B. provided the knockout animals and contributed to the discussion of the data. R.L.S. contributed to the discussion of the data and manuscript writing.\n\nData Availability\nAll data generated or analyzed during this study are included in this published article (and its Supplementary Information files).\n\nCompeting Interests\nThe authors declare no competing interests.\n==== Refs\nReferences\n1. 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"keywords": null,
"medline_ta": "Sci Rep",
"mesh_terms": "D000082:Acetaminophen; D000293:Adolescent; D018712:Analgesics, Non-Narcotic; D000818:Animals; D015415:Biomarkers; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D062787:Drug Overdose; D024243:HMGB1 Protein; D022781:Hepatocytes; D006801:Humans; D007223:Infant; D007249:Inflammation; D017114:Liver Failure, Acute; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061251:Primary Cell Culture",
"nlm_unique_id": "101563288",
"other_id": null,
"pages": "5971",
"pmc": null,
"pmid": "30979951",
"pubdate": "2019-04-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": "27862115;22886633;519312;17967565;23984999;15734795;23046676;23446148;24798499;26076366;22105604;21573002;25285195;24244295;18437239;24746113;21177328;27513538;25859823;27900388;15800420;22585050;27474782;18346862;16737880;24375466;24924744;23439908;24312451;18161828;29735026;22266604;23390034;29027228;24584064",
"title": "HMGB1 is a Central Driver of Dynamic Pro-inflammatory Networks in Pediatric Acute Liver Failure induced by Acetaminophen.",
"title_normalized": "hmgb1 is a central driver of dynamic pro inflammatory networks in pediatric acute liver failure induced by acetaminophen"
} | [
{
"companynumb": "US-JNJFOC-20190512144",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nFurther treatment with clozapine is contraindicated in any patient who has previously experienced leucopenia or neutropenia during clozapine therapy.\n\n\nOBJECTIVE\nTo investigate the results of such a rechallenge in 53 patients.\n\n\nMETHODS\nAn analysis was made of the demographic, haematological and outcome data of patients in the UK and Ireland who were rechallenged with clozapine following leucopenia or neutropenia during previous clozapine therapy.\n\n\nRESULTS\nOf 53 patients who were rechallenged, 20 (38%) experienced a further blood dyscrasia. In 17 of these 20 patients (85%) the second blood dyscrasia was more severe (P<0.001), in 12 (60%) it lasted longer (P=0.0368) and in 17 (85%) it occurred more quickly on rechallenge (P<0.001). Of the original 53 patients, 55% (29 patients) are still receiving clozapine.\n\n\nCONCLUSIONS\nNo clear risk factor for repeat blood dyscrasias was identified. Despite this, after risks and benefits have been considered, rechallenge may well be justified in some patients.",
"affiliations": "Histopathology Department, Leicester Royal Infirmary, Infirmary Square, Leicester LE1 5WW, UK. louisa.dunk@btinternet.com",
"authors": "Dunk|Louisa R|LR|;Annan|Linda J|LJ|;Andrews|Christopher D|CD|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "England",
"delete": false,
"doi": "10.1192/bjp.188.3.255",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1250",
"issue": "188()",
"journal": "The British journal of psychiatry : the journal of mental science",
"keywords": null,
"medline_ta": "Br J Psychiatry",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003024:Clozapine; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007970:Leukopenia; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D012008:Recurrence; D018570:Risk Assessment; D012559:Schizophrenia; D013997:Time Factors",
"nlm_unique_id": "0342367",
"other_id": null,
"pages": "255-63",
"pmc": null,
"pmid": "16507968",
"pubdate": "2006-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Rechallenge with clozapine following leucopenia or neutropenia during previous therapy.",
"title_normalized": "rechallenge with clozapine following leucopenia or neutropenia during previous therapy"
} | [
{
"companynumb": "GB-PFIZER INC-2016268982",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe aims of the study were to describe the case of a 73-year-old woman with bipolar disorder who developed Pisa syndrome (PS) after starting clozapine and to present a review of this particular type of dystonia.\n\n\nMETHODS\nAfter a brief introduction to the PS, we conduct a detailed description of the case and review, after a search on the PubMed database, the known risk factors, drugs associated with the onset of this syndrome, and the management of PS.\n\n\nRESULTS\nPisa syndrome is a rare type of dystonia first described in 1972 as an adverse effect of neuroleptic agents. Clozapine is known for its small potential for inducing extrapyramidal symptoms, and it is often preferred as an alternative when extrapyramidal symptoms develop over the course of treatment with other agents. Many drugs have been associated with this kind of dystonia; however, we only found 5 previous reports of clozapine-induced PS. Tardive syndromes secondary to antipsychotic medication are better treated with the reduction or interruption of the causative agent, which was effective in this case.\n\n\nCONCLUSIONS\nThe occurrence of clozapine-associated PS is rare and should be reported to further understand this phenomenon as well as the underlying risk factors.",
"affiliations": "Hospital Júlio de Matos, Centro Hospitalar Psiquiátrico de Lisboa, Lisbon, Portugal.",
"authors": "Santos|Henrique Castro|HC|0000-0001-9926-3887;Oliveira|João|J|0000-0002-5879-5788;Vieira|Ana Sofia|AS|0000-0002-0748-6248;Pereira|Joana|J|0000-0002-6004-674",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000485",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "44(6)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000368:Aged; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D003024:Clozapine; D004421:Dystonia; D005260:Female; D006801:Humans; D013577:Syndrome",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "222-224",
"pmc": null,
"pmid": "34654016",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Clozapine-Associated Pisa Syndrome: A Case Report of an Acute Reaction in a Bipolar Patient.",
"title_normalized": "clozapine associated pisa syndrome a case report of an acute reaction in a bipolar patient"
} | [
{
"companynumb": "PT-MYLANLABS-2021M1090105",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": "1",
... |
{
"abstract": "We present a case of spontaneous coronary artery dissection associated with cabergoline treatment for prolactinoma. A 31-year-old woman with history of hypertension and prolactinoma, treated with cabergoline, presented with chest pain. She had non-ST-segment elevation myocardial infarction with double vessel coronary artery dissection and was treated with coronary artery bypass grafting. (Level of Difficulty: Beginner.).",
"affiliations": "Division of Cardiothoracic Surgery, Department of Surgery, Maimonides Medical Center, Brooklyn, New York.;Department of Cardiology, Maimonides Medical Center, Brooklyn, New York.;Department of Cardiology, Maimonides Medical Center, Brooklyn, New York.;Division of Cardiothoracic Surgery, Department of Surgery, Maimonides Medical Center, Brooklyn, New York.",
"authors": "Ikeda|Shinichiro|S|;Le|Jeffrey|J|;Verma|Shivani|S|;Youdelman|Benjamin A|BA|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jaccas.2020.07.024",
"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(20)30898-6\n10.1016/j.jaccas.2020.07.024\nMini-Focus Issue: Coronaries\nCase Report: Clinical Case\nA Novel Case of Spontaneous Coronary Artery Dissection During Cabergoline Therapy for Prolactinoma\nIkeda Shinichiro MD SIkeda@maimonidesmed.org\na∗\nLe Jeffrey MD b\nVerma Shivani MD b\nYoudelman Benjamin A. MD a\na Division of Cardiothoracic Surgery, Department of Surgery, Maimonides Medical Center, Brooklyn, New York\nb Department of Cardiology, Maimonides Medical Center, Brooklyn, New York\n∗ Address for correspondence: Dr. Shinichiro Ikeda, Maimonides Medical Center, 4802 Tenth Avenue, Brooklyn, New York 11219. SIkeda@maimonidesmed.org\n15 9 2020\n9 2020\n15 9 2020\n2 11 16841687\n11 6 2020\n1 7 2020\n© 2020 The Authors\n2020\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 of spontaneous coronary artery dissection associated with cabergoline treatment for prolactinoma. A 31-year-old woman with history of hypertension and prolactinoma, treated with cabergoline, presented with chest pain. She had non–ST-segment elevation myocardial infarction with double vessel coronary artery dissection and was treated with coronary artery bypass grafting. (Level of Difficulty: Beginner.)\n\nGraphical abstract\n\nWe present a case of spontaneous coronary artery dissection associated with cabergoline treatment for prolactinoma. A 31-year-old woman with…\n\nKey Words\n\nacute coronary syndrome\ncoronary angiography\ncoronary artery bypass\nAbbreviations and Acronyms\n\nCABG, coronary artery bypass grafting\nCAD, coronary artery disease\nPCI, percutaneous coronary intervention\nRCA, right coronary artery\nSCAD, spontaneous coronary artery dissection\n==== Body\nHistory of presentation\n\nA 31-year-old woman presented with complaint of chest pain. She denied tobacco, drug, or alcohol use, and she reported there was no known family history of genetic disease, cardiac disease, or sudden death. On initial evaluation, vital signs demonstrated a heart rate of 62 beats/min and a blood pressure of 164/110 mm Hg. Physical examination was significant for an anxious female with physical distress caused by intermittent chest pain but no focal abnormal findings were identified. An electrocardiogram showed diffuse T-wave inversions in II, III, aVf, and V1 to V6. Laboratory tests showed an initial troponin I of 0.06 ng/ml (normal range, <0.40 ng/ml) but reflected a normal complete blood count and basic metabolic panel. Patient was given aspirin (325 mg) and clopidogrel (600 mg) at the outside hospital she initially presented to. On presentation to our facility, her troponin I level increased to 2.8 ng/ml.Learning Objectives\n\n• SCAD commonly occurs in young females without risk factors of atherosclerotic CAD.\n\n• The use of cabergoline to treat hyperprolactinemia could be related to its incidence.\n\n• CABG was effective in the case of a symptomatic patient with ongoing ischemia despite medical therapy. PCI could be associated with an increased risk of iatrogenic dissections or extensions of dissection.\n\nPast Medical History\n\nThe patient had a previous medical history of hypertension treated with amlodipine (10 mg/day). She delivered 1 child 11 years ago. The patient had reported symptoms characteristic of amenorrhea, galactorrhea, and infertility 2 years ago. Her prolactin level was elevated to 160 ng/ml (normal range, 2.8 to 29.2 ng/ml) but she was not treated for prolactinoma for 1 year because of noncompliance with medical recommendations. A magnetic resonance imaging detected a 2.3-cm pituitary mass and a prolactin level of 236 ng/ml 7 months ago. She was started on cabergoline (0.25 mg twice weekly) for prolactinoma. After completing 3 months of therapy, she stopped refilling her prescription. Three weeks later (3 months before this presentation), she visited the emergency department with complaint of chest pain. She was discharged home because electrocardiogram did not show significant ST-segment changes and echocardiogram revealed normal ejection fraction. Her endocrinologist restarted her back on cabergoline at her previous dose.\n\nDifferential Diagnosis\n\nBased on the initial presentation, electrocardiogram findings, and elevated troponin, differential diagnosis included non–ST-segment elevation myocardial infarction, myocarditis, and stress cardiomyopathy.\n\nInvestigation\n\nA coronary angiogram revealed normal left main, diffuse 99% stenosis of the proximal to mid left anterior descending artery, 90% stenosis at the first diagonal branch, normal left circumflex, and total occlusion of the mid right coronary artery (RCA) without visible collaterals (Figure 1, Video 1). RCA was likely an acute flow-limiting dissection and the culprit lesion. An echocardiography showed 60% of ejection fraction with hypokinesis of inferior and septal wall. A lipid panel test was not significant (cholesterol, 164 mg/dl; low-density lipoprotein, 123 mg/dl; high-density lipoprotein, 52 mg/dl; and triglyceride, 53 mg/dl).Figure 1 Pre-Operative Coronary Angiogram\n\n(A) In the right anterior oblique caudal view, left main and the left circumflex was normal. (B) In the left anterior oblique cranial view, the proximal to mid left anterior descending artery showed diffuse 99% stenosis. There was a 90% stenosis at the bifurcation of the first diagonal branch. (C) In the left anterior oblique cranial view, the mid right coronary artery was 100% occluded.\n\nOnline Video 1 Coronary Angiogram With LAO 35, CRAN 34 View\n\nLeft anterior descending artery showed diffuse stenosis.\n\nManagement\n\nConsidering the patient’s young age and staccato chest pain, which was related to high blood pressure, coronary artery dissection was suspected. Percutaneous coronary intervention (PCI) was not performed. Blood pressure control resolved chest pain. An intra-aortic balloon pump was placed and the patient was treated with intravenous heparin and nitroglycerine infusions in anticipation of coronary artery bypass grafting (CABG) for definitive treatment. Ten hours later, the patient had a recurrence of chest pain with increasing troponin I of 6.5 ng/ml and was taken for on-pump CABG. The left internal thoracic artery was anastomosed to left anterior descending artery and the right internal thoracic artery to RCA. Radial artery was anastomosed to the diagonal artery. Tissue along the diagonal artery and left anterior descending artery was inflamed and swollen (Figure 2). Once arteries were opened, they were found to have evidence of dissection with false lumen, chronic thrombosis, and a dissection flap. The RCA was similarly dissected. The chest was left open because of profound hypotension during an attempt to close.Figure 2 Intraoperative Findings of Coronary Artery Dissection\n\nThe tissue along the diagonal artery and left anterior descending artery was inflamed and swollen.\n\nDiscussion\n\nSpontaneous coronary artery dissection (SCAD) is an uncommon cause of acute coronary syndrome or sudden cardiac death (1). It is identified in 0.2% to 1.1% of coronary angiographies performed for acute coronary artery syndrome (2). SCAD predominately affects young females with some experiencing the condition in a life-threatening manner than others. Although it is a rare disease, it can be underdiagnosed because of the perception that coronary artery disease (CAD) does not affect young patients. In our case, the patient presented to the emergency department with chest pain 3 months before undergoing CABG. She may have had a SCAD event at that time, from which she recovered, followed by another event that led to the second presentation. It is clear that CAD may not likely be considered when young patients complain of chest pain. Intramural hematoma within the wall of a coronary artery is characteristic after SCAD. This is caused by intimal tear or a spontaneous hematoma arising from the vasa vasorum within the vessel wall (3). The cause of SCAD could be multifactorial, including underlying arteriopathies, genetic factors, hormonal influences, or systemic inflammatory diseases. Among arteriopathies, the association of SCAD with fibromuscular dysplasia has been reported. Fibromuscular dysplasia affects any arteries and can manifest as arterial stenosis, aneurysm, or dissection (4). There is only 1 previous case report about SCAD during use of cabergoline (5). Cabergoline is an ergot derivative, which can cause vasospasm leading to dissection of arteries (6). There may be a relationship between cabergoline and SCAD. Besides this, the underlying disease of hyperprolactinemia and associated hormonal changes may have a similar effect as pregnancy and cause SCAD.\n\nThere is not a well-established guideline for treatment of SCAD. Studies have demonstrated that SCAD can heal spontaneously in most patients, ranging from 70% to 97% (7). Therefore, SCAD can be managed conservatively as long as the patient is clinically stable. However, in cases of ongoing ischemia or hemodynamic instability, PCI or CABG should be considered. PCI for treatment is associated with an increased risk of iatrogenic dissections or extensions of dissection as a result of underlying arteriopathies (8). The indication for CABG includes left main, proximal left descending artery, or multiple vessel diseases; technical failure or complications of PCI; and refractory ischemia despite conservative management. As a result of subsequent healing of native dissected arteries leading to competitive flow, a high rate of graft occlusions has been reported (8).\n\nFollow-Up\n\nThe patient was transferred to intensive care unit. Chest closure occurred on post-operative day 2. She was extubated on post-operative day 3 and discharged home on post-operative day 9 without complications. Patient was discharged home on aspirin (81 mg/day), carvedilol (25 mg/day), isosorbide mononitrate (30 mg/day), and rosuvastatin (5 mg/day). Prolactin level during admission was 21 ng/ml (normal range, 2.8 to 29.2 ng/ml). Cabergoline was discontinued and prolactinoma was going to be followed by her endocrinologist.\n\nConclusions\n\nSCAD commonly occurs in young females without risk factors of atherosclerotic CAD. Although there are multiple factors that could cause SCAD, the use of cabergoline for the treatment of hyperprolactinemia could be related to its incidence. CABG was effective in this symptomatic patient. Further follow-up is necessary to assess long-term outcomes of CABG in SCAD. More recognition about the disease could lead to earlier diagnosis and treatment as well as prevent sudden death.\n\nAll authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Case Reportsauthor instructions page.\n\nAppendix\n\nFor a supplemental video, please see the online version of this paper.\n==== Refs\nReferences\n\n1 Motreff P. Souteyrand G. Dauphin C. Management of spontaneous coronary artery dissection: review of the literature and discussion based on a series of 12 young women with acute coronary syndrome Cardiology 115 2010 10 18 19816020\n2 Vanzetto G. Berger-Coz E. Barone-Rochette G. Prevalence, therapeutic management and medium-term prognosis of spontaneous coronary artery dissection: results from a database of 11,605 patients Eur J Cardiothorac Surg 35 2009 250 254 19046896\n3 Hayes S.N. Kim E.S.H. Saw J. Spontaneous coronary artery dissection: current state of the science: a scientific statement from the American Heart Association Circulation 137 2018 e523 e557 29472380\n4 Saw J. Ricci D. Starovoytov A. Spontaneous coronary artery dissection: prevalence of predisposing conditions including fibromuscular dysplasia in a tertiary center cohort J Am Coll Cardiol Intv 6 2013 44 52\n5 Mehta N.K. Malkani S. Ockene I. Spontaneous coronary artery dissection during cabergoline therapy Tex Heart Inst J 39 2012 92 94 22412238\n6 Al-Zubaidi A.S. Afandi B. Severe digital vasospasm caused by cabergoline Saudi Med J 26 2005 1153 1155 16047079\n7 Tweet M.S. Hayes S.N. Pitta S.R. Clinical features, management, and prognosis of spontaneous coronary artery dissection Circulation 126 2012 579 588 22800851\n8 Tweet M.S. Eleid M.F. Best P.J. Spontaneous coronary artery dissection: revascularization versus conservative therapy Circ Cardiovasc Interv 7 2014 777 786 25406203\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2666-0849",
"issue": "2(11)",
"journal": "JACC. Case reports",
"keywords": "CABG, coronary artery bypass grafting; CAD, coronary artery disease; PCI, percutaneous coronary intervention; RCA, right coronary artery; SCAD, spontaneous coronary artery dissection; acute coronary syndrome; coronary angiography; coronary artery bypass",
"medline_ta": "JACC Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101757292",
"other_id": null,
"pages": "1684-1687",
"pmc": null,
"pmid": "34317034",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": "22412238;19816020;23266235;25406203;29472380;16047079;22800851;19046896",
"title": "A Novel Case of Spontaneous Coronary Artery Dissection During Cabergoline Therapy for Prolactinoma.",
"title_normalized": "a novel case of spontaneous coronary artery dissection during cabergoline therapy for prolactinoma"
} | [
{
"companynumb": "US-ENDO PHARMACEUTICALS INC-2020-006721",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CABERGOLINE"
},
"drugadditional... |
{
"abstract": "Posterior leukoencephalopathy syndromes have been reported with hypertension, and immunosuppressive and chemotherapy agents. Cerebral vasospasm on MR angiography (MRA) has been noted in cases due to eclampsia. The authors report a case of Balint syndrome with irreversible posterior leukoencephalopathy on MRI following intrathecal methotrexate and cytarabine. Hypertension was not present. Diffuse, reversible arterial irregularities consistent with vasospasm were present on MRA during the acute illness.",
"affiliations": "Department of Neurology, Royal Brisbane Hospital, Herston, Australia. Robert_Henderson@health.qld.gov.au",
"authors": "Henderson|R D|RD|;Rajah|T|T|;Nicol|A J|AJ|;Read|S J|SJ|",
"chemical_list": "D003561:Cytarabine; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1212/01.wnl.0000042095.49520.1e",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": "60(2)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000208:Acute Disease; D000971:Antineoplastic Combined Chemotherapy Protocols; D001766:Blindness; D001927:Brain Diseases; D002536:Cerebral Arteries; D002544:Cerebral Infarction; D003561:Cytarabine; D018450:Disease Progression; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D018810:Magnetic Resonance Angiography; D008279:Magnetic Resonance Imaging; D008727:Methotrexate; D008875:Middle Aged; D015835:Ocular Motility Disorders; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D020127:Recovery of Function; D013577:Syndrome; D013610:Tachycardia; D020301:Vasospasm, Intracranial",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "326-8",
"pmc": null,
"pmid": "12552054",
"pubdate": "2003-01-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Posterior leukoencephalopathy following intrathecal chemotherapy with MRA-documented vasospasm.",
"title_normalized": "posterior leukoencephalopathy following intrathecal chemotherapy with mra documented vasospasm"
} | [
{
"companynumb": "AU-FRESENIUS KABI-FK201703386",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": n... |
{
"abstract": "OBJECTIVE\nTo describe viral retinitis following intravitreal and periocular corticosteroid administration.\n\n\nMETHODS\nRetrospective case series and comprehensive literature review.\n\n\nRESULTS\nWe analyzed 5 unreported and 25 previously published cases of viral retinitis following local corticosteroid administration. Causes of retinitis included 23 CMV (76.7%), 5 HSV (16.7%), and 1 each VZV and unspecified (3.3%). Two of 22 tested patients (9.1%) were HIV positive. Twenty-one of 30 (70.0%) cases followed one or more intravitreal injections of triamcinolone acetonide (TA), 4 (13.3%) after one or more posterior sub-Tenon injections of TA, 3 (10.0%) after placement of a 0.59-mg fluocinolone acetonide implant (Retisert), and 1 (3.3%) each after an anterior subconjunctival injection of TA (together with IVTA), an anterior chamber injection, and an anterior sub-Tenon injection. Mean time from most recent corticosteroid administration to development of retinitis was 4.2 months (median 3.8; range 0.25-13.0). Twelve patients (40.0%) had type II diabetes mellitus. Treatments used included systemic antiviral agents (26/30, 86.7%), intravitreal antiviral injections (20/30, 66.7%), and ganciclovir intravitreal implants (4/30, 13.3%).\n\n\nCONCLUSIONS\nViral retinitis may develop or reactivate following intraocular or periocular corticosteroid administration. Average time to development of retinitis was 4 months, and CMV was the most frequently observed agent. Diabetes was a frequent co-morbidity and several patients with uveitis who developed retinitis were also receiving systemic immunosuppressive therapy.",
"affiliations": "Department of Ophthalmology, California Pacific Medical Center , San Francisco, California , USA .",
"authors": "Takakura|Ako|A|;Tessler|Howard H|HH|;Goldstein|Debra A|DA|;Guex-Crosier|Yan|Y|;Chan|Chi-Chao|CC|;Brown|Diane M|DM|;Thorne|Jennifer E|JE|;Wang|Robert|R|;Cunningham|Emmett T|ET|",
"chemical_list": "D005938:Glucocorticoids",
"country": "England",
"delete": false,
"doi": "10.3109/09273948.2013.866256",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": "22(3)",
"journal": "Ocular immunology and inflammation",
"keywords": "Acute retinal necrosis; corticosteroid; cytomegalovirus; herpes virus; injection; retinitis",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": "D000328:Adult; D000368:Aged; D015828:Eye Infections, Viral; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D056965:Injections, Intraocular; D058449:Intravitreal Injections; D008297:Male; D008875:Middle Aged; D012173:Retinitis; D014605:Uveitis",
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "175-82",
"pmc": null,
"pmid": "24655372",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "15340550;16491037;23235944;22131785;16376669;25390979;18612235;25390918;18991048;12477338;17123624;19681818;21168815;17258523;21897137;23932722;21034309;17403022;20931263;20172069;22741031;20033756;20401569;23561607;23282087;16764663;25390978",
"title": "Viral retinitis following intraocular or periocular corticosteroid administration: a case series and comprehensive review of the literature.",
"title_normalized": "viral retinitis following intraocular or periocular corticosteroid administration a case series and comprehensive review of the literature"
} | [
{
"companynumb": "PHHY2014US080353",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE"
},
"drugadditional": null,
"d... |
{
"abstract": "A total of 156 patients (age range 1.3-18.0 years, median 13.2 years; 91 (58.3%) male) with newly diagnosed CML (N = 146 chronic phase (CML-CP), N = 3 accelerated phase (CML-AP), N = 7 blastic phase (CML-BP)) received imatinib up-front (300, 400, 500 mg/m2, respectively) within a prospective phase III trial. Therapy response, progression-free survival, causes of treatment failure, and side effects were analyzed in 148 children and adolescents with complete data. Event-free survival rate by 18 months for patients in CML-CP (median follow-up time 25 months, range: 1-120) was 97% (95% CI, 94.2-99.9%). According to the 2006 ELN-criteria complete hematologic response by month 3, complete cytogenetic response (CCyR) by month 12, and major molecular response (MMR) by month 18 were achieved in 98, 63, and 59% of the patients, respectively. By month 36, 86% of the patients achieved CCyR and 74% achieved MMR. Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response or intolerance (N = 9). In all, 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N = 3) or SCT-related complications (N = 2). This large pediatric trial extends and confirms data from smaller series that first-line imatinib in children is highly effective.",
"affiliations": "Pediatric Hematology and Oncology, Department of Pediatrics, University Hospital \"Carl Gustav Carus\", TU Dresden, Dresden, Germany. meinolf.suttorp@uniklinikum-dresden.de.;Institute for Medical Informatics and Biometry, Faculty of Medicine \"Carl Gustav Carus\", TU Dresden, Dresden, Germany.;Institute for Medical Informatics and Biometry, Faculty of Medicine \"Carl Gustav Carus\", TU Dresden, Dresden, Germany.;Department of Human Genetics, Hannover Medical School, Hannover, Germany.;Department of Human Genetics, Hannover Medical School, Hannover, Germany.;Pediatric Hematology and Oncology, University Children's Hospital, Erlangen, Germany.;Pediatric Hematology and Oncology, Teaching Hospital Motol, 2nd Medical School, Charles University Motol, Prague, Czech Republic.;Pediatric Hematology and Oncology, University Children's Hospital, Groningen, The Netherlands.;Pediatric Hematology and Hematopoietic Stem Cell Transplantation Unit, Clinica Pediatrica Università degli Studi di Milano Bicocca, Ospedale San Gerardo, Monza, Italy.;Department of Pediatric and Adolescent Medicine, University Hospital, Rigshospitalet, Copenhagen, Denmark.;Belarus Research Center for Pediatric Oncology, Hematology, and Immunology, Minsk, Belarus.;Department of Pediatrics, BMT Unit, Comenius University Children's Hospital, Bratislava, Slovakia.;Pediatric Hematology and Oncology, University Children's Hospital, Charité Berlin, Germany.;Pediatric Hematology and Oncology, University Children's Hospital, Charité Berlin, Germany.;Pediatric Hematology and Oncology, University Children's Hospital, Charité Berlin, Germany.;Department of Pediatrics III, University Hospital, University of Duisburg-Essen, Duisberg, Germany.;Pediatric Hematology and Oncology, University Children's Hospital, Münster, Germany.;Pediatric Hematology and Oncology, University Children's Hospital, Cologne, Germany.;University Children's Hospital, Ludwig Maximilians University, Munich, Germany.;Pediatric Oncology, Hematology, Immunology, Stuttgart Cancer Center, Klinikum Stuttgart-Olgahospital, Stuttgart, Germany.;Paediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.;Pediatric Hematology, Oncology, and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.;Pediatric Oncology, Hematology, and Immunology, University Children's Hospital, Heidelberg, Germany.;Pediatric Hematology and Oncology, University Children's Hospital, Kiel, Germany.;Pediatric Hematology and Oncology, Department of Pediatrics, University Hospital \"Carl Gustav Carus\", TU Dresden, Dresden, Germany.;Pediatric Hematology and Oncology, University Children's Hospital, Erlangen, Germany.;Pediatric Hematology and Oncology, Department of Pediatrics, University Hospital \"Carl Gustav Carus\", TU Dresden, Dresden, Germany.;Pediatric Hematology and Oncology, University Children's Hospital, Kiel, Germany.;Oncogenetic Laboratory, Pediatric Hematology and Oncology, University Children's Hospital, Giessen, Germany.;Institute of Pathology, Hannover Medical School, Hannover, Germany.;Department of Human Genetics, Hannover Medical School, Hannover, Germany.;Medical Department I, University Hospital \"Carl Gustav Carus\", TU Dresden, Dresden, Germany.",
"authors": "Suttorp|Meinolf|M|;Schulze|Philipp|P|;Glauche|Ingmar|I|http://orcid.org/0000-0002-2524-1199;Göhring|Gudrun|G|;von Neuhoff|Nils|N|;Metzler|Markus|M|;Sedlacek|Petr|P|;de Bont|Eveline S J M|ESJM|;Balduzzi|Adriana|A|;Lausen|Birgitte|B|;Aleinikova|Olga|O|;Sufliarska|Sabina|S|;Henze|Günter|G|;Strauss|Gabriele|G|;Eggert|Angelika|A|;Kremens|Bernhard|B|;Groll|Andreas H|AH|;Berthold|Frank|F|;Klein|Christoph|C|http://orcid.org/0000-0003-0956-0445;Groß-Wieltsch|Ute|U|;Sykora|Karl Walter|KW|;Borkhardt|Arndt|A|http://orcid.org/0000-0002-6121-4737;Kulozik|Andreas E|AE|http://orcid.org/0000-0003-1953-0848;Schrappe|Martin|M|;Nowasz|Christina|C|;Krumbholz|Manuela|M|;Tauer|Josephine T|JT|;Claviez|Alexander|A|;Harbott|Jochen|J|;Kreipe|Hans H|HH|;Schlegelberger|Brigitte|B|;Thiede|Christian|C|",
"chemical_list": "D000970:Antineoplastic Agents; D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate",
"country": "England",
"delete": false,
"doi": "10.1038/s41375-018-0179-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-6924",
"issue": "32(7)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D015415:Biomarkers; D001853:Bone Marrow; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D018450:Disease Progression; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007223:Infant; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D047428:Protein Kinase Inhibitors; D017211:Treatment Failure; D016896:Treatment Outcome",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "1657-1669",
"pmc": null,
"pmid": "29925908",
"pubdate": "2018-07",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Front-line imatinib treatment in children and adolescents with chronic myeloid leukemia: results from a phase III trial.",
"title_normalized": "front line imatinib treatment in children and adolescents with chronic myeloid leukemia results from a phase iii trial"
} | [
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"companynumb": "PHHY2018DE019447",
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"activesubstancename": "IMATINIB"
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"drugadditional": "3",
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{
"abstract": "Macular edema constitutes a serious pathologic entity of ophthalmology resulting in vision loss with a remarkable impact on the quality of life of patients. It is the final common pathway of various systemic diseases and underlying intraocular conditions, with diabetes mellitus being the most frequent cause. Other causes include venous occlusive disease, intraocular surgery, and inflammatory conditions of the posterior segment of the eye. Macular edema is a recognized side effect of various systemic and local medications and requires special consideration among ophthalmologists and other clinicians. Recently, antidiabetic thiazolidinediones have been implicated in the development of macular edema, and a review of the English literature revealed that other systemically administered drugs like fingolimod, recently approved for relapsing forms of multiple sclerosis, the anticancer agents tamoxifen and the taxanes, as well as niacin and interferons have been reported to cause macular edema. Ophthalmologic pharmaceutical agents, like prostaglandin analogs, epinephrine, timolol, and ophthalmic preparation preservatives have also been reported to cause macular edema as an adverse event. The purpose of this article is to provide a short, balanced overview of the available evidence in this regard. The available data and the possible pathophysiologic mechanisms leading to the development of macular edema are discussed. Possible therapeutic strategies for drug-induced macular edema are also proposed.",
"affiliations": "Department of Ophthalmology, Medical School, University of Patras, Rio, 26504 Patras, Greece.",
"authors": "Makri|Olga E|OE|;Georgalas|Ilias|I|;Georgakopoulos|Constantine D|CD|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D000970:Antineoplastic Agents; D000960:Hypolipidemic Agents; D007166:Immunosuppressive Agents; D009883:Ophthalmic Solutions; D011409:Propylene Glycols; D043823:Taxoids; D045162:Thiazolidinediones; D013629:Tamoxifen; D009525:Niacin; D013999:Timolol; D007372:Interferons; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40265-013-0055-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-6667",
"issue": "73(8)",
"journal": "Drugs",
"keywords": null,
"medline_ta": "Drugs",
"mesh_terms": "D000319:Adrenergic beta-Antagonists; D000970:Antineoplastic Agents; D000068876:Fingolimod Hydrochloride; D006801:Humans; D000960:Hypolipidemic Agents; D007166:Immunosuppressive Agents; D007372:Interferons; D008269:Macular Edema; D009525:Niacin; D009883:Ophthalmic Solutions; D011409:Propylene Glycols; D013110:Sphingosine; D013629:Tamoxifen; D043823:Taxoids; D045162:Thiazolidinediones; D013999:Timolol",
"nlm_unique_id": "7600076",
"other_id": null,
"pages": "789-802",
"pmc": null,
"pmid": "23640687",
"pubdate": "2013-06",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "9559735;2902544;17562067;21052512;18541841;21431400;19956779;12543193;18001244;12427111;12759848;14739469;17502517;20735297;15085156;15197075;18945920;20412711;3231439;8628544;10555146;18407718;11566522;18988179;17197556;18385945;16467508;17564928;22969278;15710814;1591689;22371414;10328408;21093714;3039846;10896349;9549261;20656163;23061416;8371915;22688528;19181303;16288118;647693;20195039;18327149;16541311;11860980;20089954;9602634;19038628;3174043;15751259;21708093;14522305;16858440;15126179;15356308;1267317;18644073;12204718;16157815;4743805;22023333;22231867;9154281;23040960;1987876;7148952;7880795;7225310;10958605;16770264;22376166;22688825;15944830;20212201;21149797;22511844;11544274;646688;9596509;20337282;12962163;23269859;18195237;2619152;10485530;9683162;12788145;1163585;20805460;10446691;11915838;11442189;9924387;22311604;9782427;22776935;22430294;11815593;9596510;9624021;14583425;11334422;11448335;12126225;15617942;21880238;20829314;11231772;5646032;16473243;3557860;9479285;9818590;16226541;23056052;12073061;16767207;21819259;22484725;9372723;21076526;17061999;23060727;20089952;17601434;16983587;19183764;17763235;9930158;860942;1735854;18849324;10966617;19321469;19001234;12692483;12696646;12586189;10848227;9780112",
"title": "Drug-induced macular edema.",
"title_normalized": "drug induced macular edema"
} | [
{
"companynumb": "NVSJ2019JP005891",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRAVOPROST"
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"drugadditional": "3",
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{
"abstract": "Background. Parkinson's disease (PD) is mostly characterized by alpha-synuclein (SNCA) aggregation and loss of nigrostriatal dopamine-containing neurons. In this study a novel SNCA multiplication is described in two siblings affected by severe parkinsonism featuring early onset dyskinesia, psychiatric symptoms, and cognitive deterioration. Methods. SNCA dosage was performed using High-Density Comparative Genomic Hybridization Array (CGH-Array), Multiple Ligation Dependent Probe Amplification (MLPA), and Quantitative PCR (qPCR). Genetic analysis was associated with clinical evaluation. Results. Genetic analysis of siblings showed for the first time a 351 Kb triplication containing SNCA gene along with 6 exons of MMRN1 gene in 4q22.1 and a duplication of 1,29 Mb of a genomic region flanking the triplication. Conclusions. The identification of this family indicates a novel mechanism of SNCA gene multiplication, which confirms the genomic instability in this region and provides data on the genotype-phenotype correlation in PD patients.",
"affiliations": "IRCCS Neuromed, Località Camerelle, 86077 Pozzilli, Italy.;IRCCS Neuromed, Località Camerelle, 86077 Pozzilli, Italy.;IRCCS Neuromed, Località Camerelle, 86077 Pozzilli, Italy.;IRCCS Neuromed, Località Camerelle, 86077 Pozzilli, Italy.;IRCCS Neuromed, Località Camerelle, 86077 Pozzilli, Italy ; Molecular Genetics Laboratory UILDM, Santa Lucia Foundation, 00142 Rome, Italy.;Molecular Genetics Laboratory UILDM, Santa Lucia Foundation, 00142 Rome, Italy ; Department of Biomedicine and Prevention, School of Medicine, University of Rome \"Tor Vergata\", 00133 Rome, Italy.;Fondazione Policlinico Tor Vergata, 00133 Rome, Italy.;Fondazione Policlinico Tor Vergata, 00133 Rome, Italy.;IRCCS Neuromed, Località Camerelle, 86077 Pozzilli, Italy ; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy.;IRCCS Neuromed, Località Camerelle, 86077 Pozzilli, Italy ; Department of Biomedicine and Prevention, School of Medicine, University of Rome \"Tor Vergata\", 00133 Rome, Italy.;IRCCS Neuromed, Località Camerelle, 86077 Pozzilli, Italy.;IRCCS Neuromed, Località Camerelle, 86077 Pozzilli, Italy.;IRCCS Neuromed, Località Camerelle, 86077 Pozzilli, Italy.",
"authors": "Ferese|Rosangela|R|;Modugno|Nicola|N|;Campopiano|Rosa|R|;Santilli|Marco|M|;Zampatti|Stefania|S|;Giardina|Emiliano|E|;Nardone|Annamaria|A|;Postorivo|Diana|D|;Fornai|Francesco|F|;Novelli|Giuseppe|G|;Romoli|Edoardo|E|;Ruggieri|Stefano|S|;Gambardella|Stefano|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2015/546462",
"fulltext": "\n==== Front\nParkinsons DisParkinsons DisPDParkinson's Disease2090-80832042-0080Hindawi Publishing Corporation 10.1155/2015/546462Research ArticleFour Copies of SNCA Responsible for Autosomal Dominant Parkinson's Disease in Two Italian Siblings Ferese Rosangela \n1\n\n*\nModugno Nicola \n1\nCampopiano Rosa \n1\nSantilli Marco \n1\nZampatti Stefania \n1\n\n2\nGiardina Emiliano \n2\n\n3\nNardone Annamaria \n4\nPostorivo Diana \n4\nFornai Francesco \n1\n\n5\nNovelli Giuseppe \n1\n\n3\nRomoli Edoardo \n1\nRuggieri Stefano \n1\nGambardella Stefano \n1\n1IRCCS Neuromed, Località Camerelle, 86077 Pozzilli, Italy2Molecular Genetics Laboratory UILDM, Santa Lucia Foundation, 00142 Rome, Italy3Department of Biomedicine and Prevention, School of Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy4Fondazione Policlinico Tor Vergata, 00133 Rome, Italy5Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy*Rosangela Ferese: ferese.rosangela@gmail.comAcademic Editor: Hélio Teive\n\n2015 9 11 2015 2015 54646215 6 2015 7 10 2015 8 10 2015 Copyright © 2015 Rosangela Ferese et al.2015This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground. Parkinson's disease (PD) is mostly characterized by alpha-synuclein (SNCA) aggregation and loss of nigrostriatal dopamine-containing neurons. In this study a novel SNCA multiplication is described in two siblings affected by severe parkinsonism featuring early onset dyskinesia, psychiatric symptoms, and cognitive deterioration. Methods. SNCA dosage was performed using High-Density Comparative Genomic Hybridization Array (CGH-Array), Multiple Ligation Dependent Probe Amplification (MLPA), and Quantitative PCR (qPCR). Genetic analysis was associated with clinical evaluation. Results. Genetic analysis of siblings showed for the first time a 351 Kb triplication containing SNCA gene along with 6 exons of MMRN1 gene in 4q22.1 and a duplication of 1,29 Mb of a genomic region flanking the triplication. Conclusions. The identification of this family indicates a novel mechanism of SNCA gene multiplication, which confirms the genomic instability in this region and provides data on the genotype-phenotype correlation in PD patients.\n==== Body\n1. Introduction\nParkinson's disease (PD) is caused by neuronal loss in various monoamine-containing nuclei [1], which typically involve dopamine neurons of the substantia nigra (SN). The analysis of inherited PD allowed identifying a growing number of loci and genes which associate with quite distinct clinical features. Among various genetic abnormalities, a point mutation of SNCA (synuclein, alpha [non-A4 component of amyloid precursor]), the gene coding for alpha-synuclein, was the first to be identified in 1997 in the so-called “Contursi family,” carrying an autosomic dominant inherited PD associated with an altered primary structure of alpha-synuclein [2].\n\nWhole SNCA multiplications (duplications or triplications) were described later on [3, 4] as responsible for autosomic dominant inherited PD. These patients express extra copies of SNCA leading to overexpression of the alpha-synuclein protein owing normal primary structure. Remarkably, SNCA is the only gene which produces PD even when it is expressed in a normal structure but in multiple copies, which relates directly to disease onset and severity [5–12].\n\nIn fact, increasing SNCA copies associates with earlier onset, motor and cognitive dysfunction, psychiatric disturbances, and L-Dopa-induced symptoms [13, 14]. The clinical phenotypes deriving from SNCA multiplication often shift towards dementia with Lewy Bodies (DLB) or Frontotemporal Dementia (FTD). In keeping with a dosing effect, while SNCA triplication always possesses full penetrance, this may not occur following SNCA duplication [15].\n\nPatients with four SNCA copies (either following duplication of both alleles or due to a single allele triplication associated with a normal allele) suffer from earlier disease onset and faster progression compared with patients carrying three SNCA copies [8, 9, 11, 16, 17].\n\nIn the process of establishing specific clinical phenotypes induced by various SNCA genotypes in PD, we describe here the effects induced by a novel mutation of SNCA which consists of a 351 Kb triplication containing the SNCA gene along with 6 exons of MMRN1 gene in 4q22.1 and a duplication of 1,29 Mb of the genomic region flanking the SNCA + MMRN1 triplication.\n\n2. Patients and Methods\n2.1. Patients\nThe familial pedigree of the family from central Italy shows autosomal dominant pattern of inheritance for PD (Figure 1). The siblings (III;3), a 39-year-old man and his sister (III;2) a 45-year-old woman, are affected by PD. The mother (II;2) and the maternal grandmother (I;2) were affected by PD and died at 43 and 45 years of age, respectively. The patient I;3 was reported to be affected by PD with unknown age at onset. The subjects II;3 and II;4 were unaffected dizygotic twins: II;3 died at birth for delivery complications and II;4 died at old age for cerebral neoplasia. No evidence of PD was reported in the paternal pedigree of patients. For each patient an informed written consent was obtained. This study has been approved by ethical committee.\n\n2.2. Genetic Analysis\n2.2.1. Multiple Ligation Dependent Probe Amplification (MLPA)\nThe commercially available kit P051-P052 (MRC-Holland, Amsterdam, Netherlands) was used for the multiplex dosage of exons for the following genes: TNFRSF9 (1 probe in P051), DJ1 (4 probes in P051), ATP13A2 (2 probes in P051, 2 probes in P052), SNCA (5 probes in P051, 1 probe in P052), LPA (1 probe in P051), PARKIN (12 probes in P051, 12 in P052), LRRK2 (8 probes in P052), PINK1 (8 probes in P051), GCH1 (5 probes in P052), PACRG (1 probe in P052), CAV1/2 (2 probes in P052), and UCHIL1 (4 probes in P052). The MLPA was performed on DNA from patients III;3 and III;2, and four normal subjects were used as internal controls.\n\n2.2.2. High-Density Comparative Genomic Hybridization Array (CGH-Array)\nHigh-Density Comparative Genomic Hybridization Array (CGH-Array) was carried out using a high resolution whole genome oligo-array (Cytochip Oligo 180 K, BlueGnome, Cambridge, UK).\n\nA sex-matched DNA (Promega, Madison, UK) was used as reference. Digestion, labeling, and hybridization were performed following the manufacturer's protocol (http://www.cytochip.com). Slides were scanned using an Agilent Scanner, with a 5 µm resolution. Data were analyzed using Blue Fuse Multi software (BlueGnome, Cambridge, UK).\n\n2.2.3. Quantitative PCR (qPCR)\nqPCR was performed in a CFX ConnectTM Real Time System (Bio-Rad Life Science, CA) using SYBR Green PCR Master (Applied Biosystems, Foster City, CA). Genes included in the triplication (SNCA, MMRN1), in the duplication (TIGD2), and in wild-type (CCSER1, GRID2, and PTPN13) locus were analyzed. The relative copy number was calculated through a ΔΔCT method, using β-Globin as an internal reference. qPCR was performed in triplicate for each sample. The reagents used for amplification in 15 μL reactions were 10 μL SYBR Green PCR Master (Applied Biosystems, Foster City, CA), 0.5 μM of each primer, and 5 ng of genomic DNA. The PCR conditions were 95°C for 10 min, 95°C for 30 s, and 58°C for 1 m (40 cycles).\n\n3. Results\n3.1. Patient III;3\n\nPatients III;3 came to our attention in 2011 with a hypokinetic-rigid syndrome prominent on the left side. The Unified Parkinson's Disease Rating Scale (UPDRS) III score was 35 in “off” and 14 in “on,” Hoehn and Yahr scale was 3, and motor fluctuations and some slight axial dyskinesia appeared. III;3 also presented moderate camptocormia, kinetic ataxia, and moderate dysarthria that were more evident in “off” state. During anamnesis patient reported the diagnosis of PD back in 2003 (at 28 years of age) and he reported a rapid motor deterioration; he also complained of depressed mood and altered sleep time. When we evaluated the patient (2011), he was under treatment with a dopamine agonist (rotigotine) and L-Dopa (400 mg/day).\n\nDue to the presence of symptoms reported above, therapy was changed by fractioning the daily L-Dopa administration by using L-Dopa/carbidopa/entacapone 50/12.5/200 mg 5 times per day; we maintained rotigotine (6 mg per day) and added rasagiline (1 mg per day). A few months later he developed visual hallucinations, delusion of jealousy, and aggressive behaviors. Therefore, we withdrew the dopamine agonist rotigotine and we modified L-Dopa administration switching from L-Dopa/carbidopa/entacapone 50/12.5/200 mg 5 times per day to L-Dopa/carbidopa 100/25 4 times per day therapy. We kept rasagiline (1 mg per day) while adding clozapine (50 mg/day) to treat psychiatric symptoms which indeed disappeared in few weeks.\n\nIn the years 2012-2013, there was a progression of UPDRS III score which increased (UPDRS III 42 in “off” and 23 in “on state”). At this point, camptocormia and standing and walking difficulties were evident with mild trunk bending (Pisa syndrome). Also nonmotor symptoms worsened; cognitive impairment was evident and became very severe: Mini-Mental State Examination (MMSE) score was 14/30 in 2012 whereas in 2014 the scale was not applicable anymore because the patient was unable to understand the questions and he was unable to speak fluently. Cognitive deficits at this time were severe in all domains and patients lost his autonomy in daily life. At this time we could document REM sleep disorder, dysphagia, and urinary incontinence. In a few months all motor and nonmotor symptoms further deteriorated; thus, standing and walking were impossible and dysarthria, cognitive decline, and incontinence were very severe and led soon after to the loss of autonomy in each daily activity. In the evaluation of July 2015, Hoehn and Yahr score was 4 and UPDRS was >60 in “off” and 42 in “on” state. Therapy was not modified consisting mainly in L-Dopa and clozapine. Patient is on a wheelchair or in bed. Dysphagia is severe and nasogastric tube is necessary for hydration.\n\nPET with fludeoxyglucose (FDG) shows frontotemporal and parietal degeneration. In 2011 magnetic resonance imaging (MRI) showed slight frontotemporal atrophia with some subcortical gliotic spots. In 2015 the MRI showed severe cortical and subcortical atrophia in temporoinsular and frontal regions bilaterally. Thus, brain atrophy at MRI worsened within frontal regions and mostly within temporal regions, bilaterally.\n\n3.2. Patient III;2\nPatient III;2, sister of III;3, was referred to us in 2012 at the age of 43 years reporting a diagnosis of PD dating back to 2011 year. She suffered from a mild hypokinetic-rigid syndrome on the right side. Hoehn and Yahr score was 2 and UPDRS III was 16 in “off” and 7 in “on” with a significant response to L-Dopa. Motor symptoms deteriorated but response to L-Dopa was still present. The PD score in 2015 was as follows: UPDRS III 30 in “off” and 15 in “on” and Hoehn and Yahr scale 3. She did not have cognitive decline (MMSE was 28/30 in 2011-2012), although in 2014 she worsened (MMSE 24/30). At this time cognitive functions were impaired for attention and visuospatial memory, and she also developed slight motor apraxia. She reported REM sleep behavior disorders and depressive episodes, but she refused a psychiatric evaluation. She is under therapy with L-Dopa/Carbidopa 100/25 four times per day.\n\nMRI carried out in 2012 shows mild pontocerebellar degeneration and slight millimetric gliotic spots. SPECT DatSCAN shows bilaterally reduced binding in the putamen, more pronounced on the left side.\n\n3.3. Genetic Analysis\nMLPA analysis revealed the presence of four copies of SNCA in both III;2 and III;3 (Figure 2(a)). To characterize the size of multiplicated genomic segment, we performed CGH-Array that revealed, in both III;2 and III;3, three copies of the region at 4q22.1 ranging from 90,013,153 Mb to 91,310,633 Mb (build36, hg18, involved genes are TIGD2 (MIM∗612973), GPRIN3 (MIM∗611241), SNCA (MIM∗163890), MMRN1 (Multimerin 1, MIM∗601456), and the first three exons of CCSER1 (FAM190A)) and four copies of the region ranging from 90,500,031 Mb to 90,851,296 Mb containing SNCA gene and 6 exons of MMRN1 (Figure 2(b)).\n\nTo confirm the right dosage detected with CGH-Array, we performed qPCR analysis of the 3 genes involved in the multiplicated region (SNCA, TIGD2, and CCSER1) and 2 control genes located in 4q22 not involved in the multiplication (GRID2 (human glutamate receptor delta 2) and PTPN13 (protein tyrosine phosphatase, nonreceptor type 13)). We detected the presence of four copies of SNCA, three copies of TIGD2, and two copies of CCSER1 (probe on exon 11 outside of duplication), GRID2, and PTPN13, confirming the results obtained by CGH-Array.\n\nPatients' mother (II;2) and maternal grandmother (I;2) were both affected by PD and died at ages 43 and 45, respectively, and no history of PD was recorded in the paternal ancestors. Thus, assuming the absence of inherited parkinsonism-related mutations in the paternal ancestors, the present data indicate in-cis mechanism for this mutation, with a 351 Kb triplication of locus containing SNCA and 6 exons of MMRN1 gene and a duplication of 1,29 Mb of a genomic region flanking the triplication, involving TIGD2, GPRIN3, SNCA, and MMRN1 and from exon 1 to exon 3 of CCSER1 (Figure 3).\n\n4. Discussion\nIn this study, we briefly report for the first time a multiplication of SNCA characterized by four copies of SNCA three of which derive from a triplicated region of 351 Kb containing SNCA, described with a duplication of 1,29 Mb of a genomic region flanking the triplication. Quantitative analysis performed in this paper could not provide useful information about the genome location of the triplication and duplication identified in this family.\n\nTo date, only 7 families have been reported bearing four copies of SNCA. Among these, 6 families have a triplication, and a family has a homozygote duplication of SNCA locus [4, 17–23].\n\nThe multiplication detected in our family consists of a triplication of 351 Kb, thus shorter than the triplications previously described in the Iowa family (1,6–2,1 Mb), Lister Branch I (0,9 Mb) from USA, and FPD-014 from France (2,64 Mb) [4, 17, 18]. The size of the triplication is not exactly specified in the paper by Keyser and in the Asian family reported by Sekine, the range of triplication includes whole exons of SNCA and MMRN1 and exon 1 of KIAA1680 probably (90,645,250–90,759,447) [19, 21]. Different duplication size has been reported so far, ranging from 400 Kb in family A from Japan up to more than 4 Mb in family FPD-131 from France [8–10, 17, 24–26].\n\nThe specificity of the genetic pedigree we describe here consists in a SNCA triplication which also includes the six exons of Multimerin 1 (MMRN1). MMRN1 encodes for a specific Factor V/Va binding protein found in platelets and endothelium [23]. MMRN1 deficiency is associated with Factor V Quebec, an inherited bleeding disorder, although the consequences of its overexpression remain unknown. MMRN1 is not expressed in brain; thus, wild-type overexpression of alpha-synuclein appears responsible for the predominant, neurological phenotype. So far, functional studies of brain tissue from PD patients with SNCA multiplications indicate that disease conditions depend directly on the number of copies of SNCA, while the concomitant multiplication of genes contiguous to SNCA does not play any effect [18]. However, there is lack of specific investigation on the potential role of MMRN1 which is now under analysis in our institute.\n\nThe SNCA multiplication described here for the first time is associated with severe PD symptoms in siblings and maternal ancestors.\n\nAccording to previous reports on SNCA multiplications, clinical phenotype of III;2 and III;3 consists of severe parkinsonism. This confirms the genotype-phenotype correlations for SNCA reported so far [5–12]. In particular, these siblings are characterized by early onset, rapid progression up to motor deterioration, cognitive and psychiatric symptoms, and sleep disturbances. Imaging confirmed the occurrence of brain alterations involving multiple areas beyond basal ganglia and mostly involving frontoparietal regions, thus strengthening the complex clinical phenotypes of these patients.\n\n5. Conclusion\nWe briefly report severe parkinsonism associated with a novel multiplication in the SNCA gene which confirms a deleterious correlation between expression of SNCA gene and disease severity. This is likely to depend on SNCA-induced dose-dependent toxicity. The uniqueness of SNCA multiplication consists in the onset of parkinsonism associated with a normally structured protein expressed in abnormal amount. This opens new avenues both to genetic and to environmental factors and to how they interact in PD. In fact, in the process of redefining PD [27], cell to cell disease spreading of alpha-synuclein is likely to drive the amount of affected brain regions which in turn relates to the number of nonmotor symptoms [28, 29]. In keeping with this, the spreading of alpha-synuclein appears as a key pathogenic mechanism in sporadic PD. Thus, a special emphasis should be devoted to those environmental agents which may regulate a variety of multiplications of SNCA.\n\nAcknowledgments\nThe authors wish to thank the patients enrolled in this research. Thanks are due to Dr. Francesco Fabiano for cooperation in reading MNR.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests.\n\nFigure 1 Pedigree of the family of siblings with Parkinson's disease (PD). Black boxes represent affected patients.\n\nFigure 2 \nSNCA dosage using CGH-Array and MLPA. (a) MLPA analysis. In these images, normalized peak areas relative to probes considered in MLPA kit P051 (I and III, resp., III;2 and III;3) and P052 (II and IV, resp., III;2 and III;3) are shown. (I and III) The probes related to TNFRSF9 (one probe), PARK7 (twelve probes), and ATP13A2 (two probes) genes are shown in light blue, SNCA (five probes) and two mutation specific probes for p.A30P in SNCA and p.G2019S in LRRK2 genes in brown, LPA (one probe) and PARK2 (twelve probes) genes in dark blue, and the reference probes (eight) in gray. (II and IV) The probes related to genes ATP13A2 (two probes) and UCHL1 (four probes) are shown in light blue, PARK2 (twelve probes), PACRG (one probe), LRRK2 (eight probes), and one mutation specific probe for p.G2019S in LRRK2 in dark blue, SNCA (one probe), CAV1 (one probe), CAV2 (one probe), and GCH1 (five probes) in brown, and the reference probes (nine) in gray. In both patients, an increased ratio in the peak area related to SNCA probes indicates a multiplication at 4q21 chromosomal region. In particular, ratio of SNCA probes in III;2 (SNCA ex2 ratio 1.86, SNCA ex4 ratio 1.81, SNCA ex5 ratio 2.12, SNCA ex6 ratio 1.89, SNCA ex7 ratio 2.08, and SNCA ex3 ratio 1.92) and III;3 (SNCA ex2 ratio 1.92, SNCA ex4 ratio 1.83, SNCA ex5 ratio 1.91, SNCA ex6 ratio 1.95, SNCA ex7 ratio 2.01, and SNCA ex3 ratio 2) suggests the presence of four copies of SNCA locus. (b) Array-CGH profile of chromosome 4 showing a duplication/triplication at 4q21 from 90.013 Mb to 91.26 Mb. Enlargements indicate the duplicated region, and green arrows show the triplicated region. For each analysis, Y-axis marks the distance along chromosome 4, and X-axis marks the hybridization ratio plotted on a log2 scale. Red lines indicate thresholds for clone deletion and green lines for duplication.\n\nFigure 3 Schematic representation of the multiplication described on chromosome 4, consisting of a 351 Kb triplication of a locus containing SNCA and 6 exons of MMRN1 gene (90.500.031 Mb to 90.851.296 Mb) and a duplication of 1,29 Mb of a genomic region flanking the triplication, involving TIGD2, GPRIN3, SNCA, and MMRN1 and from exon 1 to exon 3 of CCSER1 (90.013.153 Mb to 91.310.633 Mb). Scale is expressed in Megabases (Mb).\n==== Refs\n1 Berg D. Postuma R. B. Bloem B. Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson's disease Movement Disorders 2014 29 4 454 462 10.1002/mds.25844 2-s2.0-84898057951 24619848 \n2 Polymeropoulos M. H. Lavedan C. Leroy E. Mutation in the α -synuclein gene identified in families with Parkinson's disease Science 1997 276 5321 2045 2047 10.1126/science.276.5321.2045 2-s2.0-0030744876 9197268 \n3 Kasten M. Klein C. The many faces of alpha-synuclein mutations Movement Disorders 2013 28 6 697 701 10.1002/mds.25499 2-s2.0-84879601960 23674458 \n4 Singleton A. B. Farrer M. Johnson J. \nα -synuclein locus triplication causes Parkinson's disease Science 2003 302 5646 p. 841 10.1126/science.1090278 2-s2.0-0242300619 \n5 Moura K. C. V. Junior M. C. de Rosso A. L. Z. Exon dosage variations in Brazilian patients with Parkinson's disease: analysis of SNCA, PARKIN, PINK1 and DJ-1 genes Disease Markers 2012 32 3 173 178 10.3233/dma-2011-0873 2-s2.0-84858265245 22377733 \n6 Pihlstrøm L. Toft M. Genetic variability in SNCA and Parkinson's disease Neurogenetics 2011 12 4 283 293 10.1007/s10048-011-0292-7 2-s2.0-84855262350 21800132 \n7 Eriksen J. L. Przedborski S. Petrucelli L. Gene dosage and pathogenesis of Parkinson's disease Trends in Molecular Medicine 2005 11 3 91 96 10.1016/j.molmed.2005.01.001 2-s2.0-14844331731 15760766 \n8 Ibáñez P. Bonnet A.-M. Débarges B. Causal relation between α -synuclein gene duplication and familial Parkinson's disease The Lancet 2004 364 9440 1169 1171 10.1016/s0140-6736(04)17104-3 2-s2.0-4644236043 \n9 Nishioka K. Hayashi S. Farrer M. J. Clinical heterogeneity of α -synuclein gene duplication in Parkinson's disease Annals of Neurology 2006 59 2 298 309 10.1002/ana.20753 2-s2.0-32044453611 16358335 \n10 Chartier-Harlin M.-C. Kachergus J. Roumier C. \nα -synuclein locus duplication as a cause of familial Parkinson's disease The Lancet 2004 364 9440 1167 1169 10.1016/s0140-6736(04)17103-1 2-s2.0-4644290985 \n11 Uchiyama T. Ikeuchi T. Ouchi Y. Prominent psychiatric symptoms and glucose hypometabolism in a family with a snca duplication Neurology 2008 71 16 1289 1291 10.1212/01.wnl.0000327607.28928.e6 2-s2.0-54449084519 18852445 \n12 Obi T. Nishioka K. Ross O. A. Clinicopathologic study of a SNCA gene duplication patient with parkinson disease and dementia Neurology 2008 70 3 238 241 10.1212/01.wnl.0000299387.59159.db 2-s2.0-38149131788 18195271 \n13 Kara E. Kiely A. P. Proukakis C. A 6.4 Mb duplication of the α -synuclein locus causing frontotemporal dementia and Parkinsonism: phenotype-genotype correlations JAMA Neurology 2014 71 9 1162 1171 10.1001/jamaneurol.2014.994 25003242 \n14 Ikeuchi T. Kakita A. Shiga A. Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia Archives of Neurology 2008 65 4 514 519 10.1001/archneur.65.4.514 2-s2.0-42249115274 18413475 \n15 Itokawa K. Sekine T. Funayama M. A case of α -synuclein gene duplication presenting with head-shaking movements Movement Disorders 2013 28 3 384 387 10.1002/mds.25243 2-s2.0-84875520893 23124679 \n16 Elia A. E. Petrucci S. Fasano A. Alpha-synuclein gene duplication: marked intrafamilial variability in two novel pedigrees Movement Disorders 2013 28 6 813 817 10.1002/mds.25518 2-s2.0-84879605074 23744550 \n17 Fuchs J. Nilsson C. Kachergus J. Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication Neurology 2007 68 12 916 922 10.1212/01.wnl.0000254458.17630.c5 2-s2.0-34147109175 17251522 \n18 Farrer M. Kachergus J. Forno L. Comparison of kindreds with Parkinsonism and α -synuclein genomic multiplications Annals of Neurology 2004 55 2 174 179 10.1002/ana.10846 2-s2.0-10744227740 14755720 \n19 Keyser R. J. Lombard D. Veikondis R. Carr J. Bardien S. Analysis of exon dosage using MLPA in South African Parkinson's disease patients Neurogenetics 2010 11 3 305 312 10.1007/s10048-009-0229-6 2-s2.0-77954660828 20013014 \n20 Ibáñez P. Lesage S. Janin S. \nα -Synuclein gene rearrangements in dominantly inherited parkinsonism Archives of Neurology 2009 66 1 102 108 10.1001/archneurol.2008.555 19139307 \n21 Sekine T. Kagaya H. Funayama M. Clinical course of the first Asian family with Parkinsonism related to SNCA triplication Movement Disorders 2010 25 16 2871 2875 10.1002/mds.23313 2-s2.0-78650221326 20818659 \n22 Kojovic M. Sheerin U.-M. Rubio-Agusti I. Young-onset parkinsonism due to homozygous duplication of α -synuclein in a consanguineous family Movement Disorders 2012 27 14 1829 1830 10.1002/mds.25199 2-s2.0-84871789737 23208740 \n23 Hayward C. P. M. Multimerin: a bench-to-bedside chronology of a unique platelet and endothelial cell protein from discovery to function to abnormalities in disease Clinical & Investigative Medicine 1997 20 3 176 187 2-s2.0-0030943979 9189649 \n24 Sironi F. Trotta L. Antonini A. \nα -Synuclein multiplication analysis in Italian familial Parkinson disease Parkinsonism and Related Disorders 2010 16 3 228 231 10.1016/j.parkreldis.2009.09.008 2-s2.0-77149152150 19833540 \n25 Mutez E. Leprêtre F. Le Rhun E. SNCA locus duplication carriers: from genetics to Parkinson disease phenotypes Human Mutation 2011 32 4 2079 2090 10.1002/humu.21459 2-s2.0-79952775732 \n26 Nishioka K. Ross O. A. Ishii K. Expanding the clinical phenotype of SNCA duplication carriers Movement Disorders 2009 24 12 1811 1819 10.1002/mds.22682 2-s2.0-70449841367 19562770 \n27 Fornai F. Ruggieri S. Re-defining Parkinson's disease Archives Italiennes de Biologie 2013 151 4 137 142 2-s2.0-84901350725 24873922 \n28 Braak H. Rüb U. Gai W. P. Del Tredici K. Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen Journal of Neural Transmission 2003 110 5 517 536 10.1007/s00702-002-0808-2 2-s2.0-0038748401 12721813 \n29 George S. Rey N. L. Reichenbach N. Steiner J. A. Brundin P. \nα -Synuclein: the long distance runner Brain Pathology 2013 23 3 350 357 10.1111/bpa.12046 2-s2.0-84876240395 23587141\n\n",
"fulltext_license": "CC BY",
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"issue": "2015()",
"journal": "Parkinson's disease",
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"medline_ta": "Parkinsons Dis",
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"title": "Four Copies of SNCA Responsible for Autosomal Dominant Parkinson's Disease in Two Italian Siblings.",
"title_normalized": "four copies of snca responsible for autosomal dominant parkinson s disease in two italian siblings"
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"abstract": "Haemophagocytic lymphohistiocytosis (HLH) in Human Immunodeficiency Virus (HIV) infected individuals can either be due to the disease itself or due to associated infections/malignancies. The treatment for HLH requires immunosuppressive therapy but administering immunosuppressive therapy to an already immunosuppressed patient (HIV infection) is complex. We present two such cases of HLH in patients infected with HIV. In the first case, no alternate cause for HLH was found even after extensive investigations and it was attributed to the uncontrolled HIV replication. Patient was started on dexamethasone for the same but succumbed to hospital acquired pneumonia. The second patient was diagnosed with Hodgkin's lymphoma but he succumbed to his illness before initiating immunosuppressive therapy for HLH. We report these cases to highlight the dilemma and a need for further research in this direction.",
"affiliations": "Department of Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Medicine, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Fazal|Farhan|F|;Gupta|Nitin|N|;Ramu|Shivabalan Kathavarayan|SK|;Nayan|Aditya|A|;Vikram|Naval Kishore|NK|;Ray|Animesh|A|",
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"doi": "10.11604/pamj.2019.32.105.14764",
"fulltext": "\n==== Front\nPan Afr Med JPan Afr Med JPAMJThe Pan African Medical Journal1937-8688The African Field Epidemiology Network PAMJ-32-10510.11604/pamj.2019.32.105.14764Case ReportHaemophagocytic lymphohistiocytosis in patients with human immunodeficiency virus infection: to treat or not to treat Fazal Farhan 1Gupta Nitin 1Ramu Shivabalan Kathavarayan 1Nayan Aditya 1Vikram Naval Kishore 1Ray Animesh 1&1 Department of Medicine, All India Institute of Medical Sciences, New Delhi, India& Corresponding author: Animesh Ray, Department of Medicine, All India Institute of Medical Sciences, New Delhi, India06 3 2019 2019 32 10504 1 2018 28 12 2018 © Farhan Fazal et al.2019The Pan African Medical Journal - ISSN 1937-8688. This is an Open Access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Haemophagocytic lymphohistiocytosis (HLH) in Human Immunodeficiency Virus (HIV) infected individuals can either be due to the disease itself or due to associated infections/malignancies. The treatment for HLH requires immunosuppressive therapy but administering immunosuppressive therapy to an already immunosuppressed patient (HIV infection) is complex. We present two such cases of HLH in patients infected with HIV. In the first case, no alternate cause for HLH was found even after extensive investigations and it was attributed to the uncontrolled HIV replication. Patient was started on dexamethasone for the same but succumbed to hospital acquired pneumonia. The second patient was diagnosed with Hodgkin's lymphoma but he succumbed to his illness before initiating immunosuppressive therapy for HLH. We report these cases to highlight the dilemma and a need for further research in this direction.\n\nMalignancysteroidshospital acquired pneumonia\n==== Body\nIntroduction\nHaemophagocytic lymphohistiocytosis (HLH) is an aggressive syndrome of excessive immune activation. It is diagnosed using the HLH- 2004 protocol which requires fulfilling five out of eight criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or low fibrinogen, hyperferritinemia, increased soluble CD25 levels, decreased Natural killer (NK) cell activity and histopathological evidence of hemophagocytosis [1]. Out of these, NK cell activity and serum CD25 levels are not widely available, making the diagnosis of HLH often difficult. This problem becomes more complex in patients with Human Immunodeficiency Virus (HIV) infection as features such as fever, bicytopenia and splenomegaly are already common in these patients with or without presence of opportunistic infections. Once diagnosed, the treatment of such a patient is even more challenging. The biggest hurdle is the use of immunosuppression for the treatment of HLH in an already immunocompromised person. A balance has to be struck between controlling inflammation with immunosuppressive drugs and limiting the risk of life threatening opportunistic infections. We present two cases of HIV with HLH to explain our dilemma.\n\nPatient and observation\nCase 1: a 38-year old female patient, diagnosed with HIV infection in 2008, presented with complaints of intermittent high grade fever associated with chills and rigor for one month to a local hospital. This was associated with loss of appetite and generalized weakness. She was transfused two units of packed RBC. She was receiving an antiretroviral regimen consisting of tenofovir, lamivudine and efavirenz. Her CD4 count was 85/μl and the viral load was 56, 670 copies/μl. With a diagnosis of virological failure, she was shifted to an atazanavir/ritonavir based regimen. She was referred to us with persistent fever. On examination, she was febrile with a pulse rate of 120/min and a respiratory rate of 25/min. She had icterus and her jugular venous pressure was elevated. Chest examination revealed decreased bilateral breath sounds and bi-basal crepitations. On abdominal examination hepatosplenomegaly was present. The baseline laboratory evaluation revealed pancytopenia and hyperbilirubinemia (Hemoglobin- 5.9 gm/dl, total leucocyte count- 1500/cu.mm, platelet count- 18,000/cu.mm and bilirubin- 3.3gm/dl). Peripheral smear showed dimorphic hypochromic anemia with a corrected reticulocyte count of 1%. Vitamin B12 and folic acid levels were normal. Lactate dehydrogenase (LDH) levels were elevated (1154 U/l). Blood culture was sterile for bacteria, fungi and non-tubercular mycobacteria. Contrast enhanced computed tomography (CECT) scan of chest and abdomen revealed hepatosplenomegaly (liver-16.8 cm, spleen-13.4cm) and multiple enlarged non-necrotic lymph nodes in mesentery, para-aortic and inguinal region. A whole body Fluorodeoxy glucose positron emission tomography (FDGPET) scan revealed hypermetabolic bilateral supraclavicular, internal mammary lymph nodes and abdominal lymph nodes. There was avid uptake in liver, spleen and bone marrow also. The biopsy from supraclavicular lymph node showed reactive hyperplasia. Staining for acid fast bacilli, GeneXpert and Mycobacterial growth indicator tube (MGIT) culture for Mycobacterium tuberculosis were negative. A bone marrow biopsy was done which showed 60-70% cellularity. It was negative for geneXpert and Cytomegalovirus (CMV) polymerase chain reaction (PCR) assay. Also, pp65 antigen detection test in blood for CMV and rk39-antibody test for visceral leishmaniasis was negative. With a presumptive diagnosis of tuberculosis, modified anti-tubercular therapy (ATT) (levofloxacin, ethambutol and amikacin) was started as the patient had elevated bilirubin level. There was no response even after one month of ATT. Introduction of rifampicin and isoniazid was attempted but the bilirubin levels rose to 9.5g/dl. Clarithromycin was empirically added to cover for Mycobacterium avium complex (MAC) infection. On further investigations, she was found to have a triglyceride levels of 435 mg/dl, fibrinogen levels of 500 mg/dl, ferritin levels of >2000 ng/ml and decreased NK cell activity. With a diagnosis of Haemophagocytic lymphohistiocytosis (HLH), dexamethasone at a dose of 16 mg per day was started. The fever and pancytopenia improved in a week's time (Hemoglobin- 7.4gm/dl, total leucocyte count- 5300/cu.mm, platelet count- 50,000/cu.mm). The patient was doing well but she started getting dyspneic fifteen days after the initiation of steroids. Chest X-ray revealed consolidation in the right middle lobe. With a diagnosis of hospital acquired pneumonia, she was started on cefoperazone sulbactam, but she succumbed to her illness after two days.\n\nCase 2: a 46-year old male patient on tenofovir, lamivudine and efavirenz, presented with intermittent low grade fever for the last four months. This was associated with night sweats, loss of appetite and loss of weight of around five kilograms. He also complained of decrease in urine output and generalized swelling of the body. On general examination, he was febrile and was found to have enlarged right axillary lymph node (1cm x 1cm). On systemic examination, he had ascites and a palpable spleen (8 cm below the left costal margin). Fundus examination was normal. On laboratory investigations, he was found to have pancytopenia, deranged liver function and kidney function tests (Hemoglobin- 7.4g/dl, total leucocyte count-1200/mcl, platelet count-20000/mcl, aspartate transaminase/alanine transaminase-209/117 U/l and urea/creatinine- 78/1.7 mg/dl). His baseline CD4 was 221/μl and the most recent CD4 was 158/μl. Non contrast computed tomography of abdomen revealed multiple enlarged retroperitoneal lymph nodes with the largest measuring 47 x 22 mm. Lymph node biopsy could not be performed due to deranged coagulation parameters. Blood and urine cultures were sterile. Peripheral smear showed normocytic normochromic anemia. Vitamin B12 levels were normal but the folate levels were low (2.2ng/ml). Serum LDH levels were elevated (834 IU/l). Immunochromatography for rk39 antibody was negative. Ascitic fluid analysis revealed a protein of 1.9 g/dl, albumin of 0.9 g/dl, total leucocyte counts of 380/mcl (Lymphocytes 90%, Neutrophils 10%), serum-ascitic albumin gradient of 1.1g/dl and adenosine deaminase levels of 40 IU/l. Ascitic fluid cultures were sterile. With a presumptive diagnosis of disseminated tuberculosis, he was started on ATT. His ferritin levels were elevated (>2000 ng/ml) and triglyceride levels were also high (324 mg/dl). A presumptive diagnosis of HLH was made. A lymph node biopsy was performed after correction of coagulation abnormalities to identify the primary pathology. However, he succumbed to his illness before the results of biopsy were available. The biopsy was suggestive of Hodgkin's lymphoma.\n\nDiscussion\nAlthough, there are studies where hemophagocytosis has been shown in patients with HIV, reports of HIV with HLH meeting the 2004 criteria are rare [2]. These reports are even more scarce from the Indian subcontinent. A study by Kotwal et al. showed hemophagocytic picture in eight patients with HIV and haematological abnormalities but only two patients fulfilled the HLH diagnostic criteria [3]. Isolated case reports of HIV patients with leishmaniasis or histoplasmosis who developed HLH has been reported [4, 5]. HLH in HIV patient can either be due to the disease itself or because of the opportunistic infections or malignancy associated with HIV [6, 7]. In the first patient, we extensively looked for an opportunistic infection that could have caused the secondary HLH but did not find any. The first patient was treated with steroids and she did show improvement initially. But in the process of treatment, with further immunosuppression, she became prone to the hospital acquired infections and succumbed to pneumonia. The likely triggering factor in the first patient was uncontrolled HIV replication itself as she was failing on the regimen she was receiving. In a report by Kyung et al., HLH in a patient with acute HIV could not be attributed to any infection/malignancy except for HIV itself [8]. That HIV alone can cause HLH is further proven by the response to Highly Active Antiretroviral Therapy (HAART) in patients with HLH and acute HIV [9]. In the second patient, more conservative approach to initiation of steroids was taken but the patient succumbed to the primary disease which was later confirmed as Hodgkin's lymphoma. AIDS defining malignancy was the likely etiology for secondary HLH in this patient. Although, HLH, lymphoma and HIV are a rare combination, few reports are available in the published literature [6]. Since both HIV and lymphoma promote cytokine release, the likelihood of occurrence of secondary HLH in such cases increases. The treatment of HLH requires aggressive chemoimmunotherapy including steroids, etoposide and cyclosporin A. However, there is a lack of evidence regarding utility of immunosuppressants in patients with HIV who develop HLH. In a retrospective study of 58 patients with HIV and HLH by Fardet et al., there was no significant difference in survival between those who received HLH specific treatment and those who did not [10].\n\nConclusion\nWe report these cases to raise a pertinent question regarding the management of HLH in patients with HIV. Although, there is no dearth in availability of triggers in patients with HIV, there is a definite gap in the literature regarding their management. Due to the variability in the nature of these triggers, development of a standard therapeutic protocol is difficult. There is a definite need for further research in this area.\n\nCompeting interests\nThe authors declare no competing interests.\n\nAuthors’ contributions\nAll authors made substantial contributions to conception and design, acquisition of data or, analysis and interpretation of data; drafting the article or revising it critically for important intellectual content and gave their final approval of the version to be published.\n==== Refs\nReferences\n1 Henter J-I Horne A Aricó M Egeler RM Filipovich AH Imashuku S HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis Pediatr Blood Cancer 2007 2 48 2 124 31 16937360 \n2 Niedt GW Schinella RA Acquired immunodeficiency syndrome: clinicopathologic study of 56 autopsies Arch Pathol Lab Med 1985 8 109 8 727 34 2990378 \n3 Kotwal J Singh V Kotwal A Dutta V Nair V A study of haematological and bone marrow changes in symptomatic patients with human immune deficiency virus infection with special mention of functional iron deficiency, anaemia of critically ill and haemophagocytic lymphohistiocytosis Medical Journal Armed Forces India 2013 10 1 69 4 319 25 \n4 Patel KK Patel AK Sarda P Shah BA Ranjan R Immune reconstitution visceral leishmaniasis presented as hemophagocytic syndrome in a patient with AIDS from a nonendemic area: a case report Int Assoc Physicians AIDS Care (Chic) 2009 8 8 4 217 20 \n5 Chandra H Chandra S Sharma A Histoplasmosis on bone marrow aspirate cytological examination associated with hemophagocytosis and pancytopenia in an AIDS patient Korean J Hematol 2012 3 47 1 77 9 22479282 \n6 Uemura M Huynh R Kuo A Antelo F Deiss R Yeh J Hemophagocytic lymphohistiocytosis complicating T-Cell lymphoma in a patient with HIV Infection Case Rep Hematol 2013 2013 687260 24073345 \n7 Manji F Wilson E Mahe E Gill J Conly J Acute HIV infection presenting as hemophagocytic lymphohistiocytosis: case report and review of the literature BMC Infect Dis 2017 9 20 17 1 633 28931369 \n8 Park K-H Yu H-S Jung S-I Shin D-H Shin J-H Acute Human Immunodeficiency Virus Syndrome presenting with hemophagocytic lymphohistiocytosis Yonsei Med J 2008 4 30 49 2 325 8 18452272 \n9 Concetta C Roberta P Giuliana B Antonio C Vito G Silvia C Hemophagocytic syndrome in a patient with acute Human Immunodeficiency Virus infection J Clin Infect Dis 2004 6 15 38 12 1792 3 \n10 Fardet L Lambotte O Meynard J-L Kamouh W Galicier L Marzac C Reactive haemophagocytic syndrome in 58 HIV-1-infected patients: clinical features, underlying diseases and prognosis AIDS 2010 6 1 24 9 1299 306 20559036\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "32()",
"journal": "The Pan African medical journal",
"keywords": "Malignancy; hospital acquired pneumonia; steroids",
"medline_ta": "Pan Afr Med J",
"mesh_terms": "D000328:Adult; D003907:Dexamethasone; D005260:Female; D015658:HIV Infections; D006801:Humans; D007166:Immunosuppressive Agents; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "101517926",
"other_id": null,
"pages": "105",
"pmc": null,
"pmid": "31223395",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "15227632;16937360;18452272;19535493;20559036;22479282;24073345;24600136;28931369;2990378",
"title": "Haemophagocytic lymphohistiocytosis in patients with human immunodeficiency virus infection: to treat or not to treat.",
"title_normalized": "haemophagocytic lymphohistiocytosis in patients with human immunodeficiency virus infection to treat or not to treat"
} | [
{
"companynumb": "IN-CIPLA LTD.-2019IN04816",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TENOFOVIR"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo examine the effect of sildenafil on level of antiangiogenic proteins of preeclampsia. Firstly to examine the effect of sildenafil on serum biomarkers in a patient with preterm preeclampsia. Secondly, to examine the effect of sildenafil on sFlt-1 and soluble endoglin secretion from primary trophoblasts and placental explants.\n\n\nMETHODS\nThe clinical team administered 50 mg tds sildenafil to a 26-year-old primigravid woman with severe preeclampsia at the threshold of viability (24 3/7 weeks gestation) and we collected bloods to examine the effect of slidenafil on antiangiogenic factors sFlt-1 and soluble endoglin (sENG), pro-angiogenic factor PlGF and vascular cell adhesion molecule 1 (VCAM-1) and endothelin-1 (ET1). We administered sildenafil to human primary trophoblasts and placental explants and explored its effect on sFlt-1 and sENG secretion.\n\n\nMETHODS\nWe examined serum anti-angiogenic factors sFlt-1 and sENG, pro-angiogenic factor PlGF, the potent vasoconstrictor ET1 and VCAM-1 by ELISA. We explored the effect of sildenafil on sFlt-1 secretion from primary trophoblasts and sFlt-1 and sENG secretion from placental explants.\n\n\nRESULTS\nWe found a reduction in serum sFlt-1, stabilisation in sENG and PlGF in a patient with peri-viable preterm preeclampsia administered oral sildenafil 50 mg three times daily (tds). Furthermore there was an initial stabilisation in serum VCAM-1 and a decline in ET1 with sildenafil administration. This was concordant with stabilisation of clinical and biochemical features of preeclampsia. Interestingly, treating placental cells and tissues in vitro with sildenafil did not appear to change sFlt-1 or sENG secretion.\n\n\nCONCLUSIONS\nSildenafil administration was associated with a reduction in serum sFlt-1 and sENG secretion and increase in PlGF secretion in a patient with preterm preeclampsia, potentially via increasing placental perfusion rather than acting directly on the placenta.",
"affiliations": "Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Perinatal, Mercy Hospital for Women, 163 Studley Road, Heidelberg 3084, Victoria, Australia. Electronic address: Fiona.brownfoot@unimelb.edu.au.;Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Perinatal, Mercy Hospital for Women, 163 Studley Road, Heidelberg 3084, Victoria, Australia.;Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Perinatal, Mercy Hospital for Women, 163 Studley Road, Heidelberg 3084, Victoria, Australia.;Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Perinatal, Mercy Hospital for Women, 163 Studley Road, Heidelberg 3084, Victoria, Australia.;Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Perinatal, Mercy Hospital for Women, 163 Studley Road, Heidelberg 3084, Victoria, Australia.;Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Perinatal, Mercy Hospital for Women, 163 Studley Road, Heidelberg 3084, Victoria, Australia.",
"authors": "Brownfoot|Fiona C|FC|;Tong|Stephen|S|;Hannan|Natalie J|NJ|;Cannon|Ping|P|;Nguyen|Vi|V|;Kaitu'u-Lino|Tu'uhevaha J|TJ|",
"chemical_list": "D015415:Biomarkers; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.preghy.2018.04.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2210-7789",
"issue": "13()",
"journal": "Pregnancy hypertension",
"keywords": "Preeclampsia; Sildenafil; Treatment; sFlt-1 and soluble endoglin",
"medline_ta": "Pregnancy Hypertens",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D015415:Biomarkers; D005260:Female; D006801:Humans; D010920:Placenta; D011225:Pre-Eclampsia; D011247:Pregnancy; D000068677:Sildenafil Citrate; D014327:Trophoblasts; D040281:Vascular Endothelial Growth Factor Receptor-1; D014665:Vasodilator Agents",
"nlm_unique_id": "101552483",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "30177033",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Effect of sildenafil citrate on circulating levels of sFlt-1 in preeclampsia.",
"title_normalized": "effect of sildenafil citrate on circulating levels of sflt 1 in preeclampsia"
} | [
{
"companynumb": "PHHY2018AU013953",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MAGNESIUM SULFATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nHypertrophic osteoarthropathy (HOA) is a rare condition characterized by bone and joint pain and digital clubbing usually associated with bronchopulmonary diseases. Primary HOA is rare and the pathogenesis remains unclear.\n\n\nOBJECTIVE\nCases of HOA as a paraneoplastic syndrome associated with thyroid carcinoma are very rare - only 2 cases have been described in the literature.\n\n\nRESULTS\nWe present the first case of a 40-year-old patient affected by HOA associated with invasive differentiated follicular thyroid carcinoma operated in 2 stages. Both operations were followed by radioiodine ablation, and then a rapid unresectable local recurrence developed requiring cervical radiotherapy (70 Gy). A second treatment with 100 mCi of (131)I confirmed it was a refractory thyroid cancer. Further surgery confirmed a poorly differentiated follicular cancer and 12 cycles of chemotherapy by gemcitabine and oxaliplatin followed. During the 8 years of follow-up, cervical recurrence was stable, but severe episodes of hemoptysis occurred requiring iterative embolization of the bronchial and tracheal arteries. Other lung diseases were excluded. Digital clubbing appeared, which was associated with arthritis, bone pain and inflammatory syndrome. X-rays and magnetic resonance imaging found periosteal apposition in the long bones; bone scintigraphy confirmed the HOA diagnosis. Other causes of arthritis were eliminated. She was treated with colchicine, corticosteroids and nonsteroidal anti-inflammatory drugs, but only the combination of methotrexate and hydroxychloroquine reduced the morphine requirements.\n\n\nCONCLUSIONS\nHOA is exceptionally associated with thyroid cancer and we raised the hypothesis of the secretion of a circulating factor in a patient with invasive and recurrent follicular thyroid cancer, refractory to radioiodine.",
"affiliations": "Unité Thyroïde Tumeurs Endocrines, Groupe Hospitalier et Faculté de Médecine Pitié-Salpêtrière, Institut du Cancer, Université Pierre et Marie Curie, Paris, France.;Unité Thyroïde Tumeurs Endocrines, Groupe Hospitalier et Faculté de Médecine Pitié-Salpêtrière, Institut du Cancer, Université Pierre et Marie Curie, Paris, France.;Service de Médecine Interne Immuno-clinique, Groupe Hospitalier et Faculté de Médecine Pitié-Salpêtrière, Institut du Cancer, Université Pierre et Marie Curie, Paris, France.;Service de Médecine Interne 2, Groupe Hospitalier et Faculté de Médecine Pitié-Salpêtrière, Institut du Cancer, Université Pierre et Marie Curie, Paris, France.;Unité Thyroïde Tumeurs Endocrines, Groupe Hospitalier et Faculté de Médecine Pitié-Salpêtrière, Institut du Cancer, Université Pierre et Marie Curie, Paris, France.;Unité Thyroïde Tumeurs Endocrines, Groupe Hospitalier et Faculté de Médecine Pitié-Salpêtrière, Institut du Cancer, Université Pierre et Marie Curie, Paris, France.;Service de Radiothérapie, Groupe Hospitalier et Faculté de Médecine Pitié-Salpêtrière, Institut du Cancer, Université Pierre et Marie Curie, Paris, France.;Service de Chirurgie Générale et Digestive, Groupe Hospitalier et Faculté de Médecine Pitié-Salpêtrière, Institut du Cancer, Université Pierre et Marie Curie, Paris, France.;Unité Thyroïde Tumeurs Endocrines, Groupe Hospitalier et Faculté de Médecine Pitié-Salpêtrière, Institut du Cancer, Université Pierre et Marie Curie, Paris, France.",
"authors": "Tavarelli|Martina|M|;Sarfati|Julie|J|;De Gennes|Christian|C|;Haroche|Julien|J|;Buffet|Camille|C|;Ghander|Cécile|C|;Simon|Jean Marc|JM|;Ménégaux|Fabrice|F|;Leenhardt|Laurence|L|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000437052",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2235-0640",
"issue": "4(4)",
"journal": "European thyroid journal",
"keywords": "Follicular carcinoma; Hemoptysis; Hypertrophic osteoarthropathy; Paraneoplastic syndrome; Poorly differentiated thyroid cancer",
"medline_ta": "Eur Thyroid J",
"mesh_terms": null,
"nlm_unique_id": "101604579",
"other_id": null,
"pages": "266-70",
"pmc": null,
"pmid": "26835431",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": "2891996;17276498;23509104;18500342;15141388;1512778;6710059;20497387;1623674;20810794",
"title": "Hypertrophic Osteoarthropathy and Follicular Thyroid Cancer: A Rare Paraneoplastic Syndrome.",
"title_normalized": "hypertrophic osteoarthropathy and follicular thyroid cancer a rare paraneoplastic syndrome"
} | [
{
"companynumb": "FR-PFIZER INC-202200790192",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "There are a number of case reports about women undergoing long-term bisphosphonate therapy who have suffered an atypical subtrochanteric or femoral shaft fracture due to an inadequate trauma.The present case reports on a patient who underwent a subtrochanteric femur fracture with the inserted AO femur interlocking nail.",
"affiliations": "Orthopädische Klinik, Herzogin Elisabeth Hospital, Leipziger Straße 24, 38124, Braunschweig, Deutschland. h.sobotta@heh-bs.de.;Klinik für Unfallchirurgie und Orthopädische Chirurgie, Städtisches Klinikum Braunschweig, Braunschweig, Deutschland.",
"authors": "Sobotta|H-P|HP|;Gösling|T|T|",
"chemical_list": "D050071:Bone Density Conservation Agents; D019386:Alendronate",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00113-016-0270-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0177-5537",
"issue": "120(2)",
"journal": "Der Unfallchirurg",
"keywords": "Atypical femoral fracture; Implant fracture; Osteoporosis; Subtrochanteric fracture; Therapy with alendronate",
"medline_ta": "Unfallchirurg",
"mesh_terms": "D000369:Aged, 80 and over; D019386:Alendronate; D050071:Bone Density Conservation Agents; D003937:Diagnosis, Differential; D005260:Female; D005594:Fracture Fixation, Intramedullary; D006620:Hip Fractures; D006801:Humans; D017211:Treatment Failure; D016896:Treatment Outcome",
"nlm_unique_id": "8502736",
"other_id": null,
"pages": "171-175",
"pmc": null,
"pmid": "27812727",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22943389;19113931;21085935;19066707;18448990;18956132;17356148;10999794;20842676;20580684;25166043;20335571;21610533;21343577;17190895;18253985",
"title": "Atypical subtrochanteric femur fracture under alendronate therapy in spite of an intramedullar implant.",
"title_normalized": "atypical subtrochanteric femur fracture under alendronate therapy in spite of an intramedullar implant"
} | [
{
"companynumb": "DE-009507513-1709DEU002170",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": "048",
"drugau... |
{
"abstract": "Background: The fluoropyrimidine anticancer drug, especially 5- fluorouracil (5-FU) and its prodrug capecitabine are still being the backbone of chemotherapeutic regimens for colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) is the crucial enzyme in the catabolism of 5-FU. Over the past 30 years, there is substantial clinical evidence showing that DPD deficiency is strongly associated with severe and fatal fluoropyrimidine-induced toxicity. Patients and methods: A 49-year-old lady with resected stage III carcinoma of sigmoid colon was scheduled to have a course of 5-FU based adjuvant chemotherapy. She developed unexpected acute severe (grade 4) toxicity after the first cycle of chemotherapy. Genomic DNA was isolated from 3 ml peripheral blood cells for full sequencing of (the gene encoding DPD). Results: Exome sequencing confirmed that she is heterozygous for NM_000110.3: c.321+2T>C of the gene. To the best of our knowledge, this variant is a novel pathogenic splicing variant of the gene resulting in a non-functional allele. As she has a heterozygous genotype and considered having decreased DPD activity, we followed the international recommendation and restart chemotherapy with at least 50% reduction for 5-FU dose. We then titrated the 5-FU dose, and she tolerated the subsequent cycles of chemotherapy and completed the whole course of adjuvant chemotherapy. Conclusions: With a pre-emptive test on DPD deficiency before the administration of the fluoropyrimidine drugs, the aforementioned patient's life-threatening event could be avoided. This clinical utility has been confirmed by two recent large-scale studies and called for a drug label update.",
"affiliations": "Department of Clinical Oncology, Queen Mary Hospital, Hong Kong, Hong Kong.;Department of Pathology, University of Hong Kong, Pokfulam, Hong Kong.;Department of Clinical Oncology, University of Hong Kong, Pokfulam, Hong Kong.;Department of Clinical Oncology, University of Hong Kong, Pokfulam, Hong Kong.;Department of Clinical Oncology, Queen Mary Hospital, Hong Kong, Hong Kong.",
"authors": "Tong|Chi C|CC|;Lam|Ching W|CW|;Lam|Ka O|KO|;Lee|Victor H F|VHF|;Luk|Mai-Yee|MY|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2018.00279",
"fulltext": "\n==== Front\nFront OncolFront OncolFront. Oncol.Frontiers in Oncology2234-943XFrontiers Media S.A. 10.3389/fonc.2018.00279OncologyCase ReportA Novel DPYD Variant Associated With Severe Toxicity of Fluoropyrimidines: Role of Pre-emptive DPYD Genotype Screening Tong Chi C. 1*Lam Ching W. 2Lam Ka O. 3Lee Victor H. F. 3Luk Mai-Yee 11Department of Clinical Oncology, Queen Mary Hospital, Hong Kong, Hong Kong2Department of Pathology, University of Hong Kong, Pokfulam, Hong Kong3Department of Clinical Oncology, University of Hong Kong, Pokfulam, Hong KongEdited by: Robert Clarke, Georgetown University, United States\n\nReviewed by: Andrea Lapucci, Università degli Studi di Firenze, Italy; Todd Skaar, Indiana University Hospital, United States\n\n*Correspondence: Chi C. Tong tccz01@ha.org.hkThis article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Oncology\n\n24 7 2018 2018 8 27915 4 2018 04 7 2018 Copyright © 2018 Tong, Lam, Lam, Lee and Luk.2018Tong, Lam, Lam, Lee and LukThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Background: The fluoropyrimidine anticancer drug, especially 5- fluorouracil (5-FU) and its prodrug capecitabine are still being the backbone of chemotherapeutic regimens for colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) is the crucial enzyme in the catabolism of 5-FU. Over the past 30 years, there is substantial clinical evidence showing that DPD deficiency is strongly associated with severe and fatal fluoropyrimidine-induced toxicity.\n\nPatients and methods: A 49-year-old lady with resected stage III carcinoma of sigmoid colon was scheduled to have a course of 5-FU based adjuvant chemotherapy. She developed unexpected acute severe (grade 4) toxicity after the first cycle of chemotherapy. Genomic DNA was isolated from 3 ml peripheral blood cells for full sequencing of DPYD (the gene encoding DPD).\n\nResults: Exome sequencing confirmed that she is heterozygous for NM_000110.3: c.321+2T>C of the DPYD gene. To the best of our knowledge, this variant is a novel pathogenic splicing variant of the DPYD gene resulting in a non-functional allele. As she has a heterozygous genotype and considered having decreased DPD activity, we followed the international recommendation and restart chemotherapy with at least 50% reduction for 5-FU dose. We then titrated the 5-FU dose, and she tolerated the subsequent cycles of chemotherapy and completed the whole course of adjuvant chemotherapy.\n\nConclusions: With a pre-emptive test on DPD deficiency before the administration of the fluoropyrimidine drugs, the aforementioned patient's life-threatening event could be avoided. This clinical utility has been confirmed by two recent large-scale studies and called for a drug label update.\n\nnovelDPYD variantfluoropyrimidinespharmacogeneticsprecision medicine\n==== Body\nIntroduction\nDihydropyrimidine dehydrogenase (DPD) plays a key role in the catabolism of 5- fluorouracil (5-FU). The DPYD gene encodes this enzyme. There is substantial evidence showing genetic polymorphism of DPYD is the leading cause of deficiency in enzymatic activity, resulting in DPD deficiency syndrome and manifest excessive toxicity including severe diarrhea, mucositis, and pancytopenia after treatment with fluoropyrimidines (1).\n\nHere we present a case report about a patient with a novel mutation in the DPYD associated with severe toxicity of fluoropyrimidines. The role of pre-emptive DPD genotype screening to improve the efficacy versus toxicity ratio in the era of precision medicine is also discussed.\n\nCase report\nA 49-year-old lady was diagnosed to have carcinoma of sigmoid colon with laparoscopic left hemicolectomy done in early September 2016. Pathology revealed moderately differentiated adenocarcinoma; tumor involved per-colic tissue, one out of 14 regional lymph nodes was positive, all resection margins were clear, hence pathologically staged T3N1M0, stage III disease.\n\nShe was planned to have a course of adjuvant chemotherapy with CAPEOX [capecitabine (1000 mg/m2 twice daily oral for 14 days) and oxaliplatin (130 mg/m2 at day 1)] for eight cycles, with an aim to achieve 10% absolute gain in 8-year overall survival (2). The first cycle of CAPEOX was started in late October 2016.\n\nAt Day 13, she developed fever and grade 3–4 diarrhea (CTCAE v 4.0) (3) and day 14 capecitabine being withheld. She was then admitted into the hospital through Emergency Department. Complete blood count revealed that she had grade 4 marrow suppression toxicity: total white blood cell: 0.52 × 10∧9/L (normal range: 3-89–9.93 × 10∧9/L), neutrophil: 0.04 × 10∧9/L (normal range: 2.01–7.42 × 10∧9/L), platelet: 25 × 10∧9/L (normal range: 154–371 × 10∧9/L). She necessitated intravenous antibiotics with piperacillin/tazobactam and growth factors were given for neutropenic fever. She was discharged home after hospitalization care for 3 weeks.\n\nIn view of stormy side effects of chemotherapy, she was clinically highly suspected to have DPD deficiency.\n\nMethods\nThe patient signed a written informed consent for genotyping and the data being used for scientific publication. The targeted exome analysis for DPYD genotypes was performed as described previously (4).\n\nResults\nExome sequencing confirmed that she is heterozygous for NM_000110.3: c.321+2T>C of the intron 4 of the DPYD gene. This mutation is not present in a population database, i.e., ExAC database (5). The variant NM_000110.3: c.321+2T>C affects the second nucleotide of the donor splice site of intron 4 of the DPYD gene (Figure 1). Bioinformatics analysis using Human Splicing Finder1 predicted that the NM_000110.3: c.321+2T>C abolish the donor splice site of intron 4 of the DPYD gene resulting in exon skipping (Figure 2). This mutation is predicted to be a non-functional allele of the DPYD gene.\n\nFigure 1 The figure showed a heterozygous site at the second base of the donor splice site of intron 4, i.e., G(T/C) AAATTCAGA.\n\nFigure 2 Analysis and prediction by Human Splicing Finder showing the mutation abolish the donor splice site of intron 4 of the DPYD gene resulting in exon skipping.\n\nClinical Pharmacogenetics Implementation Consortium (CPIC) is an international consortium providing guidelines based on translating pharmacogenetic test result into an actionable prescribing decision for affected drugs. This can guide clinician on interpreting available genetic test results and ultimately ensuring a safer and drug delivery to patient (6).\n\nOur reported patient had a heterozygous genotype and was considered having decreased DPD activity. The recommendation is to start with at least a 50% reduction of dosage upon resuming drug, followed by titration of dose base on tolerance and side effect profiles, aim to minimize toxicity while maintaining efficacy. That is, to increase the subsequent dose if she tolerated that dosage versus decrease the subsequent dose if there is still significant toxicity.\n\nIn the 2016 statement from FDA (US), there was insufficient data to recommend a specific dose in the patient with partial DPD activity for capecitabine (7). We decided to switch the subsequent remaining chemotherapy regimen to FOLFOX (every 2 week) for 11 cycles (oxaliplatin 85 mg/m2 at day 1, leucovorin 200 mg/m2 at day 1 and 2, 5-FU iv bolus (400 mg /m2) at day 1 and 2, 5-FU (600 mg/m2) iv infusion at 22 h at day 1 and 2.\n\nWe started with 30% dose 5-FU at cycle one FOLFOX in early January 2017. As patient tolerated the chemotherapy, we then stepped up the dosage of 5-FU to 40 and 50% dose at cycle II & III FOLFOX respectively.\n\nHowever, after cycle III FOLFOX, she developed persistent grade 2–3 neutropenia for 2 weeks: neutrophil count around 0.8–1.2 (normal range 2.01–7.42), hence cycle IV FOLFOX was suspended for 3 weeks. We then stepped down the 5-FU dose back to 40% from cycle IV FOLFOX. The patient tolerated the subsequent cycles of chemotherapy and completed the whole course chemotherapy by early July 2017.\n\nSupplementary Table 1 summarizes the events and progress in chronological order.\n\nDiscussion\nIn Hong Kong, colorectal cancer has superseded lung cancer to claim the top spot in the overall ranking of new case incidence since 2013. It is also the second leading cause of cancer-related deaths in our locality2.\n\nDespite advancement/discovery of novel chemotherapeutic agents, the fluoropyrimidine anti-cancer drug, especially the (5-FU) and its prodrug capecitabine still being the backbone of chemotherapy in adjuvant as well as palliative settings for colorectal cancer3.\n\nDPD is the crucial initial enzyme for 5-FU catabolism and responsible for around 80% of degradation of 5-FU to the inactive metabolite. It has been estimated that about 3–5% of Caucasians have partial DPD deficiency and 0.2% have complete DPD deficiency (8).\n\nWhen a standard dosage of fluoropyrimidines being prescribed to complete or partially DPD deficient patients, the decreased inactivation of 5-FU will result in excessive active anabolic products of 5-FU, leading to an increased risk of severe and even fatal toxicity (8, 9).\n\nIn general, the testing approach for DPD deficiency can be genotyping based or functional measurement/phenotype of DPD. Supplementary Table 2 summarizes the advantages and limitations of tests with these two approaches (10, 11).\n\nGenetic polymorphism in DPYD is the leading cause of DPD deficiency. The DPYD gene is highly polymorphic with hundreds of mutations described so far, a few variants with genotype-guided dosing adjustment have been clinically validated, such as c.1905+1G>A (DPYD*2A), c.2846A>T, c.1679T>G, and c.1236G>A (12).\n\nBesides, new deleterious DPYD variants in the noncoding gene region have been found upon thorough sequencing of the DPYD. One of these includes a deep intronic variant in intron 10 (c.1129-5923C>G) mutation, resulting in a cryptic splice donor site, causing a shift in the reading frame and result in a premature stop codon and a truncated protein. Given the high prevalence of this mutation observed in European (2.6 % in Dutch and 3.3% in German population respectively), the authors concluded that screening for DPD deficiency should include a search for genomic rearrangements and aberrant splicing (13).\n\nPre-emptive screening of DPD deficiency before administrating fluoropyrimidine-based chemotherapy has been a standard practice in some European Countries: France (14), Italy and Netherlands 4. Majority of our current knowledge on DPYD is derived from studies on Caucasian population. Research on other ethnicities is crucial as a meta-analyses study revealed ethnical difference also has a role in genetic polymorphism in DPYD (15).\n\nIn the era of precision medicine, pharmacogenomics changes the landscape of cancer treatment and rewrite the natural history and outcome of many cancer patients/survivors.\n\nThere has been debate over the issue of cost-effectiveness on the pre-emptive screening of DPD deficiency before drug administration but recent studies achieved positive evaluation (16, 17). With the advent of Next Generation Sequencing technology, entire genome sequencing with affordable cost with a short turnaround time also enhance the feasibility of pre-emptive genotyping (18, 19).\n\nCurrent evidence supports upfront DPYD screening for four DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A), followed by genotype-guided dosing, based on dosing recommendations by the CPIC. This clinical utility has been confirmed by two recent large-scale studies (20, 21) and drug label update has been called (22).\n\nIn conclusion, with a pre-emptive test on DPYD before the administration of the fluoropyrimidine drugs, the life-threatening event in this reported case could be avoided.\n\nEthics statement\nThe study was jointly conducted at Department of Clinical Oncology, Queen Mary Hospital, Hong Kong, as well as Department of Clinical Oncology and Department of Pathology, The University of Hong Kong. The study was carried out in accordance with Declaration of Helsinki. Informed consent was obtained from the index patient and the study was approved by the Institute Review Board of Queen Mary Hospital.\n\nAuthor contributions\nCT participated in the study's design and coordination, performed acquisition of data and drafted the manuscript. CL participated in exome sequencing test, data interpretation and revised the manuscript. KL and VL participated in study's design and revised the manuscript. M-YL revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.\n\nConflict of interest statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\n1Available online at: http://www.umd.be/HSF3/ [Accessed 22 June, 2018].\n\n2Website of Hong Kong Cancer Registry, Hospital Authority: http://www3.ha.org.hk/cancereg [Accessed June, 2018]\n\n3NCCN guidelines: www.nccn.org\n\n4Available online at: www.kennisbank.knmp.nl\n\nSupplementary material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2018.00279/full#supplementary-material\n\nClick here for additional data file.\n\n Click here for additional data file.\n==== Refs\nReferences\n1. van Kuilenburg AB . Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil . Eur J Cancer (2004 ) 40 :939 –50 . 10.1016/j.ejca.2003.12.004 15093568 \n2. Sargent D Sobrero A Grothey A O'Connel MJ Buyse M Andre T . Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials . J Clin Oncol. (2009 ) 27 :872 –7 . 10.1200/JCO.2008.9.5362 19124803 \n3. CTCAE \nCommon Terminology Criteria for Adverse Events (CTCAE) version 4.0. \nNational Cancer Institute Available online at: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 22 June, 2018).\n4. Law CY Chang ST Cho SY Yau EK Ng GS Fong NC et al . Clinical whole -exome sequencing reveals a novel missense pathogenic variant of GNAO1 in a patient with infantile-onset epilepsy . Clin Chim Acta (2015 ) 451 :292 –6 . 10.1016/j.cca.2015.10.011 26485252 \n5. Karczewski KJ Weisburd B Thomas B Solomonson M Ruderfer DM Kavanagh D . The ExAC browser: displaying reference data information from over 60 000 exomes . Nucleic Acids Res. (2017 ) 45 :D840 –5 . 10.1093/nar/gkw971 27899611 \n6. Amstutz U Hernricks LM Offer SM BarBarino J Schellens JHM Swen JJ . Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing: 2017 update . Clin Pharmacol Ther. (2018 ) 103 :210 –6 . 10.1002/cpt.911 29152729 \n7. Dean L In: Pratt V McLeod H Dean L Malherio A Rubinstein W editors. Capecitabine Therapy and DPYD Genotype. Medical Genetics Summaries . [Internet]. Bethesda (MD) : National Center for Biotechnology Information (US) ; Created: September 15, 2016.\n8. Morel A Boisdron-Celle M Fey L Soulie P Craipeau MC Traore S . Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance . Mol Cancer Ther. (2006 ) 5 :2895 –904 . 10.1158/1535-7163.MCT-06-0327 17121937 \n9. Amstutz U Froehlich TK Largiadèr CR . Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity . Pharmacogenomics (2011 ) 12 :1321 –36 . 10.2217/pgs.11.72 21919607 \n10. Lunenburg CATC Henricks LM Guchelarr HJ Swen JJ Deenen MJ Schellens JHM . Prospective DPYD genotyping to reduce the risk of fluoropyrimidine-induced severe toxicity: ready for prime time . Eur J Cancer (2016 ) 54 :40 –8 . 10.1016/j.ejca.2015.11.008 26716401 \n11. Ciccolini J Gross E Dahan L Lacarelle B Mercier C \nRoutine dihydropyrimidine dehydrogenase testing for anticipating 5-Fluorouracil-related severe toxicities: hype or hope? \nClin Colorect Cancer (2010 ) 9 :224 –8 . 10.3816/CCC.2010.n.033 \n12. Meulendijks D Henricks LM Sonke GS Deenen MJ Froehich TK Amstutz U . Clinical relevance of DPYD variants c .1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. Lancet Oncol. (2015 ) 16 :1639 –50 . 10.1016/S1470-2045(15)00286-7 26603945 \n13. van Kuilenburg AB Meijer J Mul AN Meinsma R Schmid V Dobritzsch D \nIntragenic deletions and a deep intronic mutation affecting pre-mRNA splicing in the dihydropyrimidine dehydrogenase gene as novel mechanisms causing 5-fluorouracil toxicity . Hum Genetics (2010 ) 128 :529 –38 . 10.1007/s00439-010-0879-3 \n14. Loriot MA Ciccolini J Thomas F Barin-Le-Guellec C Royer B Milano G . Dihydropyrimidine dehydrogenases (DPD) deficiency screening and securing of fluoropyrimidine-based chemotherapyies: update and recommendations of the French GPCO-Unicancer and RnPGX networks . Bull Cancer (2018 ) 105 : 397 –407 . 10.1016/j.bulcan.2018.02.001 29486921 \n15. Li Q Liu Y Zhang HM Huang YP Wang TY Li DS . Influence of DPYD genetic polymorphisms on 5-fluorouracil toxicities in patients with colorectal cancer: a meta-analysis . Gastroenterol Res Pract. (2014 ) 2014 :827989 \n10.1155/2014/827989 25614737 \n16. Deenen MJ Meulendijks D Cats A Sechterberger MK Severens JL Boot H . Upfront genotyping of DPYD*2A to individualize fluoropyrimidine therapy: a safety and cost analysis . J Clin Oncol. (2016 ) 34 :227 –34 . 10.1200/JCO.2015.63.1325 26573078 \n17. Offer SM Diasio RB . Is it finally time for a personalized medicine approach for fluorouracil-based therapies? \nJ Clin Oncol. (2016 ) 34 :205 –7 . 10.1200/JCO.2015.64.2546 26644533 \n18. Gillis NK Patel JN Innocenti F . Clinical implementation of germ line cancer pharmacogenetic variants during the next-generation sequencing era . Clin Pharmacol Ther. (2014 ) 95 :269 –80 . 10.1038/clpt.2013.214 24136381 \n19. Sabour L Sabour M Ghorbian S . Clinical applications of next-generation sequencing in cancer diagnosis . Pathol Oncol Res. (2017 ) 23 :225 –34 . 10.1007/s12253-016-0124-z 27722982 \n20. Boisdron-Celle M Capitain O Faroux R Borg c Metges JP Galais MP . Prevention of 5-fluorouracil-induced early severe toxicity by pre-therapeutic dihydropyrimidine dehydrogenase deficiency screening: assessment of a multiparametric approach . Semin Oncol. (2017 ) 44 :13 –23 . 10.1053/j.seminoncol.2017.02.008 28395758 \n21. Ruzzo A Graziano F Galli F Galli F Rulli E Lonardi S . Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients . Br J Cancer (2017 ) 117 :1269 –77 . 10.1038/bjc.2017.289 29065426 \n22. Henricks LM Opdam FL Beijnen JH Cats A Schellens JHM . DPYD genotype-guided dose individualization to improve patient safety of fluoropyrimidine therapy: call for a drug label update . Ann Oncol. (2017 ) 28 :2915 –22 . 10.1093/annonc/mdx411 29045513\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "8()",
"journal": "Frontiers in oncology",
"keywords": "DPYD variant; fluoropyrimidines; novel; pharmacogenetics; precision medicine",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
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"title": "A Novel DPYD Variant Associated With Severe Toxicity of Fluoropyrimidines: Role of Pre-emptive DPYD Genotype Screening.",
"title_normalized": "a novel dpyd variant associated with severe toxicity of fluoropyrimidines role of pre emptive dpyd genotype screening"
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"abstract": "OBJECTIVE\nLangerhans cell histiocytosis (LCH) can affect any organ. Central nervous system (CNS) involvement is rare, and its management is poorly understood. This study aimed to analyze the clinical response and prognosis of pediatric LCH with central diabetes insipidus (CDI) treated with second-line therapy with cytarabine (Ara-c), cladribine (2-cdA), dexamethasone, and vindesine.\n\n\nMETHODS\nThis retrospective case series study included pediatric LCH with CDI treated at Beijing Children's Hospital affiliated with Capital Medical University (11/2012-01/2018). After the first-line 2009-LCH regimen, patients with active disease/worse response, relapse, or no significant improvement in risk organs, pituitary, or lung were given the second-line therapy. Baseline characteristics, clinical response and adverse reactions were observed.\n\n\nRESULTS\nTwenty-six children with CDI and disappearance of hyperintensity in the posterior pituitary were included. They received \"Regimen A\" Ara-c + dexamethasone + vindesine (n = 7) or \"Regimen B\" Ara-c + dexamethasone + vindesine + 2-cdA (n = 19) as second-line therapy. There were 14 patients with CDI but without pituitary stalk thickening (PST) and 12 with CDI and PST. In patients with CDI alone, 4/4 patients receiving Regimen A and 3/10 receiving Regimen B improved. All patients with CDI and PST showed improvement for PST. The reappearance of hyperintensity at the posterior pituitary was observed in 10 patients with CDI. All 26 children were alive after a median follow-up of 40.5 months. There were no chemotherapy-related deaths.\n\n\nCONCLUSIONS\nA combined therapy with Ara-c, 2-cdA, dexamethasone, and vindesine could partially alleviate pituitary disease conditions in pediatric LCH with CNS involvement, with good tolerance.",
"affiliations": "Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics, Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China.;Laboratory of Hematologic Diseases, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics, Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics, Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China.;Radiology Department, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, 100045, China.;Laboratory of Hematologic Diseases, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics, Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics, Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics, Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics, Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China.;Laboratory of Hematologic Diseases, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, 100045, China. ericlzg70@hotmail.com.;Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics, Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China. ruizh1973@126.com.",
"authors": "Lian|Hongyun|H|;Cui|Lei|L|;Yang|Ying|Y|;Wei|Ang|A|;Cheng|Hua|H|;Li|Na|N|;Zhang|Li|L|;Ma|Honghao|H|;Zhao|Xiaoxi|X|;Wang|Tianyou|T|;Li|Zhigang|Z|;Zhang|Rui|R|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1007/s11102-021-01176-x",
"fulltext": null,
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"issn_linking": "1386-341X",
"issue": null,
"journal": "Pituitary",
"keywords": "Central nervous system; Chemotherapy; Cladribine; Cytarabine; Langerhans cell histiocytosis; Pituitary gland",
"medline_ta": "Pituitary",
"mesh_terms": null,
"nlm_unique_id": "9814578",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34302575",
"pubdate": "2021-07-24",
"publication_types": "D016428:Journal Article",
"references": "25430560;28214412;23109216;26966089;26461147;7700170;11343051;27273725;10770168;25827831;27040279;30207064;18623218;20361277;30280491;15140741;32845092;20953228;27382093;22139588;16047354;12847329;1612952;24186134;24638167;24652991;24982505;15170896;16291085;26194764;8469221;22223352;23672541",
"title": "Second-line regimen for CNS-involved pediatric Langerhans cell histiocytosis.",
"title_normalized": "second line regimen for cns involved pediatric langerhans cell histiocytosis"
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"abstract": "Background Posterior reversible encephalopathy syndrome (PRES) is a rare neurological disease possibly associated with the use of calcineurin inhibitors (CNI) like cyclosporine A. Case Description The case of a patient who developed severe PRES under CNI therapy shortly after heart transplantation is presented here. Cerebral computed tomography led to the diagnose of PRES in our patient. New therapy strategy with a quadruple immunosuppressive protocol (cortisone, mycophenolate mofetil, low-dose CNI, and a mechanistic target of rapamycin inhibitor) was started. Conclusion Under the quadruple therapy, a neurologic recovery occurred. In PRES, the presented alternative therapy strategy may lead to improving neurological conditions and preserved transplant organ functions.",
"affiliations": "Department of Cardiovascular Surgery, University of Schleswig-Holstein Campus Kiel, Kiel, Germany.;Department of Cardiovascular Surgery, University of Schleswig-Holstein Campus Kiel, Kiel, Germany.;Department of Cardiovascular Surgery, University of Schleswig-Holstein Campus Kiel, Kiel, Germany.;Department of Cardiovascular Surgery, University of Schleswig-Holstein Campus Kiel, Kiel, Germany.",
"authors": "Huenges|Katharina|K|;Kolat|Philipp|P|;Panholzer|Bernd|B|;Haneya|Assad|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1055/s-0041-1732344",
"fulltext": "\n==== Front\nThorac Cardiovasc Surg Rep\nThorac Cardiovasc Surg Rep\n10.1055/s-00024355\nThe Thoracic and Cardiovascular Surgeon Reports\n2194-7635\n2194-7643\nGeorg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany\n\n10.1055/s-0041-1732344\n200386crc\nCase Report: Cardiac\nCSA-Induced PRES after Heart Transplantation—Report of Two Cases and Review\nHuenges Katharina 1\nKolat Philipp 1\nPanholzer Bernd 1\nHaneya Assad 1\n1 Department of Cardiovascular Surgery, University of Schleswig-Holstein Campus Kiel, Kiel, Germany\nAddress for correspondence Katharina Huenges, MD Department of Cardiovascular Surgery, University of Schleswig-Holstein Campus KielArnold-Heller-Straße 3, Hs 18, Kiel 24105GermanyKatharina.Huenges@uksh.de\n1 2021\n10 11 2021\n1 11 2021\n10 1 e59e60\n28 12 2020\n12 4 2021\nThe Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ )\n2021\nThe Author(s).\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.\nBackground Posterior reversible encephalopathy syndrome (PRES) is a rare neurological disease possibly associated with the use of calcineurin inhibitors (CNI) like cyclosporine A.\n\nCase Description The case of a patient who developed severe PRES under CNI therapy shortly after heart transplantation is presented here. Cerebral computed tomography led to the diagnose of PRES in our patient. New therapy strategy with a quadruple immunosuppressive protocol (cortisone, mycophenolate mofetil, low-dose CNI, and a mechanistic target of rapamycin inhibitor) was started.\n\nConclusion Under the quadruple therapy, a neurologic recovery occurred. In PRES, the presented alternative therapy strategy may lead to improving neurological conditions and preserved transplant organ functions.\n\nKeywords\n\nheart transplantation\nimmunusuppression\nrejection\n==== Body\npmcIntroduction\n\nIn end-stage cardiomyopathy, heart transplantation is still the gold standard. Despite all improvements made in the posttransplant care, there are still severe greatly feared complications that can occur after the heart transplantation.\n\nCase Description\n\nHere we report about a 48-year-old female patient with end-stage heart failure due to hypertrophic nonobstructive cardiomyopathy that underwent orthotopic heart transplantation (oHTx) in our center. The patient was bridged-to-transplant with a left ventricular assist device (LVAD). Two years after LVAD implantation, the patient was listed on high-urgency status for transplantation with hemodynamically relevant aortic insufficiency. Besides her cardiac history, there were no other relevant comorbidities; in particular, no neurologic disease was known in this patient.\n\nThe initial course after oHTx was complicated by severe bleeding in VAD-associated coagulation disorders, requiring thoracic reexploration. Finally, we could extubate the patient on the sixth postoperative day. Immunosuppression therapy was started right after the transplantation, according to our institutional standard, with a triple drug therapy consisting of cyclosporine A (CSA, target level 200 ng/mL, twice daily), mycophenolate mofetil (MMF, 2 × 1000 mg daily), and cortisone (initial 5 mg/kg bodyweight, conservation dose 5 mg daily). Induction therapy with antithymocyte globulin or similar substances was not applied in this patient.\n\nSix weeks after transplantation, the patient started to feel unspecific unwell and intermittent nausea with vomiting occurred. Electrolyte levels were massively deranged and during the immediate cause search a sudden, no self-limiting generalized cerebral seizure happened.\n\nInitial cerebral computed tomography (CCT) showed occipital hypodense white matter and no bleeding or signs of cerebral infarction. Immunosuppression levels were within normal ranges at that time. After this event, the patient was neurologically inconspicuous again. Two days later, the patient had to be transferred to intensive care-unit due to sudden somnolence.\n\nRepeated CCT revealed progredient symmetrical leukoencephalopathy including, besides the occipital, also the frontal region and morphological apposite to posterior reversible encephalopathy syndrome (PRES) with further increasing cerebral edema ( Fig. 1 ).\n\nFig. 1 Cerebral computed tomography. ( A ) PRES prior to change of immunosuppression with progredient symmetrical leukoencephalopathy. ( B ) CCT prior to discharge with reduced intracerebral lesions. AMR: antibody-mediated rejection; CCT, cerebral computed tomography; CNI, calcineurin-inhibitor; ISHLT, International Society for Heart and Lung Transplantation; LVAD, left ventricular assist device; MMF, mycophenolate mofetil; mTOR, mammalian target of rapamycin; oHTx, orthotopic heart transplantation PRES: posterior reversible encephalopathy syndrome.\n\nReviewing literature revealed that there is only scarce data about drug-induced PRES, one known risk factor is the application of calcineurin inhibitors (CNI). 1 2 3 Case reports describe the risk of tacrolimus-induced PRES higher than cyclosporine-induced PRES, 1 2 4 leaving the actual definite cause for PRES still unexplained. After excluding the other known elicitors for PRES or known causes for cerebral seizures, we were faced with the uncertain situation how to react in our patient, just 2 months after heart transplantation.\n\nTo our opinion, CNI-free immunosuppression regimen so early after transplantation may have led to an unbearable risk of heart rejection. Since PRES is more often reported in patients with tacrolimus immunosuppression, we feared that by solely switching the medication from CSA to tacrolimus in our patient the PRES symptoms could deteriorate.\n\nAfter interdisciplinary consultation and careful literature review, the immunosuppression therapy was changed to a quadruple therapy with increased cortisone (mainly to reduce the intracerebral edema), unmodified MMF dose, low-dose CSA (new target level 50–80 ng/mL), and additional mechanistic target of rapamycin inhibitor everolimus (target level 4–8 ng/mL).\n\nWithin the first days, a steady improvement in both clinical and morphological in the diagnostic imaging was detectable. First myocardial biopsy after the changed immunosuppression regimen was ISHLT 0R, AMR0. Echocardiographic examination showed no signs of acute rejection. After further stabilization and with marked improvements in general condition, the patient was able to be discharged to cardiac rehabilitation center 6 weeks after the first cerebral seizure attack.\n\nConclusion\n\nPRES occurred in this case shortly after heart transplantation. Under a quadruple therapy with cortisone, unmodified MMF, low-dose CSA, and additional everolimus, the symptoms declined. This quadruple regimen may be an alternative therapy strategy in patients with the rare disorder of PRES under standard therapy after organ transplantation.\n\nConflict of Interest None.\n==== Refs\nReferences\n\n1 Song T Rao Z Tan Q Calcineurin inhibitors associated posterior reversible encephalopathy syndrome in solid organ transplantation: report of 2 cases and literature review Medicine (Baltimore) 2016 95 14 e3173 10.1097/MD.0000000000003173 27057842\n2 Ramirez R Muskula P R Everley M P Posterior reversible encephalopathy syndrome after orthotopic heart transplantation: a case report Am J Case Rep 2017 18 487 490 http://www.ncbi.nlm.nih.gov/pubmed/28465499Accessed May 12, 202128465499\n3 Oda N Kato T S Hanatani A Reversible posterior leukoencephalopathy syndrome (RPLS) in a heart transplant recipient treated by substitution of cyclosporine A with tacrolimus Intern Med 2010 49 11 1013 1016 http://www.ncbi.nlm.nih.gov/pubmed/20519818Accessed May 12, 202120519818\n4 Loar R W Patterson M C O'Leary P W Driscoll D J Johnson J N Posterior reversible encephalopathy syndrome and hemorrhage associated with tacrolimus in a pediatric heart transplantation recipient Pediatr Transplant 2013 17 02 E67 E70 23331314\n\n",
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"issn_linking": "2194-7635",
"issue": "10(1)",
"journal": "The Thoracic and cardiovascular surgeon reports",
"keywords": "heart transplantation; immunusuppression; rejection",
"medline_ta": "Thorac Cardiovasc Surg Rep",
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"nlm_unique_id": "101629509",
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"pages": "e59-e60",
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"pmid": "34777943",
"pubdate": "2021-01",
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"title": "CSA-Induced PRES after Heart Transplantation-Report of Two Cases and Review.",
"title_normalized": "csa induced pres after heart transplantation report of two cases and review"
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"abstract": "OBJECTIVE\nWe assessed response to treatment, toxicity, time to progression, progression-free survival, and overall survival in patients newly diagnosed with multiple myeloma who were ineligible for or unwilling to undergo transplantation and who were treated with a combination of lenalidomide and low-dose dexamethasone for a fixed 6 cycles in a resource-constrained environment.\n\n\nMETHODS\nThis pragmatic study, conducted in a single tertiary cancer centre in South India, enrolled patients from May 2009 till April 2011. Treatment included lenalidomide 25 mg daily for 21 days, with dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle, for 6 cycles. Response was evaluated after the 3rd and 6th cycles of treatment. All patients were followed for 5 years.\n\n\nRESULTS\nThe study enrolled 51 patients. Median age in the group was 61 years (range: 38-76 years). Immunoglobulin G or A myeloma constituted 70.6% of the diagnoses, and light-chain myeloma constituted 29.4%. Stages i, ii, and iii (International Staging System) disease constituted 21.4%, 28.6%, and 50% of the diagnoses respectively. All patients were transplantation-eligible, but 34 (66.7%) refused for economic reasons. After treatment, 19.6% of the patients achieved a stringent complete response; 35.3%, a complete response; 5.9%, a very good partial response; and 29.4%, a partial response, for an overall response rate of 90.2%. Stable disease was seen in 3.9% of patients, and progressive disease, in 5.9%. Grade 3 or greater nonhematologic and hematologic toxicity occurred in 35.2% and 11.7% of patients respectively. Pulmonary embolism occurred in 1 patient. No patient experienced deep-vein thrombosis or peripheral neuropathy. The median follow-up duration was 66 months. All patients experienced disease progression. Median progression-free survival was 16 months. In 10 patients, re-challenge with lenalidomide and dexamethasone achieved a second complete response. At the time of writing, 19 patients had died. The overall survival rate at 5 years was 62.74%. Median overall survival is not yet reached.\n\n\nCONCLUSIONS\nIn a resource-constrained setting, lenalidomide with low-dose dexamethasone is an effective treatment with acceptable toxicity in patients newly diagnosed with multiple myeloma and not planned for transplantation. Complete responses were significantly more frequent than reported in the Western literature. Occurrence of clinical deep-vein thrombosis was rare, but hyperglycemia was common. An abbreviated course of treatment is suboptimal in multiple myeloma. Maintenance regimens should be advocated.",
"affiliations": "Department of Medical Oncology and Hematology, Cancer Institute, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Amrita University, Kochi, Kerala, India.;Department of Medical Oncology and Hematology, Cancer Institute, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Amrita University, Kochi, Kerala, India.;Department of Medical Oncology and Hematology, Cancer Institute, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Amrita University, Kochi, Kerala, India.",
"authors": "Jose|W M|WM|;Pavithran|K|K|;Ganesan|T S|TS|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3747/co.24.3574",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1198-0052",
"issue": "24(5)",
"journal": "Current oncology (Toronto, Ont.)",
"keywords": "Multiple myeloma, newly diagnosed; dexamethasone ; lenalidomide",
"medline_ta": "Curr Oncol",
"mesh_terms": null,
"nlm_unique_id": "9502503",
"other_id": null,
"pages": "e361-e367",
"pmc": null,
"pmid": "29089806",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article",
"references": "7492784;15057291;12592343;12409330;15509819;19853510;22571200;16118317;8057662;24723430;9850028;12384400;25184863;8453369;26986753;17908524;2301376",
"title": "Short-course lenalidomide plus low-dose dexamethasone in the treatment of newly diagnosed multiple myeloma-a single-centre pragmatic study.",
"title_normalized": "short course lenalidomide plus low dose dexamethasone in the treatment of newly diagnosed multiple myeloma a single centre pragmatic study"
} | [
{
"companynumb": "IN-CELGENEUS-IND-20171102480",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
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"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
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"abstract": "OBJECTIVEOpen spinal fusion surgery is often associated with significant blood loss, postoperative pain, and prolonged recovery times. Seeking to minimize surgical and perioperative morbidity, the authors adopted an endoscopic minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) technique performed without general anesthesia. In this report, they present data on the first 100 patients treated with this procedure.METHODSThe authors conducted a retrospective review of the first 100 patients who underwent awake endoscopic MIS-TLIF at a single institution between 2014 and 2017. Surgery was performed while the patient was sedated but without intubation or the use of general anesthetic or narcotic agents. Long-lasting (liposomal) bupivacaine was used for local analgesia. The discectomy and placement of an expandable interbody graft were performed endoscopically, followed by percutaneous pedicle screw implantation. Inclusion criteria for the procedure consisted of diagnosis of degenerative disc disease with grade I or II spondylolisthesis and evidence of spinal stenosis or nerve impingement with intractable symptomatology.RESULTSOf the first 100 patients, 56 were female and 44 were male. Single-level fusion was performed in 84 patients and two-level fusion in 16 patients. The most commonly fused level was L4-5, representing 77% of all fused levels. The mean (± standard deviation) operative time was 84.5 ± 21.7 minutes for one-level fusions and 128.1 ± 48.6 minutes for two-level procedures. The mean intraoperative blood loss was 65.4 ± 76.6 ml for one-level fusions and 74.7 ± 33.6 ml for two-level fusions. The mean length of hospital stay was 1.4 ± 1.0 days. Four deaths occurred in the 100 patients; all four of those patients died from complications unrelated to surgery. In 82% of the surviving patients, 1-year follow-up Oswestry Disability Index (ODI) data were available. The mean preoperative ODI score was 29.6 ± 15.3 and the mean postoperative ODI score was 17.2 ± 16.9, which represents a significant mean reduction in the ODI score of -12.3 using a two-tailed paired t-test (p = 0.000001). In four cases, the surgical plan was revised to include general endotracheal anesthesia intraoperatively and was successfully completed. Other complications included two cases of cage migration, one case of osteomyelitis, and one case of endplate fracture; three of these complications occurred in the first 50 cases.CONCLUSIONSThis series of the first 100 patients to undergo awake endoscopic MIS-TLIF demonstrates outcomes comparable to those reported in our earlier papers. This procedure can provide a safe and efficacious option for lumbar fusion with less morbidity than open surgery. Further refinements in surgical technique and technologies will allow for improved success.",
"affiliations": "Departments of1Neurological Surgery and.;Departments of1Neurological Surgery and.;Departments of1Neurological Surgery and.;2Anesthesiology, University of Miami Miller School of Medicine, Miami, Florida.;Departments of1Neurological Surgery and.",
"authors": "Kolcun|John Paul G|JPG|;Brusko|G Damian|GD|;Basil|Gregory W|GW|;Epstein|Richard|R|;Wang|Michael Y|MY|",
"chemical_list": "D000779:Anesthetics, Local; D002045:Bupivacaine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1092-0684",
"issue": "46(4)",
"journal": "Neurosurgical focus",
"keywords": "ERAS = enhanced recovery after surgery; GETA = general endotracheal anesthesia; LOS = length of stay; MIS = minimally invasive; ODI = Oswestry Disability Index; TLIF = transforaminal lumbar interbody fusion; awake fusion; enhanced recovery after surgery; length of stay; lumbar fusion; minimally invasive transforaminal lumbar interbody fusion; outcomes; rhBMP-2 = recombinant human bone morphogenetic protein–2",
"medline_ta": "Neurosurg Focus",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000758:Anesthesia; D000772:Anesthesia, Local; D000779:Anesthetics, Local; D002045:Bupivacaine; D017586:Diskectomy; D004724:Endoscopy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D055959:Intervertebral Disc Degeneration; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D019060:Minimally Invasive Surgical Procedures; D065289:Pedicle Screws; D012189:Retrospective Studies; D013123:Spinal Fusion; D013130:Spinal Stenosis; D013168:Spondylolisthesis; D016896:Treatment Outcome",
"nlm_unique_id": "100896471",
"other_id": null,
"pages": "E14",
"pmc": null,
"pmid": "30933915",
"pubdate": "2019-04-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Endoscopic transforaminal lumbar interbody fusion without general anesthesia: operative and clinical outcomes in 100 consecutive patients with a minimum 1-year follow-up.",
"title_normalized": "endoscopic transforaminal lumbar interbody fusion without general anesthesia operative and clinical outcomes in 100 consecutive patients with a minimum 1 year follow up"
} | [
{
"companynumb": "US-PACIRA-201900106",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUPIVACAINE"
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"drugadditional": null,
"... |
{
"abstract": "Patients with dementia might have higher risk for hemorrhagic complications with anticoagulant therapy prescribed for atrial fibrillation (AF).\n\n\n\nThis study assesses the risks and benefits of warfarin, antiplatelets, and no treatment in patients with dementia and AF.\n\n\n\nOf 49,792 patients registered in the Swedish Dementia Registry 2007-2014, 8,096 (16%) had a previous diagnosis of AF. Cox proportional hazards models were used to calculate the risk for ischemic stroke (IS), nontraumatic intracranial hemorrhage, any-cause hemorrhage, and death.\n\n\n\nOut of the 8,096 dementia patients with AF, 2,143 (26%) received warfarin treatment, 2,975 (37%) antiplatelet treatment, and 2,978 (37%) had no antithrombotic treatment at the time of dementia diagnosis. Patients on warfarin had fewer IS than those without treatment (5.2% versus 8.7%; p < 0.001) with no differences compared to antiplatelets. In adjusted analyses, warfarin was associated with a lower risk for IS (HR 0.76, CI 0.59-0.98), while antiplatelets were associated with increased risk (HR 1.25, CI 1.01-1.54) compared to no treatment. For any-cause hemorrhage, there was a higher risk with warfarin (HR 1.28, CI 1.03-1.59) compared to antiplatelets. Warfarin and antiplatelets were associated with a lower risk for death compared to no treatment.\n\n\n\nWarfarin treatment in Swedish patients with dementia is associated with lower risk of IS and mortality, and a small increase in any-cause hemorrhage. This study supports the use of warfarin in appropriate cases in patients with dementia. The low percentage of patients on warfarin treatment indicates that further gains in stroke prevention are possible.",
"affiliations": "Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.;Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.;Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.;Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.;Department of Clinical Science and Education, Södersjukhuset, Stockholm, Sweden.;Institute of Gerontology, School of Health and Welfare, Aging Research Network (ARN-J), Jönköping University, Jönköping, Sweden.;Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.;Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.;Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.;Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.;Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.;Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.;Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.",
"authors": "Subic|Ana|A|;Cermakova|Pavla|P|;Religa|Dorota|D|;Han|Shuang|S|;von Euler|Mia|M|;Kåreholt|Ingemar|I|;Johnell|Kristina|K|;Fastbom|Johan|J|;Bognandi|Liselia|L|;Winblad|Bengt|B|;Kramberger|Milica G|MG|;Eriksdotter|Maria|M|;Garcia-Ptacek|Sara|S|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "Netherlands",
"delete": false,
"doi": "10.3233/JAD-170575",
"fulltext": "\n==== Front\nJ Alzheimers DisJ. Alzheimers DisJADJournal of Alzheimer's Disease1387-28771875-89081387-2877IOS Press Nieuwe Hemweg 6B, 1013 BG Amsterdam, The Netherlands JAD17057510.3233/JAD-170575Research ArticleTreatment of Atrial Fibrillation in Patients with Dementia: A Cohort Study from the Swedish Dementia Registry A. Subic et al.Atrial Fibrillation in Patients with DementiaSubic Ana abc*Cermakova Pavla adReliga Dorota afgHan Shuang ehvon Euler Mia ijkKåreholt Ingemar lmJohnell Kristina mFastbom Johan mBognandi Liselia eWinblad Bengt afKramberger Milica G. abcEriksdotter Maria efGarcia-Ptacek Sara efn*\na Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden\n\nb Department of Neurology, University Medical Center, Ljubljana, Slovenia\n\nc Medical Faculty, University of Ljubljana, Ljubljana, Slovenia\n\nd National Institute of Mental Health, Klecany, Czech Republic\n\ne Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden\n\nf Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden\n\ng Polish Academy of Sciences, Mossakowski Medical Research Center, Warsaw, Poland\n\nh Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden\n\ni Department of Clinical Science and Education, Södersjukhuset, Stockholm, Sweden\n\nj Department of Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden\n\nk Department of Medicine-Solna, Karolinska Institutet, Stockholm, Sweden\n\nl Institute of Gerontology, School of Health and Welfare, Aging Research Network (ARN-J), Jönköping University, Jönköping, Sweden\n\nm Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden\n\nn Department of Internal Medicine, Neurology Section, Södersjukhuset, Stockholm, Sweden\n* Correspondence to: Ana Subic, MD, Department of Neurology, University Medical Center, Zaloska 2, 1000 Ljubljana, Slovenia. Fax: +386 01522332; E-mail: ana.subic@kclj.si and Sara Garcia-Ptacek, MD, PhD, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Novum plan 5 SE141-83, Stockholm, Sweden. E-mail: sara.garcia-ptacek@ki.se.28 12 2017 9 1 2018 2018 61 3 1119 1128 17 10 2017 © 2018 – IOS Press and the authors. All rights reserved2018This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY 4.0) License.Background:\nPatients with dementia might have higher risk for hemorrhagic complications with anticoagulant therapy prescribed for atrial fibrillation (AF).\n\nObjective:\nThis study assesses the risks and benefits of warfarin, antiplatelets, and no treatment in patients with dementia and AF.\n\nMethods:\nOf 49,792 patients registered in the Swedish Dementia Registry 2007–2014, 8,096 (16%) had a previous diagnosis of AF. Cox proportional hazards models were used to calculate the risk for ischemic stroke (IS), nontraumatic intracranial hemorrhage, any-cause hemorrhage, and death.\n\nResults:\nOut of the 8,096 dementia patients with AF, 2,143 (26%) received warfarin treatment, 2,975 (37%) antiplatelet treatment, and 2,978 (37%) had no antithrombotic treatment at the time of dementia diagnosis. Patients on warfarin had fewer IS than those without treatment (5.2% versus 8.7%; p < 0.001) with no differences compared to antiplatelets. In adjusted analyses, warfarin was associated with a lower risk for IS (HR 0.76, CI 0.59–0.98), while antiplatelets were associated with increased risk (HR 1.25, CI 1.01–1.54) compared to no treatment. For any-cause hemorrhage, there was a higher risk with warfarin (HR 1.28, CI 1.03–1.59) compared to antiplatelets. Warfarin and antiplatelets were associated with a lower risk for death compared to no treatment.\n\nConclusions:\nWarfarin treatment in Swedish patients with dementia is associated with lower risk of IS and mortality, and a small increase in any-cause hemorrhage. This study supports the use of warfarin in appropriate cases in patients with dementia. The low percentage of patients on warfarin treatment indicates that further gains in stroke prevention are possible.\n\nKeywords Atrial fibrillationdementiahemorrhageischemic strokewarfarin\n==== Body\nINTRODUCTION\nAtrial fibrillation (AF) is the most common cardiac arrhythmia and its prevalence increases with age appearing in 10% of those older than 80 years [1]. AF is responsible for about 20% of all ischemic strokes (IS) [2]. The risk of stroke is increased in patients with dementia, [3] representing an important cause of morbidity and death [4, 5]. Oral anticoagulant (OAC) therapy, traditionally warfarin, is used to prevent stroke in patients with AF. Previous studies have shown that adjusted-dose warfarin is more effective than aspirin at reducing IS, but increases bleeding complications [6–8]. However, patients with dementia have often been excluded from studies establishing the benefit of warfarin and there are still few studies on stroke prevention and treatment in this population [9].\n\nWarfarin may be underused or inconsistently prescribed in older patients with dementia [10]. Old age and dementia are associated with greater risk for hemorrhagic complications through different mechanisms, including falls, and polypharmacy leading to interactions with warfarin metabolism. Leukoaraiosis and cerebral amyloid angiopathy have been associated with higher risk for intracranial hemorrhage (ICH) [9]. Similar mechanisms may also explain the suggested increased ICH rate for aspirin treatment in patients with dementia [11].\n\nFor these reasons, the American Academy of Neurology guidelines for stroke prevention in AF state that data in patients with AF who have moderate to severe dementia are insufficient to determine whether anticoagulants are safe [12]. European Stroke Organisation guidelines do not specifically contraindicate OAC in dementia patients, but do not recommend them in patients with co-morbid conditions such as falls or poor compliance [13]. The European Society of Cardiology guidelines do not consider dementia to be a contraindication for anticoagulation unless compliance cannot be ensured [14].\n\nThe present cohort study aims to assess the risks and benefits of OAC and antiplatelet use for stroke prevention in AF in patients with dementia, and evaluate the association between treatment and risk of ischemic and hemorrhagic stroke, any-cause hemorrhage, and death.\n\nMETHODS\nWe performed a longitudinal cohort study on patients registered in the Swedish Dementia Registry (SveDem). Information on AF, treatment, and comorbidities was obtained from the Swedish Patient Register and the Swedish Prescribed Drug Register. Data on death was obtained from the Swedish Population Register.\n\nThis study complies with the Declaration of Helsinki and was approved by the regional ethical review board in Stockholm, Sweden. Patients were informed of registration in SveDem and could decline participation. Data were de-identified before analysis.\n\nStudy population\nSveDem is a national registry that aims to improve the quality of diagnostic workup, treatment, and care of patients with dementia in Sweden. The registration process and variables in SveDem have been previously described [15, 16]. Briefly, patients with newly diagnosed dementia are registered by physicians in specialist or primary care together with demographic and treatment variables. For this study, the diagnoses were classified as Alzheimer’s dementia (AD), vascular dementia, mixed Alzheimer’s and vascular dementia, or other dementia disorders. Information on age, sex, Mini-Mental State Examination (MMSE) score, and living conditions was obtained from SveDem at the time of dementia diagnosis.\n\nInformation about co-morbidities occurring from 1998 until the end of 2014 coded according to International Classification of Diseases 10 (ICD-10) [17] was collected from the Swedish Patient Register. This register covers inpatient and outpatient specialist care encounters in Sweden [18]. Patients with AF were identified by the code I48 present either as main or contributory diagnosis at any point between the year 1998 and the date of dementia diagnosis. Other comorbidities identified as either main or contributory diagnosis from 1998 until the time of dementia diagnosis were diabetes mellitus (E10-E13), hypertension (I10-I15), liver diseases (K70-77), kidney diseases (N10-19), heart failure (I50), presence of cardiac pacemaker (Z950, DF016, DF014, FPE, FPF, FPG, FPJ, DZXG40, or ZXG50), and ischemic heart disease (I20-I25).\n\nFurthermore, previous main diagnoses of stroke of any type (I64), IS (I63), nontraumatic ICH (I60-I62), and traumatic ICH (S063-S068) from 1998 until the time of dementia diagnosis were identified. A composite variable of main diagnoses of systemic and intracranial hemorrhage, both traumatic and spontaneous was considered (any-cause hemorrhage). Any-cause hemorrhage included traumatic ICH (S063-S068); nontraumatic ICH (I60-I62); hemorrhage from respiratory passages (R04); anemia (D50 and D62); hemorrhage unspecified (R58); gastrointestinal bleeding (K92); and traumatic shock (T794). For outcomes, we used a record of the disease occurring as main diagnosis after the date of dementia diagnosis: IS (ICD-10 I63), nontraumatic ICH (ICD-10 I60-I62), any-cause hemorrhage (described above), and death (obtained from the Swedish Death Register).\n\nDrug use 2005–2014 was obtained from the Swedish Prescribed Drug Register, which includes all prescription-drugs dispensed to a patient in any pharmacy in Sweden [19]. For each individual, a medication list at the date of measure was constructed according to the filled prescriptions registered in the Swedish Prescribed Drug Register during the three month period preceding the date of dementia diagnosis.\n\nDrugs were coded according to the Anatomical Therapeutic Chemical classification system: acetylsalicylic acid (B01AC06, N02BA01, N02BA51), warfarin (B01AA03), and clopidogrel (B01AC04). Patients treated with novel oral anticoagulants (NOACs) were excluded because these treatments were uncommon in Sweden during the study period. The following groups of treatment were considered: 1) patients receiving only warfarin treatment at the time of dementia diagnosis (patients with coexisting antiplatelet treatment were excluded), 2) patients with only antiplatelet treatment (receiving only aspirin, only clopidogrel or combination of aspirin with clopidogrel), and 3) patients without any antiplatelet or anticoagulant treatment. Drug prescription was decided by their physician and was not randomized. The number of habitual drugs taken at the time of dementia diagnosis was used as a proxy for comorbidity, calculated after excluding warfarin and antiplatelets [16, 20].\n\nStatistical analyses\nFrom 49,792 patients, 8,485 (17%) had a diagnosis of AF. After exclusion of patients who used both antiplatelets and warfarin or other kinds of anticoagulants, the final study sample of patients with dementia and AF was 8,096 (Fig. 1). Baseline characteristics of the patients at the time of dementia diagnosis and the outcomes during follow-up were compared between treatment groups using chi-square test or T-test. Descriptives are shown as means±standard deviation (SD), median and interquartile range (IQR), or frequency (number—n and percentage–%), as appropriate.\n\nFig.1 Selection of the study sample.\n\nSurvival analyses to identify factors associated with risk for IS, ICH, any-cause hemorrhage, and death were performed using Cox proportional hazards regression models to estimate hazard ratios (HR) with 95% confidence intervals (CI). The proportionality of hazards was checked using visual procedures. Models adjusted for age and sex were performed. Subjects with observation time <1 day were excluded (n = 6). The final adjusted models were arrived at by testing any variables that presented baseline differences between the groups with p < 0.25 in univariate comparisons and other variables previously shown to affect mortality in Swedish patients with dementia [16]: variables were then kept in the survival models if they were significant and/or substantially improved the model. The final models were adjusted for age, sex, number of medication, MMSE, dementia type (AD versus others), nursing home placement, and previous diagnosis of diabetes, hypertension, heart failure, IS, any-cause hemorrhage, liver diseases, and kidney diseases. Models were repeated for all four outcomes: IS, ICH, any-cause hemorrhage, and death. Adjusted and unadjusted models for all four outcomes were repeated with stratification by sex, previous pacemaker, previous IS, and previous any-cause hemorrhage. We performed post-hoc propensity score adjusted models. These were obtained from multiple logistic regression including the variables age, sex, number of medication, MMSE, dementia type (AD versus others), nursing home placement, previous diagnosis of diabetes, hypertension, heart failure, pacemaker IS, any-cause hemorrhage, anemia, gastrointestinal bleeding, hip fracture, liver diseases, and kidney diseases. The interactions between number of medications and liver or kidney diseases were tested. Two linear splines with a node at 79 years (sample median) were used for age, while MMSE and number of drugs were entered as linear variables. Comorbidities were entered as dichotomous variables as described above.\n\nTwo tailed p < 0.05 was considered to be statistically significant in all analytical procedures. Analyses were performed using the Statistical Package for the Social Sciences software version 22 (IBM Corporation, Armonk, NY, USA) and STATA® version 12.1 (StataCorp, College Station, TX, USA).\n\nRESULTS\nThis study included 8,096 patients with dementia and AF (82 years old; 52% women; Table 1). At the time of dementia diagnosis, 2,143 (26%) patients received warfarin, 2,975 (37%) antiplatelets, and 2,978 (37%) neither antiplatelet nor anticoagulant treatment. Patients on warfarin were younger (81 years versus 83 antiplatelet versus 82 years no treatment, p < 0.001), less frequently women (48% versus 52% in the antiplatelet group and 55% in no-treatment groups; p < 0.001), and had higher MMSE (22 versus 21 patients with antiplatelets or without treatment; p < 0.001). Patients were followed up for a median of 636 days (IQR 805) until death or the end of 2014.\n\nTable 1 Baseline characteristics of study population\n\nAF present at the time of dementia diagnosis (N = 8,096)\tPatients without treatment (n = 2,978; 37%)\tPatients treated with warfarin (n = 2,143; 27%)\tp-value for dif. to no treatment\tPatients with antiplatelet treatment (n = 2,975; 37%)\tp-value for dif. to warfarin\t\nAge at diagnosis (mean±SD)\t82.3±6.5\t80.8±5.8\t<0.001\t83.3±6.2\t<0.001\t\nFemale gender, n (%)\t1544 (51.8)\t1028 (48.0)\t0.006\t1627 (54.7)\t<0.001\t\nMMSE, med (IQR)\t21 (29)\t22 (30)\t<0.001\t21 (28)\t<0.001\t\nType of dementia\t\n AD, n (%)\t582 (19.5)\t462 (21.6)\t0.077\t555 (18.7)\t0.010\t\n MD, n (%)\t662 (22.2)\t433 (20.2)\t0.081\t661 (22.2)\t0.083\t\n VaD, n (%)\t801 (26.9)\t630 (29.4)\t0.049\t811 (27.3)\t0.093\t\n OD, n (%)\t933 (31.3)\t618 (28.8)\t0.056\t948 (31.9)\t0.020\t\nLiving alone, n (%)\t1309 (48.4)\t793 (39.4)\t<0.001\t1499 (58.2)\t<0.001\t\nLiving in an institution, n (%)\t458 (15.4)\t155 (7.2%)\t<0.001\t565 (19.1)\t<0.001\t\nAF, atrial fibrillation, n (%), number of patients in each category and percentage relative to the whole cohort; SD, standard deviation; IQR, interquartile range, MMSE, Mini-Mental State Examination, AD, Alzheimer’s dementia; VaD, vascular dementia; MD, mixed AD and VaD; OD, other dementia diagnoses including Parkinson’s disease with dementia, dementia with Lewy bodies, frontotemporal dementia, and unspecified dementia. Missing values: Age at diagnosis, dementia type and sex had no missing values. MMSE had 422 (5.2%) missing values, living alone 803 (9.9%), living in institution 27 (0.3%).\n\nDuring the follow-up, 111 (5.2%) IS occurred in the warfarin group, compared to 180 (6.0%) in the antiplatelet (p = 0.187) and 260 (8.7%) in the no-treatment group (p < 0.001). ICH appeared in 1.9% of patients on warfarin compared to 1.6% on antiplatelets (p = 0.553) and 1.3% with no treatment (p = 0.136). There were no significant differences in the rates of any-cause hemorrhage. During follow-up, 3,094 deaths occurred: in the warfarin group 600 (28%) died, compared to 1,389 (46.7%) in the antiplatelet, and 1,105 (37.1%) in the no-treatment groups (p < 0.001). Comorbidities of the patients are listed on Table 2.\n\nTable 2 Comorbidities in patients with atrial fibrillation before and after dementia diagnosis\n\nAtrial fibrillation (N = 8,096)\tNo treatment (n = 2,978; 37%)\tWarfarin (n = 2,143; 27%)\tp-value for dif. to no treatment\tAntiplatelets (n = 2,975; 37%)\tp-value for dif. to warfarin\t\nNumber of drugs, med (IQR)\t5.0 (23)\t6.0 (21)\t<0.001\t6.0 (23)\t<0.001\t\nComorbidities at dementia diagnosis\t\n Diabetes mellitus, n (%)\t520 (17.5)\t460 (21.5)\t<0.001\t596 (20.0)\t0.212\t\n Hypertension, n (%)\t1817 (61.0)\t1400 (65.3)\t0.002\t1908 (64.1)\t0.378\t\n Liver disease, n (%)\t50 (1.7)\t20 (0.9)\t0.023\t34 (1.1)\t0.469\t\n Kidney disease, n (%)\t334 (11.2)\t179 (8.4)\t0.001\t327 (11.0)\t0.002\t\n Heart failure, n (%)\t1062 (35.7)\t841 (39.2)\t0.009\t1100 (37.0)\t0.099\t\n Pacemaker, n (%)\t388 (13)\t351 (16.4)\t0.001\t291 (9.8)\t<0.001\t\n Previous ischemic heart disease, n (%)\t985 (33.1)\t750 (35.0)\t0.152\t1202 (40.4)\t<0.001\t\n Previous all stroke, n (%)\t659 (22.4)\t503 (23.5)\t0.258\t704 (23.7)\t0.873\t\n Previous ischemic stroke, n (%)\t494 (16.6)\t432 (20.2)\t0.001\t533 (17.9)\t0.043\t\n Previous nontraumatic intracranial hemorrhage, n (%)\t116 (3.9)\t23 (1.1)\t<0.001\t97 (3.3)\t<0.001\t\n Previous traumatic intracranial hemorrhage, n (%)\t81 (2.7)\t22 (1.0)\t<0.001\t65 (2.2)\t0.002\t\n Previous any hemorrhage, n (%)\t571 (19.2)\t284 (13.3)\t<0.001\t467 (15.7)\t0.015\t\nOutcomes after dementia diagnosis\t\n All stroke, n (%)\t243 (8.2)\t176 (8.2)\t0.946\t338 (11.4)\t<0.001 \t\n Ischemic stroke, n (%)\t180 (6.0)\t111 (5.2)\t0.187\t260 (8.7)\t<0.001\t\n Nontraumatic intracranial hemorrhage, n (%)\t40 (1.3)\t40 (1.9)\t0.136\t49 (1.6)\t0.553\t\n Traumaticintracranial hemorrhage, n (%)\t32 (1.1)\t23 (1.1)\t0.996\t35 (1.2)\t0.731\t\n Any hemorrhage, n (%)\t199 (6.7)\t160 (7.5)\t0.278\t205 (6.9)\t0.430\t\n Death, n (%)\t1105 (37.1)\t600 (28.0)\t<0.001\t1389 (46.7)\t<0.001\t\nAF, atrial fibrillation, N (%), number of patients in each category and percentage relative to the whole cohort, IQR, interquartile range. For number of drugs there were 339 (4.2%) missing.\n\nTable 3 Hazard ratios (HR) of ischemic stroke, nontraumatic intracranial hemorrhage, any hemorrhage and death compared to no treatment\n\n\tHR for ischemic stroke (95% CI)\tHR for nontraumatic intracranial hemorrhage (95% CI)\tHR for any hemorrhage (95% CI)\tHR for death (95% CI)\t\nNo treatment\tRef.\tRef.\tRef.\tRef.\t\nWarfarin\t0.76 (0.59–0.98)*\t1.47 (0.91–2.37)\t1.08 (0.87–1.35)\t0.84 (0.59–0.98)**\t\nAntiplatelets\t1.25 (1.01–1.54)*\t1.29 (0.81–2.04)\t0.84 (0.68–1.04)\t0.91 (0.83–0.99)*\t\nHazard ratios (HR) and 95% confidence intervals (CI) for the association of treatment with warfarin or antiplatelets (aspirin or clopidogrel) and risk of ischemic or nontraumatic intracranial hemorrhage and death after dementia diagnosis, as obtained from Cox Hazards regression models. Adjusted for age, sex, number of drugs, Mini-Mental State Examination, dementia type (Alzheimer’s dementia versus other), nursing home placement, previous diabetes, hypertension, heart failure, ischemic stroke, any-cause hemorrhage, liver and kidney disease.\n\nTable 4 Hazard ratios of ischemic stroke, nontraumatic intracranial hemorrhage, any hemorrhage and death compared to antiplatelet treatment\n\n\tHR for ischemic stroke (95% CI)\tHR for nontraumatic intracranial hemorrhage (95% CI)\tHR for any hemorrhage (95% CI)\tHR for death (95% CI)\t\nAntiplatelets\tRef.\tRef.\tRef.\tRef.\t\nWarfarin\t0.62 (0.49–0.78)***\t1.16 (0.75–1.80)\t1.28 (1.03–1.59)*\t0.93 (0.84–1.03)\t\nNo treatment\t0.80 (0.65–0.99)*\t0.81 (0.51–1.28)\t1.19 (0.96–1.47)\t1.12 (1.02–1.23)*\t\nSame analyses as presented in Table 3, but with antiplatelets as reference category. Adjusted for age, sex, number of drugs, Mini-Mental State Examination, dementia type (Alzheimer’s dementia versus other), nursing home placement, previous diabetes, hypertension, heart failure, ischemic stroke, any-cause hemorrhage, liver and kidney disease.\n\nSurvival analyses\nCompared to no treatment, in the fully-adjusted model, warfarin was associated with a lower risk for IS (HR 0.76, 95% CI 0.59–0.98), while antiplatelets were associated with increased risk (HR 1.25, 95% CI 1.01–1.54). In sex-stratified analyses, warfarin was associated with reduced risk of IS compared to no treatment in women (HR 0.65, 95% CI 0.45–0.94), with non-significant results in men (HR 0.89, 95% CI 0.62–1.27).\n\nThere were no significant associations for ICH in patients on warfarin compared to no treatment (HR 1.47, 95% CI 0.91–2.37) or antiplatelets (HR 1.16, 95% CI 0.75–1.80). No significant difference for ICH was found between antiplatelets and no treatment (HR 1.29, 95% CI 0.81–2.04).\n\nSimilarly, there was no significant association for any-cause hemorrhage between warfarin or antiplatelets compared to no treatment (warfarin HR 1.08, 95% CI 0.87–1.35; antiplatelets HR 0.85, 95% CI 0.68–1.04). However, compared to antiplatelets there was a higher risk of hemorrhage with warfarin (HR 1.28, 95% CI 1.03–1.59). Stratifying by sex, the association between any-cause hemorrhage and warfarin was shown only in men (HR 1.43, 95% CI 1.05–1.96). In men, there was an association with lower risk for any-cause hemorrhage in patients on antiplatelets compared to no treatment (HR 0.71, 95% CI 0.52–0.97).\n\nTreatment with warfarin or antiplatelets was associated with lower HR for death compared to no treatment (warfarin: HR 0.84, 95% CI 0.59–0.98, antiplatelets: HR 0.91, 95% CI 0.83–0.99). However, in propensity score adjusted models, treatment with antiplatelets was not associated with lower risk for death compared to no treatment (HR 0.99, 95% CI 0.90–1.08) (Supplementary Table 1). In patients without previous IS, there was an association between warfarin and lower HR for death compared to no-treatment (HR 0.84, 95% CI 0.74–0.95). In patients without previous hemorrhage there was lower HR for death in patients with warfarin compared to no treatment (HR 0.84, 95% CI 0.75–0.95), which was also present in the antiplatelet group (HR 0.90, 95% CI 0.81–1.00). Hazard ratio analysis is presented in Tables 3 and 4.\n\nDISCUSSION\nIn this Swedish cohort of dementia patients with AF, warfarin treatment at the time of dementia diagnosis was associated with lower risk of IS than antiplatelets or no treatment. This is in line with the protective effect of warfarin for stroke in patients with AF observed in the general [6–8, 21] and older [22] populations, as well as in patients with recently diagnosed dementia [23].\n\nIn our study, rates of IS were in the range from 5.2% in the warfarin group, 6.0% in the antiplatelet to 8.7% in the no-treatment group, which would correspond to annual rates 3% in warfarin group, 3.4% in the antiplatelet, and 5.0% in the no-treatment group, which is relatively low compared to other studies. The average IS rate in the general AF population (mean age 71 years) was 4.6% for warfarin for secondary prevention and 1.8% per year for primary prevention in previous studies [6]. With antiplatelet treatment this rises to 10.5% for secondary and 3.9% for primary prevention compared to 13.0% per year for secondary prevention and 4.1% per year for primary prevention in untreated participants [6]. However, in patients with dementia there may be a general underdiagnosis of stroke, if cognitive symptoms obscure new neurological focality or if patients in palliative stages are not sent to hospital. This could explain lower annual rates of stroke found in our study.\n\nThe most common adverse effects of warfarin and antiplatelets are hemorrhages, and most studies on primary and secondary stroke prevention in AF show increase in absolute risk for ICH and major bleeding [6–8, 21]. In our study the crude rates of hemorrhagic stroke and any-cause hemorrhage did not differ between the treatment groups, although in adjusted survival analyses an association was found between warfarin and risk of any-cause hemorrhage compared to antiplatelet treatment. In a previous study on an older population with AF, no significant differences were found in the rate of ICH or major hemorrhage with warfarin compared to aspirin [22], and another smaller study among octogenarians did not detect major bleedings in any of the treatment groups [24]. Lower incidence of ICH with warfarin in these studies can be partly explained by patient selection: in the Birmingham Atrial Fibrillation Treatment of the Aged Study patients for whom warfarin was clearly indicated were excluded because of ethical reasons, so participation in study was restricted to patients with lower risk for stroke, for whom there was clinical uncertainty which of the two treatments should be used [22]. Additionally, pooled data from five randomized trials indicated almost no increase in frequency of major bleeding with antithrombotic treatment (1.3% for the warfarin group, 1.0% for the aspirin group, and 1.0% for the control group) [25]. A meta-analysis on twenty-nine randomized controlled trials investigating long-term antithrombotic therapy in patients with AF found that the risk for ICH doubled with warfarin compared to aspirin, although the absolute risk increase was small (0.2% /year) [6]. There was a similar absolute rate increase for major extracranial bleeding events for warfarin versus control (3%), warfarin versus aspirin (2%), and for aspirin versus control (2%) [6]. These studies were conducted among older patients, with a mean age of 71 years.\n\nIn the European/Australasian Stroke Prevention in Reversible Ischaemia Trial, which investigated secondary prevention of stroke and compared OAC with a target international normalized ratio (INR) between 2.0–3.0 with aspirin treatment, the annual incidence of ICH was between 0.31–1.21% in anticoagulated patients [26]. The incidence of ICH for aspirin was 0.39% per year [27]. This compares with the incidence of ICH in the present study which ranges from 1.3 to 1.9% over a follow-up which is approximately 1.7 years, which translates approximately into 1.12% ICH per year in dementia patients treated with warfarin. Our findings suggest that the hemorrhagic risk in patients with dementia is similar to what has previously been reported among older patients. When evaluating warfarin prescription, the risk of IS must be weighed against the risk of ICH and other hemorrhagic complications. In our data, the absolute rate of IS during follow-up was approximately 3–5 times higher than that for ICH, which is comparable to other studies [28].\n\nIn our cohort, there was an association with increased risk for ICH with advanced age, previous hypertension, and previous hemorrhage. Previous studies that investigated use of warfarin for prevention of thromboembolism in AF showed higher rate of bleeding in the older age groups, but also higher rate of IS indicating a greater need for anticoagulation [29, 30]. However, in previous studies older patients (aged > 75) were significantly underrepresented [9]. In many of these studies, it was also shown that occurrence of ICH is mainly related to the intensity of anticoagulant therapy. For example, in the Stroke Prevention in Reversible Ischaemia Trial, the incidence of major hemorrhages in patients with INR between 2.0–3.0 was two thirds lower than in those with INR 3.0–4.5 [27].\n\nFor this reason, maintaining an INR within the target range is critical to treatment success and nonadherence or drug-drug interactions that threaten this balance are sufficient reasons to withhold or withdraw treatment [13]. Dementia has been shown to be one of the main risk factors for nonadherence to OAC therapy [31]. In a recent study on cognitive function and adherence to anticoagulation treatment, 46.8% of patients with cognitive disorders had low levels of medication adherence [32]. However, another study in patients with AF who received a new diagnosis of dementia has shown good anticoagulation control, as measured according to time in therapeutic range (TTR) (mean TTR before dementia diagnosis was 58.8±22.6% for all patients on warfarin, 62.0±18.4% for those who remained on warfarin after diagnosis with dementia and 65.8±18.9% for those without dementia) [23].\n\nIn our study, a high proportion of patients with dementia and AF were living alone (40% with warfarin treatment, 48% with antiplatelets, and 58% with no treatment). Monitoring and care of patients with AF in Sweden is well organized, with many patients receiving help with medication administration and INR control in their own homes—and this must be kept in mind before generalizing the findings of this study to other countries [33]. Cardiovascular medication use in patients with dementia shows regional variations, which must be taken into account when extrapolating these results to other cohorts [34]. Warfarin and antiplatelet treatment were associated with lower risk for death compared to no treatment in the present study. Compared to antiplatelet treatment, there was a non-significant trend toward lower risk for death with warfarin. Some previous studies reported better survival with warfarin compared to placebo [6, 35], while others comparing warfarin to antiplatelet therapy found no significant differences in survival [8, 21]. Pooled data from twenty-nine randomized controlled trials showed lower all-cause mortality for warfarin versus controls (RRR, relative risk reduction, 26%), for warfarin versus aspirin (RRR, 9%), and for aspirin versus controls (RRR, 14%) [6]. Warfarin was associated with lower mortality (HR 0.72, 95% CI 0.60–0.87, p < 0.001) also in patients with dementia [23]. This effect has to be interpreted with caution, because there can be bias occurring if patients with a lower life expectancy were not treated at all. In our study, when stratifying by sex, treatment with warfarin compared to no treatment was associated with reduced risk of IS in women, while results in men were not significant. This finding is in line with previous studies showing that women with AF have an increased risk of IS, [36] and would therefore benefit more from warfarin.\n\nThe current study has several limitations. The data has been obtained from registries, and important factors affecting treatment decisions, such as possible contraindications for warfarin treatment, patient preferences, compliance, INR at the time of occurrence of the adverse events and TTR, were not available. Patients were classified according to their treatment status at the time of dementia diagnosis. Therefore, patients could have changed treatment groups in the course of follow-up. These changes could possibly have led to the underestimation of the protective effect of warfarin on stroke risk, but also an underestimation of the hemorrhagic complications, if as expected, patients are taken off warfarin as cognitive deterioration progresses. The Patient Registry covers all inhospital and specialist clinic diagnosis: since acute stroke is primarily a hospital diagnosis, the coverage for this outcome should be good, although diagnostic precision is always a concern. The estimated coverage of SveDem is approximately 35% [15]. There are no studies on the differences between dementia patients in SveDem and non-registered patients, however, we can assume that patients included in the quality register are in general healthier [37]. This may bias the generalizability of the results towards a healthier group of patients and may lead to an underestimation of the comorbidities and their influence on risk of stroke and death.\n\nThis is an observational study and treatment was not randomly allocated, so there may be important differences between patients in the different treatment groups. Antithrombotic treatment is often withheld in patients with poor survival prognosis. The data to assess frailty index and information on number of falls was not available and controlling for comorbidities and cognitive level may not adequately account for this. The low incidence of ICH and any hemorrhage in the warfarin group in this study could be partly explained because possible contraindications for warfarin were taken into consideration when prescribing the medication, which could have eliminated differences between the treatment groups. The excess risk for IS found with antiplatelets could indicate that this group of patients were prescribed antiplatelets for reasons other than AF (confounding by indication), which would imply a higher risk for atherothrombotic stroke, in addition to the embolic stroke risk. Confounding by indication could also explain the lower risk of ICH in men taking antiplatelets, compared to no treatment. For outcomes, we included only IS without peripheral emboli, which can be also caused by AF, although much rarer and often clinically silent [38]. This study does not include the new generation of oral anticoagulants because their use has only recently increased in Sweden and the number of patients and follow-up time during the study period was limited.\n\nOne of the strengths of this study is the inclusion of a uniquely large sample of patients with dementia from a nationwide register. Moreover, the diagnoses of AF, comorbidities and information on drugs were obtained from Swedish health registers that have a complete national coverage. The diagnosis of AF and comorbidities were obtained from Swedish National Patient register, which has high overall diagnostic validity (85–95%) [18]. Monitoring of the data in SveDem is performed by random cross-checks of histories and entries [15] and around 5% of dementia diagnoses change during the first year of follow-up [16]. Despite the irruption of NOACs, warfarin remains the most prescribed anticoagulant worldwide and studies examining the risk-benefits of warfarin treatment among patients with dementia are still clinically relevant. Since randomized studies in this subject are ethically and methodologically challenging, cohort studies represent the next-best option in answering these questions. The low percentage of treated patients is also a surprising finding, and implies that great gains can be made in stroke prevention in patients with dementia and AF in Sweden by extending treatment to all appropriate cases. However, as treatment is extended to borderline cases, the risk of complications would increase and future cohort studies should monitor trends in treatment, complications, and the effects of the introduction of NOACs among patients with dementia in Sweden.\n\nConclusions\nIn this nationwide cohort study of patients with dementia and AF, the use of warfarin compared to no treatment was associated with lower risk of ischemic stroke and mortality. The use of warfarin compared to antiplatelets was associated with lower risk of ischemic stroke. There was no significant increase in hemorrhagic complications with warfarin compared to no treatment, and no differences in nontraumatic ICH. A higher risk of any-cause hemorrhage was shown with warfarin compared to antiplatelet treatment but the absolute risk was small. The crude rates of IS were 3–5 times higher than the rates of ICH, which is in line with previous studies. This supports the use of warfarin in appropriate cases in patients with dementia, and indicates that current patient selection and warfarin control in Sweden have succeeded in avoiding excess hemorrhagic complications.\n\nSupplementary Material\nSupplementary Material\nClick here for additional data file.\n\n ACKNOWLEDGMENTS\nThe authors are grateful to SveDem and all patients, caregivers and staff. SveDem is supported by the Swedish Association of Local Authorities and Regions and Swedish Brain Power. This study has been financially supported by Johanniterorden i Sverige/Swedish Order of St John, the Swedish Stroke Association, Loo and Hans Osterman’s Foundation for Medical Research, the Foundation for Geriatric Diseases at Karolinska Institutet, the Foundation to the Memory of Sigurd and Elsa Goljes, Gun and Bertil Stohne’s Foundation, Swedish Research Council (523-2012-2291), FORTE (grant 2017-01646), Stiftelsen Dementia, Swedish Society for Medical Research (SSMF) and Sustainability for the National Institute of Mental Health (grant LO1611), with financial support from the Ministry of Education, Youth and Sports of the Czech Republic. The funding organizations did not participate in study design or data interpretation.\n\nAuthors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/17-0575r2).\n\nSUPPLEMENTARY MATERIAL\nThe supplementary material is available in the electronic version of this article: http://dx.doi.org/10.3233/JAD-170575.\n==== Refs\nREFERENCES\n[1] \n\nHeeringa \nJ \n, \nvan der Kuip \nDA \n, \nHofman \nA \n, \nKors \nJA \n, \nvan Herpen \nG \n, \nStricker \nBH \n, \nStijnen \nT \n, \nLip \nGY \n, \nWitteman \nJC \n (2006 ) Prevalence, incidence and lifetime risk of atrial fibrillation: The Rotterdam study . Eur Heart J \n27 , 949 –953 .16527828 \n[2] \n\nSandercock \nP \n, \nBamford \nJ \n, \nDennis \nM \n, \nBurn \nJ \n, \nSlattery \nJ \n, \nJones \nL \n, \nBoonyakarnkul \nS \n, \nWarlow \nC \n (1992 ) Atrial fibrillation and stroke: Prevalence in different types of stroke and influence on early and long term prognosis (Oxfordshire community stroke project) . 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Cerebrovasc Dis \n25 , 457 –507 .18477843 \n[14] \n\nKirchhof \nP \n, \nBenussi \nS \n, \nKotecha \nD \n, \nAhlsson \nA \n, \nAtar \nD \n, \nCasadei \nB \n, \nCastella \nM \n, \nDiener \nHC \n, \nHeidbuchel \nH \n, \nHendriks \nJ \n, \nHindricks \nG \n, \nManolis \nAS \n, \nOldgren \nJ \n, \nPopescu \nBA \n, \nSchotten \nU \n, \nVan Putte \nB \n, \nVardas \nP \n, \nAgewall \nS \n, \nCamm \nJ \n, \nBaron Esquivias \nG \n, \nBudts \nW \n, \nCarerj \nS \n, \nCasselman \nF \n, \nCoca \nA \n, \nDe Caterina \nR \n, \nDeftereos \nS \n, \nDobrev \nD \n, \nFerro \nJM \n, \nFilippatos \nG \n, \nFitzsimons \nD \n, \nGorenek \nB \n, \nGuenoun \nM \n, \nHohnloser \nSH \n, \nKolh \nP \n, \nLip \nGY \n, \nManolis \nA \n, \nMcMurray \nJ \n, \nPonikowski \nP \n, \nRosenhek \nR \n, \nRuschitzka \nF \n, \nSavelieva \nI \n, \nSharma \nS \n, \nSuwalski \nP \n, \nTamargo \nJL \n, \nTaylor \nCJ \n, \nVan Gelder \nIC \n, \nVoors \nAA \n, \nWindecker \nS \n, \nZamorano \nJL \n, \nZeppenfeld \nK \n (2016 ) 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS . Eur Heart J \n37 , 2893 –2962 .27567408 \n[15] \n\nReliga \nD \n, \nFereshtehnejad \nSM \n, \nCermakova \nP \n, \nEdlund \nAK \n, \nGarcia-Ptacek \nS \n, \nGranqvist \nN \n, \nHallback \nA \n, \nKawe \nK \n, \nFarahmand \nB \n, \nKilander \nL \n, \nMattsson \nUB \n, \nNagga \nK \n, \nNordstrom \nP \n, \nWijk \nH \n, \nWimo \nA \n, \nWinblad \nB \n, \nEriksdotter \nM \n (2015 ) SveDem, the Swedish Dementia Registry - a tool for improving the quality of diagnostics, treatment and care of dementia patients in clinical practice . PLoS One \n10 , e0116538 .25695768 \n[16] \n\nGarcia-Ptacek \nS \n, \nFarahmand \nB \n, \nKareholt \nI \n, \nReliga \nD \n, \nCuadrado \nML \n, \nEriksdotter \nM \n (2014 ) Mortality risk after dementia diagnosis by dementia type and underlying factors: A cohort of 15,209 patients based on the Swedish Dementia Registry . J Alzheimers Dis \n41 , 467 –477 .24625796 \n[17] World Health Organization S (1992 ) ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines,World Health Organization (WHO), Albany, NY, USA.\n[18] \n\nLudvigsson \nJF \n, \nAndersson \nE \n, \nEkbom \nA \n, \nFeychting \nM \n, \nKim \nJL \n, \nReuterwall \nC \n, \nHeurgren \nM \n, \nOlausson \nPO \n (2011 ) External review and validation of the Swedish national inpatient register . BMC Public Health \n11 , 450 .21658213 \n[19] \n\nWettermark \nB \n, \nHammar \nN \n, \nFored \nCM \n, \nLeimanis \nA \n, \nOtterblad Olausson \nP \n, \nBergman \nU \n, \nPersson \nI \n, \nSundstrom \nA \n, \nWesterholm \nB \n, \nRosen \nM \n (2007 ) The new Swedish Prescribed Drug Register–opportunities for pharmacoepidemiological research and experience from the first six months . Pharmacoepidemiol Drug Saf \n16 , 726 –735 .16897791 \n[20] \n\nJohnell \nK \n, \nReliga \nD \n, \nEriksdotter \nM \n (2013 ) Differences in Drug Therapy between Dementia Disorders in the Swedish Dementia Registry: A Nationwide Study of over 7,000 Patients . Dement Geriatr Cogn Disord \n35 , 239 –248 .23485654 \n[21] \n\nAguilar \nMI \n, \nHart \nR \n, \nPearce \nLA \n (2007 ) Oral anticoagulants versus antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no history of stroke or transient ischemic attacks . Cochrane Database Syst Rev , CD006186 .17636831 \n[22] \n\nMant \nJ \n, \nHobbs \nFD \n, \nFletcher \nK \n, \nRoalfe \nA \n, \nFitzmaurice \nD \n, \nLip \nGY \n, \nMurray \nE \n, \ninvestigators \nB \n, Midland Research Practices N (2007 ) Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): A randomised controlled trial . Lancet \n370 , 493 –503 .17693178 \n[23] \n\nOrkaby \nAR \n, \nOzonoff \nA \n, \nReisman \nJI \n, \nMiller \nDR \n, \nZhao \nS \n, \nRose \nAJ \n (2017 ) Continued use of warfarin in veterans with atrial fibrillation after dementia diagnosis . J Am Geriatr Soc \n65 , 249 –256 .28039854 \n[24] \n\nRash \nA \n, \nDownes \nT \n, \nPortner \nR \n, \nYeo \nWW \n, \nMorgan \nN \n, \nChanner \nKS \n (2007 ) A randomised controlled trial of warfarin versus aspirin for stroke prevention in octogenarians with atrial fibrillation (WASPO) . Age Ageing \n36 , 151 –156 .17175564 \n[25] (1994 ) Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials . Arch Intern Med \n154 , 1449 –1457 .8018000 \n[26] \nEsprit (2003 ) Oral anticoagulation in patients after cerebral ischemia of arterial origin and risk of intracranial hemorrhage . Stroke \n34 , e45 –e46 .12730559 \n[27] The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group (1997 ) A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group . Ann Neurol \n42 , 857 –865 .9403477 \n[28] \n\nAlbers \nGW \n, \nDalen \nJE \n, \nLaupacis \nA \n, \nManning \nWJ \n, \nPetersen \nP \n, \nSinger \nDE \n (2001 ) Antithrombotic therapy in atrial fibrillation . Chest \n119 , 194S –206S .11157649 \n[29] \n\nTorn \nM \n, \nBollen \nWL \n, \nvan der Meer \nFJ \n, \nvan der Wall \nEE \n, \nRosendaal \nFR \n (2005 ) Risks of oral anticoagulant therapy with increasing age . Arch Intern Med \n165 , 1527 –1532 .16009869 \n[30] \n\nSenoo \nK \n, \nLip \nGY \n (2015 ) Relationship of age with stroke and death in anticoagulated patients with nonvalvular atrial fibrillation: AMADEUS Trial . Stroke \n46 , 3202 –3207 .26463692 \n[31] \n\nGumbinger \nC \n, \nHolstein \nT \n, \nStock \nC \n, \nRizos \nT \n, \nHorstmann \nS \n, \nVeltkamp \nR \n (2015 ) Reasons underlying non-adherence to and discontinuation of anticoagulation in secondary stroke prevention among patients with atrial fibrillation . Eur Neurol \n73 , 184 –191 .25633474 \n[32] \n\nJankowska-Polanska \nB \n, \nKatarzyna \nL \n, \nLidia \nA \n, \nJoanna \nJ \n, \nDudek \nK \n, \nIzabella \nU \n (2016 ) Cognitive function and adherence to anticoagulation treatment in patients with atrial fibrillation . J Geriatr Cardiol \n13 , 559 –565 .27605935 \n[33] \n\nBjörck \nF \n, \nSandén \nP \n, \nRenlund \nH \n, \nSvensson \nPJ \n, \nSjälander \nA \n (2015 ) Warfarin treatment quality is consistently high in both anticoagulation clinics and primary care setting in Sweden . Thromb Res \n136 , 216 –220 .25935649 \n[34] \n\nGarre-Olmo \nJ \n, \nGarcia-Ptacek \nS \n, \nCalvo-Perxas \nL \n, \nTurro-Garriga \nO \n, \nLopez-Pousa \nS \n, \nEriksdotter \nM \n (2016 ) Diagnosis of dementia in the specialist setting: A comparison between the Swedish Dementia Registry (SveDem) and the Registry of Dementias of Girona (ReDeGi) . J Alzheimers Dis \n53 , 1341 –1351 .27392854 \n[35] \n\nLip \nGY \n, \nEdwards \nSJ \n (2006 ) Stroke prevention with aspirin, warfarin and ximelagatran in patients with non-valvular atrial fibrillation: A systematic review and meta-analysis . Thromb Res \n118 , 321 –333 .16198396 \n[36] \n\nWagstaff \nAJ \n, \nOvervad \nTF \n, \nLip \nGY \n, \nLane \nDA \n (2014 ) Is female sex a risk factor for stroke and thromboembolism in patients with atrial fibrillation? A systematic review and meta-analysis . QJM \n107 , 955 –967 .24633256 \n[37] \n\nAspberg \nS \n, \nStenestrand \nU \n, \nKoster \nM \n, \nKahan \nT \n (2013 ) Large differences between patients with acute myocardial infarction included in two Swedish health registers . Scand J Public Health \n41 , 637 –643 .23567645 \n[38] \n\nBekwelem \nW \n, \nConnolly \nSJ \n, \nHalperin \nJL \n, \nAdabag \nS \n, \nDuval \nS \n, \nChrolavicius \nS \n, \nPogue \nJ \n, \nEzekowitz \nMD \n, \nEikelboom \nJW \n, \nWallentin \nLG \n, \nYusuf \nS \n, \nHirsch \nAT \n (2015 ) Extracranial systemic embolic events in patients with nonvalvular atrial fibrillation: Incidence, risk factors, and outcomes . Circulation \n132 , 796 –803 .26224811\n\n",
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"title": "Treatment of Atrial Fibrillation in Patients with Dementia: A Cohort Study from the Swedish Dementia Registry.",
"title_normalized": "treatment of atrial fibrillation in patients with dementia a cohort study from the swedish dementia registry"
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"abstract": "Although thymomas are the most frequent primary tumours of the anterior mediastinum, thymic carcinoma is very infrequent and more aggressive. Combination chemotherapy is the first-line treatment for the advanced stages, but because of the lack of evidence from randomised trials, the management of the successive lines is a challenging field. We report a partial radiological response in the seventh line of a thymic carcinoma stage IV with an oral regimen.",
"affiliations": "Medical Oncology Department, Hospital Universitario Ramón y Cajal, Ctra de Colmenar Viejo km 9, Madrid 28034, Spain.;Medical Oncology Department, Hospital Universitario Ramón y Cajal, Ctra de Colmenar Viejo km 9, Madrid 28034, Spain.;Medical Oncology Department, Hospital Universitario Ramón y Cajal, Ctra de Colmenar Viejo km 9, Madrid 28034, Spain.;Medical Oncology Department, Hospital Universitario Ramón y Cajal, Ctra de Colmenar Viejo km 9, Madrid 28034, Spain.;Medical Oncology Department, Hospital Universitario Ramón y Cajal, Ctra de Colmenar Viejo km 9, Madrid 28034, Spain.",
"authors": "Del Toro|Jacobo Muñoz|JM|;Castedo|Patricia Cortez|PC|;Salgado|Alfonso Cortés|AC|;García|M Eugenia Olmedo|ME|;López|Pilar Garrido|PG|",
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"fulltext": "\n==== Front\nEcancermedicalscienceEcancermedicalscienceecancermedicalscienceecancermedicalscience1754-6605Cancer Intelligence 10.3332/ecancer.2014.494can-8-494Case ReportMetronomics for thymic carcinoma del Toro Jacobo Muñoz Castedo Patricia Cortez Salgado Alfonso Cortés García M Eugenia Olmedo López Pilar Garrido Medical Oncology Department, Hospital Universitario Ramón y Cajal, Ctra de Colmenar Viejo km 9, Madrid 28034, SpainCorrespondence to: Jacobo Muñoz del Toro. jacobomdeltoro@gmail.com2014 18 12 2014 8 49421 8 2014 © the authors; licensee ecancermedicalscience.2014This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Although thymomas are the most frequent primary tumours of the anterior mediastinum, thymic carcinoma is very infrequent and more aggressive. Combination chemotherapy is the first-line treatment for the advanced stages, but because of the lack of evidence from randomised trials, the management of the successive lines is a challenging field. We report a partial radiological response in the seventh line of a thymic carcinoma stage IV with an oral regimen.\n\nmetronomicsrecurrent thymic carcinomatreatment\n==== Body\nIntroduction\nThymic epithelial tumours are divided into two categories, thymomas and thymic carcinomas. Although thymic tumours are rare (0.2–1.5% of all malignancies; 1.3 cases per million population in the US [1]), thymomas are the most frequent primary tumours of the anterior mediastinum [2]. On the other hand, thymic carcinoma is responsible for less than 1% of thymic neoplasms. It is more aggressive than thymoma and often metastasizes [3–4]. The differential diagnosis between thymoma and thymic carcinoma is complex and mainly based on histological and immunohistochemical differences [5]. We report the case of a patient with an initial stage IVA Masaoka-Koga staging system thymic carcinoma lasting 11 years who achieved a partial response by using a metronomic approach in his seventh line of treatment.\n\nCase report\nThe patient was a 41-year-old male with no relevant medical history who in October 2001 was diagnosed by biopsy of a stage IVA (pleural involvement) thymic carcinoma. The patient received first-line chemotherapy in other hospital. The selected regimen was cisplatin, adriamycin, and cyclophosphamide (CAP) followed by etoposide, ifosfamide, and cisplatin (VIP) completing six cycles, achieving a partial response and passing to monitoring. After a progression-free interval of 4 years, a relapse was diagnosed including pulmonary metastasis together with positivity for somatostatin receptor scintigraphy. The patient was staged as stage IVB, and for the next 7 years, the patient received several treatment lines successively, including lanreotide and steroids, gefitinib, paclitaxel, carboplatin, etoposide, sunitinib as well as palliative radiotherapy. The patient achieved prolonged stabilizations as best response lasting less than 1 year each.\n\nOn February 2012, the patient was admitted to our hospital, where a new line of treatment was offered. The regimen included continuous oral cyclophosphamide (50 mg/day) and prednisone (100 mg per day) plus monthly intramuscular lanreotide at a dose of 60 mg. After two cycles, a partial response was visible on the CT scan (Figure 1). The patient continued with the same regimen except cyclophosphamide that had to be abandoned after the fourth cycle due to a progressive deterioration of the renal function. Additionally, the patient had anaemia grade 2 and fatigue grade 1 as more relevant toxicity. With this schema, the patient showed a clinically significant benefit and radiological partial response for more than 1 year. Finally, a pulmonary progression was detected, and the patient died in November 2013.\n\nDiscussion\nThe behaviour of thymic carcinomas is more aggressive than thymomas, with a 5-year overall survival around 40% [3–4]. The recommended first-line treatment for advanced stages is combination chemotherapy, usually platinum-based schemes, with the most common being CAP, ADOC (cisplatin, doxorubicin, vincristine, and cyclophosphamide) and carboplatin-paclitaxel regimes, and an overall response rate ranging between 30% and 50% and a median progression-free interval of approximately 6 months [6–8]. Unfortunately, the evidence of the benefit of treatment with successive lines is scarce, mainly based on studies with a few patients or an isolated case report. There are small amounts of data published using chemotherapeutic drugs (ifosfamide, cisplatin, etoposide, irinotecan, or pemetrexed) and other agents (octreotide with or without prednisone, belinostat, erlotinib, gefinitib, imatinib, sacaratinib, sorafenib, sunitinib, or cetuximab) [9–11].\n\nMetronomic treatment is the chronic administration of chemotherapy at low, minimally toxic doses on a frequent schedule of administration, with no prolonged drug-free breaks [12]. Although the mechanism of action of metronomic chemotherapy is not fully defined, antiangiogenic and antitumor effects—by restoration of the immune system—have been postulated [12, 14]. In this particular area, Kivrak et al [13] recently published a case report showing a complete response in a patient with recurrent thymic carcinoma treated with cyclophosphamide and etoposide in a metronomic strategy. Moreover, André et al proposed a new strategy based on the combination of metronomic chemotherapy and drug reposition named metronomics [15, 16]. In our patient, this metronomics approach was successful, offering to the patient a relevant clinical benefit with low toxicity and a partial radiological response in his seventh line of treatment, being the only objective response since 2005. In our experience, the metronomics approach deserves further investigation in this subset of patients.\n\nConclusions\nThe interest of this case lies in the response to the therapy used, taking into account that it was a thymic carcinoma with an evolution of 11 years, and that all components of the scheme had already been used in previous lines, but not using a metronomic approach. To our knowledge, there are no published studies using this combination in such as advanced line. The good tolerability and the advantages of the oral administration suggest that this combination should be further analysed.\n\nConflicts of interest\nThe authors have no conflicts of interest to declare.\n\nFigure 1. The response after metronomic treatment.\n==== Refs\nReferences\n1. Engels EA Epidemiology of thymoma and associated malignancies J Thorac Oncol 2010 5 260 5 10.1097/JTO.0b013e3181f1f62d 20101151 \n2. Muller-Hermelink HK The pathological basis of thymoma-associated myasthenia gravis Ann NY Acad Sci 1993 681 56 65 10.1111/j.1749-6632.1993.tb22869.x 7689313 \n3. Strollo DC Rosado de Christenson ML Jett JK Primary mediastinal tumors Part 1: tumors of the anterior mediastinum Chest 1997 112 511 22 10.1378/chest.112.2.511 9266892 \n4. Eng TY Thymic carcinoma: a state of the art review Int J Radiat Oncol Biol Phys 2004 59 654 64 10.1016/j.ijrobp.2003.11.021 15183468 \n5. Marx A Thymic carcinoma: is it a separate entity? From molecular to clinical evidence Thorac Surg Clin 2011 21 25 31 v vi 10.1016/j.thorsurg.2010.08.010 21070984 \n6. Loehrer PJ Sr Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southern Oncology Group, Southwest Oncology Group and Southeastern Cancer Study Group J Clin Oncol 1994 12 1164 8 8201378 \n7. Fornasiero A Chemotherapy for invasive thymoma. A 13 year experience Cancer 1991 68 30 3 10.1002/1097-0142-(19910701)68:1<30::AID-CNCR2820680106>3.0.CO;2-4 2049749 \n8. Okuma Y Key components of chemotherapy for thymic malignancies: a systematic review and pooled analysis for anthracycline-, carboplatin- or cisplatin-based chemotherapy J Cancer Res Clin Oncol 2014 8 22 10.1007/s00432-014-1800-6 \n9. Koppitz H State-of-the-art classification and multimodality treatment of malignant thymoma Cancer Treatment 2012 38 540 8 10.1016/j.ctrv.2011.11.010 \n10. Kelly RJ Thymic malignancies: from clinical management to targeted therapies J Clin Oncol 2011 29 2840 7 10.1200/JCO.2011.36.0487 \n11. Ettinger DS Thymomas and thymic carcinomas: Clinical Practice Guidelines in Oncology J Natl Compr Canc Netw 2013 11 5 562 76 23667206 \n12. Pasquier E Kavallaris M André N Metronomic chemotherapy: new rationale for new directions Nat Rev Clin Oncol 2010 7 455 65 10.1038/nrclinonc.2010.82 20531380 \n13. Kivrak D Metronomic maintenance chemotherapy in patients presenting with paraneoplastic autoimmune hepatitis with recurrent thymic carcinoma J Oncol Pharm Pract 2014 9 16 10.1177/1078155214551318 \n14. Kerbel RS Kamen BA The anti-angiogenic basis of metronomic chemotherapy Nat Rev Cancer 2004 4 23 36 10.1038/nrc1369 14681688 \n15. Ashburn TT Thor KB Drug repositioning: identifying and developing new uses for existing drugs Nat Rev Drug Discov 2004 3 673 83 10.1038/nrd1468 15286734 \n16. André N Has the time come for metronomics in low-income and middle-income countries? Lancet Oncol 2013 14 6 e239 48 10.1016/S1470-2045(13)70056-1 23639324\n\n",
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"keywords": "metronomics; recurrent thymic carcinoma; treatment",
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"title": "Metronomics for thymic carcinoma.",
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"abstract": "Neuroleptic malignant syndrome (NMS) is a potentially fatal manifestation of antipsychotic use associated with symptoms that include mental status changes, muscle rigidity, fever and autonomic dysfunction. An occurrence of NMS with clozapine has been reported in the past but there are very few reports of successfully rechallenging the drug in individuals who have developed the syndrome. This case report discusses one of the few instances in literature where clozapine has been re-administered successfully to a patient without a reoccurrence of NMS. In conclusion, a rechallenge of clozapine after neuroleptic malignant syndrome can be done if care is taken to avoid concurrent use of lithium and other psychotropics, monitoring for NMS symptoms and titrating the dose upward slowly after a reasonable period of time.",
"affiliations": "University of Missouri, One Hospital Drive, Columbia, MO, 65212, USA, anbalagane@health.missouri.edu.",
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"title": "Rechallenging clozapine after neuroleptic malignant syndrome.",
"title_normalized": "rechallenging clozapine after neuroleptic malignant syndrome"
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"abstract": "OBJECTIVE\nTo report our experience on complex percutaneous interventions of the abdominal aorta and its branches in six children with Takayasu arteritis (TA).\n\n\nMETHODS\nA review of records of children with TA, who underwent percutaneous interventions of the abdominal aorta and its major branches.\n\n\nRESULTS\nIn this analysis, we included six children with TA who underwent intervention of the abdominal aorta and its major branches. The endovascular interventions were performed mostly for treatment-resistant renovascular hypertension and mesentery artery ischemia. Mean age (±SD) at time of intervention was 10.6 ± 2.5 years (four boys and two girls). Percutaneous interventions included stenting of abdominal aorta (n = 2), renal arteries (n = 4), mesenteric arteries (n = 2), repeat stenting for renal artery in-stent restenosis (n = 1), and renal autotransplantation (n = 4). All 13 interventions were successful and enabled us to obtain good control of blood pressure.\n\n\nCONCLUSIONS\nWe hereby report six children with TA who were successfully managed with complex percutaneous interventions of the abdominal aorta and its major branches. Balloon dilatation and stent placement constitutes the mainstay of management of TA with stenosis of the large vessels.",
"affiliations": "Department of Cardiology, Advanced Cardiac Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Allergy Immunology Unit, Department of Paediatrics, Advanced Paediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Allergy Immunology Unit, Department of Paediatrics, Advanced Paediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Allergy Immunology Unit, Department of Paediatrics, Advanced Paediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Allergy Immunology Unit, Department of Paediatrics, Advanced Paediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Renal Transplant Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Radiodiagnosis and Imaging, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Cardiology, Advanced Cardiac Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Allergy Immunology Unit, Department of Paediatrics, Advanced Paediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India.",
"authors": "Vijayvergiya|Rajesh|R|http://orcid.org/0000-0001-5250-4735;Jindal|Ankur K|AK|http://orcid.org/0000-0002-7954-0661;Pilania|Rakesh K|RK|http://orcid.org/0000-0002-9015-1704;Suri|Deepti|D|http://orcid.org/0000-0001-5009-8761;Gupta|Anju|A|;Sharma|Ashish|A|;Sinha|Saroj K|SK|;Singhal|Manphool|M|http://orcid.org/0000-0002-1311-7203;Bahl|Ajay|A|http://orcid.org/0000-0002-4705-9945;Singh|Surjit|S|http://orcid.org/0000-0002-6716-1883",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/1756-185X.13420",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1756-1841",
"issue": "22(1)",
"journal": "International journal of rheumatic diseases",
"keywords": "Takayasu arteritis; abdominal aorta; drug-eluting stent; hypertension; mesenteric artery stent; renal artery in-stent restenosis; renal artery stent; renal auto-transplantation; stent fracture",
"medline_ta": "Int J Rheum Dis",
"mesh_terms": "D000293:Adolescent; D000367:Age Factors; D000800:Angioplasty, Balloon; D001012:Aorta, Abdominal; D001027:Aortography; D001157:Arterial Occlusive Diseases; D002648:Child; D000072226:Computed Tomography Angiography; D005260:Female; D006801:Humans; D007194:India; D008297:Male; D008499:Medical Records; D015607:Stents; D013625:Takayasu Arteritis; D062606:Tertiary Care Centers; D016896:Treatment Outcome",
"nlm_unique_id": "101474930",
"other_id": null,
"pages": "140-151",
"pmc": null,
"pmid": "30398008",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Complex interventions of abdominal aorta and its branches in children with Takayasu arteritis: Clinical experience from a tertiary care center in north-west India.",
"title_normalized": "complex interventions of abdominal aorta and its branches in children with takayasu arteritis clinical experience from a tertiary care center in north west india"
} | [
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"abstract": "Renal artery stenosis can be diagnosed during pregnancy and treated at the same time. A 30-year-old woman had a sudden, severe but asymptomatic hypertensive crisis at 21 weeks of gestation. The diagnosis of renal artery stenosis suspected on Doppler ultrasonography was confirmed and treated by renal angioplasty, which reduced her blood pressure. At 27 weeks of gestation, her blood pressure increased again, associated with significant proteinuria, suggesting pre-eclampsia. A cesarean section was performed giving birth to a healthy 940-g child. Renal artery stenosis should be considered when sudden and early-onset hypertension appears during pregnancy.",
"affiliations": "Department of Gynecology, Obstetrics and Reproductive Medicine, University of Poitiers, Poitiers, France.;Department of Radiology and Ultrasonography, University of Poitiers, Poitiers, France.;Obstetric Medicine Clinic, Department of Internal Medicine, University of Poitiers, Poitiers, France.;Department of Gynecology, Obstetrics and Reproductive Medicine, University of Poitiers, Poitiers, France.",
"authors": "Margueritte|François|F|;Velasco|Stephane|S|;Pourrat|Olivier|O|;Pierre|Fabrice|F|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.12886",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "42(3)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "angioplasty; hypertension; pre-eclampsia; pregnancy; renal artery stenosis",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000328:Adult; D017130:Angioplasty; D005260:Female; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications; D012078:Renal Artery Obstruction; D016896:Treatment Outcome",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "341-5",
"pmc": null,
"pmid": "26818942",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful angioplasty during pregnancy for renal artery stenosis.",
"title_normalized": "successful angioplasty during pregnancy for renal artery stenosis"
} | [
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"companynumb": "FR-MYLANLABS-2016M1013870",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
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"activesubstancename": "MAGNESIUM"
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"abstract": "BACKGROUND\nSorafenib is an orally active multikinase tyrosine kinase inhibitor (TKI) that targets B-type Raf kinase (BRAF), vascular endothelial growth factor receptors (VEGFR) 1 and 2, and rearranged during transfection (RET), inducing anti-angiogenic and pro-apoptotic actions in a wide range of solid tumors. A side effect of sorafenib is the occurrence of cutaneous squamous tumors.\n\n\nMETHODS\nHere we describe three patients with a history of sorafenib treatment for advanced radioactive iodine refractory papillary thyroid cancer (two with a BRAF c.1799 T > A and one carrying a rare c.1799-1801het_delTGA mutation) who presented with secondary non-cutaneous lesions. The first patient was diagnosed with a squamous cell carcinoma (SCC) of the tongue, the second patient with a primary adenocarcinoma of the lung, and the third with a SCC originating from the cricoid. Secondary analysis was required to show that the latter two presentations were in fact recurrent thyroid cancer.\n\n\nCONCLUSIONS\nThese findings suggest that drugs such as sorafenib may induce metaplasia/clonal divergence of metastatic thyroid cancer and thus cause diagnostic misclassification. Furthermore, sorafenib is potentially involved in the tumorigenesis of secondary non-cutaneous SCC. These observations should now be confirmed in larger series of patients treated with drugs such as sorafenib.",
"affiliations": "Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. j.morreau@lumc.nl.",
"authors": "Schneider|Tatiana C|TC|;Kapiteijn|Ellen|E|;van Wezel|Tom|T|;Smit|Jan W A|JWA|;van der Hoeven|Jacobus J M|JJM|;Morreau|Hans|H|",
"chemical_list": "C117307:KRAS protein, human; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-016-2060-4",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 206010.1186/s12885-016-2060-4Case Report(Secondary) solid tumors in thyroid cancer patients treated with the multi-kinase inhibitor sorafenib may present diagnostic challenges Schneider Tatiana C. +31 (0)71 526 3057t.c.schneider@lumc.nl Kapiteijn Ellen +31 (0)71 526 3206h.w.kapiteijn@lumc.nl van Wezel Tom +31 (0)71 526 6629t.van_wezel@lumc.nl Smit Jan W. A. +31 (0)24 361 1111jan.smit@radboudumc.nl van der Hoeven Jacobus J. M. +31 (0)71 526 3057j.j.m.van_der_hoeven@lumc.nl Morreau Hans +31 (0)71 526 6630j.morreau@lumc.nl Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands Department of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands 19 1 2016 19 1 2016 2016 16 3124 10 2014 10 1 2016 © Schneider et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nSorafenib is an orally active multikinase tyrosine kinase inhibitor (TKI) that targets B-type Raf kinase (BRAF), vascular endothelial growth factor receptors (VEGFR) 1 and 2, and rearranged during transfection (RET), inducing anti-angiogenic and pro-apoptotic actions in a wide range of solid tumors. A side effect of sorafenib is the occurrence of cutaneous squamous tumors.\n\nCase presentation\nHere we describe three patients with a history of sorafenib treatment for advanced radioactive iodine refractory papillary thyroid cancer (two with a BRAF c.1799 T > A and one carrying a rare c.1799-1801het_delTGA mutation) who presented with secondary non-cutaneous lesions. The first patient was diagnosed with a squamous cell carcinoma (SCC) of the tongue, the second patient with a primary adenocarcinoma of the lung, and the third with a SCC originating from the cricoid. Secondary analysis was required to show that the latter two presentations were in fact recurrent thyroid cancer.\n\nConclusion\nThese findings suggest that drugs such as sorafenib may induce metaplasia/clonal divergence of metastatic thyroid cancer and thus cause diagnostic misclassification. Furthermore, sorafenib is potentially involved in the tumorigenesis of secondary non-cutaneous SCC. These observations should now be confirmed in larger series of patients treated with drugs such as sorafenib.\n\nKeywords\nSorafenibDifferentiated thyroid cancerSquamous cell carcinomaSquamous differentiationClonal divergenceissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nSorafenib (BAY-43-9006) is an orally active multikinase tyrosine kinase inhibitor (TKI) that activates anti-angiogenic and pro-apoptotic pathways, targeting the B-type Raf kinase (BRAF), vascular endothelial growth factor receptors (VEGFR) 1 and 2, and rearranged during transfection (RET). Sorafenib is widely approved for the treatment of patients with hepatocellular carcinoma (HCC) and advanced renal cell carcinoma (RCC) in well-defined phases of disease. Since June 2015 sorafenib is also registered for the treatment of patients with thyroid cancer by the European Medicines Agency (EMA). Multiple clinical trials have been conducted in a wide range of cancers (lung, thyroid, breast, colorectal) using sorafenib as a single agent or in combination treatment (www.clinicaltrials.gov).\n\nRecently published results of a phase III trial of sorafenib in patients with advanced radioactive iodine 131-I (RAI) refractory differentiated thyroid carcinoma (DTC) showed that sorafenib has clinically relevant antitumor activity and a generally well-tolerated profile of adverse events (AEs). The most commonly reported sorafenib-related AEs in DTC include hand-foot syndrome, hypertension, weight loss, diarrhea and rash [1, 2]. Recent reports have also suggested a possible causal link between sorafenib therapy and the development of cutaneous squamous cell carcinomas (SCC) [3–8].\n\nWe now describe three patients who received sorafenib during treatment for advanced RAI refractory DTC and presented with secondary non-cutaneous squamous lesions.\n\nMaterials and methods\nThe presence of somatic DNA mutations including BRAF (V600E and V600K), KRAS (codon 12/13), and PIK3CA (exons 9 and 20) were determined by quantitative real-time PCR (qPCR) with hydrolysis probes (Custom TaqMan® Assay Design Tool, Applied Biosystems, Nieuwerkerk a/d IJssel, NL), and when indicated, by standard Sanger DNA sequencing on an ABI 3739 automated sequencer (Applied Biosystems, Foster City, CA, USA) [9]. Tissues were microdissected to enrich for tumor cells and tumor areas were selected based on the analysis of a hematoxylin eosin (HE)-stained tissue slide. Tumor DNA was subsequently isolated using the Nucleospin Tissue kit (Marcherey-Nagel, Bethlehem, PA, USA) according to manufacturer’s protocol.\n\nCase presentation \nPatient 1\nA 67-year-old female was diagnosed with a well differentiated papillary thyroid carcinoma (PTC, BRAF c.1799 T > A; p.V600E mutation positive), stage T2N0M0, in 1989. She underwent a total thyroidectomy and RAI ablation therapy. Local recurrent disease was diagnosed ten years later and treated with a left-sided modified radical neck dissection, followed by RAI therapy. The post-therapy scintigraphy showed no RAI uptake. Six years later routine follow-up with computed tomography (CT) identified metastatic disease with multiple lung lesions, the largest measuring 5 mm (2005). A total body scintigraphy after RAI therapy showed no uptake of RAI despite elevated thyroglobulin levels (68 ug/l), indicating RAI refractory disease. Due to the progression of disease two years later (2007) the patient received sorafenib (2 x 400 mg/day initially, reduced to 1 x 200 mg/day after 6 months) in the context of a phase II study [2, 10]. Follow-up showed stable disease according to the Response Evaluation Criteria in Solid Tumours (RECIST) 1.0 [11]. Thirty-nine months after starting sorafenib, with ongoing stable disease, the patient stopped therapy mainly due to diarrhea.\n\nAfter starting sorafenib treatment, the patient developed several skin lesions (for a summary see Table 1). Furthermore, within 2 months of beginning sorafenib therapy the patient developed left-sided tongue complaints, originally histologically diagnosed and treated as mucosal hyperplasia with Candida albicans infection. The symptoms persisted however and eventually led, 46 months after the initial complaints, to the diagnosis of a T2N2cM0 functional irresectable SCC of the tongue (thyroid transcription factor (TTF)-1 and thyroglobulin immunohistochemically negative; BRAF p.V600E negative) with ipsi-lateral lymph node metastasis (Fig. 1). Despite chemo-radiation therapy with 7 rounds of cisplatin, the patient died 5 months after diagnosis of the SSC.Table 1 Summary of lesions seen in patient 1 after starting sorafenib treatment November 2007\n\nDate\tLesion\t\nFebruary 2008\tSCC on the back\nCandida infection of the tongue\t\nApril 2008\tReactive epithelial skin lesion on the back without obvious atypia\nLeukokeratosis of the tongue with atypia and inflammation\t\nJune 2008\tLesion with inverted follicular keratosis on the lower left leg\t\nSeptember 2009\tTrichilemmoma of the nose\t\nMarch 2010\tIrritated verruca seborrhoica upper right leg\t\nMay 2010\tReactive epithelial hyperplasia of the tongue due to a candida infection\t\nAugust 2011\tInvasive squamous cell carcinoma of the tongue\nMultiple lymph node metastasis of the SCC in the neck region\t\nDecember 2011\tSCC lymph node metastasis in the left axilla\t\nFig. 1 Lymph node metastasis of the SCC of the tongue in patient 1. HE staining of a fine needle aspirate (FNA) of a cervical lymph node using a standard embedding procedure of cytology material and histologic processing. Atypical squamous cells with (para-)keratotic horn were seen, indicative of metastasized SCC\n\n\n\nPatient 2\nThe second (male) patient was diagnosed with a T4N1Mx PTC without squamous metaplasia (positive for the rare BRAF mutation c.1799-1801het_delTGA, Fig. 2) at the age 67 [12–14]. He underwent a total thyroidectomy with a right-sided lymph node dissection, followed by RAI ablation therapy in 2001. In 2004 the patient had recurrent disease, and a bilateral para-tracheal lymph node dissection was performed. A year later he presented with local recurrent disease and the presence of multiple pulmonary metastases. A whole body scintigraphy after RAI therapy showed no RAI uptake, while thyroglobulin levels were 133 ug/l, thus demonstrating RAI refractory disease. In 2007, the patient was referred to our hospital for inclusion in a phase II trial and received sorafenib 400 mg twice daily [2, 10]. Despite initial stable disease, the patient became progressive under sorafenib after 19 months of therapy. The patient was subsequently enrolled in a clinical study (RAD001, www.clinicaltrials.gov CRAD001CNL08T) to determine the efficacy of everolimus in patients with progressive irresectable recurrent or metastatic differentiated, undifferentiated (anaplastic) and medullary thyroid carcinoma. The patient ceased everolimus therapy 18 months later due to progressive disease. A CT showed a new pulmonary lesion and a number of (non)target lesions according to RECIST 1.0 [11]. Since all conventional or study-based treatment options had been exhausted, the patient was referred back to his own hospital where he presented 2 months later with progressive dyspnea due to malignant pleural effusion. A CT showed multiple bilateral pulmonary metastases and a large right para-tracheal lesion. Surprisingly, right-sided pleural fluid cytology elsewhere revealed a primary adenocarcinoma of the lung. Immunohistochemistry of embedded cytological material showed TTF-1 and cytokeratin (CK) 7 positivity and absence of staining for thyroglobulin, cluster of differentiation (CD) 56 and CK20. Additional paired box (PAX) 8 and CK19 staining in our institute were however positive, indicative of metastatic PTC (Fig. 3). Molecular testing confirmed this diagnosis with the presence of the previous identified BRAF mutation. The patient died a month later due to disease progression.Fig. 2 \nBRAF DNA sequencing. Identification of a rare BRAF mutation c.1799-1801het_delTGA\n\nFig. 3 Pathological analysis of pleural effusion in patient 2. FNA of a right-sided pleural effusion after embedding and histological processing. a HE; b: TTF1 immunohistochemistry (IHC); c: PAX8 IHC\n\n\n\nPatient 3\nA 60-year-old male was diagnosed with a T2N0M0 poorly differentiated PTC (BRAF c.1799 T > A; V600E mutation positive) in 2002. The patient was treated by total thyroidectomy with a left-sided lymph node dissection, followed by RAI ablation therapy. Three years later (2005) he presented with multiple pulmonary lesions, non-RAI avid on whole body scintigraphy after RAI therapy, and thyroglobulin levels of 127 ug/l. Due to disease progression in 2008 the patient was included in a phase II trial (and received 2 x 400 mg sorafenib daily) [2, 10]. In the first 6 months a partial response was achieved, which was ongoing until therapy discontinuation 32 months later due to complaints of diarrhea and hand-foot syndrome. A CT four months after therapy discontinuation still showed an ongoing partial response per RECIST 1.0 [11]. However, seven weeks later the patient presented with respiratory failure due to airway obstruction. A large tumor originating from the cricoid was visible on CT scan. Initial histological examination elsewhere concluded that the lesion was a SCC originating from the cricoid. Revision of the tumor showed a lesion with squamous differentiation (Fig. 4). Although P63 staining (indicative of squamous differentiation) was positive in a subset of cells, immunohistochemistry also showed TTF-1 and thyroglobulin to be focally positive, indicative of a PTC recurrence. Surprisingly, the BRAF mutation present in the primary tumor was not recovered from this tumor, possibly suggesting clonal divergence after sorafenib treatment. Given the fact that local treatment was not an option the patient received a tracheal stoma followed by radiotherapy. He died 8 months later due to tumor progression.Fig. 4 PTC recurrence in the laryngeal cricoid of patient 3. In a biopsy from the laryngeal cricoid solid sheets of tumor cells were seen with focal keratinisation. Panel a shows the HE stained tissue. Immunohistochemical analysis of TTF-1 (panel b) and P63 (Panel c) is shown. A large proportion of the cells stained positive for P63, supporting the squamous features. However, there was a fraction a cells that stained moderately positive for TTF-1 (thick arrow in panel b), partly overlapping with P63 positivity (thin arrow in panel c). Thyroglobulin also stained focally positive (not shown). Due to the TTF-1 and thyroglobulin positivity, we favoured the diagnosis of recurrent papillary thyroid cancer with remarkable squamous metaplasia over a primary laryngeal squamous carcinoma\n\n\n\nDiscussion\nThe cases described here present three interesting observations. Firstly, (although lacking proven causality) our demonstration of a primary tongue carcinoma that arose after long-term sorafenib treatment suggests that treatment with the multikinase inhibitor sorafenib may cause other effects additional to squamous skin lesions [3–8]. However, since patient 2 was subsequently treated with everolimus, a combined effect of sorafenib and everolimus cannot be ruled out. Secondly, we note that metaplastic changes or clonal divergence can result in the misdiagnosis of recurrences of thyroid cancer. Indeed, clonal divergence at the molecular level might be an aspect of PTC with BRAF c.1799 T > A; p.V600E mutations. Thirdly, we identified a rare BRAF mutation, c.1799-1801het_delTGA, which will be missed by the allele-specific assays currently in use in daily practice in many laboratories.\n\nIt has been proposed that BRAF kinase inhibitors can stimulate proliferation in cells lacking mutant BRAF via a paradoxical activation of RAF-MEK-ERK1/2 pathway signaling in the presence of upstream activation of RAS, thus possibly explaining the development of cutaneous SCC [3–8]. This hypothesis was supported by a study that analyzed oncogenic mutations in cutaneous SCCs in melanoma patients treated with the BRAF inhibitor vemurafenib. This study found that 13 out of 21 tumors harbored a RAS mutation [15]. Furthermore, there are several reports on patients treated with a BRAF inhibitor who developed secondary tumors. One case has been described of a patient on vemurafenib treatment for a melanoma who developed a RAS-mutant leukemia correlating with enhanced extracellular signal-regulated kinases (ERK) signaling [16]. Another study reports the development of four colonic adenomas, one hyperplastic colonic polyp and six gastric polyps in a patient also treated with vemurafenib for a melanoma. However, no evidence of RAS mutations was reported in any of the adenomas identified in this patient [17]. In addition, progression of a previously present KRAS mutated colon carcinoma due to stimulated ERK signaling was reported in a patient with a melanoma treated with dabrafenib [18]. A similar molecular explanation might be relevant to the cases we now present, although the presence of RAS mutations was not completely tested in the lesions with squamous metaplasia.\n\nConclusions\nIn summary, we described three patients with advanced RAI refractory DTC and a history of sorafenib treatment who presented with a secondary non-cutaneous lesion. The first patient was diagnosed with a SCC of the tongue; the remaining two patients had recurrent disease with altered morphology and molecular biology suggesting clonal divergence, initial diagnosed as a primary adenocarcinoma and SCC, originating from the lung and cricoid respectively. Although the possibility that these tumors were already present in the form of micrometastases prior to sorafenib treatment cannot be excluded, these observations are quite remarkable. It is therefore important that a pathologist is familiar with the patient’s medical history and treatment and that the possibility of unusual presentation is kept in mind when considering secondary lesions.\n\nConsent\nWritten informed consent was obtained from the patients for publication of this case report and any accompanying images. A copy of the written consents is available for review by the Editor of this journal.\n\nAbbreviations\nAEAdverse event\n\nBRAFB-type Raf kinase\n\nCDCluster of differentiation\n\nCKCytokeratin\n\nCTComputed tomography\n\nDTCDifferentiated thyroid carcinoma\n\nEMAEuropean Medicines Agency\n\nERKExtracellular signal-regulated kinases\n\nFNAFine needle aspirate\n\nHCCHepatocellular carcinoma\n\nHEHematoxylin eosin\n\nIHCImmunohistochemistry\n\nTKITyrosine kinase inhibitor\n\nPAXPaired box\n\nPTCPapillary thyroid carcinoma\n\nqPCRQuantitative real-time PCR\n\nRAIRadioactive iodine\n\nRCCRenal cell carcinoma\n\nRECISTResponse evaluation criteria in solid tumours\n\nRETRearranged during transfection\n\nSCCSquamous cell carcinoma\n\nTTFThyroid transcription factor\n\nVEGFRVascular endothelial growth factor receptor.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nConception and design: TS, EK, JS, JH, JM. Collection and assembly of patient data: TS, EK, JS, JH. Collection and assembly of pathological data: TS, HM, TW. Data analysis and interpretation: all authors. Manuscript writing and final approval of manuscript: all authors.\n\nThe authors do not have any acknowledgements.\n==== Refs\nReferences\n1. Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet [epub ahead of print].\n2. Schneider TC Abdulrahman RM Corssmit EP Morreau H Smit JW Long-term analysis of the efficacy and tolerability of sorafenib in advanced radio-iodine refractory differentiated thyroid carcinoma: final results of a phase II trial Eur J Endocrinol 2012 167 5 643 650 10.1530/EJE-12-0405 22918300 \n3. Arnault JP Mateus C Escudier B Tomasic G Wechsler J Hollville E Skin tumors induced by sorafenib; paradoxic RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1 Clin Cancer Res 2012 18 1 263 272 10.1158/1078-0432.CCR-11-1344 22096025 \n4. Dubauskas Z Kunishige J Prieto VG Jonasch E Hwu P Tannir NM Cutaneous squamous cell carcinoma and inflammation of actinic keratoses associated with sorafenib Clin Genitourin Cancer 2009 7 1 20 23 10.3816/CGC.2009.n.003 19213663 \n5. Hong DS Reddy SB Prieto VG Wright JJ Tannir NM Cohen PR Multiple squamous cell carcinomas of the skin after therapy with sorafenib combined with tipifarnib Arch Dermatol 2008 144 6 779 782 10.1001/archderm.144.6.779 18559769 \n6. Raymond AK Puri PK Selim MA Tyler DS Nelson KC Regional squamous cell carcinomas following systemic sorafenib therapy and isolated limb infusion for regionally advanced metastatic melanoma of the limb Arch Dermatol 2010 146 12 1438 1439 10.1001/archdermatol.2010.367 21173337 \n7. Smith KJ Haley H Hamza S Skelton HG Eruptive keratoacanthoma-type squamous cell carcinomas in patients taking sorafenib for the treatment of solid tumors Dermatol Surg 2009 35 11 1766 1770 10.1111/j.1524-4725.2009.01289.x 19660024 \n8. Williams VL Cohen PR Stewart DJ Sorafenib-induced premalignant and malignant skin lesions Int J Dermatol 2011 50 4 396 402 10.1111/j.1365-4632.2010.04822.x 21413947 \n9. van Eijk R van Puijenbroek M Chhatta AR Gupta N Vossen RH Lips EH Sensitive and specific KRAS somatic mutation analysis on whole-genome amplified DNA from archival tissues J Mol Diagn 2010 12 27 34 10.2353/jmoldx.2010.090028 19959798 \n10. Hoftijzer H Heemstra KA Morreau H Stokkel MP Corssmit EP Gelderblom H Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma Eur J Endocrinol 2009 161 923 931 10.1530/EJE-09-0702 19773371 \n11. Therasse P Arbuck SG Eisenhauer EA Wanders J Kaplan RS Rubinstein L New guidelines to evaluate the response to treatment in solid tumors J Natl Cancer Inst 2009 92 205 216 10.1093/jnci/92.3.205 10655437 \n12. Lee YW Peptide nucleic acid clamp polymerase chain reaction reveals a deletion mutation of the BRAFgene in papillary thyroid carcinoma: A case report Exp Ther Med 2013 6 1550 1552 24255689 \n13. Lee SR Jung CK Kim TE Bae JS Jung SL Choi YJ Molecular genotyping of follicular variant of papillary thyroid carcinoma correlates with diagnostic category of fine-needle aspiration cytology: values of RAS mutation testing Thyroid 2013 11 1416 1422 10.1089/thy.2012.0640 23590130 \n14. Jang MA Lee ST Oh YL Kim SW Chung JH Ki CS Identification of a rare 3 bp BRAF gene deletion in a thyroid nodule by mutant enrichment with 3'-modified oligonucleotides polymerase chain reaction Ann Lab Med 2012 3 238 241 10.3343/alm.2012.32.3.238 22563563 \n15. Su F Viros A Milagre C Trunzer K Bollag G Spleiss O RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors N Engl J Med 2012 366 207 15 10.1056/NEJMoa1105358 22256804 \n16. Callahan MK1 Rampal R Harding JJ Klimek VM Chung YR Merghoub T Progression of RAS-mutant leukemia during RAF inhibitor treatment N Engl J Med 2012 367 2316 21 10.1056/NEJMoa1208958 23134356 \n17. Chapman P Metz D Sepulveda AR Development of colonic adenomas and gastric polyps in BRAF mutant melanoma patients treated with vemurafenib Pigment Cell Melanoma Res 2012 25 847 \n18. Andrews MC Behren A Chionh F Mariadason J Vella LJ BRAF inhibitor-driven tumor proliferation in a KRAS-mutated colon carcinoma is not overcome by MEK1/2 inhibition J Clin Oncol 2013 31 e448 51 10.1200/JCO.2013.50.4118 24190114\n\n",
"fulltext_license": "CC BY",
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"mesh_terms": "D000368:Aged; D017209:Apoptosis; D063646:Carcinogenesis; D002294:Carcinoma, Squamous Cell; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D009389:Neovascularization, Pathologic; D009536:Niacinamide; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D000077157:Sorafenib; D013964:Thyroid Neoplasms",
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"title": "(Secondary) solid tumors in thyroid cancer patients treated with the multi-kinase inhibitor sorafenib may present diagnostic challenges.",
"title_normalized": "secondary solid tumors in thyroid cancer patients treated with the multi kinase inhibitor sorafenib may present diagnostic challenges"
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"abstract": "The \"pontine warning syndrome\" is characterized by recurrent episodes of motor hemiparesis, dysarthria and horizontal gaze palsy associated with basilar artery branch infarction. We report a case of a patient who presented with recurrent, self-limited episodes of locked-in syndrome, related to a bilateral pontine infarction. As far as we know, this clinical presentation as a subtype of pontine warning syndrome has never been described. We discuss the case, the differential diagnosis of the neuroimaging and the possible underlying mechanism.",
"affiliations": "Acute Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Spain carlosgesperon@yahoo.es.;Acute Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Spain.;Acute Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Spain.;Acute Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Spain.;Interventional Neuroradiology Unit, Hospital Universitari Germans Trias i Pujol, Spain.;MRI Unit, Institut de Diagnòstic per la Imatge (IDI), Hospital Universitari Germans Trias i Pujol, Spain.;Acute Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Spain.",
"authors": "García-Esperón|Carlos|C|;López-Cancio|Elena|E|;Martín-Aguilar|Lorena|L|;Millán|Mónica|M|;Castaño|Carlos|C|;Munuera|Josep|J|;Dávalos|Antoni|A|",
"chemical_list": "D010959:Tissue Plasminogen Activator",
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"keywords": "Stroke; capsular warning syndrome; locked-in; pontine warning syndrome",
"medline_ta": "Neuroradiol J",
"mesh_terms": "D020520:Brain Infarction; D006801:Humans; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D015835:Ocular Motility Disorders; D010291:Paresis; D011149:Pons; D010959:Tissue Plasminogen Activator",
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"title": "Fluctuating locked-in syndrome as a presentation of a bilateral pontine infarction.",
"title_normalized": "fluctuating locked in syndrome as a presentation of a bilateral pontine infarction"
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"abstract": "Clear-cell sarcoma is a rare and malignant soft tissue tumor most commonly located at the distal end of extremities and rarely at the trunk. Data on the clinical features of the tumor is limited, complicating the analysis of prognosis and establishment of treatment protocols. In our study, we present a case diagnosed with clear-cell sarcoma in his right scapula and treated with tumor resection and chemotherapy, combination of dacarbazine, pharmorubicin and cisplatin. The patient died due to multiple organ failure eight months after operation. Early diagnosis, attentive care, and extended surgical resection combined with adjuvant therapy is of essence in treatment of clear-cell sarcoma.",
"affiliations": "Department of VIP Ward, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79th, Qingchun Road, Hangzhou 310003, Zhejiang, China. Electronic address: zhangxian821030@163.com.;Department of Orthopedics, Zhongnan Hospital of Wuhan University, No. 169th, Donghu Road, Wuchang District, Wuhan 430071, Hubei, China. Electronic address: huchao1982@hotmail.com.;Department of Orthopedics, Zhongnan Hospital of Wuhan University, No. 169th, Donghu Road, Wuchang District, Wuhan 430071, Hubei, China. Electronic address: guke3559@aliyun.com.",
"authors": "Zhang|Xian|X|;Hu|Chao|C|;Cai|Lin|L|",
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"fulltext": "\n==== Front\nActa Orthop Traumatol TurcActa Orthop Traumatol TurcActa Orthopaedica et Traumatologica Turcica1017-995X2589-1294Turkish Association of Orthopaedics and Traumatology S1017-995X(16)30017-710.1016/j.aott.2016.07.004ArticleA giant clear cell sarcoma on right scapular: A case report Zhang Xian zhangxian821030@163.coma1Hu Chao huchao1982@hotmail.comb1Cai Lin guke3559@aliyun.comb∗a Department of VIP Ward, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79th, Qingchun Road, Hangzhou 310003, Zhejiang, Chinab Department of Orthopedics, Zhongnan Hospital of Wuhan University, No. 169th, Donghu Road, Wuchang District, Wuhan 430071, Hubei, China∗ Corresponding author. Fax: +86 27 67812892. guke3559@aliyun.com1 These authors contributed equally to this study.\n\n21 7 2016 8 2016 21 7 2016 50 4 473 476 2 5 2014 9 10 2014 29 1 2015 © 2016 Turkish Association of Orthopaedics and Traumatology. Publishing services by Elsevier B.V.2016Turkish Association of Orthopaedics and TraumatologyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Clear-cell sarcoma is a rare and malignant soft tissue tumor most commonly located at the distal end of extremities and rarely at the trunk. Data on the clinical features of the tumor is limited, complicating the analysis of prognosis and establishment of treatment protocols.\n\nIn our study, we present a case diagnosed with clear-cell sarcoma in his right scapula and treated with tumor resection and chemotherapy, combination of dacarbazine, pharmorubicin and cisplatin. The patient died due to multiple organ failure eight months after operation. Early diagnosis, attentive care, and extended surgical resection combined with adjuvant therapy is of essence in treatment of clear-cell sarcoma.\n\nKeywords\nClear cell sarcomaGiantScapular\n==== Body\nClear cell sarcoma (CCS) is a malignant soft tissue tumor with rare incidence. Enzinger reported and explored the histogenesis of CCS in 1965.1 Generally, CCS ranges from 2 cm to 7 cm in diameter and locates at distal end of extremities and rarely at trunk. Only one case of scapula intrusion has been reported so far with diameter around 4.5 cm,2 and this patient’s tumor is the largest one occurring at joint. The clinical features of CCS have only been described to a very limited extent, which significantly inhibits analysis of prognosis and establishment of treatment principle.\n\nHere we report a CCS case with incidence site at right scapula. The patient with giant CCS at right scapular was admitted to our hospital in 2011. After scapula artificial shoulder arthroplasty and ten days of chemotherapy, right scapular mass, right submaxillary lymphadenectasis, ascites and pulmonary metastasis were observed six months post operation. Multiple organ failure caused the death of patient eight months post operation.\n\nCase report\nThe patient was a 63 years old male. He was admitted to our hospital because “the right scapular pain had been felt for 7 months, and an enclosed mass had been found on the right scapular for more than 4 months” on February 18, 2011. The patient had felt a sense of pain in the right shoulder since July 2010, mainly nocturnal pain, aggravated while moving. He had been treated as “frozen shoulder” for several weeks before transfer. However, relief of symptoms was not observed. The size of painful mass at right scapular had been described as “increasing” since October 2010.\n\nPhysical examination indicated that a mass with size of 15 cm × 10 cm × 10 cm in the right scapular region, without surface swelling and with moderate skin temperature. The mass was hard, tender, difficult to push away, and the enlarged left supraclavicular lymph nodes could be felt.\n\nLaboratory tests showed that the serum concentration of CEA reached 17.64 ng/ml. Imaging: X-ray (Fig. 1a) showed the destruction of the right scapula, and a shadow of soft tissue mass in right scapular region; CT (Fig. 1b) showed right scapula destructed, surrounded by irregular low-density mass shadow. MRI (Fig. 1c, d) showed a shadow of soft tissue mass inside of right shoulder, two rounded nodule below the right clavicle, considering as a malignant tumor of the right scapula, right subclavian lymph node metastasis. Emission computed tomography (ECT) showed high metabolism activity in the right scapula, right shoulder and right clavicle bone (Fig. 2). Preoperative needle biopsy report: clear cell sarcoma (Fig. 3); immunohistochemical staining: PCK (−), LCA (−), Melanoma (−), Syn (+), desmin (−), S-100 (+), CD68 (±), vimentin (+).Fig. 1 (a), X-ray images show right scapula and that distal clavicle is destructed by tumor. (b), CT images show that right scapula is destructed and surrounded by irregular low-density mass shadow. (c), (d), MRI images show a shadow of soft tissue mass inside of right shoulder and two subclavian lymph nodes metastasis sites.\n\nFig. 1Fig. 2 ECT showed high metabolism activity in the right scapula, right shoulder and right clavicle bone.\n\nFig. 2Fig. 3 Histological features. The optical image shows that tumor cells are nested and in shape of polygon or spindle, with nuclear vacuolization and prominent nucleoli (HE × 100).\n\nFig. 3\n\nAn artificial total shoulder was customized, and the operation of the right scapular tumor resection and tumor type with to wholly the scapula artificial shoulder arthroplasty and lesions lymph node including the pathological lymph node below right subclavian and above left supraclavicular dissection had been performed in March 2011 (Fig. 4a, b). To achieve full exposure of scapular and tumor, scapular notch was implemented, approximately 2 cm of the distal end of right clavicle excised. Then the original tumor and the 3 cm area surrounding it together with whole right acromioclavicular joint was removed, followed by fixing biceps long head tendon to stump of clavicle and prosthesis installment. After discharge from our hospital, ten days of chemotherapy, combination of dacarbazine, pharmorubicin and cisplatin, was applied in patient in May 2011 in another hospital and given up due to anorexia and vomit. Right scapular mass, right submaxillary lymphadenectasis, and ascites were observed. Nodules in superior lobe of right lung and inferior lobe of left lung were observed in CT results (Fig. 5a, b, c) which suggested potential pulmonary metastases in September 2011. Multiple organ failure caused the death of patient in November 2011.Fig. 4 Postoperative X-ray test. Images show that shoulder joint prosthesis is well placed.\n\nFig. 4Fig. 5 CT images show nodules in superior lobe of right lung and inferior lobe of left lung.\n\nFig. 5\n\nThe patient,s wife was informed that data from the case would be submitted for publication and gave her consent.\n\nDiscussion\nThe incidence of CCS is rare, accounting for 1% of soft tissue sarcomas, and the main symptom is localized pain. Generally, CCS ranges in size from 2 cm to 7 cm. The preoperative diagnosis of CCS is difficult because the diagnosis must rely on pathological examination and immunohistochemistry assays. The CCS is characterized with poor prognosis, high rate of local recurrence and metastasis, and poor 5-year survival rate. Lymph node metastasis is frequently observed in CCS at early stage. In this case, left supraclavicular lymphadenectasis had been found in preoperative physical examination, MRI result showed possible right subclavian lymph nodes metastasis and pathological examination post surgery confirmed the lymph node metastasis. The description of this case is in line with the characteristics of the CCS.\n\nThe main treatment of CCS is surgery.3 During operation, in order to explore the possible invasion of brachial plexus and blood vessels by tumor, pectoralis major deltoid ditch approach was performed and then outside of the 1/3 of the clavicle was exposed. If nerve or blood vessels are invaded by tumor, limb salvage surgery should not be performed. However, based on preoperative MRI results and intraoperative exploration, invasion of nerves and blood vessels by tumor was not observed in this case. Exposure and protection of brachial plexus, axillary artery, particularly musculocutaneous nerve and axillary nerve in operation is critical to reserve full biceps elbow flexion and part of shoulder abduction of patient. The benefit of radical lymph node dissection of CCS is not yet fully understood,4 therefore, selective lymph node dissection was performed in this case. After operation, right elbow, wrist and hand functioned normally, right shoulder remained normal appearance, and the outreach function was partially reserved.\n\nPreoperative and postoperative adjuvant radiotherapy and chemotherapy has become the conventional means of the treatment for malignant tumors, however therapeutic effect of radiotherapy and chemotherapy on CCS is still not clear,5, 6 and has side effects, including long treatment cycle, preoperatively rapid growth of tumor, and obvious pain. Therefore, to achieve better surgery tolerance, radiotherapy and chemotherapy was not applied preoperatively. Chemotherapy and radiotherapy were scheduled immediately post-operation, but only chemotherapy was applied one month post-operation for 10 days and terminated due to patient's low tolerance to the side effects. In this case, invasion of distal clavicle of right scapula by CCS and lymph node metastasis were observed. The tumor was approximately 15 × 10 × 10 cm in size. Although evaluation of prognosis based on lymph node metastasis and bone invasion is inconclusive, size of CCS acts as a significant factor contributing to prognosis of patients.7 Kawai8 and Ipach9 have revealed that worse prognosis was observed for CCS with diameter greater than 5 cm, and the 5-year and 10-year survival rate was 59% and 41% respectively.7\n\nThe patients died eight month post operation as a result of delayed diagnosis, large tumor volume and un-standardized postoperative chemotherapy and radiotherapy. This is consistent with the reported prognosis.\n\nCCS is a rare but highly malignant tumor. Clinically, it should be paid more attention and early diagnosis, surgical extended resection and combined adjuvant therapy are suggested. Due to the poor prognosis, further exploration of advanced diagnosis and treatment approaches for CCS is required.\n\nConflicts of interest\nNo conflicts declared.\n\nPeer review under responsibility of Turkish Association of Orthopaedics and Traumatology.\n==== Refs\nReferences\n1 Enzinger F.M. Clear-cell sarcoma of tendons and aponeuroses. An analysis of 21 cases Cancer 18 1965 1163 1174 14332545 \n2 Kazakos C.J. Galanis V.G. Giatromanolaki A. Verettas D.A. Sivridis E. Clear cell sarcoma of the scapula. A case report and review of the literature World J Surg Oncol 4 2006 48 16893467 \n3 Liu X. Zhang H. Dong Y. Primary clear cell sarcoma of humerus: case report World J Surg Oncol 9 2011 163 22151733 \n4 Kuiper D.R. Hoekstra H.J. Veth R.P. Wobbes T. The management of clear cell sarcoma Eur J Surg Onco 29 2003 568 570 \n5 Karita M. Tsuchiya H. Yamamoto N. Shirai T. Hayashi K. Nishida H. Caffeine-potentiated chemotherapy for clear cell sarcoma: a report of five cases Int J Clin Oncol 18 2013 33 37 22041928 \n6 Jones R.L. Constantinidou A. Thway K. Chemotherapy in clear cell sarcoma Med Oncol 28 2011 859 863 20390470 \n7 Hocar O. Le Cesne A. Berissi S. Clear cell sarcoma (malignant melanoma) of soft parts: a clinicopathologic study of 52 cases Dermatol Res Pract 2012 2012 984096 22693489 \n8 Kawai A. Hosono A. Nakayama R. Clear cell sarcoma of tendons and aponeuroses: a study of 75 patients Cancer 109 2007 109 116 17133413 \n9 Ipach I. Mittag F. Kopp H.G. Kunze B. Wolf P. Kluba T. Clear-cell sarcoma of the soft tissue–a rare diagnosis with a fatal outcome Eur J Cancer Care Engl 21 2012 412 420 22150806\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1017-995X",
"issue": "50(4)",
"journal": "Acta orthopaedica et traumatologica turcica",
"keywords": "Clear cell sarcoma; Giant; Scapular",
"medline_ta": "Acta Orthop Traumatol Turc",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D003606:Dacarbazine; D015251:Epirubicin; D017809:Fatal Outcome; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018227:Sarcoma, Clear Cell; D012983:Soft Tissue Neoplasms; D014055:Tomography, Emission-Computed",
"nlm_unique_id": "9424806",
"other_id": null,
"pages": "473-6",
"pmc": null,
"pmid": "27452744",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17133413;20390470;14332545;22041928;16893467;12943620;22150806;22693489;22151733",
"title": "A giant clear cell sarcoma on right scapular: A case report.",
"title_normalized": "a giant clear cell sarcoma on right scapular a case report"
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"abstract": "We report the case of a 77-year-old woman with diabetic chorea, which presented as hemiballism of the right limbs. Initial blood examination revealed that sugar and hemoglobin A1c levels were 732 mg/dl and 12.2%, respectively. Thus, a diagnosis of hyperglycemic hyperosmolar syndrome was made at a previous hospital. Ballism of the right limbs developed after 10 days and progressively worsened. After a month, the patient was admitted to our hospital. Brain MRI (axial T1-weighted imaging) revealed a high-signal-intensity area in the left striatum. Dopamine transporter SPECT demonstrated reduced 123I-ioflupane binding in the bilateral striatum with left side predominance. Although haloperidol and risperidone were ineffective for her involuntary movement, chlorpromazine had a little effect. Levodopa and gabapentin combination treatments were effective in decreasing the symptoms. It was considered that dopamine antagonist was the medical treatment for diabetic chorea and that levodopa could worsen neurological symptoms such as chorea-ballism. However, in our case, levodopa treatment was effective.",
"affiliations": "Department of Neurology, Kasugai City Hospital.;Department of Neurology, Kasugai City Hospital.;Department of Neurology, Kasugai City Hospital.;Department of Neurology, Kasugai City Hospital.;Department of Neurology, Kasugai City Hospital.;Department of Neurology, Kasugai City Hospital.",
"authors": "Yokoi|Katsunori|K|;Kazuta|Tomoyuki|T|;Torii|Ryouta|R|;Endo|Toshihiro|T|;Araki|Amane|A|;Terao|Shinichi|S|",
"chemical_list": "D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D050483:Dopamine Plasma Membrane Transport Proteins; D007980:Levodopa; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin",
"country": "Japan",
"delete": false,
"doi": "10.5692/clinicalneurol.cn-001041",
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"issn_linking": "0009-918X",
"issue": "57(10)",
"journal": "Rinsho shinkeigaku = Clinical neurology",
"keywords": "ballism; diabetic chorea; dopamine transporter SPECT; levodopa",
"medline_ta": "Rinsho Shinkeigaku",
"mesh_terms": "D000368:Aged; D000588:Amines; D002819:Chorea; D003342:Corpus Striatum; D003509:Cyclohexanecarboxylic Acids; D048909:Diabetes Complications; D050483:Dopamine Plasma Membrane Transport Proteins; D004359:Drug Therapy, Combination; D020820:Dyskinesias; D005260:Female; D000077206:Gabapentin; D006801:Humans; D006944:Hyperglycemic Hyperosmolar Nonketotic Coma; D007980:Levodopa; D015899:Tomography, Emission-Computed, Single-Photon; D016896:Treatment Outcome; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "0417466",
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"pages": "591-594",
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"pmid": "28954970",
"pubdate": "2017-10-27",
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"references": null,
"title": "Effectiveness of levodopa treatment for diabetic chorea with reduced striatal accumulation in dopamine transporter SPECT: a case report.",
"title_normalized": "effectiveness of levodopa treatment for diabetic chorea with reduced striatal accumulation in dopamine transporter spect a case report"
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"abstract": "Temozolomide is an oral alkylating agent indicated for the treatment of patients with glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment. We report the case of a patient who developed toxic epidermal necrolysis (TEN) while she was being treated with chemoradiotherapy and several drugs. Cutaneous tests were performed with the drugs involved with negative result. Although the occurrence of TEN contraindicates suspected drug readministration, we based the decision to perform the controlled administration of temozolomide on the following reasons: (1) the poor prognosis of the underlying disease, (2) the lack of therapeutic alternatives, (3) the suspicion that other drugs taken by the patient simultaneously may be responsible (as anticonvulsants and trimethoprim sulfamethoxazole [TMP-SMX]), and (4) temozolomide was the first choice for treating the patient's disease. The administration of a cumulative dose of 60 mg of temozolomide caused a slight skin reaction. Given this result, we conducted controlled administration of other drugs involved. Dexamethasone, codeine, omeprazole and levetiracetam were well tolerated. However, TMP-SMX produced a similar reaction to that caused by temozolomide. In conclusion, we present the first case of TEN induced by temozolomide and TMP-SMX associated with cranial radiotherapy confirmed by controlled administration. Radiotherapy in combination with these drugs could have favored TEN, as some authors have postulated, but we cannot prove this.",
"affiliations": "Department of Allergology and Clinical Immunology, Infanta Cristina University Hospital, Badajoz, Spain.;Department of Allergology and Clinical Immunology, Infanta Cristina University Hospital, Badajoz, Spain.;Department of Allergology and Clinical Immunology, Infanta Cristina University Hospital, Badajoz, Spain.;Department of Allergology and Clinical Immunology, Infanta Cristina University Hospital, Badajoz, Spain.;Department of Dermatology, Infanta Cristina University Hospital, Badajoz, Spain.;Department of Anatomical Pathology, Infanta Cristina University Hospital, Badajoz, Spain.",
"authors": "Pérez-Calderón|Remedios|R|;Gonzalo-Garijo|M Angeles|MA|;Corrales-Vargas|Silvia|S|;Jiménez-Ferrera|Gloria|G|;Rodríguez-Nevado|Isabel|I|;Díaz-Delgado|Mario|M|",
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"doi": "10.4168/aair.2015.7.2.199",
"fulltext": "\n==== Front\nAllergy Asthma Immunol ResAllergy Asthma Immunol ResAAIRAllergy, Asthma & Immunology Research2092-73552092-7363The Korean Academy of Asthma, Allergy and Clinical Immunology; The Korean Academy of Pediatric Allergy and Respiratory Disease 10.4168/aair.2015.7.2.199Case ReportToxic Epidermal Necrolysis in Polymedicated Patient Treated With Radiotherapy Pérez-Calderón Remedios 1Gonzalo-Garijo M. Angeles 1Corrales-Vargas Silvia 1Jiménez-Ferrera Gloria 1Rodríguez-Nevado Isabel 2Díaz-Delgado Mario 31 Department of Allergology and Clinical Immunology, Infanta Cristina University Hospital, Badajoz, Spain.2 Department of Dermatology, Infanta Cristina University Hospital, Badajoz, Spain.3 Department of Anatomical Pathology, Infanta Cristina University Hospital, Badajoz, Spain.\nCorrespondence to: M. Ángeles Gonzalo-Garijo MD, PhD, Department of Allergology and Clinical Immunology, Hospital Universitario Infanta Cristina, Sección de Alergología, Carretera de Portugal, s/n. 06080, Badajoz, Spain. Tel: +34 924 219834; Fax: +34 924 218110; magonzalog@gmail.com3 2015 19 9 2014 7 2 199 201 07 2 2014 27 5 2014 23 6 2014 Copyright © 2015 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Temozolomide is an oral alkylating agent indicated for the treatment of patients with glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment. We report the case of a patient who developed toxic epidermal necrolysis (TEN) while she was being treated with chemoradiotherapy and several drugs. Cutaneous tests were performed with the drugs involved with negative result. Although the occurrence of TEN contraindicates suspected drug readministration, we based the decision to perform the controlled administration of temozolomide on the following reasons: (1) the poor prognosis of the underlying disease, (2) the lack of therapeutic alternatives, (3) the suspicion that other drugs taken by the patient simultaneously may be responsible (as anticonvulsants and trimethoprim sulfamethoxazole [TMP-SMX]), and (4) temozolomide was the first choice for treating the patient's disease. The administration of a cumulative dose of 60 mg of temozolomide caused a slight skin reaction. Given this result, we conducted controlled administration of other drugs involved. Dexamethasone, codeine, omeprazole and levetiracetam were well tolerated. However, TMP-SMX produced a similar reaction to that caused by temozolomide. In conclusion, we present the first case of TEN induced by temozolomide and TMP-SMX associated with cranial radiotherapy confirmed by controlled administration. Radiotherapy in combination with these drugs could have favored TEN, as some authors have postulated, but we cannot prove this.\n\nDrug hypersensitivityradiotherapytemozolomidetoxic epidermal necrolysistrimethoprim sulfamethoxazole\n==== Body\nINTRODUCTION\nTemozolomide is an oral alkylating agent indicated for the treatment of patients with glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment.1 Toxic epidermal necrolysis (TEN) is an acute life-threatening mucocutaneous disorder with detachment of body surface area >30%. The majority of cases of TEN are the result of a hypersensitivity reaction to a drug.2 We report the case of a patient who developed TEN while she was being treated with chemoradiotherapy and several drugs.\n\nCASE REPORT\nA 37-year-old woman was being treated for a frontal glioblastoma multiforme with temozolomide (160 mg daily), cranial radiotherapy (60 Gy daily from Monday to Friday), levetiracetam, trimethoprim-sulfamethoxazole (TMP-SMX), omeprazole, codeine and dexamethasone. All drugs were started simultaneously. At 3-4 weeks of treatment, the patient started with eye symptoms (conjunctival hyperemia, epiphora, itching and discharge mucopurulent) that were attributed to radiotherapy by doctors in the Emergency Room. Four days later she added burning sensation and macular rash on her face, and in the next 24 hours erythematous violaceous macules appeared in cranial region, face, ears and neck with intense burning. Besides skin involvement, she had genital burning, but no malaise, fever or itching. The patient continued treatment and she was treated with methylprednisolone and dexchlorpheniramine on three occasions in the emergency services. One week later, she was evaluated in our clinics for worsening with dysphagia, malaise, bullous lesions on ears and face, and violaceous macules (not blanched on pressure) and confluent target-like lesions in the abdomen, proximal part of the upper extremities and legs, palms and soles. The patient had fever (37.5℃) and Nikolsky's sign was positive. The evaluation by ophthalmologist revealed crusty lid margins, tarsal and bulbar hyperemia, left inferior tarsus membranes, clear corneas without ulcers and transparent media with normal iris. Previous ocular symptoms had worsened and the patient also had ocular pain and photophobia.\n\nThe patient was hospitalized with a SCORTEN (Severity of Illness Score for Toxic Epidermal Necrolysis) of 2.3 On admission, the blood count and coagulation studies were normal, biochemistry parameters were within their respective reference ranges except total cholesterol (308 mg/dL), and blood cultures proved negative. Radiotherapy and medication that the patient was taking were discontinued, and she was treated with supportive measures and intravenous methylprednisolone, antihistamines and ranitidine. Nevertheless, the blistering rash became widespread in about 24 hours with palmoplantar involvement and denudation of the skin over 30% of her body surface. In addition to previous treatment, she was treated with dexamethasone and erythromycin eye drops, mouthwashes with lidocaine, intravenous amoxicillin-clavulanate and subcutaneous enoxaparin. The patient gradually improved within 4 weeks, and the only sequel was just dry eye. The skin biopsy performed the day after hospital admission was consistent with TEN and showed keratinocyte necrosis and subepidermal blisters (Figure). Six weeks after the reaction, patch tests and intradermal tests were performed with negative result (Table 1).\n\nAlthough the occurrence of TEN contraindicates suspected drug readministration, we based the decision to perform the controlled administration of temozolomide on the following reasons: (1) the poor prognosis of the underlying disease, (2) the lack of therapeutic alternatives, (3) the suspicion that other drugs taken by the patient simultaneously may be responsible (as anticonvulsants and trimethoprim sulfamethoxazole [TMP-SMX]), and (4) temozolomide was the first choice for treating the patient's disease.1 Ten weeks after cessation of radiotherapy, and once the patient signed the informed consent (July 20), we administered 20 mg of temozolomide orally and 30 minutes later 40 mg. Half an hour later the patient had burning sensation and redness in her face, anterior chest and arms with macules on her back. She improved in about 2 hours after administration of methylprednisolone and dexchlorpheniramine. The patient was kept in hospital and 6 hours later erythema and skin burning sensation reappeared and was controlled with the same treatment by one hour. Given this result, we conducted controlled administration of other drugs involved. Omeprazole (September 4), codeine (September 5), dexamethasone (September 27) and levetiracetam (November 29) were well tolerated. However, administration of a quarter of a tablet of TMP-SMX (160/800 mg) (October 20) produced at 30 minutes a similar reaction to that caused by temozolomide, but slighter, that disappeared within one hour after corticosteroids and antihistamines administration (there was no delayed reaction).\n\nDISCUSSION\nThe main problem when a severe reaction occurs in a patient polymedicated is to identify the responsible drug. Unfortunately, there are no diagnostic tests useful in the case of TEN and in vivo tests must be made with caution. In our case, the serious situation of the patient motivated us to search for the causative drug by skin tests, but they were not useful (as in other publications4).\n\nHypersensitivity reactions (as erythema multiforme, erythroderma, urticaria, exantema, anaphylaxis, and angioedema) have been rarely described with temozolomide.1,4,5 In the literature, we have found one case of Stevens-Johnson syndrome (SJS) and TEN overlap in a patient treated with oral temozolomide, cranial radiotherapy, diclofenac and phenytoin,6 and other case of TEN in a patient treated with the same drugs excepting diclofenac.7 In the first case, the authors assumed that temozolomide was responsible for the reaction, since the patient did not discontinue phenytoin and diclofenac despite the reaction, and he improved.6 In the second case, both phenytoin and temozolomide could be responsible for the reaction, and the authors further pointed out the possibility that radiation can promote reactions with some drugs such as phenytoin and other anticonvulsants.7\n\nObtaining a positive result with temozolomide with mild reaction encouraged us to test the rest of the drugs, as all of them were necessary to improve the quality of life of the patient. However, we were surprised by the positivity of TMP-SMX, as it is not common to find multiple etiologies in TEN. Interestingly, there is a reported case of a patient with a history of allergy to TMP-SMX that presented an anaphylaxis reaction with temozolomide.4\n\nIn the literature, it is postulated that radiotherapy could enhance the ability of some drugs to produce TEN, overall anticonvulsivants and aminofostine.8 Several mechanisms have been proposed for the involvement of radiotherapy in the development of SJS and TEN. The addition of radiotherapy may cause an enzyme inhibition or deficiency, which in turn would prevent biotransformation of the reactive metabolites. As these accumulate, they may act as haptens and initiate a secondary immunologic response. On the other hand, radiotherapy could also modify the pool of T-suppressor lymphocytes.7 In our case, the reactions due to controlled administration of temozolomide and TMP-SMX without radiotherapy were earlier and milder than the first reaction. It has been described that upon readministration of the implicated drug, TEN may develop within hours,2 and the earlier the causative drug is withdrawn, the better the prognosis.3 In our case, we administered the drug fractionally and the patient had a mild and early reaction with sub-therapeutic doses. We immediately treated this reaction, which could prevent the progression of the reaction. There is no experience in the literature on controlled drug challenge when TEN is suspected, so we unknown if these milder reactions would be expected. In addition to that, we propose as a hypothesis that radiotherapy administered with the drugs involved could have influenced the severity of the reaction, but obviously we cannot prove this.\n\nIn conclusion, we present the first case of TEN induced by temozolomide and TMP-SMX associated with cranial radiotherapy confirmed by controlled administration. Radiotherapy in combination with these drugs could have favored TEN, as some authors have postulated.\n\nThere are no financial or other issues that might lead to conflict of interest.\n\nFigure Histology of TEN. The skin biopsy performed the day after hospital admission was consistent with TEN and showed keratinocyte necrosis and subepidermal blisters.\nTable Cutaneous tests with the drugs involved\nDrug\tPatch tests*\tIntradermal tests§\tResults\t\nCodeine\t30% pet\tND\tNegative\t\nDexamethasone\t30% pet\t0.04-0.4 mg/mL\tNegative\t\nLevetiracetam\t30% pet\tND\tNegative\t\nOmeprazole\t30% pet\t0.1-1 mg/mL\tNegative\t\nTemozolomide\t5% pet†\tND‡\tNegative\t\n5% water†\t\tNegative\t\nTrimethoprim\t30% pet\t0.001 mg/mL\tNegative\t\nSulfamethoxazole\t30% pet\t10 mg/mL\tNegative\t\n*Reading at 48 and 96 hours; †Concentrations described in reference 4; ‡These tests were not performed with temozolomide because of lack of knowledge on its potential skin toxicity; §Immediate and delayed readings at 6, 24, and 48 hours.\n\nND, Not done.\n==== Refs\n1 European Medicines Agency (GB) Annex I: summary of product characteristics [Internet] London European Medicines Agency 2013 cited 2013 Dec 4 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001128/WC500079539.pdf \n2 Schwartz RA McDonough PH Lee BW Toxic epidermal necrolysis: Part I. Introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis J Am Acad Dermatol 2013 69 173.e1 173.e13 23866878 \n3 Schwartz RA McDonough PH Lee BW Toxic epidermal necrolysis: Part II. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment J Am Acad Dermatol 2013 69 187.e1 187.e16 23866879 \n4 Mónica RG De Las Heras Gozalo M de la Barrera EH Dominguez JS Successful desensitization with temozolomide Ann Allergy Asthma Immunol 2011 106 541 542 21624758 \n5 Alonso-Llamazares A Vega-Castro A Beitia-Mazuecos JM Mateo-Borrega B Cardenas-Contreras R Rapid desensitization with temozolomide in patients with delayed maculopapular rash J Investig Allergol Clin Immunol 2012 22 448 449 \n6 Sarma N Stevens-Johnson Syndrome and toxic epidermal necrolysis overlap due to oral temozolomide and cranial radiotherapy Am J Clin Dermatol 2009 10 264 267 19489660 \n7 Poletti ED Muñoz Sandoval R Guzmán Perera G González Fisher RF Márquez Díaz F Melanoma metastásico, radioterapia holocraneal y dermatitis por aumento de la radiación Dermatología Rev Mex 2011 55 388 394 \n8 Vern-Gross TZ Kowal-Vern A Erythema multiforme, Stevens Johnson syndrome, and toxic epidermal necrolysis syndrome in patients undergoing radiation therapy: a literature review Am J Clin Oncol 2014 37 506 513 22892429\n\n",
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"title": "Toxic epidermal necrolysis in polymedicated patient treated with radiotherapy.",
"title_normalized": "toxic epidermal necrolysis in polymedicated patient treated with radiotherapy"
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"abstract": "This case report reviews the hospital course of a 15-month-old girl admitted to the PICU for acute respiratory failure due to enterovirus infection; who subsequently had multiple extubation failures secondary to acute transverse myelitis. This rare presentation highlights the importance of assessing the neurological status in a patient with rhino-enteroviral respiratory infection and of considering acute transverse myelitis as an etiology for difficulty with extubation.",
"affiliations": "The Children's Hospital of San Antonio, San Antonio, TX, USA.;The Children's Hospital of San Antonio, San Antonio, TX, USA.",
"authors": "Annamalai|M R|MR|;Bhalala|U|U|",
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"doi": "10.4103/jpgm.JPGM_883_20",
"fulltext": "\n==== Front\nJ Postgrad Med\nJ Postgrad Med\nJPGM\nJournal of Postgraduate Medicine\n0022-3859\n0972-2823\nWolters Kluwer - Medknow India\n\n33835055\nJPGM-67-106\n10.4103/jpgm.JPGM_883_20\nCase Report\nMultiple extubation failures following a rhino-enteroviral infection: A unique case report in a pediatric patient\nAnnamalai MR\nBhalala U\nThe Children's Hospital of San Antonio, San Antonio, TX, USA\nAddress for correspondence: Dr. Bhalala U, E-mail: utpal.bhalala@bcm.edu\nApr-Jun 2021\n03 4 2021\n67 2 106108\n25 7 2020\n28 12 2020\n06 1 2021\nCopyright: © 2021 Journal of Postgraduate Medicine\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nThis case report reviews the hospital course of a 15-month-old girl admitted to the PICU for acute respiratory failure due to enterovirus infection; who subsequently had multiple extubation failures secondary to acute transverse myelitis. This rare presentation highlights the importance of assessing the neurological status in a patient with rhino-enteroviral respiratory infection and of considering acute transverse myelitis as an etiology for difficulty with extubation.\n\nKEY WORDS:\n\nAcute transverse myelitis\nenterovirus\nextubation failure\n==== Body\nIntroduction\n\nExtubation failure in critically ill pediatric patients has been shown to be independently associated with up to a five-fold increased risk of mortality.[1] Although risk factors for extubation failures have been well described, which include young age, prolonged mechanical ventilation, sedative usage, and recently diaphragm atrophy, the etiologies underlying extubation failures are still poorly understood.[2] We describe a case report of a toddler with multiple failed extubation attempts secondary to rare complications of an enterovirus infection, reported in only two other pediatric patients.\n\nCase History\n\nA 15-month-old previously healthy and developmentally normal female presented to an outside hospital emergency department (ED) with 5 days of cough and congestion. While in the ED, she developed hypoxia and significant respiratory distress, requiring intubation and subsequent transfer to our institution's pediatric intensive care unit for further management.\n\nShe was intubated with a 4.0 uncuffed ET tube, discovered to be in the right mainstem bronchus and subsequently drawn back to the appropriate location upon admission. A respiratory panel PCR obtained was positive for rhinovirus/enterovirus. The transport team placed the patient on sedation infusions during medical transport, which was continued upon ICU admission. Because the patient was stable on mechanical ventilation with a source for respiratory failure, sedation was not weaned to attempt a thorough neurological examination upon admission. The only neurological examination performed was a pupillary examination revealing adequate sedation. Extubation was attempted on day one of her hospitalization. Prior to this extubation event and each extubation event thereafter, the team ensured improvement in her lung pathology using clinical and radiologic evidence, including an exam that revealed good sounds bilaterally without crackles or wheezes and pre-extubation x-rays that revealed significant improvement in lung pathology including atelectasis, pulmonary edema, and pleural effusions. Additionally, the patient tolerated continuous positive airway pressure (CPAP) trials and was weaned to minimal ventilation support. The first extubation attempt was unsuccessful and she was re-intubated that day with a 3.5 cuffed ET tube situated appropriately. After providing the patient with increased positive end-expiratory pressure (PEEP) and frequency of pulmonary toilet regimen, respiratory status gradually improved with settings able to be weaned. On hospital day seven, the patient underwent a second attempt at extubation that was unsuccessful, and the patient was subsequently re-intubated with a 3.5 cuffed ET tube situated appropriately. Pulmonology was consulted to assist with management and performed a bronchoscopy that was unremarkable and ruled out anatomical defects. On hospital day 16 after continued improvement in respiratory status, the patient underwent a third extubation attempt that was successful. The patient quickly transitioned from bilevel positive airway pressure (BiPAP) to high flow nasal cannula (HFNC).\n\nOn hospital day 18, the patient required an increase in respiratory support back to BiPAP and was noted to have movement in her bilateral lower extremities but not in her bilateral upper extremities. All sedation was subsequently held. Neurology was consulted and upon examination noted intact cranial nerves, diffuse hypotonia, 0/5 motor strength in bilateral upper extremities and 3/5 motor strength in bilateral lower extremities, absence of deep tendon reflexes throughout all extremities, and indeterminate sensation in all extremities. An MRI of her brain and spine under sedation was obtained for further workup. MRI showed lesions involving predominantly white matter in the cervical cord from the C2 to T2 levels [see Figure 1], suggestive of a viral myelitis. Repeat MRI with DWI was obtained and ruled out infarction. Infectious disease was consulted and recommended obtaining an LP with CSF and send-out serum autoimmune and demyelinating panels, particularly neuromyelitis optica and lupus. All laboratory tests obtained in this stage of the workup, including infectious and autoimmune conditions, came back normal [Table 1].\n\nFigure 1 Cervical spine magnetic resonance imaging (MRI) with and without contrast showing patchy T2 hyperintensity involving predominantly white matter from second cervical spine to second thoracic spine (C2 to T2) levels on T2 turbo spin echo (TSE) imaging. There is myelomalacia at the third cervical spine to seventh cervical spine (C3 to C7) levels. Repeat imaging showed no definite enhancement or diffusion restriction\n\nTable 1 CSF study results obtained from the first lumbar puncture\n\nCSF parameters\tResults\t\nWBC (/mm3)\t<1\t\nRBC (/mm3)\t3\t\nGlucose (mg/dL)\t75\t\nTotal protein (mg/dL)\t20.8\t\nMeningitis/encephalitis viral panel\tNot detected\t\nWest Nile IgM Ab\t0 (negative)\t\nNMO*/aquaporin-4 IgG Ab\t<1:1 (negative)\t\nVDRL†\tnegative\t\n*NMO=Neuromyelitis optica †VDRL=Venereal Disease Research Laboratory\n\nDue to high index of suspicion for an autoimmune process while waiting for the send-out tests to result, this patient received high dose steroids for 5 days started on hospital day 21, followed by five doses of plasmapheresis in conjunction with hydrocortisone started on hospital day 24, and finally a five-day course of IVIG started on hospital day 36.\n\nFollowing her initial MRI, the patient returned with an LMA and was re-intubated soon afterwards due to mixed respiratory failure. The patient continued to have no change in symptoms following the intense medication regimen. Due to inability to wean off mechanical ventilation, the patient underwent tracheostomy on hospital day 39 and was eventually transitioned to a trilogy ventilator. The patient was admitted to the inpatient rehabilitation service on hospital day 57. She received a gastrostomy tube on hospital day 74. She was discharged on hospital day 107 with diagnosis of transverse myelitis secondary to enterovirus resulting in tetraplegia, dependence on tracheostomy, ventilator, and gastrostomy tube [Figure 2].\n\nFigure 2 Timeline of patient course throughout hospitalization. CPAP = Continuous Positive Airway Pressure, BiPAP = Bilevel Positive Airway Pressure, MRI = Magnetic Resonance Imaging, ID = Infectious Disease, LP = Lumbar Puncture, PLEX = Plasma Exchange, IVIG = Intravenous Immunoglobulin\n\nDiscussion\n\nOur case described here is a unique report of respiratory failure secondary to acute transverse myelitis (ATM) caused by enterovirus in a young child who had multiple extubation failures. Two main types of acute myelitis exist: AFM and ATM.[3] AFM has an incidence of 14 children out of every 1,000,000 and is characterized by lesions primarily restricted to the anterior horn cells resulting in primarily motor weakness. AFM has been shown to be temporally associated with enterovirus D68 and A71, although its causality has yet to be proven.[4] The typical clinical course of AFM involves unilateral paralysis of an extremity that may spread to other extremities. ATM, which our patient was diagnosed with, is less common, with an incidence of two out of 1,000,000 children affected each year. Etiology is thought to be immune mediated, but no identifiable marker has been elicited, and most cases are associated with infectious prodrome.[5] Lesions in both gray and white matter result in sensory, motor, and autonomic dysfunction. Paralysis is typically bilateral and can be rapid. Very few case reports describe enterovirus-associated ATM, and most of these cases have been described in adults.[678910] The only documented case reports of enteroviral-associated ATM in pediatric patients include two patients in a 14 patient case series from Western Australia, in which both patients presented with rapid-onset acute flaccid paralysis and resulted in quadriparesis similar to our patient.[11]\n\nThe diagnostic criteria for ATM consist of exclusion of compressive lesions and confirmation of spinal cord inflammation as detected by either: A gadolinium-enhancing lesion in MRI, or CSF evidence of either pleocytosis or elevated immunoglobulin type G (IgG) index. Additionally, exclusion of demyelinating conditions, such as neuromyelitis optica and systemic autoimmune conditions, such as lupus is necessary.[6]\n\nTreatment for ATM includes high dose steroids, intravenous immunoglobulin (IVIG), and plasmapheresis, but no prospective trials have demonstrated efficacy to date. Retrospective analysis has shown improved outcomes with high dose steroids and plasmapheresis in pediatric patients with ATM, and efficacy of IVIG is limited to case reports and series.[1213] Treatment with high dose steroids is preferable as soon as ATM is suspected given that outcomes of patients with mimics of the disease do not worsen with treatment.[13] There is a paucity of literature discussing respiratory dysfunction or the optimal supportive management in acute transverse myelitis. Borrowing from management strategies for acute respiratory failure in neuromuscular disorders, non-invasive ventilation (NIV) is initially used by many institutions although the efficacy of NIV over mechanical ventilation has not been well studied.[14]\n\nIn our patient, the respiratory panel PCR being positive for rhino-enteroviral infection and an extubation failure warranted further investigation into underlying etiologies. The patient's young age put her at increased risk of extubation failure but given that she had failed extubation twice within 7 days of hospitalization, prolonged mechanical ventilation, and sedation were not likely risk factors. Successful CPAP trials and pre-extubation dexamethasone prior to the second and third attempt preceded all extubation attempts. Additionally, there were no confounding factors of high-dose steroids, paralytic drug infusions, or drug-induced myopathy prior to diagnosis of ATM.\n\nDeclaration of patient consent\n\nThe authors certify that appropriate patient consent was obtained.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\n1 Edmunds S Weiss I Harrison R Extubation failure in a large pediatric ICU population Chest 2001 119 897 900 11243974\n2 Silva-Cruz AL Velarde-Jacay K Carreazo NY Escalante-Kanashiro R Risk factors for extubation failure in the intensive care unit Rev Bras Ter Intensiva 2018 30 294 300 30304083\n3 Theroux LM Brenton JN Acute transverse and flaccid myelitis in children Curr Treat Options Neurol 2019 21 64 31792626\n4 Fatemi Y Chakraborty R Acute flaccid myelitis: A clinical overview for 2019 Mayo Clin Proc 2019 94 875 81 31054607\n5 Absoud M Greenberg BM Lim M Lotze T Thomas T Deiva K Pediatric transverse myelitis Neurology 2016 87 9 Suppl 2 S46 52 27572861\n6 Ooi M Wong S Lewthwaite P Cardosa M Solomon T Clinical features, diagnosis, and management of enterovirus 71 Lancet Neurol 2010 9 1097 105 20965438\n7 Teoh H Mohammad S Britton P Kandula T Lorentzos M Booy R Clinical characteristics and functional motor outcomes of enterovirus 71 neurological disease in children JAMA Neurol 2016 73 300 7 26785318\n8 Cação G Martins J Pereira JP Correia AP Damásio J A rare infectious cause of transverse myelitis Can J Neurol Sci 2017 44 110 11 28004628\n9 Araujo B Dalcol A Vasconcellos A Victal S Seabra A Case report: Transverse myelitis caused by enterovirus infection Arch Dis Child 2012 97 Suppl 2 A163 4\n10 Jeffery D Mandler R Davis L Transverse myelitis: Retrospective analysis of 33 cases, with differentiation of cases associated with multiple sclerosis and parainfectious events Arch Neurol 1993 50 532 5 8489410\n11 McMinn P Stratov I Nagarajan L Davis S Neurological manifestations of enterovirus 71 infection in children during an outbreak of hand, foot, and mouth disease in western Australia Clin Infect Dis 2001 32 236 42 11170913\n12 Noland DK Greenberg BM Safety and efficacy of plasma exchange in pediatric transverse myelitis Neurol Clin Pract 2008 8 327 30\n13 Nosadini M Mohammad SS Suppiej A Sartori S Dale RC Intravenous immunoglobulin in paediatric neurology: Safety, adherence to guidelines, and long-term outcome Dev Med Child Neurol 2016 58 1180 92 27242065\n14 Luo F Annane D Orlikowski D He L Yang M Zhou M Invasive versus non-invasive ventilation for acute respiratory failure in neuromuscular disease and chest wall disorders Cochrane Database Syst Rev 2017 12 CD008380 29199768\n\n",
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"issue": "67(2)",
"journal": "Journal of postgraduate medicine",
"keywords": "Acute transverse myelitis; enterovirus; extubation failure",
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"title": "Multiple extubation failures following a rhino-enteroviral infection: A unique case report in a pediatric patient.",
"title_normalized": "multiple extubation failures following a rhino enteroviral infection a unique case report in a pediatric patient"
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"abstract": "Echinocandins represent the first-line therapy of candidemia. Echinocandin resistance among Candida spp. is mainly due to acquired FKS mutations. In this study, we report the emergence of FKS-mutant Candida albicans/glabrata in Switzerland and provide the microbiological and clinical characteristics of 9 candidemic episodes. All patients were previously exposed to echinocandins (median 26 days; range 15-77). Five patients received initial echinocandin therapy with persistent candidemia in 4 of them. Overall mortality was 33%.",
"affiliations": "Institute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.;Service of Infectious Diseases, Centre Hospitalier Universitaire Vaudois, Lausanne University Hospital and University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland.;Institute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.;Division of Infectious Diseases and Hospital Epidemiology, University and University Hospital of Basel, Basel, Switzerland.;Division of Clinical Bacteriology and Mycology, University and University Hospital of Basel, Basel, Switzerland.;Clinica Luganese Moncucco, Lugano, Switzerland.;SYNLAB Suisse SA, Bioggio, Switzerland.;Division of Infectious Diseases and Hospital Epidemiology, Kantonsspital St.Gallen, St.Gallen, Switzerland.;Service of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland.;Service of Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland.;Institute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.;Institute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.;Institute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. frederic.lamoth@chuv.ch.",
"authors": "Coste|A T|AT|;Kritikos|A|A|;Li|J|J|;Khanna|N|N|;Goldenberger|D|D|;Garzoni|C|C|;Zehnder|C|C|;Boggian|K|K|;Neofytos|D|D|;Riat|A|A|;Bachmann|D|D|;Sanglard|D|D|;Lamoth|F|F|http://orcid.org/0000-0002-1023-5597;|||",
"chemical_list": "D000935:Antifungal Agents; D054714:Echinocandins",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-020-01475-8",
"fulltext": "\n==== Front\nInfection\nInfection\nInfection\n0300-8126 1439-0973 Springer Berlin Heidelberg Berlin/Heidelberg \n\n1475\n10.1007/s15010-020-01475-8\nBrief Report\nEmerging echinocandin-resistant Candida albicans and glabrata in Switzerland\nCoste A. T. 1 Kritikos A. 2 Li J. 12 Khanna N. 3 Goldenberger D. 4 Garzoni C. 5 Zehnder C. 6 Boggian K. 7 Neofytos D. 8 Riat A. 9 Bachmann D. 1 Sanglard D. 1 http://orcid.org/0000-0002-1023-5597Lamoth F. frederic.lamoth@chuv.ch 12 The Fungal Infection Network of Switzerland (FUNGINOS)Lamoth F. Khanna N. Boggian K. Sanglard D. 1 grid.8515.90000 0001 0423 4662Institute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland \n2 grid.8515.90000 0001 0423 4662Service of Infectious Diseases, Centre Hospitalier Universitaire Vaudois, Lausanne University Hospital and University of Lausanne, Rue du Bugnon 46, 1011 Lausanne, Switzerland \n3 grid.410567.1Division of Infectious Diseases and Hospital Epidemiology, University and University Hospital of Basel, Basel, Switzerland \n4 grid.410567.1Division of Clinical Bacteriology and Mycology, University and University Hospital of Basel, Basel, Switzerland \n5 grid.483007.80000 0004 0514 9525Clinica Luganese Moncucco, Lugano, Switzerland \n6 SYNLAB Suisse SA, Bioggio, Switzerland \n7 grid.413349.80000 0001 2294 4705Division of Infectious Diseases and Hospital Epidemiology, Kantonsspital St.Gallen, St.Gallen, Switzerland \n8 grid.150338.c0000 0001 0721 9812Service of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland \n9 grid.150338.c0000 0001 0721 9812Service of Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland \n13 7 2020 \n13 7 2020 \n2020 \n48 5 761 766\n22 5 2020 28 6 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Echinocandins represent the first-line therapy of candidemia. Echinocandin resistance among Candida spp. is mainly due to acquired FKS mutations. In this study, we report the emergence of FKS-mutant Candida albicans/glabrata in Switzerland and provide the microbiological and clinical characteristics of 9 candidemic episodes. All patients were previously exposed to echinocandins (median 26 days; range 15–77). Five patients received initial echinocandin therapy with persistent candidemia in 4 of them. Overall mortality was 33%.\n\nFUNGINOSissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2020\n==== Body\nIntroduction\nThe pathogenic yeasts Candida spp. are an important cause of nosocomial bloodstream infections, which are associated with high mortality rates [1]. Candida albicans represents the most frequent cause of candidemia, but a progressive epidemiological shift towards more resistant non-albicans Candida spp. (e.g., Candida glabrata) is reported all over the world [1]. In this context, echinocandins (e.g., anidulafungin, caspofungin and micafungin) have become the first-line antifungal therapy because of their better efficacy and broader antifungal spectrum against Candida spp. compared to azoles [2]. However, increased use of echinocandins has been associated with the emergence of resistance to these drugs, which affects particularly C. albicans and C. glabrata [3]. Echinocandin resistance in Candida spp. results from well-defined mutations in hotspot regions of the FKS gene that encodes for the 1,3-beta-d-beta-glucan synthase, the target of echinocandins [4]. These mutations usually result in pan-echinocandin resistance and affect mainly C. glabrata (prevalence range 2–13%) and more rarely C. albicans (< 1%) [3, 5–9]. Previous echinocandin exposure has been identified as the main risk factor and was observed in most cases [3, 5]. Because of the limited therapeutic alternatives, in particular for C. glabrata candidemia, mortality rates are high (60%) [5]. In Switzerland, a recent nationwide survey of candidemia (2004–2013) reported a very low rate of FKS-mutant C. albicans and C. glabrata (2 out of 1624 isolates, 0.12%) [10]. However, several echinocandin-resistant isolates harbouring various types of FKS mutations have been reported from different centers since that time. The aim of this study was to characterize these strains and to report the clinical characteristics and outcome of their associated candidemic episodes.\n\nMaterials and methods\nPatients and data collection\nClinical isolates of candidemic C. albicans and C. glabrata that were non-susceptible to micafungin and/or anidulafungin according to the clinical breakpoints defined by the Clinical and Laboratory Standards Institute (CLSI) [11] were retrospectively identified by (i) screening of a nationwide survey of candidemia by the Fungal Infection Network of Switzerland (FUNGINOS) conducted from 2004 to 2013 in 25 university and university-affiliated medical centers of Switzerland, and (ii) a call to the microbiologists of the university hospitals to screen and send their candidemic Candida spp. isolates with phenotypic echinocandin resistance to the reference laboratory (Lausanne University Hospital) for the period 2013–2019. Demographic characteristics and clinical data were collected via a standard clinical report form (CRF) including underlying conditions, risk factors for candidemia, previous courses of antifungal therapy within the last 3 months, clinical characteristics, treatment and outcome of Candida infection.\n\nAntifungal susceptibility testing and sequencing\nAll Candida isolates were handled in our reference laboratory. Minimum inhibitory concentrations (MIC) of anidulafungin, micafungin, caspofungin and fluconazole were retested in duplicates by microbroth dilution method according to the protocol M27 (4th edition) of the CLSI [11]. Susceptibility (S), dose-dependent susceptibility (SDD) or resistance (R) were defined according to the CLSI breakpoints, which are for anidulafungin and caspofungin (in µg/mL): C. albicans\nS ≤ 0.25, R ≥ 1, C. glabrata\nS ≤ 0.12, R ≥ 0.5, for micafungin: C. albicans\nS ≤ 0.25, R ≥ 1, C. glabrata\nS ≤ 0.06, R ≥ 0.25, and for fluconazole: C. albicans\nS ≤ 2, R ≥ 8, C. glabrata SDD ≤ 32, R ≥ 64. Isolates for which MICs were confirmed to be above the susceptibility clinical breakpoints (i.e., classified as non-susceptible according to the CLSI breakpoints) for micafungin and/or anidulafungin were selected for genotypic characterization of FKS genes (of note, isolated elevated caspofungin MIC was not considered as a reliable predictor of FKS mutations on the basis of previous publications [10, 12]). PCR and sequencing of the hotspot regions (HS) of the FKS genes (HS1 and HS2 of FKS1 for C. albicans and C. glabrata and HS1 and HS2 of FKS2 for C. glabrata) were performed using the primers previously described [10].\n\nEthical statement\nThis study was approved by the Swiss ethics committee on research involving humans for retrospective use of clinical data (Swissethics reference # 2019-00484_1904).\n\nResults\nA total of 9 cases of candidemia due to echinocandin-resistant Candida spp. (4 C. albicans and 5 C. glabrata) were identified. Two cases with confirmed FKS mutations were obtained from the FUNGINOS nationwide survey from 2004 to 2013. Seven additional cases were reported from 4 hospitals from 2013 to 2019. In total, 5 of the 9 cases were observed within the last 2 years (2018–2019). For 4 cases, a susceptible isolate of the same Candida species was obtained from previous blood cultures (4–19 days before the candidemic episode attributed to the resistant isolate). MIC of anidulafungin, micafungin, caspofungin and fluconazole, as well as results of FKS hotspots sequencing for all the 9 cases (13 isolates, including the 9 echinocandin-resistant strains and the 4 previously susceptible strains) are shown in Table 1. The most frequent mutations were S645P (n = 3) for C. albicans and S663P in FKS2 (n = 3) for C. glabrata. The 3 remaining echinocandin-resistant isolates were one C. albicans with R1361G mutation and two C. glabrata isolates with S629P (FKS1) and F659_(FKS2) mutations, respectively. All 9 isolates were classified as non-susceptible to all three echinocandins according to CLSI breakpoints. One of the four echinocandin-resistant C. albicans isolates and all C. glabrata isolates were classified as susceptible dose-dependent to fluconazole. Absence of FKS mutations was confirmed for the 4 susceptible isolates obtained from the previous candidemic episodes.Table 1 Results of antifungal susceptibility testing and FKS sequencing of C. albicans and C. glabrata from candidemic episodes\n\nCases\tSpecies\tEpisode\tMIC µg/mL (CLSI classification)*\tFKS hotspot mutations**\t\nAND\tMCF\tCSP\tFLC\tFKS1\tFKS2\t\nHS1\tHS2\tHS1\tHS2\t\n1\tC. albicans\t1st\t0.25 (S)\t0.125 (S)\t0.5 (I)\t4 (SDD)\t–\t–\tna\t\n2nd\t2 (R)\t2 (R)\t4 (R)\t4 (SDD)\tS645P\t–\t\n2\tC. albicans\t1st\t2 (R)\t4 (R)\t8 (R)\t2 (S)\tS645P\t–\t\n3\tC. albicans\t1st\t2 (R)\t4 (R)\t > 16 (R)\t < 0.5 (S)\tS645P\t–\t\n4\tC. albicans\t1st\t2 (R)\t1 (R)\t1 (R)\t < 0.5 (S)\t–\tR1361G\t\n5\tC. glabrata\t1st\t2 (R)\t4 (R)\t > 16 (R)\t4 (SDD)\t–\t–\tS663P\t–\t\n6\tC. glabrata\t1st\t4 (R)\t4 (R)\t16 (R)\t4 (SDD)\t–\t–\tF659_\t–\t\n7\tC. glabrata\t1st\t0.25 (I)\t0.06 (S)\t0.25 (I)\t1 (SDD)\t–\t–\t–\t–\t\n2nd\t4 (R)\t4 (R)\t > 16 (R)\t1 (SDD)\t–\t–\tS663P\t–\t\n8\tC. glabrata\t1st\t0.12 (S)\t0.015 (S)\t0.06 (S)\t8 (SDD)\t–\t–\t–\t–\t\n2nd\t4 (R)\t4 (R)\t > 16 (R)\t4 (SDD)\t\t\tS663P\t\t\n9\tC. glabrata\t1st\t0.015 (S)\t0.015 (S)\t0.03 (S)\t4 (SDD)\t–\t–\t–\t–\t\n2nd\t0.25 (I)\t4 (R)\t16 (R)\t8 (SDD)\tS629P\t–\t–\t–\t\nMIC minimal inhibitory concentration, CLSI Clinical and Laboratory Standards Institute, AND anidulafungin, MCF micafungin, CSP caspofungin, FLC fluconazole, HS hotspot, R resistant, I intermediate, S susceptible, SDD susceptible dose-dependent\n\n*CLSI breakpoints [µg/mL]: anidulafungin and caspofungin: C. albicans S ≤ 0.25, R ≥ 1, C. glabrata S ≤ 0.12, R ≥ 0.5; Micafungin: C. albicans S ≤ 0.25, R ≥ R ≥ 1, C. glabrata S ≤ 0.06, R ≥ 0.25; Fluconazole: C. albicans S ≤ 2, R ≥ 8, C. glabrata SDD ≤ 32, R ≥ 64\n\n**All the indicated non-synonymous mutations were already demonstrated as responsible for echinocandin resistance. In bold: resistant isolates harboring FKS mutations. If available, sequencing and antifungal susceptibility testing results of previous candidemic episodes are shown (not in bold)\n\n\n\nClinical characteristics of the 9 cases are shown in Table 2. All patients have been exposed to echinocandins before the candidemic episode with the resistant isolate (median duration: 26 days, range 15–77). Five episodes were breakthrough candidemia (i.e., occurring while echinocandin treatment was ongoing). Five cases had a deep focus of infection (3 abdominal and 2 urinary), while candidemia was primary or originating from a catheter in 4 cases. Five patients received initial echinocandin therapy (duration 7–18 days) with persistent candidemia (duration between first and last positive blood cultures: 5–40 days) in 4 of them. In these cases, candidemia was cleared after switch to another antifungal drug (liposomal amphotericin B in most cases). Three of the nine patients died within 6 weeks from the candidemia and death was at least partially attributed to candidemia (i.e., active disease at time of death) in two cases.Table 2 Clinical characteristics of echinocandin-resistant C. albicans and C. glabrata candidemic episodes\n\nCase (year)\tUnderlying diseases\tCandida species\tPrior echinocandin exposure, days (drug)\tOrigin of candidemia\tDuration of candidemia (days first-last positive culture)\tTreatment\tOutcome (days from diagnosis) role of candidemia\t\n1 (2014)\tMale, 78 y.o\n\nProstatic cancer\n\nUrinary tract surgery\n\n\tC. albicans\t20 (CSP)\tUrinary\t5\tSurgery\n\nCatheter removal\n\nFLC (17 days)\n\n\tDied (day 23) Partial\t\n2 (2018)\tMale, 31 y.o\n\nMyeloablative chemotherapy for acute promyelocytic leukemia\n\n\tC. albicans\t15 (CSP)\tCatheter\t0\tL-AMB (1 day)\tDied (day 2) Major\t\n3 (2018)\tMale, 70 y.o\n\nSecondary peritonitis after vascular graft implantation\n\n\tC. albicans\t27 (CSP)\tAbdominal\t0\tSurgery\n\nFLC (nd)\n\n\tDied (day 42) No\t\n4 (2013)\tFemale, 74 y.o\n\nAbdominal surgery\n\n\tC. albicans\t61 (AND/CSP)\tAbdominal\t14\tCSP (7 days), then L-AMB (28 days)\n\nCatheter removal\n\n\tCured\t\n5 (2008)\tMale, 26 y.o\n\nMitochondrial encephalomyopathy\n\nAbdominal surgery\n\nAllogeneic HSCT\n\n\tC. glabrata\t25 (CSP)\tCatheter\t0\tCSP (14 days)\n\nCatheter removal\n\n\tCured\t\n6 (2015)\tMale, 60 y.o\n\nAcute myeloid leukemia\n\nAllogeneic HSCT\n\n\tC. glabrata\t-\tCatheter\t40\tCSP (18 days), then L-AMB (43 days)\n\nCatheter removal\n\n\tCured\t\n7 (2019)\tMale, 84 y.o\n\nGallbladder surgery\n\n\tC. glabrata\t18 (CSP)\tUrinary\t5\tCSP (7 days), then L-AMB (16 days), then FLC (20 days)\tCured\t\n8 (2019)\tFemale, 52 y.o\n\nAbdominal surgery, secondary peritonitis\n\n\tC. glabrata\t77 (CSP)\tAbdominal\t2\tCatheter removal\n\nL-AMB (13 days)\n\n\tCured\t\n9 (2019)\tFemale, 25 y.o\n\nAbdominal surgery, tertiary peritonitis\n\nRenal transplantation\n\n\tC. glabrata\t47 (CSP/AND)\tCatheter\t21\tCatheter removal\n\nAND (17 days), then L-AMB (7 days), then FLC (22 days)\n\n\tCured\t\ny.o. year old, HSCT hematopoietic stem cell transplantation, AND Anidulafungin, CSP Caspofungin, L-AMB liposomal amphotericin B, FLC fluconazole\n\n\n\nDiscussion\nIn this study, we described the microbiological and clinical characteristics of nine episodes of candidemia due to FKS-mutant C. albicans/glabrata that were observed in Switzerland between 2004 and 2019. The actual prevalence of these FKS mutations among C. albicans/glabrata candidemic episodes was assessed for the period 2004–2013 via a national surveillance program of the Fungal Infection Network of Switzerland (FUNGINOS) collecting all candidemic isolates from 25 Swiss medical centers (including all university and most university-affiliated hospitals) [10]. Only 2 FKS-mutant isolates were recovered from this 10-year period (prevalence 0.12%). We could not assess the prevalence for the period 20,014–2019, where only isolates with phenotypic resistance from a limited subset of university hospitals were sent to our laboratory for FKS sequencing. However, the fact that we identified 7 FKS-mutant C. albicans/glabrata from 4 different Swiss centers over this 6-year period suggests an increase of the rate of FKS-mutant echinocandin resistant isolates. The incidence of candidemia remained relatively stable in Switzerland over the last decade according to our national surveillance systems (unpublished data), but we have observed a constant increase of echinocandin consumption since 2004, as previously reported [10]. Echinocandin pre-exposure was previously identified as the main risk factor for FKS mutations [3, 5]. In our study, all patients received previous echinocandin treatment for > 15 days, which is in keeping with previous reports (median 3–4 weeks) [3, 5]. Caspofungin is the most used echinocandin drug in Switzerland and a recent publication suggests that it is associated with a higher risk of inducing FKS mutations in comparison to other echinocandins [13]. Other risk factors of acquired FKS mutations have been suggested, such as the existence of hidden reservoirs or uncontrolled sources of infection [14], which was probably the case for more than half (5/9) patients of our series with complicated intra-abdominal candidiasis or persistent urinary tract colonization. Among the 5 patients who received initial echinocandin therapy fo R ≥ 7 days, 4 failed to respond (i.e., persistent candidemia under echinocandin therapy) and ultimately survived after switch for another antifungal drug. The patient who responded to echinocandin therapy despite high MIC values had an intravascular catheter infection and was possibly cured by catheter removal only. The cases for which echinocandin therapy was initially continued, despite resistance to this antifungal drug class, were mainly patients with severe comorbidities (including renal dysfunction) who were infected with C. glabrata, a species exhibiting some degree of natural resistance to azoles. This outlines the difficulty to treat such infections because of the lack of therapeutic alternatives. Amphotericin B formulations often remain the unique option and their use could be limited by renal toxicity. However, our results clearly suggest that echinocandin therapy should not be continued against these FKS-mutant Candida species, even in those with moderate MIC elevation (e.g., 2–4 µg/mL), and is associated with failure to therapy. Overall mortality was 33%, which is in the usual ranges of mortality rates that have been reported for candidemia in general [1].\n\nFKS mutations observed in our study were diverse, but predominantly S645P in C. albicans and S663P (FKS2) in C. glabrata. All FKS-mutant isolates of our study exhibited echinocandin MICs that were classified as non-susceptible according to the CLSI breakpoints. However, MIC values varied between 0.25 and > 16 µg/mL with caspofungin MIC being usually higher compared to anidulafungin or micafungin MICs.\n\nEchinocandin resistance among Candida spp. remains rare. Previous observations are limited to small case-series (7–25 cases) with sometimes incomplete clinical data and mainly reported from the North American continent [3, 5, 6, 8, 9]. The present report of these 9 cases suggests that echinocandin resistance due to acquired FKS mutations is an emerging concern in Europe. These cases were associated with failure of echinocandin therapy, which is particularly concerning for C. glabrata due to the limited therapeutic options. Echinocandin resistance should be suspected in patients with previous echinocandin exposure (> 15 days), particularly in the presence of hidden or uncontrolled reservoirs, such as abdominal candidiasis or urinary tract colonization.\n\nAvailability of data and material\nThe sequences of FKS hotspots regions of all Candida isolates of this study have been deposited at the National Center for Biotechnology Information (NCBI) under Accession Numbers MT396587 to MT396628.\n\nA. T. Coste and A. Kritikos authors equally contributed to the work\n\nAcknowledgements\nOpen access funding provided by University of Lausanne.\n\nAuthor contributions\nATC: laboratory testing, data collection, data analyses, redaction of manuscript, AK: data collection, data analyses, redaction of manuscript, LJ: laboratory testing, data analyses, NK: data collection, review of manuscript, DG: data collection, review of manuscript,, CG: data collection, review of manuscript, CZ: data collection, review of manuscript, KB: data collection, review of manuscript, DN: data collection, review of manuscript, AR: data collection, review of manuscript, DB: laboratory testing; DS: data analyses, review of manuscript, FL: study design, data analyses, redaction of manuscript.\n\nFunding\nThis study was funded by the Fungal Infection Network of Switzerland (FUNGINOS).\n\nCompliance with ethical standards\nConflict of interest\nAuthor Zehnder C. was employed by company SYNLAB Suisse SA, Bioggio, Switzerland. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1. Lamoth F Lockhart SR Berkow EL Calandra T Changes in the epidemiological landscape of invasive candidiasis J Antimicrob Chemother. 2018 73 i4 i13 10.1093/jac/dkx444 29304207 \n2. Cornely OA Bassetti M Calandra T Garbino J Kullberg BJ Lortholary O ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients Clin Microbiol Infect 2012 18 19 37 10.1111/1469-0691.12039 23137135 \n3. Shields RK Nguyen MH Press EG Cumbie R Driscoll E Pasculle AW Rate of FKS Mutations among Consecutive Candida Isolates Causing Bloodstream Infection Antimicrob Agents Chemother 2015 59 7465 7470 10.1128/AAC.01973-15 26392494 \n4. Arendrup MC Cuenca-Estrella M Lass-Florl C Hope WW Breakpoints for antifungal agents: an update from EUCAST focussing on echinocandins against Candida spp. and triazoles against Aspergillus spp Drug Resist Updat. 2013 16 81 95 10.1016/j.drup.2014.01.001 24618110 \n5. Beyda ND John J Kilic A Alam MJ Lasco TM Garey KW FKS mutant Candida glabrata: risk factors and outcomes in patients with candidemia Clin Infect Dis 2014 59 819 825 10.1093/cid/ciu407 24879785 \n6. Shields RK Nguyen MH Press EG Updike CL Clancy CJ Anidulafungin and micafungin MIC breakpoints are superior to that of caspofungin for identifying FKS mutant Candida glabrata strains and Echinocandin resistance Antimicrob Agents Chemother 2013 57 6361 6365 10.1128/AAC.01451-13 24060873 \n7. Astvad KMT Johansen HK Roder BL Rosenvinge FS Knudsen JD Lemming L Update from a 12-Year Nationwide Fungemia Surveillance: Increasing Intrinsic and Acquired Resistance Causes Concern J Clin Microbiol. 2018 10.1128/JCM.01564-17 29212705 \n8. Fuller J Dingle TC Bull A Shokoples S Laverdiere M Baxter MR Species distribution and antifungal susceptibility of invasive Candida isolates from Canadian hospitals: results of the CANWARD 2011–16 study J Antimicrob Chemother. 2019 74 iv48 iv54 10.1093/jac/dkz287 31505645 \n9. Alexander BD Johnson MD Pfeiffer CD Jimenez-Ortigosa C Catania J Booker R Increasing echinocandin resistance in Candida glabrata : clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations Clin Infect Dis 2013 56 12 1724 1732 10.1093/cid/cit136 23487382 \n10. Kritikos A Neofytos D Khanna N Schreiber PW Boggian K Bille J Accuracy of Sensititre YeastOne echinocandins epidemiological cut-off values for identification of FKS mutant Candida albicans and Candida glabrata : a 10 year national survey of the Fungal Infection Network of Switzerland (FUNGINOS) Clin Microbiol Infect 2018 24 1214e1 e4 10.1016/j.cmi.2018.05.012 29909005 \n11. Clinical and Laboratory Standards Institute (CLSI). Reference method for broth dilution antifungal susceptibility testing of yeasts (4th ed.), CLSI, Wayne, PA (M27-Ed4). 2017.\n12. Espinel-Ingroff A Arendrup MC Pfaller MA Bonfietti LX Bustamante B Canton E Interlaboratory variability of Caspofungin MICs for Candida spp. Using CLSI and EUCAST methods: should the clinical laboratory be testing this agent? Antimicrob Agents Chemother 2013 57 5836 42 10.1128/AAC.01519-13 24018263 \n13. Shields RK Kline EG Healey KR Kordalewska M Perlin DS Nguyen MH Spontaneous Mutational Frequency and FKS Mutation Rates Vary by Echinocandin Agent against Candida glabrata Antimicrob Agents Chemother 2019 10.1128/AAC.01692-18 31636064 \n14. Shields RK Nguyen MH Clancy CJ Clinical perspectives on echinocandin resistance among Candida species Curr Opin Infect Dis 2015 28 6 514 522 10.1097/QCO.0000000000000215 26524326\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0300-8126",
"issue": "48(5)",
"journal": "Infection",
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"medline_ta": "Infection",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents; D002176:Candida albicans; D041221:Candida glabrata; D058387:Candidemia; D025141:Drug Resistance, Fungal; D054714:Echinocandins; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013557:Switzerland",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "761-766",
"pmc": null,
"pmid": "32661647",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
"references": "29304207;23137135;26392494;24879785;24060873;29212705;31505645;23487382;24018263;31636064;26524326",
"title": "Emerging echinocandin-resistant Candida albicans and glabrata in Switzerland.",
"title_normalized": "emerging echinocandin resistant candida albicans and glabrata in switzerland"
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{
"abstract": "Double pylorus (DP), or duplication of the pylorus, is an uncommon condition that can be either congenital or acquired. Acquired DP (ADP) occurs when a peptic ulcer erodes and creates a fistula between the duodenal bulb and the distal stomach. The clinical features and endoscopic characteristics of four patients with ADP were reviewed and compared with previously reported cases. An accessory channel connects the lesser curvature of the prepyloric antrum with the duodenal bulb, and in all cases, a peptic ulcer was located in or immediately adjacent to the accessory channel. In one of the patients, the bridge between the double-channel pylorus disappeared, resulting in a single large opening and duodenal kissing ulcer after two years and three months. Finally, nonsteroidal anti-inflammatory drugs, Helicobacter pylori and other risk factors associated with ADP are assessed.",
"affiliations": "Jing-Jing Lei, Li Zhou, Qi Liu, Department of Gastroenterology, the Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang 550014, Guizhou Province, China.;Jing-Jing Lei, Li Zhou, Qi Liu, Department of Gastroenterology, the Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang 550014, Guizhou Province, China.;Jing-Jing Lei, Li Zhou, Qi Liu, Department of Gastroenterology, the Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang 550014, Guizhou Province, China.;Jing-Jing Lei, Li Zhou, Qi Liu, Department of Gastroenterology, the Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang 550014, Guizhou Province, China.",
"authors": "Lei|Jing-Jing|JJ|;Zhou|Li|L|;Liu|Qi|Q|;Xu|Chun-Fang|CF|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000897:Anti-Ulcer Agents; D054328:Proton Pump Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v22.i6.2153",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "22(6)",
"journal": "World journal of gastroenterology",
"keywords": "Acquired double pylorus; Gastrointestinal hemorrhage; Helicobacter pylori; Nonsteroidal anti-inflammatory drugs; Peptic ulcer",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D000897:Anti-Ulcer Agents; D004378:Duodenal Diseases; D016145:Endoscopy, Digestive System; D005260:Female; D005747:Gastric Fistula; D006801:Humans; D007412:Intestinal Fistula; D008297:Male; D008875:Middle Aged; D010438:Peptic Ulcer Hemorrhage; D011237:Predictive Value of Tests; D054328:Proton Pump Inhibitors; D011708:Pylorus; D012307:Risk Factors; D013276:Stomach Ulcer; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "2153-8",
"pmc": null,
"pmid": "26877621",
"pubdate": "2016-02-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19517171;7733094;12072995;17440876;17230626;11577308;5764600;19025318;10779821;15731948;3971837;4327269;25435588;21234144;26031868;7974109;16240226;24987320;1276583;11323608;11479415;2916530;20617870;16531146;24829646",
"title": "Acquired double pylorus: Clinical and endoscopic characteristics and four-year follow-up observations.",
"title_normalized": "acquired double pylorus clinical and endoscopic characteristics and four year follow up observations"
} | [
{
"companynumb": "CN-LUPIN PHARMACEUTICALS INC.-2016-01312",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DICLOFENAC"
},
"drugadditiona... |
{
"abstract": "BACKGROUND\nWomen with inherited metabolic disorders, including those with previously life-limiting conditions such as MMA, are reaching child-bearing age more often due to advances in early diagnosis and improved pediatric care. Information surrounding maternal and fetal complications associated with the underlying disorders remains largely unexplored.\n\n\nMETHODS\nPregnancies affected by maternal MMA were ascertained through study 04-HG-0127 \"Clinical and Basic Investigations of Methylmalonic Acidemia and Related Disorders\" (clinicaltrials.gov identifier: NCT00078078) and via literature review. Prenatal and delivery records in study participants were reviewed.\n\n\nRESULTS\nSeventeen pregnancies were identified in women with isolated MMA, including three abortions, one termination, and 13 completed pregnancies [three cases with cblA (four pregnancies), four cases of mut- (one cobalamin responsive, three non-responsive), five cases with unknown type of MMA]. Seventeen percent (3/17) of the pregnancies resulted in a first trimester abortion, while 38.5% (5/13) of the completed pregnancies resulted in preterm deliveries. A cesarean delivery rate of 53.8% (7/13) was noted among the cohort. Fetal distress or nonreassuring fetal status was the indication for 57% (4/7) cesarean deliveries. One patient was reported to have metabolic crisis as well as episodes of mild hyperammonemia. Malformations or adverse outcomes in the progeny were not observed.\n\n\nCONCLUSIONS\nAlthough there have been a small number of pregnancies identified in women with MMA, the cumulative results suggest that the majority of pregnancies can be complicated by cesarean delivery and increased risk of prematurity. A pregnancy registry could clarify perinatal complications and define management approaches needed to ensure optimal maternal and fetal outcomes in this growing patient population.",
"affiliations": "Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.",
"authors": "Raval|Donna B|DB|;Merideth|Melissa|M|;Sloan|Jennifer L|JL|;Braverman|Nancy E|NE|;Conway|Robert L|RL|;Manoli|Irini|I|;Venditti|Charles P|CP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s10545-014-9802-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0141-8955",
"issue": "38(5)",
"journal": "Journal of inherited metabolic disease",
"keywords": null,
"medline_ta": "J Inherit Metab Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000592:Amino Acid Metabolism, Inborn Errors; D002585:Cesarean Section; D005260:Female; D047109:Fetal Development; D006801:Humans; D007231:Infant, Newborn; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "7910918",
"other_id": null,
"pages": "839-46",
"pmc": null,
"pmid": "25567501",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "8601112;16147658;16182581;16763906;17138789;17597648;21918856;23711287;20830523;24385074;24686805;25205257;6061291;10863939;12114914;12118529;7892853;8237918;8747516;10518278;15868474",
"title": "Methylmalonic acidemia (MMA) in pregnancy: a case series and literature review.",
"title_normalized": "methylmalonic acidemia mma in pregnancy a case series and literature review"
} | [
{
"companynumb": "US-MYLANLABS-2017M1025312",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARNITINE"
},
"drugadditional": "3",
... |
{
"abstract": "Cesarean scar pregnancy (CSP) is a rare type of ectopic pregnancy, which occurs in previous cesarean section scar tissue, with an incidence of 1 in 1800-3000 pregnancies. Transvaginal ultrasound-guided local methotrexate (MTX) administration presents as a non-systemic option with possible better penetration to the pregnancy site. We present the management of 18 patients with CSP solely by transvaginal ultrasound-guided local MTX administration. All patients were treated with local MTX with a dose of 50 mg/m(2) . Eleven (61.1%) of the patients did not need any further intervention. Four patients (22.2%) were treated with additional single-dose systemic MTX due to inadequate alteration in blood β-human chorionic gonadotrophin levels. Three patients (16.7%) required hysteroscopy and/or laparotomy. We suggest that transvaginal ultrasound-guided local MTX treatment may be considered as a first-line treatment for CSP.",
"affiliations": "Department of Obstetrics and Gynecology, School of Medicine, Baskent University, Ankara, Turkey.",
"authors": "Cok|Tayfun|T|;Kalayci|Hakan|H|;Ozdemir|Halis|H|;Haydardedeoglu|Bulent|B|;Parlakgumus|Ayse H|AH|;Tarim|Ebru|E|",
"chemical_list": "D000020:Abortifacient Agents, Nonsteroidal; D008727:Methotrexate",
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.12627",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "41(5)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "cesarean scar pregnancy; ectopic pregnancy; local; methotrexate; ultrasound-guided",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000020:Abortifacient Agents, Nonsteroidal; D000328:Adult; D002585:Cesarean Section; D002921:Cicatrix; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008727:Methotrexate; D011247:Pregnancy; D011271:Pregnancy, Ectopic; D012189:Retrospective Studies; D016896:Treatment Outcome; D018084:Ultrasonography, Interventional",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "803-8",
"pmc": null,
"pmid": "25491022",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Transvaginal ultrasound-guided local methotrexate administration as the first-line treatment for cesarean scar pregnancy: Follow-up of 18 cases.",
"title_normalized": "transvaginal ultrasound guided local methotrexate administration as the first line treatment for cesarean scar pregnancy follow up of 18 cases"
} | [
{
"companynumb": "TR-MYLANLABS-2017M1011883",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nQuantification of the risk of an allergic drug reaction through the medical history is essential in clinical decision making. However, in normal clinical practice, this evaluation is generally entirely subjective.\n\n\nOBJECTIVE\nThe objective of this study was to construct a mathematical model to predict the risk of allergic drug reactions using the data collected in the medical history.\n\n\nMETHODS\nA total of 696 active principles, corresponding to 466 patients aged more than 14 years attending the Allergy Service of the University Hospital of Salamanca, were included. Simple binary logistic regression was used to determine associations between variables from the medical history and the final diagnosis, to construct a predictive model.\n\n\nRESULTS\nVariables useful in predicting a final diagnosis of allergic drug reaction were age, sex, drug class, number of active principles, time to the reaction, number of doses, clinical presentation suggestive of allergic disease, and time to medical consultation. True adverse drug reactions were estimated to occur in 20% of active principles. However, possible allergic reactions could only be ruled out in 52.2%.\n\n\nCONCLUSIONS\nThe use of mathematical models could greatly improve the discriminatory capacity of the medical history. Both the overdiagnosis and underdiagnosis of allergic drug reactions should be considered a public health problem.",
"affiliations": "Department of Allergy, Rio Hortega University Hospital, Valladolid, Spain.;San Juan Community Health Centre, Primary Care Management of Salamanca, Salamanca, Spain.;Department of Statistics, University of Salamanca, Salamanca, Spain.;Department of Preventive Medicine and Public Health, University of Salamanca, Salamanca, Spain.;Department of Allergy, Rio Hortega University Hospital, Valladolid, Spain. Electronic address: aliciaarmentia@gmail.com.",
"authors": "Hierro Santurino|Beatriz|B|;Mateos Conde|Javier|J|;Cabero Morán|María Teresa|MT|;Mirón Canelo|José Antonio|JA|;Armentia Medina|Alicia|A|",
"chemical_list": "D000485:Allergens; D000700:Analgesics; D010406:Penicillins",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "4(2)",
"journal": "The journal of allergy and clinical immunology. In practice",
"keywords": "Allergic drug reaction; Analgesics; Diagnosis; Drug hypersensitivity; Medical history; Penicillin; Predictive model",
"medline_ta": "J Allergy Clin Immunol Pract",
"mesh_terms": "D000328:Adult; D000485:Allergens; D000700:Analgesics; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D008297:Male; D008487:Medical History Taking; D008875:Middle Aged; D008962:Models, Theoretical; D010406:Penicillins; D011379:Prognosis; D012306:Risk; D013030:Spain",
"nlm_unique_id": "101597220",
"other_id": null,
"pages": "292-300.e3",
"pmc": null,
"pmid": "26852067",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Predictive Model for the Diagnosis of Allergic Drug Reactions According to the Medical History.",
"title_normalized": "a predictive model for the diagnosis of allergic drug reactions according to the medical history"
} | [
{
"companynumb": "ES-GLAXOSMITHKLINE-ES2017GSK108601",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC"
},
"drugadditional": "3"... |
{
"abstract": "The primary limitations of granulocyte transfusions include low component cell dose and leukocyte incompatibility. Component cell dose improved with granulocyte colony-stimulating factor (G-CSF) mobilization, and the transfusion of G-CSF-mobilized, human leukocyte antigen (HLA)-matched granulocyte components resulted in significant, sustained absolute neutrophil count (ANC) increments. However, the effect of leukocyte compatibility on outcomes with G-CSF-mobilized granulocyte transfusions is unclear. The objectives were to determine the effect of leukocyte compatibility on ANC increments and selected clinical outcomes after transfusion of prophylactic, G-CSF-mobilized granulocyte components into neutropenic recipients of autologous peripheral blood stem cell (PBSC) transplants. Beginning on transplant day 2, 23 evaluable recipients were scheduled to receive 4 alternate-day transfusions of granulocyte components apheresed from a single donor given G-CSF. G-CSF was also given to recipients after transplantation. Recipient ANC was determined before and sequentially after each granulocyte transfusion to determine the peak ANC increment. Leukocyte compatibility was determined at study entry only by a lymphocytotoxicity screening assay (s-LCA) against a panel of HLA-defined cells. Eight recipients had positive s-LCA. On days 2 and 4, the mean peak ANC increments after granulocyte transfusion were comparable between the cohorts with positive and negative s-LCA. However, the mean peak ANC increments on day 6 (246/microL vs 724/microL; P =.05) and day 8 (283/microL vs 1079/microL; P =.06) were lower in the cohort with positive s-LCA, in spite of the transfusion of comparable component cell doses. Adverse reactions occurred with only 5 of 87 (5.7%) granulocyte transfusions and were not associated with leukocyte compatibility test results. Platelet increments, determined 1 hour after granulocyte transfusion, were comparable between the cohorts. Although the 2 cohorts received PBSC components with similar CD34(+) cell doses, the cohort with a positive s-LCA had delayed neutrophil engraftment and a greater number of febrile days and required more days of intravenous antibiotics and platelet transfusions. Leukocyte incompatibility adversely affected ANC increments after the transfusion of G-CSF-mobilized granulocyte components and clinical outcomes after PBSC transplantation.",
"affiliations": "Department of Internal Medicine, Division of Bone Marrow Transplantation and Stem Cell Biology, Washington University School of Medicine, St Louis, MO 63110-1093, USA.",
"authors": "Adkins|D R|DR|;Goodnough|L T|LT|;Shenoy|S|S|;Brown|R|R|;Moellering|J|J|;Khoury|H|H|;Vij|R|R|;DiPersio|J|J|",
"chemical_list": "D000017:ABO Blood-Group System; D016179:Granulocyte Colony-Stimulating Factor",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "95(11)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000017:ABO Blood-Group System; D000293:Adolescent; D000328:Adult; D000368:Aged; D001782:Blood Donors; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006098:Granulocytes; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells; D006650:Histocompatibility Testing; D006801:Humans; D007937:Leukapheresis; D007958:Leukocyte Count; D017708:Leukocyte Transfusion; D008297:Male; D008875:Middle Aged; D009504:Neutrophils; D009679:Nuclear Family; D016896:Treatment Outcome",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "3605-12",
"pmc": null,
"pmid": "10828051",
"pubdate": "2000-06-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effect of leukocyte compatibility on neutrophil increment after transfusion of granulocyte colony-stimulating factor-mobilized prophylactic granulocyte transfusions and on clinical outcomes after stem cell transplantation.",
"title_normalized": "effect of leukocyte compatibility on neutrophil increment after transfusion of granulocyte colony stimulating factor mobilized prophylactic granulocyte transfusions and on clinical outcomes after stem cell transplantation"
} | [
{
"companynumb": "US-AMGEN-USASP2021031478",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": "1",
... |
{
"abstract": "A 68-year-old man having a descending colon cancer with multiple metastases of up to 9.5 cm in the right lobe of the liver(T3, N0, M1a)underwent laparoscopic colon resection for anemia control. Chemotherapy with mFOLFOX6 plus Bmab was administered postoperatively. Because this treatment had little effect, FOLFIRI plus Pmab was initiated 3 months later. A significant reduction in the tumor size was observed. Therefore, we performed laparotomy. However, the liver metastasis had invaded the inferior vena cava, which was not resectable. After the second surgery, we introduced the 5-FU hepatic arterial injection port ia plus Pmab iv, which was effective for 8 months. We then restarted chemotherapy with FOLFIRI plus Pmab. However, the tumor became more enlarged; therefore, we changed the chemotherapy regimen to SOX plus Bmab. Partial reduction in the tumor size was observed again, and the effects lasted for a while. The patient continued visiting the outpatient clinic with almost no symptoms for more than 1 year. He died of the primary cancer 3 years and 8 months after the first visit. We report a case of liver metastasis of colon cancer that could have been controlled successfully by repeatedly using the same pharmacotherapy.",
"affiliations": "Dept. of Surgery, Hasuda Hospital.",
"authors": "Hasegawa|Kumi|K|;Otomo|Mayuko|M|;Takatsuno|Yasushi|Y|;Maejima|Kentaro|K|;Kaneko|Jun|J|;Maejima|Shizuaki|S|;Isogai|Jun|J|",
"chemical_list": "D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "48(1)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003082:Colectomy; D003110:Colonic Neoplasms; D005472:Fluorouracil; D006801:Humans; D008113:Liver Neoplasms; D008297:Male",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "115-117",
"pmc": null,
"pmid": "33468739",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Colon Cancer with Synchronous Multiple Metastases Successfully Treated with Combined Chemotherapy.",
"title_normalized": "a case of colon cancer with synchronous multiple metastases successfully treated with combined chemotherapy"
} | [
{
"companynumb": "JP-AMGEN-JPNSP2021131996",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo characterize the clinical and pathological features of anti-HMGCR myopathy.\n\n\nMETHODS\nThe presence of anti-HMGCR antibody in the serum of 227 patients with idiopathic inflammatory myopathy (IIM) and 100 healthy control individuals was assessed by ELISA. All ELISA positive samples were retested by indirect immunofluorescence assay (IIFA) on HEK293 cells. The clinical findings, muscle pathological features, and treatment outcomes of patients with anti-HMGCR myopathy, along with comparisons between anti-HMGCR myopathy with and without dermatomyositis (DM)-like skin rashes, and among MSA-based subgroups were analyzed.\n\n\nRESULTS\nWe established an optimized ELISA cutoff for anti-HMGCR antibody positivity as ≥ 5.28 U. The overall concordance between ELISA and IIFA was 96.83%. Twenty-one out of 227 IIM patients were anti-HMGCR-positive by both assays. Of these 21 patients, 9 had DM-like skin rashes, and 16 showed remarkable muscle inflammation; 5 patients were juvenile-onset, and 2 received statin treatment. The muscle biopsies from these patients demonstrated variable muscle necrosis and T cell infiltration. Most anti-HMGCR-positive patients achieved favorable outcomes following prednisone and additional immunotherapies. The anti-HMGCR myopathy patients with DM-like rashes, compared to those without DM-like rashes, were younger and had a shorter disease duration.\n\n\nCONCLUSIONS\nOptimization of cutoff of anti-HMGCR antibody assays with confirmation by alternative assays can result in higher sensitivity and specificity. DM-like skin rashes and lymphocytic infiltrates were not rare in patients with anti-HMGCR myopathy. These findings suggest that while anti-HMGCR myopathy may overlap with DM-like rash, it is pathologically different from classic DM, and should be considered a distinct subgroup of IIM.",
"affiliations": "Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 West Wenhua Road, Jinan, Shandong, China.;Department of Central Laboratory and Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China.;Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xian, China.;Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 West Wenhua Road, Jinan, Shandong, China.;Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 West Wenhua Road, Jinan, Shandong, China.;Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 West Wenhua Road, Jinan, Shandong, China.;Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 West Wenhua Road, Jinan, Shandong, China.;Neuropathology Section, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.;Inova Diagnostics, San Diego, CA, USA.;Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 West Wenhua Road, Jinan, Shandong, China. chuanzhuyan@163.com.",
"authors": "Hou|Ying|Y|http://orcid.org/0000-0001-8116-4928;Shao|Kai|K|http://orcid.org/0000-0003-1563-5722;Yan|Yaping|Y|;Dai|Tingjun|T|;Li|Wei|W|;Zhao|Yuying|Y|;Li|Duoling|D|;Lu|Jian-Qiang|JQ|;Norman|Gary L|GL|http://orcid.org/0000-0001-8992-1866;Yan|Chuanzhu|C|http://orcid.org/0000-0002-2191-5184",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00415-021-10621-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-5354",
"issue": null,
"journal": "Journal of neurology",
"keywords": "Anti-HMGCR myopathy; Dermatomyositis; Idiopathic inflammatory myopathy; Muscle inflammation; Skin lesion",
"medline_ta": "J Neurol",
"mesh_terms": null,
"nlm_unique_id": "0423161",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34021410",
"pubdate": "2021-05-21",
"publication_types": "D016428:Journal Article",
"references": "27491568;21360500;20496415;26632738;28075491;30234722;30208379;30129477;29582188;15099594;29221629;25521389;27343066;27147697;26710068;30205933;26090508;27761483;25737145;31801390;24995343;26192196;24484965;27640317;29079590;31791867;25064497;31060889;27086869;22302543;18851928;29522204;12622228;22933019",
"title": "Anti-HMGCR myopathy overlaps with dermatomyositis-like rash: a distinct subtype of idiopathic inflammatory myopathy.",
"title_normalized": "anti hmgcr myopathy overlaps with dermatomyositis like rash a distinct subtype of idiopathic inflammatory myopathy"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-334819",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "Current guidelines recommend close monitoring of electrolytes in transgender patients using spironolactone given the risk of hyperkalemia from mineralocorticoid antagonism. In patients taking spironolactone for other conditions, the rate of hyperkalemia is low, and the utility of frequent monitoring has been questioned.\nWe hypothesized that the rate of hyperkalemia in gender-diverse adolescents taking spironolactone is low and, when present, clinically insignificant.\nA retrospective chart review of adolescents seen in a specialty gender clinic at a tertiary care pediatric hospital over 10 years identified patients prescribed spironolactone for gender transition. Study outcomes were the incidence of hyperkalemia, defined as serum potassium concentration >5.0 mmol/L, and the relationship between potassium levels and spironolactone dose and duration.\nRecords were reviewed for 85 subjects with a mean ± SD age of 16.6 ± 1.7 years. There were a total of 269 potassium measurements (80 prior to spironolactone initiation and 189 during spironolactone treatment). Six potassium measurements in five subjects were >5.0 mmol/L, indicating a rate of hyperkalemia of 2.2%. None of the subjects had symptoms of hyperkalemia, and all elevated measurements were normal when repeated. Only one subject discontinued spironolactone after an elevated potassium measurement. There was no relationship between hyperkalemia and spironolactone dose. Potassium measurements decreased with increasing treatment duration.\nHyperkalemia in patients taking spironolactone for gender transition is rare and when present is transient and asymptomatic. In the absence of other medical comorbidities, routine electrolyte monitoring in this population may be unnecessary.",
"affiliations": "Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts.;Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, Massachusetts.;Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts.",
"authors": "Millington|Kate|K|0000-0001-5222-5787;Liu|Enju|E|;Chan|Yee-Ming|YM|0000-0003-0554-8502",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1210/js.2019-00030",
"fulltext": "\n==== Front\nJ Endocr SocJ Endocr SocjesJournal of the Endocrine Society2472-1972Endocrine Society Washington, DC js_20190003010.1210/js.2019-00030Clinical Research ArticlesReproductive Biology and Sex-Based MedicineThe Utility of Potassium Monitoring in Gender-Diverse Adolescents Taking Spironolactone http://orcid.org/0000-0001-5222-5787Millington Kate 1Liu Enju 2http://orcid.org/0000-0003-0554-8502Chan Yee-Ming Yee-Ming.Chan@childrens.harvard.edu11 Division of Endocrinology, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts2 Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital, Boston, MassachusettsCorrespondence: Yee-Ming Chan, MD, Division of Endocrinology, Boston Children’s Hospital, 300 Longwood Ave, Boston, Massachusetts 02115. E-mail: Yee-Ming.Chan@childrens.harvard.edu.01 5 2019 04 4 2019 3 5 1031 1038 21 1 2019 29 3 2019 Copyright © 2019 Endocrine Society2019This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).Abstract\nContext\nCurrent guidelines recommend close monitoring of electrolytes in transgender patients using spironolactone given the risk of hyperkalemia from mineralocorticoid antagonism. In patients taking spironolactone for other conditions, the rate of hyperkalemia is low, and the utility of frequent monitoring has been questioned.\n\nObjective\nWe hypothesized that the rate of hyperkalemia in gender-diverse adolescents taking spironolactone is low and, when present, clinically insignificant.\n\nDesign and Outcomes\nA retrospective chart review of adolescents seen in a specialty gender clinic at a tertiary care pediatric hospital over 10 years identified patients prescribed spironolactone for gender transition. Study outcomes were the incidence of hyperkalemia, defined as serum potassium concentration >5.0 mmol/L, and the relationship between potassium levels and spironolactone dose and duration.\n\nResults\nRecords were reviewed for 85 subjects with a mean ± SD age of 16.6 ± 1.7 years. There were a total of 269 potassium measurements (80 prior to spironolactone initiation and 189 during spironolactone treatment). Six potassium measurements in five subjects were >5.0 mmol/L, indicating a rate of hyperkalemia of 2.2%. None of the subjects had symptoms of hyperkalemia, and all elevated measurements were normal when repeated. Only one subject discontinued spironolactone after an elevated potassium measurement. There was no relationship between hyperkalemia and spironolactone dose. Potassium measurements decreased with increasing treatment duration.\n\nConclusions\nHyperkalemia in patients taking spironolactone for gender transition is rare and when present is transient and asymptomatic. In the absence of other medical comorbidities, routine electrolyte monitoring in this population may be unnecessary.\n\ntransgendergender diversegender dysphoriaspironolactonehyperkalemiaantiandrogenNational Institutes of Health (US)T32-DK007699National Institutes of Health (US)R01-HD082554\n==== Body\nMedical treatment of gender-diverse adolescents includes GnRH analogs to suppress puberty, gender-affirming sex steroids, and adjunctive medications to suppress the unwanted effects of endogenous hormones. Spironolactone is an aldosterone antagonist routinely used for its antiandrogenic properties in the treatment of transgender female patients [1]. Specifically, spironolactone is thought to promote feminization via inhibition of testosterone synthesis by decreasing the activity of 17α-hydroxylase in the testes, competition at androgen receptors, and direct stimulation of the estrogen receptor [2, 3]. Spironolactone may be superior to other antiandrogen treatments, such as finasteride and cyproterone acetate, in treating hirsutism [4]. Because of its effectiveness in reducing unwanted male-pattern hair growth and its relatively low cost, spironolactone is a frequently used medication in medical gender transition.\n\nBecause of its mineralocorticoid antagonist activity, there is a concern that spironolactone may decrease renal potassium excretion and lead to hyperkalemia. Increased use of spironolactone in adults with heart failure has been linked to an increased incidence of hyperkalemia [5]. However, in healthy male volunteers, spironolactone did not cause a change in serum potassium [6]. In a large study of patients taking spironolactone for acne, only 13 (0.72%) of 1802 potassium measurements were >5.0 mmol/L. Six of the elevated potassium measurements were normal when remeasured. The remainder of the elevated measurements did not lead to repeat testing. There were no cases of symptomatic hyperkalemia [7, 8].\n\nMultiple studies of transfeminine transgender adolescents and adults have noted no cases of hyperkalemia in otherwise healthy individuals taking spironolactone [9–11]. However, current guidelines recommend serial electrolyte monitoring for transgender patients on this medication [12, 13]. We hypothesized that the prevalence of hyperkalemia in gender-diverse adolescents taking spironolactone is low and that clinically significant hyperkalemia is rare.\n\n1. Materials and Methods\nA. Subjects and Protocol\nWe performed a retrospective chart review of gender-diverse youth of any age seen in the Gender Management Service Program at Boston Children’s Hospital from 2007 to 2017. Patients who were prescribed spironolactone for the purposes of gender transition were included in the analysis. Hyperkalemia was defined as a serum potassium concentration >5.0 mmol/L.\n\nThe study protocol was approved by the Institutional Review Board of Boston Children’s Hospital.\n\nB. Statistical Analysis\nDescriptive statistics were used to summarize patient demographics and clinical characteristics. Frequencies (%) were reported for categorical variables, and mean values ± SD were reported for continuous variables. Generalized estimating equations for a binary outcome with the log link function and exchangeable working correlation structure were used to assess the association between dose of spironolactone and risk of hyperkalemia. All analyses were performed using SAS 9.4. A P value <0.05 was considered statistically significant\n\n2. Results\nA. Study Cohort\nNinety gender-diverse adolescents were prescribed spironolactone during the study period (Table 1). Two patients were prescribed spironolactone for indications other than gender transition and were excluded. Three patients were excluded because there were no potassium measurements recorded after spironolactone was initiated. The 85 subjects included in the analysis had a total of 269 potassium measurements. Of these, 80 measurements were performed before the initiation of spironolactone, and 189 measurements were performed during spironolactone treatment (Fig. 1). Most subjects (n = 70; 82%) had potassium measured before starting spironolactone. Thirty-six subjects (42%) had at least one potassium measurement within the first 3 months of spironolactone therapy, and 48 subjects (56%) had a measurement within the first 6 months. Potassium measurements were available for up to 7 years of spironolactone therapy. Doses of spironolactone ranged from 25 to 400 mg/d, with a mean ± SD daily dose of 105 ± 85 mg/d. The majority of subjects (n = 73; 86%) were using spironolactone as an adjunct to estrogen. Subjects had a mean ± SD of 3.2 ± 1.9 potassium measurements (Table 1).\n\nTable 1. Characteristics of Subjects\n\nVariable\tAll Subjects (n = 85)\tSubjects Without Hyperkalemia (n = 79)\tSubjects With Hyperkalemia (n = 6)\t\nAge at spironolactone start, mean (SD), y\t16.6 (1.7)\t16.7 (1.7)\t16.0 (1.4)\t\nFemale gender identity, n (%)\t82 (96)\t76 (96)\t6 (100)\t\nNonbinary gender identity, n (%)\t3 (4)\t3 (4)\t0 (0)\t\nRace\t\t\t\t\n White, n (%)\t59 (69)\t54 (68)\t5 (83)\t\n Black or African American, n (%)\t2 (2)\t2 (3)\t0 (0)\t\n Asian, n (%)\t2 (2)\t2 (3)\t0 (0)\t\n Other, n (%)\t8 (9)\t8 (10)\t0 (0)\t\n Unknown, n (%)\t14 (16)\t13 (16)\t1 (17)\t\n Hispanic or Latino, n (%)\t5 (6)\t5 (6)\t0 (0)\t\nUsing GnRH analog, n (%)\t19 (22)\t18 (23)\t1 (17)\t\nUsing estrogen, n (%)\t73 (86)\t68 (86)\t5 (83)\t\nNumber of potassium measurements per subject, median (range)\t3 (1–10)\t3 (1–10)\t4.5 (1–8)\t\nBaseline potassium measurement available, n (%)\t70 (82)\t65 (82)\t5 (83)\t\nSerum potassium, mean (SD), mmol/L\t4.25 (0.4)\t4.20 (0.3)\t4.65 (0.5)\t\nSpironolactone dose, mean (SD), mg/d\t105 (42)\t105 (42)\t108 (49)\t\nFigure 1. Flowchart of subject selection and potassium measurements. Five subjects were excluded from the analysis because they were prescribed spironolactone for indications other than gender transition or did not have sufficient follow-up measurements. Of the 85 subjects included in the analysis, 70 (82%) had a baseline potassium measurement.\n\nB. Incidence of Hyperkalemia\nEight potassium measurements in six subjects exceeded 5.0 mmol/L. Hemolysis was noted in two measurements in the same subject, including one measurement performed prior to spironolactone initiation. (Fig. 2). When these measurements were excluded, the rate of hyperkalemia was 2.2%. There were no cases of hyperkalemia in the baseline measurements. All cases of hyperkalemia occurred early in the treatment course (<6 months after starting spironolactone). There were no potassium measurements >6.0 mmol/L.\n\nFigure 2. Outcomes of cases of elevated potassium measurements. Eight potassium measurements in six subjects were >5.0 mmol/L. Two samples in the same subject were noted to be hemolyzed. In only one case was spironolactone discontinued. All potassium measurements in all cases were normal when repeated.\n\nC. Features of Subjects With Hyperkalemia\nFive subjects had potassium measurements >5.0 mmol/L in the absence of hemolysis (Fig. 2); all had normal baseline potassium concentrations. None of the subjects with hyperkalemia had symptoms of hyperkalemia. One subject had a potassium measurement >5.0 mmol/L 2 weeks after initiation of 50 mg/d of spironolactone. Spironolactone was continued, and the potassium measurement was normal when repeated 2 weeks later. This subject’s potassium was again elevated 3 months after spironolactone initiation and was normal 2 weeks later.\n\nIn two additional subjects, hyperkalemia was observed at 1 and 6 months after spironolactone initiation. Spironolactone was continued, and all repeat measurements were in the normal range.\n\nOne subject had an elevated potassium measurement 1 month after starting spironolactone. All subsequent potassium measurements were normal. This subject had a history of eosinophilic esophagitis and received gastrostomy-tube feeds overnight in addition to a proton pump inhibitor.\n\nSpironolactone was discontinued in one subject who had hyperkalemia 5 months after spironolactone initiation. It was restarted after a repeat potassium measurement 2 weeks later was normal. All subsequent potassium measurements were normal in this subject.\n\nD. Presence of Medical Comorbidities\nIn our study cohort there were eight subjects with medical comorbidities, which included asthma (three subjects), migraine headaches, narcolepsy, eosinophilic esophagitis, macrophage activation syndrome, hypertension, and chronic congestive heart failure secondary to hypoplastic left heart syndrome. The subject with underlying hypertension did not have hyperkalemia. The subject with congestive heart failure was started on a low dose of spironolactone (25 mg/d) and did not have any episodes of hyperkalemia despite concurrent use of an angiotension-converting enzyme inhibitor.\n\nE. Predictors of Hyperkalemia\nThe most common starting spironolactone dose was 100 mg/d. Larger doses of spironolactone were not associated with a higher risk of hyperkalemia (Table 2). One subject had normal potassium measurements while taking 400 mg of spironolactone daily. There was no significant correlation between the dose of spironolactone and serum potassium concentration overall (Fig. 3). There was a significant trend toward lower serum potassium concentration with increasing duration of spironolactone treatment (Fig. 4). When the elevated potassium measurements, which all occurred early in the treatment course, were excluded, the correlation between treatment duration and potassium concentration was no longer significant.\n\nTable 2. Association Between Dose of Spironolactone and Hyperkalemia\n\nDose of Spironolactone\tNumber of Potassium Measurements >5.0 mmol/L/Total Number of Potassium Measurements (%)\tRelative Risk (95% CI)\t\nP Value\t\n\t\t\t\t\n<100 mg/d\t2/17 (11.8)\t1.0\t\t\n100–200 mg/d\t2/74 (2.7)\t0.23 (0.03–1.52)\t0.13\t\n>200 mg/d\t3/98 (3.1)\t0.26 (0.05–1.44)\t0.12\t\nBaseline potassium measurements were excluded. A spironolactone dose of 100 mg/d was the most common starting dose. A dose of spironolactone <100 mg/dL was designated as the reference. There was no increased risk of hyperkalemia with higher spironolactone dose categories.\n\nFigure 3. Serum potassium concentration is not correlated with spironolactone dose. The solid black line indicates regression line. The shaded area indicates the 95% confidence intervals for the expected mean. Dashed lines indicate the 95% confidence interval for the individual predicted value.\n\nFigure 4. Correlation between duration of spironolactone treatment and serum potassium concentration. Baseline measurements and two measurements that were the result of a hemolyzed sample were excluded. Black circles indicate serum potassium concentrations >5.0 mmol/L. Dashed lines indicate 95% CI of potassium concentration normal range. There is a significant trend toward lower serum potassium concentration with longer duration of treatment. When the potassium measurements >5.0 mmol/L were excluded, there was no correlation between serum potassium concentration and duration of spironolactone exposure.\n\n3. Discussion\nSimilar to other studies of otherwise healthy patients taking spironolactone for its anti-androgenic effects, we identified a low rate of hyperkalemia (2.2%) in our population of gender-diverse adolescents. Although this is higher than the rate of hyperkalemia reported in other healthy populations taking spironolactone, the cases of hyperkalemia we identified were likewise transient and not clinically significant [8].\n\nHyperkalemia is an important side effect in patients receiving spironolactone for heart failure. These patients are frequently also prescribed medications that affect renal potassium handling, such as angiotension-converting enzyme inhibitors [5]. In a large study of patients with congestive heart failure taking spironolactone, the risk of hyperkalemia increased with increasing doses of spironolactone from 13.5% in patients taking 25 mg/d to 41.4% in those taking 50 mg/d [14]. We did not find an increased risk of hyperkalemia with increasing doses of spironolactone despite routine use of larger doses (up to 400 mg/d) compared with those used in treating patients with congestive heart failure. It is the clinical context in which spironolactone is used, not the dose alone, that predicts risk of hyperkalemia.\n\nAll cases of hyperkalemia we identified occurred within the first 6 months of starting treatment. We monitored patients taking spironolactone for up to 7 years but did not identify additional cases of hyperkalemia. This observation suggests that if there is no evidence of hyperkalemia in the early treatment period, there is no increased risk with duration of spironolactone exposure.\n\nIndeed, we noted a downward trend in serum potassium concentrations over the duration of spironolactone use. Although this association between potassium measurements and treatment duration may have been caused by the resolution of hyperkalemia in affected subjects, it also raises the possibility that there is renal accommodation to mineralocorticoid antagonism that leads to a slightly lower potassium set point and thus a lower risk for hyperkalemia over time. Renal accommodation may also explain why we did not see an effect of higher spironolactone doses on serum potassium concentrations and why all cases of hyperkalemia were early, transient, and self-resolved.\n\nBeyond increasing the financial and time burden for patients, laboratory monitoring, if unneeded, may further increase barriers to gender-affirming care for an already vulnerable population [15]. Requiring frequent laboratory monitoring not only increases the complexity of caring for patients who desire gender transition but may also suggest that spironolactone, a commonly used gender-affirming medication, is risky and has concerning side effects.\n\nThe generalizability of this study is limited by the relatively small sample size and the use of only one study site. Its retrospective nature introduces potential selection bias; for example, clinicians may have avoided spironolactone use in patients with premorbid conditions or prior hyperkalemia. Further studies with a larger sample size are needed to confirm our findings.\n\nWe have shown that the risk of hyperkalemia in an otherwise healthy population taking spironolactone is low and that the risk of clinically important hyperkalemia is even lower. Additionally, when hyperkalemia occurs, it does so early in the treatment course and irrespective of spironolactone dose. We propose that close potassium monitoring beyond the first 6 months of therapy should be reserved for patients with medical comorbidities or for those who are taking medications that may impair renal potassium handling.\n\nAcknowledgments\nWe thank Molly Plovanich and Alexandra Charrow of Brigham and Women’s Hospital for early guidance in this project and Joseph Wolfsdorf of Boston Children’s Hospital for thoughtful comments on the manuscript.\n\n\nFinancial Support: Y-M.C. was supported by National Institute of Health (NIH) Grant R01 HD082554 and K.M. was supported by NIH Grant T32 DK007699.\n\n\nDisclosure Summary: The authors have nothing to disclose.\n==== Refs\nReferences and Notes\n1. \nPrior JC , Vigna YM , Watson D \nSpironolactone with physiological female steroids for presurgical therapy of male-to-female transsexualism . Arch Sex Behav . 1989 ;18 (1 ):49 –57 .2540730 \n2. \nCorvol P , Michaud A , Menard J , Freifeld M , Mahoudeau J \nAntiandrogenic effect of spirolactones: mechanism of action . Endocrinology . 1975 ;97 (1 ):52 –58 .166833 \n3. \nSciarra F , Toscano V , Concolino G , Di Silverio F \nAntiandrogens: clinical applications . J Steroid Biochem Mol Biol . 1990 ;37 (3 ):349 –362 .2147859 \n4. \nBrown J , Farquhar C , Lee O , Toomath R , Jepson RG Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. Cochrane Database Syst. Rev.2009 ;April15(2):CD000194.\n5. \nJuurlink DN , Mamdani MM , Lee DS , Kopp A , Austin PC , Laupacis A , Redelmeier DA \nRates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study . N Engl J Med . 2004 ;351 (6 ):543 –551 .15295047 \n6. \nStripp B , Taylor AA , Bartter FC , Gillette JR , Loriaux DL , Easley R , Menard RH \nEffect of spironolactone on sex hormones in man . J Clin Endocrinol Metab . 1975 ;41 (4 ):777 –781 .1176584 \n7. \nYemisci A , Gorgulu A , Piskin S \nEffects and side-effects of spironolactone therapy in women with acne . J Eur Acad Dermatol Venereol . 2005 ;19 (2 ):163 –166 .15752283 \n8. \nPlovanich M , YuWeng Q, Mostaghimi A. Low usefulness of potassium monitoring among healthy young women taking spironolactone for acne. JAMA Dermatol\n2015 ;151:941–944.\n9. \nFernandez JD , Tannock LR \nMetabolic effects of hormone therapy in transgender patients . Endocr Pract . 2016 ;22 (4 ):383 –388 .26574790 \n10. \nJarin J , Pine-Twaddell E , Trotman G , Stevens J , Conard LA , Tefera E , Gomez-Lobo V \nCross-sex hormones and metabolic parameters in adolescents with gender dysphoria . Pediatrics . 2017 ;139 (5 ):e20163173 .28557738 \n11. \nKhatchadourian K , Amed S , Metzger DL \nClinical management of youth with gender dysphoria in Vancouver . J Pediatr . 2014 ;164 (4 ):906 –911 .24315505 \n12. \nColeman E , Bockting W , Botzer M , Cohen-Kettenis P , DeCuypere G , Feldman J , Fraser L , Green J , Knudson G , Meyer WJ , Monstrey S , Adler RK , Brown GR , Devor AH , Ehrbar R , Ettner R , Eyler E , Garofalo R , Karasic DH , Lev AI , Mayer G , Meyer-Bahlburg H , Hall BP , Pfaefflin F , Rachlin K , Robinson B , Schechter LS , Tangpricha V , van Trotsenburg M , Vitale A , Winter S , Whittle S , Wylie KR , Zucker K \nStandards of care for the health of transsexual, transgender, and gender-nonconforming people, version 7 . Int J Transgenderism . 2012 ;13 (4 ):165 –232 .\n13. \nHembree WC , Cohen-Kettenis PT , Gooren L , Hannema SE , Meyer WJ , Murad MH , Rosenthal SM , Safer JD , Tangpricha V , T’Sjoen GG \nEndocrine treatment of gender-dysphoric/gender-incongruent persons: an endocrine society clinical practice guideline . J Clin Endocrinol Metab . 2017 ;102 (11 ):3869 –3903 .28945902 \n14. \nVardeny O , Claggett B , Anand I , Rossignol P , Desai AS , Zannad F , Pitt B , Solomon SD ; Randomized Aldactone Evaluation Study (RALES) Investigators . Incidence, predictors, and outcomes related to hypo- and hyperkalemia in patients with severe heart failure treated with a mineralocorticoid receptor antagonist . Circ Heart Fail . 2014 ;7 (4 ):573 –579 .24812304 \n15. \nSafer JD , Coleman E , Feldman J , Garofalo R , Hembree W , Radix A , Sevelius J \nBarriers to healthcare for transgender individuals . Curr Opin Endocrinol Diabetes Obes . 2016 ;23 (2 ):168 –171 .26910276\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2472-1972",
"issue": "3(5)",
"journal": "Journal of the Endocrine Society",
"keywords": "antiandrogen; gender diverse; gender dysphoria; hyperkalemia; spironolactone; transgender",
"medline_ta": "J Endocr Soc",
"mesh_terms": null,
"nlm_unique_id": "101697997",
"other_id": null,
"pages": "1031-1038",
"pmc": null,
"pmid": "31065620",
"pubdate": "2019-05-01",
"publication_types": "D016428:Journal Article",
"references": "1176584;15295047;15752283;166833;19370553;2147859;24315505;24812304;2540730;25796182;26574790;26910276;28557738;28945902",
"title": "The Utility of Potassium Monitoring in Gender-Diverse Adolescents Taking Spironolactone.",
"title_normalized": "the utility of potassium monitoring in gender diverse adolescents taking spironolactone"
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"companynumb": "US-TEVA-2019-US-1087202",
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"patient": {
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"activesubstancename": "SPIRONOLACTONE"
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"abstract": "Zolpidem is widely prescribed for the treatment of insomnia and is used to both induce and maintain sleep. Previously, zolpidem was thought to have low abuse potential; however, several reports have documented dose escalation and abuse in the past two decades. Here, we report the case of a patient with high-dose zolpidem dependence who underwent polysomnography (PSG) and the Multiple Sleep Latency Test (MSLT). The patient, a 29-year-old man, was administered zolpidem at doses of 300 to 1,200 mg/day, but he abused zolpidem to feel energetic. Consequently, he had a car accident while on a high dose, which the PSG revealed caused activation instead of sedation. The MSLT showed excessive daytime sleepiness despite a lack of subjective sleepiness under this condition. Our findings suggest that disrupted sleep and daytime sleepiness caused by supratherapeutic zolpidem doses could place individuals at high risk for accidents, including those who are unaware of sleepiness.",
"affiliations": "Department of Neuropsychiatry, Kurume University School of Medicine, Kurume, Fukuoka, Japan.;Department of Neuropsychiatry, Kurume University School of Medicine, Kurume, Fukuoka, Japan.;Department of Neuropsychiatry, Kurume University School of Medicine, Kurume, Fukuoka, Japan.;Department of Neuropsychiatry, Kurume University School of Medicine, Kurume, Fukuoka, Japan.;Department of Neuropsychiatry, Kurume University School of Medicine, Kurume, Fukuoka, Japan.;Department of Neuropsychiatry, Kurume University School of Medicine, Kurume, Fukuoka, Japan.;Department of Neuropsychiatry, Kurume University School of Medicine, Kurume, Fukuoka, Japan.",
"authors": "Ohshima|Hayato|H|;Kotorii|Nozomu|N|;Takii|Minoru|M|;Hiejima|Hiroshi|H|;Habukawa|Mitsunari|M|;Kuwahara|Hiroo|H|;Uchimura|Naohisa|N|",
"chemical_list": "D000077334:Zolpidem",
"country": "United States",
"delete": false,
"doi": "10.5664/jcsm.7500",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1550-9389",
"issue": "14(11)",
"journal": "Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine",
"keywords": "abused; polysomnography; zolpidem",
"medline_ta": "J Clin Sleep Med",
"mesh_terms": "D000063:Accidents, Traffic; D000328:Adult; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D017286:Polysomnography; D007319:Sleep Initiation and Maintenance Disorders; D000077260:Sleepiness; D019966:Substance-Related Disorders; D000077334:Zolpidem",
"nlm_unique_id": "101231977",
"other_id": null,
"pages": "1949-1952",
"pmc": null,
"pmid": "30373692",
"pubdate": "2018-11-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "14519173;19954851;20148031;21301324;24467433;8942145;10619672",
"title": "Polysomnographic Sleep Disturbances Due to High-Dose Zolpidem Use: A Case Report.",
"title_normalized": "polysomnographic sleep disturbances due to high dose zolpidem use a case report"
} | [
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"activesubstancename": "QUAZEPAM"
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"drugadditional": "3",
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"abstract": "An 86-year-old man presented with enlarged left submandibular, left inguinal, and superficial femoral lymph nodes. He was diagnosed with Langerhans cell sarcoma (LCS) on the basis of the histopathological findings of the left inguinal lymph node biopsy. In addition, laboratory examinations revealed normocytic normochromic anemia, and bone marrow aspiration and biopsy led to a diagnosis of idiopathic cytopenia of undetermined significance (ICUS). Because of the patient's age, he was administered a regimen of cyclophosphamide, pirarubicin, vincristine, and prednisolone (THP-COP), and achieved a partial response after six courses. However, he developed acute myeloid leukemia (AML) 11 months after completion of the THP-COP therapy, and received only supportive care until his death. LCS is an extremely rare and aggressive dendritic cell neoplasm. To the best of our knowledge, only 67 cases have been reported in the literature. There are case reports describing the concurrence of hematological malignancies. Herein, we report the first documented development of LCS in a patient with ICUS who progressed to AML, and summarize the published data on the epidemiology of and therapeutic options for LCS.",
"affiliations": "Department of Hematology and Oncology, Oji General Hospital.",
"authors": "Hamaguchi|Kota|K|;Hashimoto|Akari|A|;Fujimi|Akihito|A|;Kanisawa|Yuji|Y|;Shibata|Takanori|T|;Nakajima|Chisa|C|;Hayasaka|Naotaka|N|;Yamada|Shota|S|;Okuda|Toshinori|T|;Minami|Shinya|S|;Kamihara|Yusuke|Y|;Ohshima|Koichi|K|;Kato|Junji|J|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.56.2456",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "56(12)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": null,
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D006801:Humans; D054752:Langerhans Cell Sarcoma; D015470:Leukemia, Myeloid, Acute; D008297:Male; D012008:Recurrence; D012074:Remission Induction",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "2456-61",
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"abstract": "BACKGROUND\nDelayed interval intertwin delivery rates are expected to rise during the next years as potent and targeted tocolytic agents are employed and antenatal surveillance methods become more sophisticated and specific in predicting the critical delivery timepoint of optimal perinatal outcome.\n\n\nMETHODS\nWe present a case of delayed intertwin delivery after delivery of the first twin due to premature prelabor rupture of the membranes. Maternal serum White Blood Cells and C-Reactive Protein levels remained high until delivery of the second twin (34 days after the first was delivered), although maternal temperature remained constant. The mother underwent close antenatal surveillance and she was hospitalized. She had an uncomplicated delivery of the second twin at 29+ 2 weeks by cesarean section due to an abnormal Non-Stress Test.\n\n\nCONCLUSIONS\nWe strongly suggest future evaluation of maternal serum inflammatory markers among these rare cases as these could predict intraamniotic infection.",
"affiliations": "1st Department of Obstetrics and Gynecology, Athens Medical School , Alexandra General Hospital, 9 Aristeidou Street , 17563 P. Faliro, Athens, Greece.;1st Department of Obstetrics and Gynecology, Athens Medical School , Alexandra General Hospital, 9 Aristeidou Street , 17563 P. Faliro, Athens, Greece. fotinopoulos@hotmail.com.;3rd Department of Obstetrics and Gynecology, Athens Medical School, Attikon General Hospital, Athens, Greece.;1st Department of Obstetrics and Gynecology, Athens Medical School , Alexandra General Hospital, 9 Aristeidou Street , 17563 P. Faliro, Athens, Greece.;1st Department of Obstetrics and Gynecology, Athens Medical School , Alexandra General Hospital, 9 Aristeidou Street , 17563 P. Faliro, Athens, Greece.;1st Department of Obstetrics and Gynecology, Athens Medical School , Alexandra General Hospital, 9 Aristeidou Street , 17563 P. Faliro, Athens, Greece.;3rd Department of Obstetrics and Gynecology, Athens Medical School, Attikon General Hospital, Athens, Greece.;1st Department of Obstetrics and Gynecology, Athens Medical School , Alexandra General Hospital, 9 Aristeidou Street , 17563 P. Faliro, Athens, Greece.",
"authors": "Daskalakis|George|G|;Fotinopoulos|Panagiotis|P|http://orcid.org/0000-0002-2416-9279;Pergialiotis|Vasilios|V|;Theodora|Mariana|M|;Antsaklis|Panagiotis|P|;Sindos|Michail|M|;Papantoniou|Nikolaos|N|;Loutradis|Dimitrios|D|",
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"fulltext": "\n==== Front\nBMC Pregnancy ChildbirthBMC Pregnancy ChildbirthBMC Pregnancy and Childbirth1471-2393BioMed Central London 184810.1186/s12884-018-1848-4Case ReportDelayed interval delivery of the second twin in a woman with altered markers of inflammation Daskalakis George gdaskalakis@yahoo.com 1http://orcid.org/0000-0002-2416-9279Fotinopoulos Panagiotis +30 6949066870fotinopoulos@hotmail.com 1Pergialiotis Vasilios pergialiotis@yahoo.com 2Theodora Mariana martheodr@gmail.com 1Antsaklis Panagiotis panosant@gmail.com 1Sindos Michail sindosgyn@hotmail.com 1Papantoniou Nikolaos 2Loutradis Dimitrios loutradi@otenet.gr 11 0000 0001 2155 0800grid.5216.01st Department of Obstetrics and Gynecology, Athens Medical School , Alexandra General Hospital, 9 Aristeidou Street , 17563 P. Faliro, Athens, Greece 2 0000 0001 2155 0800grid.5216.03rd Department of Obstetrics and Gynecology, Athens Medical School, Attikon General Hospital, Athens, Greece 4 6 2018 4 6 2018 2018 18 20620 7 2017 23 5 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nDelayed interval intertwin delivery rates are expected to rise during the next years as potent and targeted tocolytic agents are employed and antenatal surveillance methods become more sophisticated and specific in predicting the critical delivery timepoint of optimal perinatal outcome.\n\nCase presentation\nWe present a case of delayed intertwin delivery after delivery of the first twin due to premature prelabor rupture of the membranes. Maternal serum White Blood Cells and C-Reactive Protein levels remained high until delivery of the second twin (34 days after the first was delivered), although maternal temperature remained constant. The mother underwent close antenatal surveillance and she was hospitalized. She had an uncomplicated delivery of the second twin at 29+ 2 weeks by cesarean section due to an abnormal Non-Stress Test.\n\nConclusion\nWe strongly suggest future evaluation of maternal serum inflammatory markers among these rare cases as these could predict intraamniotic infection.\n\nKeywords\nIntertwin Delayed Delivery Monitoring Inflammationissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nThe rate of multiple pregnancies over the last three decades has increased dramatically due to extended implementation of Artificial Reproduction Techniques (ART) [1]. The rate of twin pregnancies in the U.S. has climbed to 33.2 per 1.000 births in 2009 (increased by 76% since 1980) [2] . Higher order pregnancies remained constant from 2001 until a steep rise of 4% (153.5 per 100,000 births) in 2009 [2]. About 50% of live births in twins are preterm (< 37 weeks of gestational age), whereas higher order pregnancies are almost entirely born premature preterm. Furthermore it seems that ART twin pregnancies (regardless as to whether they are In Vitro Fertilization or not) have a tendency to be born prematurely than the naturally conceived ones [3] .\n\nAlthough preterm deliveries seem to rise the last 20years, an unexpected inverse variance with birth weight is also noted, leading to the assumption that fetal growth is improved, possibly due to better antenatal surveillance [4]. Perinatal outcome is negatively affected by low and very low birth weight. Therefore, all efforts by means of improved antenatal surveillance and therapeutic tocolysis should be focused on controlling prolongation of the pregnancy. Twin pregnancy that is complicated by very preterm delivery of the first fetus is a challenge in modern obstetrics and, to date, evidence regarding the optimal time of delivery of the second twin is lacking. Although, clinical chorioamnionitis (including fever, uterine tenderness and presence of contractions) is an absolute indication for delivery, to date, there is no consensus regarding the method of antenatal surveillance of twin pregnancies that are complicated with expulsion of the first fetus in the second, or early third trimester. In the present study we report a case of delayed interval delivery of the second twin 34 days following delivery of the first.\n\nCase presentation\nA thirty four years-old G2P1 woman was admitted in the high risk pregnancy unit of our The First Dpt of Obstetrics and Gynecology at 23+ 4 weeks of twin gestation due to premature prelabor rupture of the membranes (PPROM). The twins were dichorionic according to the first trimester ultrasound scan. The patient reported the presence of increased “vaginal discharge” during the last week. Nitrazine tape test was positive showing amniotic fluid leakage. She had an uncomplicated previous singleton term vaginal delivery 3 years ago. Her personal medical history revealed the presence of hypothyroidism that was treated with thyroxine 175 mcg twice a day, an appendicectomy 12 years ago and cervical cryotherapy for Human Papilloma Virus (HPV) 1 year ago.\n\nDuring physical examination, she was normotensive, afebrile and the cervix was not dilated or effaced. Laboratory examinations at admission were obtained and revealed the presence of mild leucocytosis (12,300/μl) and an elevated C- Reactive Protein (CRP) (40.98 mg/L with upper normal laboratory limit of 1.0 mg/L), while both dipstick urine examination and urinary cultures were normal. The patient received amoxicillin and metronidazole regimen eight hourly for 10 days and betamethasone 12 mg intramuscularly with a repeated dose at 24 h. Ultrasound examination revealed the presence of two embryos with positive cardiac function that weighted 535 and 606 g. The first of them had an amniotic fluid index (AFI) of 5 cm and the second an AFI of 14 cm. The patient’s cervical length was 28 mm and funneling was not noted. Ultrasonographic and laboratory assessment was performed every 3 days. Three days later WBCs were raised (14,200/μl) whereas CRP value declined at 2.90 mg/L.\n\nOne week following admission (24+ 4) the patient experienced blood stained brownish vaginal secretions and the vaginal examination revealed a Bishop score of 8. She was transferred to the labor ward where she delivered a female that weighted 550 g. Manual extraction of the placenta failed and the umbilical cord was ligated just above the level of the external cervical os. The vagina was rinsed with antiseptic solution (povidone iodine, Betadine®) and she remained in the labor ward under close surveillance of vital signs and fetal heart rate for the next 4 h. No signs of active labor were noticed. After informed consent and detailed counselling about the possible benefits and complications, the woman opted for delayed delivery of the second twin.\n\nThe next day the delivered twin died from respiratory distress syndrome. Blood samples were obtained from the patient that once again revealed raised white blood cells (WBCs) (12,400/μl) and increased CRP (13.14 mg/L). The patient remained in the high-risk pregnancy department and 5 days later she had a new blood and urine examination along with urine cultures that revealed elevated WBCs (13.900/μl), an a steep rise in CRP (31.78 mg/L) along with the presence of enterobacteriae spp. An expert in infectious diseases was advised and the patient received cefuroxime 750 mg eight hourly for 7 days. The surveillance protocol involved close laboratory assessment (WBC and CRP levels three times a week), ultrasonographic evaluation twice a week, vital signs clinical assessment (arterial pressure, heart rate, temperature) and electronic fetal monitoring (non stress test, NST) twice a day . The fluctuations of CRP and WBC values during the patient’s hospitalization are shown in the Fig. 1. She remained afebrile with no clinical evidence of chorioamnionitis. A repeated dose of steroids was administered to the patient during her 26th and 27th day of hospitalization (28th week of gestation).\n\nThe second female fetus was finally delivered 34 days after the first fetus (29+ 2) with cesarean section due to an abnormal NST. The neonate weighed 1150 g and had an Apgar score of 7 at the first minute and 9 at 5 minutes. It remained in the Neonatal Intensive Care Unit (NICU) for about 4 weeks.\n\nDiscussion\nPrematurity and very low birth weight pose great risks for the neonate due to inability of its organs to adapt. Respiratory Distress Syndrome (RDS), sepsis, necrotizing enterocolitis, intraventricular hemorrhage and periventricular leucomalacia) are common complications that are attributed to prematurity. In a previous study, tocolytics, antenatal steroids and surfactant administration within the first 2 hours following delivery were the most important predictors of neonatal survival for twins born between 22 and 26 weeks of gestational age [5]. The advancement of gestational age is very important in extremely premature neonates (less than 27 weeks of gestational age) as each day improves survival rates and decrease the duration of hospitalization in the NICU [6] . In singleton, neonatal survival following delivery at 24, 25, and 26 weeks is estimated to be 31.2, 59.1, and 75.3%, respectively [7]. In multiple gestations, the mortality rate reaches 32% from 23 to 25 weeks’ gestational age, compared to 19.2% from 26 to 27 weeks’ gestational age and 11.1% in all gestational age [8].\n\nIn multiple gestations with preterm delivery of the first baby, the second is usually delivered within a short time frame. Occasionally, however, uterine contractions stop and the cervix reconstitutes.The condition is referred to as Delayed Interval Delivery (DID) of the second twin. Due to the rarity of DID, standard protocols for the management of these patients don’t exist. Contraindication for delayed delivery are fetal distress, congenital abnormalities, preterm rupture of membranes of the remaining fetus, chorioamnionitis, monoamniotic or monochorionic pregnancies, and severe vaginal blood loss. The aseptic ligation of the umbilical cord stump close to the placenta reduces the risk of developing infection due to maceration and is practiced in these cases. Some authors routinely perform cervical cerclage immediately after the first delivery while others don’t recommend it. Arabin and van Eyck (2009) suggest that cerclage should be best avoided due to concerns of chorioamnionitis. On the contrary, Zhang et al. (2003) support cerclage, because it can minimize fetal membranes’ exposure to vaginal bacteria and acidity, prolonging delay interval.\n\nNumerous studies were published during the last decade addressing the case of delayed interval delivery of the second twin. One of the largest series was recorded from a population based study in the U.S. [9] .The authors concluded that when fetal expulsion of the first twin occurred between 22 and 23 weeks the prolongation of the intertwin interval could decrease perinatal mortality of the second twin. Interestingly, however, this beneficial effect persisted up to 3 weeks following delivery of the first twin. When the interval was prolonged more than 4 weeks the incidence of a Small for Gestational Age (SGA) second twin was also increased. Although 5 min Apgar scores less than 7 significantly decreased, they were not accompanied by a subsequent reduction in rates of respiratory distress syndrome. Arabin et al. confirmed these results stating that although the prolongation of the interval led to decreased perinatal mortality and morbidity of the second twin it was followed by an increase in the prevalence of SGA neonates [10]. The same authors extended their study in triplet gestations and found that regardless the interval between the first and second fetus, the third triplet was delivered at a maximum interval of 2 days, following delivery of the second triplet.\n\nFarkouh et al. observed in pregnancies with delivery of the first twin during the 22th week of gestation that the concurrent placement of cerclage increased the intertwin delivery interval compared to pregnancies with delivery of the first twin after removal of an elective cerclage (≥49 vs ≤26 days) [11] . The same authors concluded that even modest intervals of delivery could improve neonatal morbidity and mortality. However, we must underline the fact that all women in their series received routine antibiotic and tocolytic therapy and amniocentesis of the remaining twin was offered prior to cerclage placement to preclude intraamniotic infection. Furthermore, all pregnant women were informed that although the procedure could increase the intertwin delivery interval, the fetal outcome and the occurrence of maternal morbidity could not be excluded. Zhang et al. retrospectively analyzed 7 cases that were offered cervical cerclage after delivery of the first twin and found that the procedure did not increase the risk for intrauterine infection [12]. Recent systematic review by Feys et al., shows clear evidence of lower mortality risk of the second twin with DID [13] .\n\nIn our case, the leading twin after PPROM and amniotic fluid leakage was finally delivered by normal labor. We chose not to perform an episiotomy during its delivery. Maternal laboratory examinations were initially suggestive of the presence of infection, however there was no clinical evidence, as uterine tenderness and fever were absent. The mother was informed regarding the potential existence of chorioamnionitis and was offered the chance to perform amniocentesis to preclude infection; however she declined the operation and wished to continue her pregnancy with conservative treatment. WBCs and CRP were routinely assessed every 3 days, or once a day when a steep rise was observed (Fig. 1).Fig. 1 Time-trends in WBC (cells/ mm3, solid line) and CRP (mg/L, dotted line) values during hospitalization• Delayed interval delivery of the second twin represents a clinical challenge.• Subclinical chorioamnionitis cannot be excluded and its impact on the pregnancy course and perinatal outcome remains unknown• WBCs and CRP may provide evidence of deterioration of the patients` pregnancy course• Future studies are needed to investigate the predictive accuracy of these indices.\n\n\n\nWBCs fluctuated between higher normal limits (12,000/μl) and 24,700/μl, whereas CRP was continuously at least 2-fold higher than higher normal laboratory limit (although the fluctuation of its levels could not be clinically interpreted). During delivery the vagina was cleansed with antiseptic solution and a high umbilical cord ligation was performed (above the level of the external cervical os). Given the presence of biochemical signs of infection we chose to avoid cervical cerclage and tocolytic therapy. The patient remained hospitalized. In a retrospective evaluation of 73 women with PPROM investigators found that maternal CRP levels were not effective in predicting chorioamnionitis [14]. However, an increased CRP could potentially predict future chorioamnionitis development. In another study, maternal CRP levels of more than 20 mg/L were found predictive of funisitis among singleton pregnancies [15]. In their systematic review Van de Laar et al. conclude that although CRP was found to be a moderate predictor of chorioamnionitis, its use isn’t yet supported [16]. Popowski et al. noted that maternal WBC count has a poor predictive value, and is only considered highly specific when the threshold of 16,000/μl is exceeded [17]. Park et al. suggested that the evaluation of maternal WBC and CRP levels, along with parity and gestational age could be used as a predictive model of intraamniotic infection in singletons with PPROM [18]. The area under the curve of the model was particularly high (0.848 (95% CI 0.788–0.908) and its sensitivity and specificity reached values of 81 and 75% respectively. Our case differs from the aforementioned studies, as the latter are focused in singleton pregnancies, therefore not taking into account the potential confounders that may lead to extrauterine infection after the live birth of the first twin.\n\nConclusions\nDelayed interval intertwin delivery rates are expected to increase during the next years as antenatal surveillance becomes more intensive and new tocolytic agents become more popular. Elective cerclage may be considered in twin pregnancies with delivery of the first twin before 23 weeks of gestation. However, this approach should be taken into account in women with no signs of infection. Although we strongly suggest routine performance of amniocentesis for the evaluation of the amniotic fluid for inflammatory markers and routine cultures, a number of patients may still deny this invasive technique. Close antenatal surveillance of both mother and fetus is strongly suggested among these special cases. Given the fact that subclinical chorioamnionitis cannot be precluded, and its effects on the pregnancy course remain undetermined in cases of delayed interval delivery of the second twin, laboratory assessment of markers of inflammation could be potentially considered in these special cases. White blood cells WBCs and CRP have been widely adopted to trace down infections in internal medicine and to follow the course of infectious diseases. Their actual predictive value in delayed delivery of the second twin remains uninvestigated. Our case report presents such a case and may be used as a reference for future studies in this field. These should specifically investigate the sensitivity and specificity of blood biomarkers in predicting chorioamnionitis and fetal infection to help reduce perinatal maternal and neonatal morbidity and mortality.\n\nAbbreviations\nAFIAmniotic fluid index\n\nARTArtificial reproduction techniques\n\nCRPC- reactive protein\n\nDIDDelayed interval delivery\n\nNICUNeonatal intensive care unit\n\nNSTNon stress test\n\nPPROMPremature prelabor rupture of the membranes\n\nRDSRespiratory distress syndrome\n\nSGASmall for gestational age\n\nWBCWhite blood cells\n\nAvailability of data and materials\nAll data generated or analysed during this study are included in this published article.\n\nAuthors’ contributions\nAll authors made substantial contributions during the acquisition and interpretation of data, and during the writing process. Furthermore, all authors gave their final approval for the present version and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Specifically, DG conceived of the study, and participated in its design, writing and coordination. Also, participated in the clinical assessment of the patient and the clinical and therapeutical decisions during hospital stay of the patient. FP helped to draft the manuscript and revised the manuscript. PV helped to draft the manuscript and revised the manuscript. TM participated in the clinical assessment of the patient and the clinical and therapeutical decisions during her admission, wrote and revised the manuscript. AP helped to draft the manuscript and revised the manuscript. SM participated in the clinical assessment of the patient and the clinical and therapeutical decisions during her admission, wrote and revised the manuscript. PN provided supervision and clinical evidence during the critical intertwin delivery period, wrote and revised the manuscript. LD provided supervision and clinical evidence during the critical intertwin delivery period, wrote and revised the manuscript.\n\nAuthors’ information\nDG is associate Professor of Obstetrics and Gynecology in Athens Medical School and Head of Fetal-Maternal and High-Risk Pregnancy Unit in the 1st Department of Obstetrics and Gynecology, Athens Medical School, Alexandra General Hospital.\n\nFP is Academic fellow in Fetal-Maternal and High-Risk Pregnancy Unit in the 1st Department of Obstetrics and Gynecology, Athens Medical School, Alexandra General Hospital.\n\nPV is Academic fellow in the 3rd Department of Obstetrics and Gynecology, Athens Medical School, Attikon General Hospital.\n\nTM is lecturer in Fetal-Maternal and High-Risk Pregnancy Unit in the 1st Department of Obstetrics and Gynecology, Athens Medical School, Alexandra General Hospital.\n\nAP is Academic fellow in Fetal-Maternal and High-Risk Pregnancy Unit in the 1st Department of Obstetrics and Gynecology, Athens Medical School, Alexandra General Hospital.\n\nSM is Consultant in Fetal-Maternal and High-Risk Pregnancy Unit in the 1st Department of Obstetrics and Gynecology, Athens Medical School, Alexandra General Hospital.\n\nPN is Professor of Obstetrics and Gynecology in Athens Medical School and Director in the 3rd Department of Obstetrics and Gynecology, Athens Medical School, Attikon General Hospital.\n\nLD is Professor of Obstetrics and Gynecology in Athens Medical School and Director in the 1st Department of Obstetrics and Gynecology, Athens Medical School, Alexandra General Hospital.\n\nEthics approval and consent to participate\nThe patient has signed informed consent for delayed intertwin delivery of the second twin and Alexandra Hospital ethics committee approved this practice.\n\nConsent for publication\nThe patient approved the publication of the current case report (and provided written informed consent to have patient information included, including, gender, age and clinical data) and the Ethics committee of our hospital also approved publication of this article.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Callahan TL Hall JE Ettner SL Christiansen CL Greene MF Crowley WF Jr The economic impact of multiple-gestation pregnancies and the contribution of assisted-reproduction techniques to their incidence N Engl J Med 1994 331 244 249 10.1056/NEJM199407283310407 8015572 \n2. Martin JA, Hamilton BE, Ventura SJ, et al. Births: final data for 2009. Natl Vital Stat Rep 2011;60:1–70. https://www.cdc.gov/nchs/data/nvsr/nvsr60/nvsr60_01.pdf. Accessed 7/2017.\n3. Verstraelen H, Goetgeluk S, Derom C, et al. Preterm birth in twins after subfertility treatment: population based cohort study. BMJ 2005;331:1173. http://www.bmj.com/content/331/7526/1173.long. Accessed 7/2017.\n4. Gielen M, van Beijsterveldt CE, Derom C, et al. Secular trends in gestational age and birthweight in twins. Hum Reprod 2010;25:2346–2353. https://academic.oup.com/humrep/article/25/9/2346/2915542. Accessed 7/2017.\n5. Fellman V, Hellstrom-Westas L, Norman M, et al. One-year survival of extremely preterm infants after active perinatal care in Sweden. JAMA 2009;301:2225–33. http://jamanetwork.com/journals/jama/fullarticle/184015. Accessed 7/2017.\n6. Markestad T, Kaaresen PI, Ronnestad A, et al. Early death, morbidity, and need of treatment among extremely premature infants. Pediatrics 2005;115:1289–98. http://pediatrics.aappublications.org/content/115/5/1289.long?sso=1&sso_redirect_count=1&nfstatus=401&nftoken=00000000–0000–0000-0000-000000000000&nfstatusdescription=ERROR%3a+No+local+token. Accessed 7/2017.\n7. P.-Y. Ancel, F. Goffinet, P. Kuhn et al., Survival and morbidity of preterm children born at 22 through 34 weeks’ gestation in France in 2011: results of the EPIPAGE-2 cohort study, JAMA Pediatr, vol. 169, no. 3, pp. 230–238, 2011. http://jamanetwork.com/journals/jamapediatrics/fullarticle/2091623. Accessed 7/2017.\n8. Yeo KT, Lee QY, Quek WS et al., Trends in morbidity and mortality of extremely preterm multiple gestation newborns, Pediatrics 2015 Aug;136(2):263–271. http://pediatrics.aappublications.org/content/136/2/263.long. Accessed 7/2017.\n9. Oyelese Y, Ananth CV, Smulian JC, Vintzileos AM. Delayed interval delivery in twin pregnancies in the United States: impact on perinatal mortality and morbidity. Am J Obstet Gynecol 2005;192:439–444. http://www.ajog.org/article/S0002-9378(04)00839-7/fulltext. Accessed 7/2017.\n10. Arabin B, van Eyck J. Delayed-interval delivery in twin and triplet pregnancies: 17 years of experience in 1 perinatal center. Am J Obstet Gynecol 2009;200:154 e1–154 e8. http://www.ajog.org/article/S0002-9378(08)00982-4/fulltext. Accessed 7/2017.\n11. Farkouh LJ, Sabin ED, Heyborne KD, Lindsay LG, Porreco RP. Delayed-interval delivery: extended series from a single maternal-fetal medicine practice. Am J Obstet Gynecol 2000;183:1499–503. http://www.ajog.org/article/S0002-9378(00)68860-9/fulltext. Accessed 7/2017.\n12. Zhang J, Johnson CD, Hoffman M. Cervical cerclage in delayed interval delivery in a multifetal pregnancy: a review of seven case series. Eur J Obstet Gynecol Reprod Biol 2003;108:126–30. http://www.ejog.org/article/S0301-2115(02)00479-7/fulltext. Accessed 7/2017.\n13. Feys S Jacquemyn Y Delayed-interval delivery can save the second twin: evidence from a systematic review Facts Views Vis Obgyn 2016 8 4 223 231 28210482 \n14. Smith EJ, Muller CL, Sartorius JA, White DR, Maslow AS. C-reactive protein as a predictor of chorioamnionitis. J Am Osteopath Assoc 2012;112:660–664. http://jaoa.org/article.aspx?articleid=2094391. Accessed 7/2017.\n15. Perrone G, Anceschi MM, Capri O, et al. Maternal C-reactive protein at hospital admission is a simple predictor of funisitis in preterm premature rupture of membranes. Gynecol Obstet Investig 2012;74:95–99. https://www.karger.com/Article/Abstract/337717. Accessed 7/2017.\n16. Van de Laar R, van der Ham DP, Oei SG, Willekes C, Weiner CP, Mol BW. Accuracy of C-reactive protein determination in predicting chorioamnionitis and neonatal infection in pregnant women with premature rupture of membranes: a systematic review. Eur J Obstet Gynecol Reprod Biol 2009;147:124–129. https://www.ejog.org/article/S0301-2115(02)00479-7/fulltext. Accessed 7/2017.\n17. Popowski T, Goffinet F, Batteux F, Maillard F, Kayem G. [Prediction of maternofetal infection in preterm premature rupture of membranes: serum maternal markers]. Gynecol Obstet Fertil 2011;39:302–308. https://www.ncbi.nlm.nih.gov/pubmed/21515086. Accessed 7/2017.\n18. Park KH, Kim SN, Oh KJ, Lee SY, Jeong EH, Ryu A. Noninvasive prediction of intra-amniotic infection and/or inflammation in preterm premature rupture of membranes. Reprod Sci 2012;19:658–665. http://journals.sagepub.com/doi/abs/10.1177/1933719111432869?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&. Accessed 7/2017.\n\n",
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"mesh_terms": "D000328:Adult; D001721:Birth Intervals; D002585:Cesarean Section; D036861:Delivery, Obstetric; D005260:Female; D005322:Fetal Membranes, Premature Rupture; D006801:Humans; D007231:Infant, Newborn; D018836:Inflammation Mediators; D011247:Pregnancy; D059285:Pregnancy, Twin; D047928:Premature Birth; D013997:Time Factors; D015149:Tocolytic Agents; D014427:Twins",
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"abstract": "Spinal epidural abscess caused by MRSA, a life-threatening organism resistant to methicillin and other antibiotics, is a rare but important infectious pathology due to its potential damage to the spinal cord. We present the case of a 74-year-old man who hematogenously seeded his entire epidural spinal canal from C1 to sacrum with MRSA bacteria and remained infected even after maximal treatment with vancomycin and daptomycin. Ceftaroline, a new 5th generation antibiotic with recently described clearance of widespread MRSA infection in epidural complex spine infections, was added to vancomycin as dual therapy for his MRSA infection. A 74-year-old diabetic man with prior right total knee arthroplasty and MRSA infection presented with persistent bacteremia and sepsis. He was transferred to our academic center after diagnosis of entire spine epidural abscesses from C1 to sacral levels with midthoracic MRI T2 hyperintensities of the vertebral bodies and disc concerning for osteomyelitis and discitis. Despite surgery and IV vancomycin with MIC of 1, suggesting extreme susceptibility, the patient's blood cultures remained persistently bacteremic at day 5 of treatment. After 48 hours of dual antibiotic therapy with vancomycin and ceftaroline, his blood cultures came back showing no growth. The patient's outcome was unfavorable due to the advanced nature of his infection and multiple comorbidities, but his negative blood cultures after the addition of ceftaroline to his regime require further investigation into this dual therapy. Randomized controlled trials of 5th generation or combinatorial antibiotics should be considered for this disease.",
"affiliations": "Department of Neurosurgery, Mayo Clinic, Jacksonville, Florida, USA.;Department of Neurosurgery, Mayo Clinic, Jacksonville, Florida, USA.;Department of Neurosurgery, Mayo Clinic, Jacksonville, Florida, USA.;Department of Infectious Disease, Mayo Clinic, Jacksonville, Florida, USA.;Department of Infectious Disease, Mayo Clinic, Jacksonville, Florida, USA.",
"authors": "Ebot|James|J|0000-0001-9412-0836;Freeman|W D|WD|;Wharen|Robert|R|;Diaz|Mark Anthony|MA|;Libertin|Claudia|C|0000-0001-9649-6802",
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"fulltext": "\n==== Front\nCase Rep Infect DisCase Rep Infect DisCRIIDCase Reports in Infectious Diseases2090-66252090-6633Hindawi 10.1155/2019/7413089Case ReportMRSA Spinal Epidural Abscess as a Neurosurgical and Infectious Disease Emergency with Unresolved Antimicrobial Solution http://orcid.org/0000-0001-9412-0836Ebot James ebot.james@mayo.edu\n1\nFreeman W. D. \n1\nWharen Robert \n1\nDiaz Mark Anthony \n2\nhttp://orcid.org/0000-0001-9649-6802Libertin Claudia \n2\n\n1Department of Neurosurgery, Mayo Clinic, Jacksonville, Florida, USA\n2Department of Infectious Disease, Mayo Clinic, Jacksonville, Florida, USAAcademic Editor: Tomoyuki Shibata\n\n2019 30 1 2019 2019 741308926 7 2018 11 12 2018 14 1 2019 Copyright © 2019 James Ebot et al.2019This 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.Spinal epidural abscess caused by MRSA, a life-threatening organism resistant to methicillin and other antibiotics, is a rare but important infectious pathology due to its potential damage to the spinal cord. We present the case of a 74-year-old man who hematogenously seeded his entire epidural spinal canal from C1 to sacrum with MRSA bacteria and remained infected even after maximal treatment with vancomycin and daptomycin. Ceftaroline, a new 5th generation antibiotic with recently described clearance of widespread MRSA infection in epidural complex spine infections, was added to vancomycin as dual therapy for his MRSA infection. A 74-year-old diabetic man with prior right total knee arthroplasty and MRSA infection presented with persistent bacteremia and sepsis. He was transferred to our academic center after diagnosis of entire spine epidural abscesses from C1 to sacral levels with midthoracic MRI T2 hyperintensities of the vertebral bodies and disc concerning for osteomyelitis and discitis. Despite surgery and IV vancomycin with MIC of 1, suggesting extreme susceptibility, the patient's blood cultures remained persistently bacteremic at day 5 of treatment. After 48 hours of dual antibiotic therapy with vancomycin and ceftaroline, his blood cultures came back showing no growth. The patient's outcome was unfavorable due to the advanced nature of his infection and multiple comorbidities, but his negative blood cultures after the addition of ceftaroline to his regime require further investigation into this dual therapy. Randomized controlled trials of 5th generation or combinatorial antibiotics should be considered for this disease.\n==== Body\n1. Introduction\nSpinal epidural abscess is a rare but important infectious pathology, and prompt diagnosis and management is paramount to avoid potential complications to the spinal cord such as paralysis. The source of infection may be via hematogenous spread, direct extension from nearby tissues, or iatrogenic, from spinal procedures. The most common pathogen is Staphylococcus aureus, identified in about 75% of the cases [1]. Spinal decompression of the epidural abscess coupled with antimicrobial therapy, especially for those with neurologic deficits is the management of choice, but most institutions adopt a multidisciplinary approach to care with treatments tailored to individual patient presentation. The last decade has seen a rise in the incidence of spinal epidural abscesses mostly attributed to increase in spinal procedures and instrumentation, as well as increased use of injected drugs of abuse. Penetration of antistaphylococcal antimicrobials into the epidural space after surgical debridement is imperative for excellent outcomes. Vancomycin penetrates fairly well into inflamed meninges [2]. As vancomycin minimum inhibitory concentrations (MIC) creep higher, careful antimicrobial management is as critical as early and complete debridement of the abscess.\n\nWe present a case of a 74-year-old gentleman who was diagnosed with early prosthetic joint infection (PJI) following a right total knee arthroplasty (TKA) which was associated with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. The MRSA bacteremia seeded other joints and the spinal epidural space. Despite prolonged antimicrobial therapy on two occasions and surgical debridement of joints, he developed a large spinal epidural abscess and refractory MRSA bacteremia [3] that required combination of ceftaroline and vancomycin for bacteremia clearance. This case highlights several management features regarding spinal epidural abscesses and the need for awareness of drug penetration into the CNS by providers.\n\n2. Case Report\nThe patient is a 74-year-old male with comorbidities of coronary artery disease, congestive heart failure, hypertension, and renal insufficiency who presented to an outside hospital with back pain and left upper extremity weakness associated with high fevers and urinary incontinence. Outside spinal imaging showed a large spinal abscess; therefore, he was transferred to our institution for a higher level of care. On presentation, the patient was in septic shock requiring fluid boluses and inotropic agents to stabilize him. Further history was obtained from the family as follows:On November 2016, he underwent an elective right TKA complicated by an early MRSA PJI associated with bacteremia\n\nOn May 0f 2017, he underwent resection of the hardware in the knee, incision and drainage, followed by 12 weeks of daptomycin therapy\n\nFive months later, on October of 2017, due to relapse, he had a second debridement of the right knee for source control as well as left ankle incision and debridement followed by another 8 weeks of daptomycin for this relapse of infection\n\nA daptomycin-susceptible, vancomycin-susceptible MRSA was isolated from blood and both surgical sites, knee and ankle, on both occasions\n\nHe had ongoing thoracic back pain since 2016 which was monitored radiographically by his local providers, until the development of spinal epidural abscess with upper extremity weakness, which prompted his current hospitalization in January of 2018\n\n\n\nReview of systems on presenting to our institution was significant for general weakness and malaise, right shoulder and thoracic back pain, and constipation from narcotics. He was hemodynamically unstable requiring inotropic support. He was awake and oriented, following commands with intact speech. There were no cranial nerve deficits. On motor testing, he had normal muscle bulk with generalized hypotonia. There was no movement of his left upper extremity. He had 2/5 strength on his right upper extremity and 2/5 strength on his bilateral lower extremity. There was decreased sensation to light touch on his left side. Reflexes were globally decreased with negative Hoffman and Babinski signs. The white blood cell count was 30,000/L, and procalcitonin was 4.88 ng/ml. Blood cultures grew MRSA rapidly. Repeat imaging of the brain and spine at our institution showed extensive epidural phlegmon throughout the cervical, thoracic, and lumbar spine with intracranial expansion into the posterior fossa beneath the cerebellum with pockets of possible early organizing abscess within the phlegmon (Figure 1). Brain imaging identified no discrete abscess or leptomeningeal enhancement.\n\nNeurosurgery immediately evaluated the patient and promptly performed a cervical spine decompression of C1–C7 and thoracic spine decompression of T5–T7. Operatively, a large epidural abscess was found, drained, and washed out. He was started on vancomycin every 12 hours with trough vancomycin levels being therapeutic. The patient subsequently underwent irrigation and debridement of the right knee, left ankle, and left great toe as well at our institution; all surgical sites grew MRSA with vancomycin MIC of 1 mcg/ml. Despite attempts at source control and optimal pharmacokinetic dosing of vancomycin with a trough level of 20.5 mcg/ml on day 5, he had refractory MRSA bacteremia. Infectious disease deemed he had failed daptomycin therapy; therefore, ceftaroline 600 mg every 8 hours (MIC of 0.38 mcg/ml) was added to vancomycin. Repeat blood cultures showed clearance of bacteremia after 48 hours of initiation of the combination therapy. His left ankle and right knee continued to yield MRSA. Due to his multiple comorbidities and need for more aggressive source control of his infection, i.e., amputation of the leg, palliative care was sought by the family, and he died a few days later.\n\n3. Discussion\nPrompt and definitive management by all providers is paramount for successful outcomes and prevention of neurological deficits among those with epidural infections [1]. The above-discussed case of disseminated S. aureus PJI involved other joints (ankle and toe) and the epidural space through seeding from the blood stream infection. An early PJI was the original source of the bacteremia which was appropriately managed [4] with resection and prolonged targeted antimicrobial with 12 weeks of daptomycin. However, a relapse occurred after the initial completion of 12 weeks of daptomycin leading to repeat knee debridement, with new incision and drainage of the left ankle followed by an additional 8 weeks of daptomycin. The MRSA isolate was susceptible to daptomycin and never developed resistance to daptomycin. It is difficult to precisely determine when the seeding of the epidural space may have occurred, but the patient complained of new onset of back pain months before presentation to our institution. Back pain is a common symptom among those presenting with epidural abscesses and should be quickly investigated especially in settings where bacteremia precedes the pain. We suspect the epidural abscess occurred weeks, if not months, before his presentation to our institution based on the maturity of the abscess on gross operative observation and the extensiveness of the abscess noted on the MRI (Figure 1). This case highlights that a high degree of clinical suspicion is mandatory to diagnose epidural infections early to avoid poor outcomes and that antimicrobial therapy alone may not be successful in curing MRSA once seeded to the CNS site.\n\nCentral nervous system (CNS) infections caused by pathogens with a reduced sensitivity to drugs are a therapeutic challenge. This is particularly true for infections caused by penicillin-resistant pneumococci, methicillin-resistant staphylococci, multiresistant Gram-negative aerobic bacilli, or other organisms that affect primarily the CNS. This patient received daptomycin therapy following each knee surgical debridement. However, data on daptomycin penetration into the CNS is limited [5] as well as its use in CNS infections [6]. Also, providers must have an awareness of the peculiarities of the pharmacokinetics of anti-infectives within the CNS [7]. The intracranial-intraspinal space consists of several compartments. Even in individual regions of one compartment, e.g., cerebrospinal fluid (CSF), strong differences in drug concentrations can occur between the ventricular, cisternal, and lumbar parts of the compartment [8]. The complexities of CNS pharmacokinetics of antibiotics and lack of clinical trials make selection of anti-MRSA antibiotics a dilemma for even infectious disease specialists in such cases. The combination of ceftaroline and vancomycin was used to quickly eradicate the refractory MRSA bacteremia to avoid further dissemination of the pathogen. At our institution, vancomycin was chosen over daptomycin due to its documented penetration into the CNS [9] and then combined with ceftaroline due to reports of synergistic activity between vancomycin and ceftaroline [10]. Rapid bacteremia clearance occurred within 48 hours of the use of both agents. Whether or not it would have been successful in curing the epidural infection remains unknown. For patients with inflamed meninges, bactericidal CSF concentrations of vancomycin against susceptible pathogens are reached during high intravenous doses [2] which was achieved. Ceftaroline, a fifth-generation cephalosporin, had been used as salvage therapy in a case of MRSA epidural abscess [11–15]. Infectious disease felt that ceftaroline may enter the CNS like other cephalosporins, but data to support that hypothesis were lacking. Unfortunately, the patient's family opted for hospice care before further monitoring of the spinal infection could be done.\n\nThis case of early MRSA PJI of a TKA with dissemination to other joints and the spine demonstrates the need for early source control of the infection. Without aggressive debridement of the source(s) of infection, which may be at more than one location, relapses occur. This case also unfortunately highlights the importance of early recognition of epidural abscesses to avoid neurologic deficits and the extent to which the abscess can grow (Figure 1). Lastly, infectious disease consultation is indicated and the standard of care for any S. aureus bacteremia [16] in that 30 and 90 day mortalities are significantly reduced and management of S. aureus bacteremia significantly are improved. We confirmed that the combination of ceftaroline and vancomycin rapidly cleared MRSA bacteremia refractory to vancomycin monotherapy. Regarding CNS penetration of ceftaroline, further investigation is needed to determine its role in the management of MRSA epidural infections.\n\nDisclosure\nThis case has been presented as a poster at the Mayo Clinic Neurosurgery and Critical Care Updates in Orlando, Florida, on May 11th, 2018, but not published elsewhere.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this paper.\n\nFigure 1 There is extensive epidural phlegmon throughout the cervical (c), thoracic (a, d), and lumbar spine (b) with intracranial extension into the posterior fossa beneath the cerebellum (c). There are small pockets of possible early abscess organization within this phlegmon, but no drainable collection is yet present. The phlegmon causes severe cord compression at C7–T1 (c) and T5–T10 (a, d) levels. There is extension inferiorly through the sacral level (b). There is relative increased T2 signal in the anterior and posterior bony elements at the T1-T2 and T6–T8 levels (d).\n==== Refs\n1 Mackenzie A. R. Laing R. B. S. Smith C. C. Kaar G. F. Smith F. W. Spinal epidural abscess: the importance of early diagnosis and treatment Journal of Neurology, Neurosurgery & Psychiatry 1998 65 2 209 212 10.1136/jnnp.65.2.209 2-s2.0-0031874955 \n2 Albanese J. Leone M. Bruguerolle B. Ayem M.-L. Lacarelle B. Martin C. Cerebrospinal fluid penetration and pharmacokinetics of vancomycin administered by continuous infusion to mechanically ventilated patients in an intensive care unit Antimicrobial Agents and Chemotherapy 2000 44 5 1356 1358 10.1128/aac.44.5.1356-1358.2000 2-s2.0-0034006869 10770777 \n3 Lewis P. O. Heil E. L. Covert K. L. Cluck D. B. Treatment strategies for persistent methicillin-resistant Staphylococcus aureus bacteraemia Journal of Clinical Pharmacy and Therapeutics 2018 43 5 614 625 10.1111/jcpt.12743 2-s2.0-85050633356 30003555 \n4 Osmon D. R. Berbari E. F. Berendt A. R. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America Clinical Infectious Diseases 2012 56 1 e1 e25 10.1093/cid/cis803 2-s2.0-84871247727 23223583 \n5 Kullar R. Chin J. N. Edwards D. J. Parker D. Coplin W. M. Rybak M. J. Pharmacokinetics of single-dose daptomycin in patients with suspected or confirmed neurological infections Antimicrobial Agents and Chemotherapy 2011 55 7 3505 3509 10.1128/aac.01741-10 2-s2.0-79959194183 21502620 \n6 Erritouni M. Ktaich N. Rahal J. J. Use of daptomycin for the treatment of methicillin-resistant coagulase-negative staphylococcal ventriculitis Case Reports in Medicine 2012 2012 2 593578 10.1155/2012/593578 2-s2.0-84876702711 \n7 Nau R. Sorgel F. Eiffert H. Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections Clinical Microbiology Reviews 2010 23 4 858 883 10.1128/cmr.00007-10 2-s2.0-78049397500 20930076 \n8 Shapiro W. R. Young D. F. Mehta B. M. Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections New England Journal of Medicine 1975 293 4 161 166 10.1056/nejm197507242930402 2-s2.0-0016803892 806016 \n9 Ricard J. -D. Wolff M. Lacherade J.-C. Levels of vancomycin in cerebrospinal fluid of adult patients receiving adjunctive corticosteroids to treat pneumococcal meningitis: a prospective multicenter observational study Clinical Infectious Diseases 2007 44 2 250 255 10.1086/510390 2-s2.0-33846155255 17173226 \n10 Gritsenko D. Fedorenko M. Ruhe J. J. Altshuler J. Combination therapy with vancomycin and ceftaroline for refractory methicillin-resistant Staphylococcus aureus bacteremia: a case series Clinical Therapeutics 2017 39 1 212 218 10.1016/j.clinthera.2016.12.005 2-s2.0-85009814758 28038791 \n11 Bucheit J. Collins R. Joshi P. Methicillin-resistant Staphylococcus aureus epidural abscess treated with ceftaroline fosamil salvage therapy American Journal of Health-System Pharmacy 2013 71 2 110 113 10.2146/ajhp130246 2-s2.0-84906074043 \n12 Burnett Y. J. Echevarria K. Traugott K. A. Ceftaroline as salvage monotherapy for persistent MRSA bacteremia Annals of Pharmacotherapy 2016 50 12 1051 1059 10.1177/1060028016664361 2-s2.0-84994137862 27520326 \n13 Sakoulas G. Moise P. A. Casapao A. M. Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline Clinical Therapeutics 2014 36 10 1317 1333 10.1016/j.clinthera.2014.05.061 2-s2.0-84908310810 25017183 \n14 Watkins R. R. Yendewa G. Burdette S. D. DISC: describing infections of the spine treated with ceftaroline Journal of Global Antimicrobial Resistance 2018 13 146 151 10.1016/j.jgar.2018.01.001 2-s2.0-85046639686 29337085 \n15 White B. P. Barber K. E. Stover K. R. Ceftaroline for the treatment of methicillin-resistant Staphylococcus aureus bacteremia American Journal of Health-System Pharmacy 2017 74 4 201 208 10.2146/ajhp160006 2-s2.0-85012888009 28179245 \n16 Tissot F. Calandra T. Prod’hom G. Mandatory infectious diseases consultation for MRSA bacteremia is associated with reduced mortality Journal of Infection 2014 69 3 226 234 10.1016/j.jinf.2014.05.004 2-s2.0-84908287690 24844825\n\n",
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"title": "MRSA Spinal Epidural Abscess as a Neurosurgical and Infectious Disease Emergency with Unresolved Antimicrobial Solution.",
"title_normalized": "mrsa spinal epidural abscess as a neurosurgical and infectious disease emergency with unresolved antimicrobial solution"
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"abstract": "Use of novel agents, including proteasome inhibitors and immunomodulatory drugs, has markedly improved outcomes in multiple myeloma (MM) patients. However, most MM patients eventually relapse and require salvage treatments. We report herein the result of a phase I/II study, performed from 2014 to 2017 to assess the feasibility and efficacy of a maximum tolerated dose (MTD) of lenalidomide (Len) combined with a fixed dose of once weekly subcutaneous (sc) 1.3 mg/m2 of bortezomib plus 20 mg of dexamethasone (scVRd regimen) in relapsed/refractory MM patients in the Japanese population. In the phase I part, dose-limiting toxicities were observed in three of six patients treated with 20 mg of Len; the MTD was accordingly defined as 15 mg in our cohort. In the phase II part, the recommended dose of the scVRD regimen showed a 71.4% best overall response rate, with a median overall survival of 14.8 months and a median progression-free survival of 8 months. Severe adverse events (≥ grade 3) were observed in ~ 15% of the patients, indicating the tolerability and efficacy of the regimen. Less prior treatment was associated with higher probability of durable response. This scVRd regimen may thus be a better fit for MM patients in early-stage relapse.",
"affiliations": "Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.;Department of Hematology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.;Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.;Department of Hematology/Oncology, Japan Community Health Care Organization (JCHO) Kyushu Hospital, Fukuoka, Japan.;Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan.;Department of Hematology, Fukuoka Red Cross Hospital, Fukuoka, Japan.;Department of Hematology, Harasanshin Hospital, Fukuoka, Japan.;Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan.;Department of Hematology/Oncology, Japan Community Health Care Organization (JCHO) Kyushu Hospital, Fukuoka, Japan.;Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.;Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. toshmiya@intmed1.med.kyushu-u.ac.jp.",
"authors": "Mori|Yasuo|Y|;Choi|Ilseung|I|;Yoshimoto|Goichi|G|;Muta|Tsuyoshi|T|;Yamasaki|Satoshi|S|;Tanimoto|Kazuki|K|;Kamimura|Tomohiko|T|;Iwasaki|Hiromi|H|;Ogawa|Ryosuke|R|;Akashi|Koichi|K|;Miyamoto|Toshihiro|T|http://orcid.org/0000-0002-6533-1594;|||",
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"keywords": "Combination therapy; Immunomodulatory drug; Multiple myeloma; Proteasome inhibitor; Relapsed/refractory",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D003907:Dexamethasone; D006801:Humans; D000077269:Lenalidomide; D009101:Multiple Myeloma; D012008:Recurrence; D016896:Treatment Outcome",
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"title": "Phase I/II study of bortezomib, lenalidomide, and dexamethasone treatment for relapsed and refractory multiple myeloma.",
"title_normalized": "phase i ii study of bortezomib lenalidomide and dexamethasone treatment for relapsed and refractory multiple myeloma"
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"abstract": "A 68-year-old woman with a history of stage IIIC (T3bN1bM0) melanoma with metastases to her right axilla status after 10 cycles of nivolumab presented with right shoulder pain. Radiographs showed a progressive erosive glenohumeral joint lesion. The workup was negative for metastasis and infection. Her clinical and radiographic findings were consistent with erosive arthritis. The patient underwent shoulder hemiarthroplasty and experienced substantial improvements.\n\n\n\nThis is an unusual case of inflammatory arthritis associated with nivolumab, an antiprogrammed cell death protein 1, and is an important reminder of the musculoskeletal toxicities associated with immunotherapies.",
"affiliations": "Department of Orthopaedics and Rehabilitation, Oregon Health and Science University, Portland, Oregon.;Operative Care Division, Portland VA Medical Center, Portland, Oregon.;Department of Pathology, Portland VA Medical Center, Portland, Oregon.;Department of Orthopaedics and Rehabilitation, Oregon Health and Science University, Portland, Oregon.",
"authors": "Lindsay|Sarah E|SE|0000-0002-4452-002;Wurster|Lindsey|L|0000-0002-1154-9336;Woolf|Kirsten|K|0000-0002-4507-1078;Gundle|Kenneth R|KR|0000-0003-0451-0561",
"chemical_list": null,
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"pmid": "34669677",
"pubdate": "2021-10-20",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "An Unusual Presentation of Inflammatory Shoulder Arthritis Associated with Nivolumab: A Case Report.",
"title_normalized": "an unusual presentation of inflammatory shoulder arthritis associated with nivolumab a case report"
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"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-2022-038418",
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"abstract": "BACKGROUND\nThe role of chemotherapy in high-risk soft tissue sarcoma is controversial. Though many patients undergo initial curative resection, distant metastasis is a frequent event, resulting in 5-year overall survival rates of only 50-60%. Neo-adjuvant and adjuvant chemotherapy (CTX) has been applied to achieve pre-operative cytoreduction, assess chemosensitivity, and to eliminate occult metastasis. Here we report on the results of our non-randomized phase II study on neo-adjuvant treatment for high-risk STS.\n\n\nMETHODS\nPatients with potentially curative high-risk STS (size ≥ 5 cm, deep/extracompartimental localization, tumor grades II-III [FNCLCC]) were included. The protocol comprised 4 cycles of neo-adjuvant chemotherapy (EIA, etoposide 125 mg/m(2) iv days 1 and 4, ifosfamide 1500 mg/m2 iv days 1 - 4, doxorubicin 50 mg/m(2) day 1, pegfilgrastim 6 mg sc day 5), definitive surgery with intra-operative radiotherapy, adjuvant radiotherapy and 4 adjuvant cycles of EIA.\n\n\nRESULTS\nBetween 06/2005 and 03/2010 a total of 50 subjects (male = 33, female = 17, median age 50.1 years) were enrolled. Median follow-up was 30.5 months. The majority of primary tumors were located in the extremities or trunk (92%), 6% originated in the abdomen/retroperitoneum. Response by RECIST criteria to neo-adjuvant CTX was 6% CR (n = 3), 24% PR (n = 12), 62% SD (n = 31) and 8% PD (n = 4). Local recurrence occurred in 3 subjects (6%). Distant metastasis was observed in 12 patients (24%). Overall survival (OS) and disease-free survival (DFS) at 2 years was 83% and 68%, respectively. Multivariate analysis failed to prove influence of resection status or grade of histological necrosis on OS or DFS. Severe toxicities included neutropenic fever (4/50), cardiac toxicity (2/50), and CNS toxicity (4/50) leading to CTX dose reductions in 4 subjects. No cases of secondary leukemias were observed so far.\n\n\nCONCLUSIONS\nThe current protocol is feasible for achieving local control rates, as well as OS and DFS comparable to previously published data on neo-/adjuvant chemotherapy in this setting. However, the definitive role of chemotherapy remains unclear in the absence of large, randomized trials. Therefore, the current regimen can only be recommended within a clinical study, and a possibly increased risk of secondary leukemias has to be taken into account.\n\n\nBACKGROUND\nClinicalTrials.gov NCT01382030, EudraCT 2004-002501-72.",
"affiliations": "Department of Hematology, Oncology, and Rheumatology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. thomas.schmitt@med.uni-heidelberg.de",
"authors": "Schmitt|Thomas|T|;Lehner|Burkhard|B|;Kasper|Bernd|B|;Bischof|Marc|M|;Roeder|Falk|F|;Dietrich|Sascha|S|;Dimitrakopoulou-Strauss|Antonia|A|;Strauss|Ludwig G|LG|;Mechtersheimer|Gunhild|G|;Wuchter|Patrick|P|;Ho|Anthony D|AD|;Egerer|Gerlinde|G|",
"chemical_list": "D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D005047:Etoposide; D004317:Doxorubicin; D000069585:Filgrastim; D007069:Ifosfamide",
"country": "England",
"delete": false,
"doi": "10.1186/1471-2407-11-510",
"fulltext": "\n==== Front\nBMC CancerBMC Cancer1471-2407BioMed Central 1471-2407-11-5102215212010.1186/1471-2407-11-510Research ArticleA phase II study evaluating neo-/adjuvant EIA chemotherapy, surgical resection and radiotherapy in high-risk soft tissue sarcoma Schmitt Thomas 1thomas.schmitt@med.uni-heidelberg.deLehner Burkhard 2burkhard.lehner@med.uni-heidelberg.deKasper Bernd 3bernd.kasper@umm.deBischof Marc 4marc.bischof@med.uni-heidelberg.deRoeder Falk 4Falk.Roeder@med.uni-heidelberg.deDietrich Sascha 1sascha.dietrich@med.uni-heidelberg.deDimitrakopoulou-Strauss Antonia 5ads@ads-lgs.deStrauss Ludwig G 5lgs@ads-lgs.deMechtersheimer Gunhild 6gunhild.mechtersheimer@med.uni-heidelberg.deWuchter Patrick 1patrick.wuchter@med.uni-heidelberg.deHo Anthony D 1anthony.ho@med.uni-heidelberg.deEgerer Gerlinde 1gerlinde.egerer@med.uni-heidelberg.de1 Department of Hematology, Oncology, and Rheumatology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany2 Department of Orthopedics, Heidelberg University Hospital, Schlierbacher Landstraße 200A, 69118 Heidelberg, Germany3 University Medical Centre Mannheim, Theodor-Kutzer Ufer 1-3, 68167 Mannheim, Germany4 Department of Radiation Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany5 Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany6 Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 220/221, 69120 Heidelberg, Germany2011 7 12 2011 11 510 510 16 6 2011 7 12 2011 Copyright ©2011 Schmitt et al; licensee BioMed Central Ltd.2011Schmitt et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract\nBackground\nThe role of chemotherapy in high-risk soft tissue sarcoma is controversial. Though many patients undergo initial curative resection, distant metastasis is a frequent event, resulting in 5-year overall survival rates of only 50-60%. Neo-adjuvant and adjuvant chemotherapy (CTX) has been applied to achieve pre-operative cytoreduction, assess chemosensitivity, and to eliminate occult metastasis. Here we report on the results of our non-randomized phase II study on neo-adjuvant treatment for high-risk STS.\n\nMethod\nPatients with potentially curative high-risk STS (size ≥ 5 cm, deep/extracompartimental localization, tumor grades II-III [FNCLCC]) were included. The protocol comprised 4 cycles of neo-adjuvant chemotherapy (EIA, etoposide 125 mg/m2 iv days 1 and 4, ifosfamide 1500 mg/m2 iv days 1 - 4, doxorubicin 50 mg/m2 day 1, pegfilgrastim 6 mg sc day 5), definitive surgery with intra-operative radiotherapy, adjuvant radiotherapy and 4 adjuvant cycles of EIA.\n\nResult\nBetween 06/2005 and 03/2010 a total of 50 subjects (male = 33, female = 17, median age 50.1 years) were enrolled. Median follow-up was 30.5 months. The majority of primary tumors were located in the extremities or trunk (92%), 6% originated in the abdomen/retroperitoneum. Response by RECIST criteria to neo-adjuvant CTX was 6% CR (n = 3), 24% PR (n = 12), 62% SD (n = 31) and 8% PD (n = 4). Local recurrence occurred in 3 subjects (6%). Distant metastasis was observed in 12 patients (24%). Overall survival (OS) and disease-free survival (DFS) at 2 years was 83% and 68%, respectively. Multivariate analysis failed to prove influence of resection status or grade of histological necrosis on OS or DFS. Severe toxicities included neutropenic fever (4/50), cardiac toxicity (2/50), and CNS toxicity (4/50) leading to CTX dose reductions in 4 subjects. No cases of secondary leukemias were observed so far.\n\nConclusion\nThe current protocol is feasible for achieving local control rates, as well as OS and DFS comparable to previously published data on neo-/adjuvant chemotherapy in this setting. However, the definitive role of chemotherapy remains unclear in the absence of large, randomized trials. Therefore, the current regimen can only be recommended within a clinical study, and a possibly increased risk of secondary leukemias has to be taken into account.\n\nTrial registration\nClinicalTrials.gov NCT01382030, EudraCT 2004-002501-72\n==== Body\nBackground\nSoft tissue sarcomas (STS) comprise a large variety of histologically distinct, rare malignant tumors. Overall, they account for less than 1% of all adult malignancies [1]. STS can occur in all anatomical sites, although approximately 60% are found in the extremities with predilection of the lower limb [2]. A mainstay of curative treatment is complete surgical resection with negative histological margins of the primary tumor and all metastases, if possible. As treatment is complex, therapy decisions should be made in an interdisciplinary team involving oncologic surgeons, medical oncologists, sarcoma pathologists, and radiation oncologists. Referral to an experienced center is strongly recommended for this rare entity. Although many patients undergo initial curative resection, distant metastasis is a frequent event in up to 60% of all subjects, resulting in 5-year overall survival rates of approximately 50-60% for newly diagnosed sarcoma patients [3-5].\n\nFor extremity tumors, improved local control rates have been achieved by applying external beam radiotherapy with doses of ≥ 50 Gy [6,7]. The timing of irradiation, post- versus pre-operatively, does not seem to influence local control rates. However, higher rates of wound complications have been associated with pre-operative radiotherapy, whereas post-operative irradiation might lead to increased fibrosis and worse functional results [8]. As the outcome for patients with distant metastasis is grim, strategies with neo-adjuvant and/or adjuvant chemotherapy (CTX) have been explored to provide pre-operative cytoreduction, eliminate occult metastases, and assess chemosensitivity. However, previous studies on CTX for high-risk STS have yielded inconsistent results, and contemporary approaches with surgery and radiotherapy alone have shown excellent local control rates and overall survival [8]. So the definite role of CTX in this setting remains controversial. Ifosfamide and doxorubicin are considered the single most active substances in STS. Historic trials report on response rates of 20-30% by conventional Response Evaluation Criteria in Solid Tumors (RECIST) for anthracycline-based regimens [9,10]. However, more recent studies suggest lower response rates of only 10-15% [11]. Many centers will use combination regimens, especially in younger patients, including epirubicin/ifosfamide, doxorubicin/ifosfamide/mesna (AIM) and doxorubicin/ifosfamide/mesna/dacarbazine (MAID). Unfortunately, the promising overall response rates of ≥ 50% by RECIST in phase II studies with aggressive CTX regimens in advanced or metastatic disease could not be confirmed by phase III results, and certainly do not reflect clinical routine [12]. Even further dose intensifications with autologous stem cell transplants have been explored, but cannot be recommended outside a clinical trial [13].\n\nIn 2001 Issels et al. reported on a promising CTX regimen combining etoposide, ifosfamide and adriamycin (EIA) with regional hyperthermia [14]. We adopted this regimen for our current protocol, choosing a neo- and adjuvant CTX approach combined with definitive surgery, intra-operative radiotherapy and post-operative irradiation. The results of the corresponding phase III trial by Issels et al. have been published recently: hyperthermia added to EIA did significantly increase response rate, local progression-free survival and disease-free survival, compared to CTX alone [15]. Here we report on the final results of our study.\n\nMethods\nPatients\nPatients with potentially curable, high-risk STS were included in our phase II trial on \"Neo-adjuvant Therapy In Patients With High-Risk Soft Tissue Sarcoma\" (NeoWTS trial, ClinicalTrials.gov NCT01382030, EudraCT 2004-002501-72). High-risk was defined as tumor size ≥ 5 cm, Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade II/III, deep or extracompartimental localization, and patients with local relapse or inadequate previous therapy. Inadequate previous therapy was defined as an initial, non-oncologic surgical procedure on the primary tumor. Tumors with sizes ≤ 5 cm after such a procedure were also eligible, as per study protocol. Eligibility criteria furthermore comprised classical soft tissue sarcoma histology according to the WHO classification of soft tissue tumors (e.g. liposarcoma, leiomyosarcoma, malignant fibrous histiocytoma, synovial sarcoma, etc.), age 18 - 65 years, normal liver-, renal-, cardiac- and bone marrow function, as well as a Karnofsky index ≥ 80%. Ewing's sarcoma, osteosarcoma, chondrosarcoma, Kaposi's sarcoma and chordoma histology was not permitted. Angiosarcoma were excluded, as distinct susceptibility to taxane-based regimens has been shown for metastatic disease [16,17]. The study was carried out according to Good Clinical Practice and the principles set in the Declaration of Helsinki in 1964, as well as all subsequent revisions. Written informed consent was obtained from all patients before participation in the trial. The study protocol was approved by the corresponding institutional ethics committee and authorities. Histologies were centrally reviewed by a reference pathologist (GM) and classified according to the FNCLCC system. The same pathologist graded the operative specimen for tumor necrosis according to Salzer-Kuntschik [18].\n\nImaging studies\nStaging with MRI and/or CT scans of primary tumor site, fluorine-18-fluorodeoxyglucose PET (FDG-18-PET) and chest CT to exclude pulmonary metastases was performed at study entry. Target lesions were re-assessed after two cycles of EIA with MRI and/or CT scans and FDG-18-PET. Tumor response was graded according to RECIST criteria by a radiologist experienced in musculoskeletal imaging at the local department of radiology. Scans did not undergo external review. Follow-up exams with MRI and/or CT scans were scheduled every two cycles of CTX, pre-operatively, post-operatively and after study completion every 3 months for the first 2 years. Dynamic PET studies were performed after intravenous injection of 300-370 MBq FDG for 60 min. The analysis of the PET images was performed together by two nuclear medicine physicians (ADS and LGS) using the software package PMod (PMod Technologies Ltd., Adlisvil, Switzerland) [19].\n\nChemotherapy\nPatients received neo-adjuvant and adjuvant CTX as an inpatient regimen consisting of ifosfamide 1500 mg/m2 iv days 1-4, etoposide 125 mg/m2 iv days 1 and 4, and adriamycin 50 mg/m2 iv day 1 (EIA regimen, 8 cycles total). Mesna was given with 300 mg/m2 0 h, 4 h and 8 h after start of ifosfamide infusion. Pegfilgrastim 6 mg sc was administered on day 5 to avoid cycle delay or dose reductions. Granisetron 2 mg po days 1-5 or an equivalent 5-HT3 antagonist was used as antiemetic prophylaxis. Therapy was continued on day +22 and required platelets ≥ 75/nl and leukocytes ≥ 2,0/nl. Chemotherapy was administered through an implantable port-catheter system or central venous line.\n\nAdjuvant therapy\nDefinitive surgery was scheduled after 4 cycles of neo-adjuvant CTX. The protocol design furthermore comprised intra-operative irradiation, adjuvant radiation and adjuvant CTX (as previously described). If patients showed tumor progression after 2 cycles of neo-adjuvant CTX by conventional RECIST criteria, subjects were referred to definitive surgery immediately.\n\nRadiation therapy\nIrradiation was applied as intra-operative therapy (IORT) and as adjuvant external beam radiation, as soon as possible after definitive surgery. The post-operative approach was chosen because of the lower risk of wound complications. The recommended dose was calculated for each patient, under consideration of the individual situation and nearby structures. Median target doses for trunk and extremity tumors were 15 Gy during IORT and 45 Gy for post-operative irradiation. Patients who did not undergo IORT received adjuvant radiotherapy with a target dose ≥ 60 Gy. Lower doses were applied in patients with abdominal tumors, due to radiosensitive structures (e.g. intestines).\n\nToxicity analysis\nClinical toxicities occurring after CTX were collected by review of laboratory values and patients' charts including hematological toxicity, nausea/vomiting, changes in liver function tests, changes in renal function and CNS toxicity. Cardiac function was monitored by echocardiograms. Toxicities were graded according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE), published March 31, 2003, by the National Cancer Institute (NCI) [20].\n\nStudy design and statistical analysis\nA prospective, non-randomized, phase II study design was chosen. Sample size was calculated to complete study accrual within approximately 5 years, based on the frequency of newly diagnosed high-risk sarcoma patients presenting at our center. Disease-free survival (DFS) and overall survival (OS) were estimated using the method of Kaplan and Meier. DFS was defined as the time interval from the date of definitive surgery to radiologically proven local or distant failure, or patient's death due to sarcoma-related causes. OS was defined as the time interval from the date of therapy induction to patient's death or last follow-up. Significance levels were set at 0.05. A Cox regression model was applied for uni- and multivariate analysis. Differences in survival were assessed by log-rank test. A logistic regression was used to distinguish treatment response. Calculations were made using SPSS software (version 16). Data was analyzed as of January 17, 2011.\n\nResults\nFrom 06/2005 to 03/2010 a total number of n = 51 subjects were included in the study. One patient was excluded after the first cycle of neo-adjuvant EIA, as reference pathology revised histology to angiosarcoma which was not permitted by the study protocol. Therefore the current analysis comprised 50 patients (male = 33, female = 17, median age 50.1 years [range 24-65]). Characteristics and results are summarized in Tables 1 and 2. Median follow-up was 30.5 months. The majority of tumors were located in the extremities or trunk (92%). Only 6% originated in the abdomen/retroperitoneum. Localizations in detail were: upper extremity (8%, n = 4), lower extremity (62%, n = 31), trunk (22%, n = 11), abdomen/retroperitoneum (6%, n = 3) and head/neck (2%, n = 1). Histological subtypes included liposarcoma (including 6 patients with myxoid/round cell histology; overall 24%, n = 12), synovial sarcoma (18%, n = 9), sarcoma not otherwise specified (NOS, 18%, n = 9), malignant fibrous histiocytoma (MFH, 16%, n = 8), leiomyosarcoma (10%, n = 5), and others (14%, n = 7) with tumor grades II (42%, n = 21) and III (58%, n = 29). Initial tumor size at diagnosis was 5-10 cm (60%, n = 30) and ≥ 10 cm (40%, n = 20). Overall, 21 patients (42%) had undergone previous surgery (excluding planned incisional biopsy to establish diagnosis) before definitive resection in the study protocol. This resulted in tumor sizes ≤ 5 cm in 22% of patients (n = 11) at study enrollment.\n\nTable 1 Patients' characteristics\n\nPatients:\tn = \t\n Male\t33\t\n\t\n Female\t17\t\n\t\n Median age\t50.1 years (range 24 - 65)\t\n\t\nHistologies:\t\t\n\t\n Liposarcoma\t12\t\n\t\n Synovial Sarcoma\t9\t\n\t\n Sarcoma not otherwise specified (NOS)\t9\t\n\t\n Malignant fibrous histiocytoma (MFH)\t8\t\n\t\n Leiomyosarcoma\t5\t\n\t\n Others\t7\t\n\t\nLocalization:\t\t\n\t\n Upper extremity\t4\t\n\t\n Lower extremity\t31\t\n\t\n Trunk\t11\t\n\t\n Abdomen/Retroperitoneum\t3\t\n\t\n Head/Neck\t1\t\n\t\nTumor grade (FNCLCC):\t\t\n\t\n Grade II\t21\t\n\t\n Grade III\t29\t\n\t\nTumor size at diagnosis:\t\t\n\t\n 5 - 10 cm\t30\t\n\t\n >10 cm\t20\t\n\t\nTotal number of patients:\t50\t\nTable 2 Treatment results\n\nResponse by RECIST criteria to nCTX:\tn = \t\n Complete response (CR)\t3\t\n\t\n Partial response (PR)\t12\t\n\t\n Stable disease (SD)\t31\t\n\t\n Progressive disease (PD)\t4\t\n\t\nAdjuvant treatment:\t\t\n\t\n Surgery + RTX + aCTX\t31\t\n\t\n Surgery + RTX\t11\t\n\t\n Surgery without further adj. treatment\t2\t\n\t\n RTX\t4\t\n\t\n No definitive surgery\t5\t\n\t\nTumor necrosis (Salzer-Kuntschik):\t\t\n\t\n Grade 1 (no vital tumor)\t8\t\n\t\n Grade 2 (single vital tumor cells)\t4\t\n\t\n Grade 3 (vital tumor < 10%)\t4\t\n\t\n Grade 4 (vital tumor 10-50%)\t11\t\n\t\n Grade 5 (vital tumor >50%)\t16\t\n\t\n Grade 6 (completely vital tumor) \t2\t\n\t\nRadiotherapy\t\t\n\t\n Intra-operative RTX\t37\t\n\t\n Median dose\t15 Gy (10 - 15 Gy)\t\n\t\n Adjuvant RTX\t45\t\n\t\n Median dose \t45.0 Gy (20 - 66 Gy)\t\n\t\nTherapy failure:\t\t\n\t\n Distant metastases:\t12\t\n\t\n Pulmonary\t9\t\n\t\n Lymph nodes\t3\t\n\t\n Other\t1\t\n\t\n Local failure\t3\t\n\t\n Distant and local failure:\t1\t\n\t\nToxicity assessment (≥ CTCAE 3)\t\t\n\t\n Hematological tox.\t18\t\n\t\n Neutropenic fever\t4\t\n\t\n Cardiac tox. (any grade)\t2\t\n\t\n Ifosfamide-induced encephalopathy\t4\t\n\t\n Nausea/Vomiting\t7\t\nResponse by RECIST criteria to neo-adjuvant CTX was complete response (CR, 6%, n = 3), partial remission (PR, 24%, n = 12), stable disease (SD, 62%, n = 31) and progressive disease (PD, 8%, n = 4). A total of five patients did not undergo definitive surgery while participating in the protocol: two non-extremity patients were regarded inoperable due to technical reasons, one patient was diagnosed concomitantly with rectal cancer, one patient declined surgery for the extent of the procedure, and one patient had extensive tumor progression with distant metastasis. After neo-adjuvant CTX, patients received surgery, radiotherapy and adjuvant chemotherapy as per protocol (62%, n = 31); surgery and radiotherapy (22%, n = 11); radiotherapy alone (8%, n = 4) or surgery without any further adjuvant treatment (4%, n = 2). One patient refused radiotherapy but received adjuvant CTX after surgery. Furthermore, one subject did not undergo definitive surgery but received a total of 8 cycles EIA. Overall, 30% of patients (15/50) did not receive the adjuvant treatment, as per protocol. Surgical status after neo-adjuvant CTX was R0 (82%, n = 37), R1 (13%, n = 6) and R2 (4%, n = 2). Tumor necrosis in operative specimen was Salzer-Kuntschik grade 1 (no vital tumor cells, 18%, n = 8), grade 2 (single vital tumor cells, 9%, n = 4), grade 3 (vital tumor < 10%, 9%, n = 4), grade 4 (vital tumor 10-50%, 24%, n = 11), grade 5 (vital tumor >50%, 36%, n = 16) and grade 6 (completely vital tumor, 4%, n = 2). Intra-operative radiotherapy was feasible in 37 subjects with a median dose of 15 Gy (range 10-15 Gy). Adjuvant irradiation was administered in 45 patients with a median dose of 45.0 Gy (range 20-66 Gy).\n\nLocal recurrence after definitive surgery occurred in 3 subjects (6%). Of the 5 patients not undergoing definitive surgery in the protocol, all had progressive disease and 4 out of 5 died. Distant metastases were observed in 12 patients (24%) with pulmonary and lymph node metastases in 9 and 3 cases, respectively. One individual presented with pulmonary and lymph node metastases at the same time, one patient showed osseous and cerebral metastases, and one subject had concomitant local and distant failure.\n\nOS and DFS at 2 years were 83% and 68%, respectively (Figures 1 and 2). Median OS and DFS were not yet reached. Multivariate analysis failed to prove influence of histological subtype, resection status or grade of histological necrosis on OS or DFS.\n\nFigure 1 Overall survival. Overall survival (in months) was calculated from start of therapy to patient's death or last follow-up, using the method of Kaplan and Meier.\n\nFigure 2 Disease-free survival. Disease-free survival (in months) was calculated from definitive surgery to radiologically proven local or distant failure or patient's death due to sarcoma-related causes, using the method of Kaplan and Meier.\n\nOverall, the chemotherapy regimen was well tolerated. Severe toxicities included neutropenic fever in 8% (CTCAE grade 3, 4/50), cardiac toxicity in 4% (CTCAE grade 2, 2/50), and ifosfamide-induced encephalopathy in 8% (CTCAE grade 3, 4/50) of patients, leading to CTX dose reductions in the subsequent cycles in 4 subjects. Hematological toxicity (leukopenia, thrombocytopenia or anemia CTCAE grade ≥ 3) was observed in 36% (18/50). Nausea and vomiting (CTCAE grade ≥ 3) occurred in 14% of patients (7/50). During the study, there were no relevant cases of renal- or hepatic toxicity reported. One subject had an allergic reaction (CTCAE grade 3) to etoposide during the first treatment cycle. Subsequent doses were received with anti-allergic premedication, and were well tolerated. Furthermore, one patient experienced Coombs negative hemolysis (CTCAE grade 3) after receiving the 2nd adjuvant CTX cycle. The 3 rd CTX cycle had to be postponed for 2 weeks. Hemolysis resolved spontaneously. No CTX-related deaths or cases of secondary leukemia were reported so far.\n\nPET exams were performed in 34 patients with data on dynamic PET available in 31 subjects. The data of this subgroup analysis has already been published [21]. Combining 2 variables (mean SUV and influx) of the baseline, as well as follow-up study after completion of 2 cycles of neo-adjuvant CTX, allowed patient categorization into responders (defined as ≤ 10% viable tumor cells in tumor specimen after neo-adjuvant CTX) or non-responders (defined as ≥ 10% viable tumor cells in tumor specimen after neo-adjuvant CTX), with an accuracy of 83%. A linear correlation was found between mean SUV of the first study and overall survival (r = - 0.5501, p < 0.05).\n\nDiscussion\nThe role of CTX in potentially curative, high-risk STS remains controversial. Known risk factors in STS include patient age, tumor size and depth, histological subtype, tumor grade, vascular invasion, necrosis and growth pattern [22,23]. Neo-adjuvant regimens have been applied to achieve pre-operative cytoreduction, eliminate occult metastases and assess chemo-sensitivity. To our knowledge, there is only one prospective trial published addressing the effect of neo-adjuvant CTX in a randomized fashion [24]. The 5-year overall- and disease-free survival rates for the CTX arm (doxorubicin and ifosfamide) were reported with 65% and 56%. There was no statistically significant difference from the non-CTX arm (64% and 52%, respectively). Although not empowered to prove definitive benefit of one arm, Gortzak et al. concluded that after a follow-up of 7 years, major survival benefits for the CTX arm seemed unlikely. In contrast, a retrospective analysis by Grobmyer et al. using doxorubicin and ifosfamide containing neo-adjuvant regimens, indicated a significant improvement in the 3-year disease-specific survival (83% vs. 62%) in patients with high-grade extremity STS >10 cm [25].\n\nThe adjuvant setting faces a similar uncertain situation. A meta-analysis including 1953 patients published by Pervaiz et al. suggested a better overall survival for subjects receiving adjuvant CTX [26]. Furthermore, a recent multivariate analysis of the French sarcoma database indicated a benefit of adjuvant CTX, especially in FNCLCC grade III tumors [27]. In contrast, Le Cesne et al. found no statistically significant difference in overall survival for patients with completely resected tumors analyzing the combined data of the two largest, randomized EORTC trials [28]. Summarizing these results, the role of CTX for high-risk STS remains uncertain, as an improvement in overall survival could not be ultimately proven so far.\n\nHere we present the data of our non-randomized phase II trial on neo-adjuvant EIA CTX, followed by surgery, radiation therapy and adjuvant EIA CTX. Two-year overall and disease-free survival rates of 83% and 68%, and local and distant failure rates of 3% and 24% respectively, were achieved.\n\nKraybill et al. reported with a median follow-up of 7.7 years on a study similar to our currently presented protocol [29]. Neo- and adjuvant MAID CTX (mesna, doxorubicin, ifosfamide, and dacarbazine) was combined with surgery and radiotherapy. Estimated 5-year rates for disease-free, distant disease-free-, and overall survival were reported with 56.1%, 64.1% and 71.2%, respectively. At 2 years, overall and disease-free survival rates were 89.1% and 65.6%. Local and distant failure occurred in 22.2% and 28.1% of patients after 5 years. Interestingly, the majority of patients relapsed within the first 2 years (local failure in 15.6% and distant metastasis in 26.6%). Overall, these results resemble our own experience.\n\nIn 2001, Issels et al. reported on a phase II study combining EIA CTX with regional hyperthermia in high-risk STS [14]. We adopted the CTX regimen for our current protocol. The results of the corresponding phase III trial were published in 2010 [15]. Hyperthermia significantly increased the benefit of EIA CTX compared to EIA alone; regarding response rate, as well as disease-free and local progression-free survival. Overall survival was improved in patients receiving complete induction EIA (4 cycles) and regional hyperthermia therapy. In the CTX arm, DFS and OS rates at 2 years for the extremity subgroup were reported with 57% and 81%, respectively. Treatment response to EIA alone was 1% CR, 12% PR, 58% SD and 21% PD, and was significantly better in the hyperthermia arm (p = .002). We observed similar DFS and OS rates, however our response data more closely resembles the combination therapy arm. Local progression at 2 years and distant failure rate for EIA alone were 30% and 26%, respectively. The higher rate of local progression is most probably attributable to a high proportion of non-extremity STS in the above mentioned study. It can be hypothesized that the additional effect of hyperthermia is accentuated in those patients where local control is hard to achieve. The reported non-hematological toxicity profile (e.g. nausea/vomiting, cardiotoxicity, neurotoxicity) was similar to our experience. However, the leukopenia rate (CTCAE grade ≥ 3) of 63.5% appears higher than in our data. Two factors might have influenced the hematological (combined anemia, leukopenia and thrombocytopenia, CTCAE grade ≥ 3) toxicity rate of 36% in our study. As per study protocol, patients were only recommended to have blood draws once weekly in between treatment cycles, and were allowed to have them with their local general practitioner. Collecting the hematological toxicity data, we were not able to retrieve all results, so the rate of grade 3 and 4 toxicities might be underestimated. Furthermore, all of our patients received pegfilgrastim 24 h after each CTX cycle.\n\nWith a median follow-up time of 34 months, 5 cases of secondary leukemia were reported, most probably attributable to addition of etoposide in the current regimen. Issels et al. therefore concluded that they will abandon the EIA regimen in further studies. We did not observe any cases of secondary leukemia so far. However, since the activity of etoposide in STS is questionable, and its additional leukemogenic potential, we will also not pursue the EIA regimen in further studies.\n\nPrevious studies found a statistically significant impact of grade of necrosis after neo-adjuvant treatment, surgical status, and histological subtype on OS and/or DFS [30-33]. We were unable to reproduce these results in uni- and multivariate analysis. This might be attributable to the fact that 30% (15/50) did not receive the adjuvant treatment as per protocol, and also to small patient numbers in subgroups, although OS and DFS seem comparable to the previously outlined studies.\n\nWhich patients benefit from CTX remains a challenging question, and there has been an ongoing debate about whether response by conventional RECIST criteria reflects the specific biology of STS [34,35]. Strategies with functional imaging (e.g. FDG-18-PET and dynamic MRI scans) have been used to assess early tumor response to neo-adjuvant treatment [36-38]. Our own, already published data, supports this [21]. Combining mean SUV and influx of the baseline, and follow-up FDG-PET study after completion of 2 cycles of neo-adjuvant CTX, allowed patient categorization into responders (defined as ≤ 10% viable tumor cells in tumor specimen after neo-adjuvant CTX) or non-responders (defined as ≥ 10% viable tumor cells in tumor specimen after neo-adjuvant CTX), with an accuracy of 83%. Further research will be needed to validate these results and translate them into clinical practice.\n\nIt is most likely that due to the wide spectrum of histological subtypes, systemic treatment for STS will change in the upcoming years as more of the underlying pathophysiological pathways are elucidated and treatment is individualized. Combination regimens of classical CTX with new substances like pazopanib, a angiogenesis inhibitor with promising activity in metastatic disease [39], are currently tested in phase II studies.\n\nConclusion\nThe current protocol is feasible with a manageable spectrum of side effects. No treatment-related deaths or cases of secondary leukemia were observed so far. The reported DFS and OS rates at 2 years (68% and 83%, respectively) are in line with previously published studies, but the additional beneficial effect of regional hyperthermia combined with EIA as shown by Issels et al. has to be taken into account. Still it is most likely that not all patients benefit from CTX, and the definitive role of CTX in STS remains unclear in the absence of large, randomized trials. In our opinion, CTX can be considered on an individual basis for high-risk patients. However, possible advantages and disadvantages have to be discussed with the patient in detail. Due to the questionable activity of etoposide and the increased risk of secondary leukemias, we would not recommend the currently presented EIA regimen outside a clinical trial, and will not pursue it in further studies. Further research is needed to assess treatment response early on and spare non-responders from toxic side effects. The identification of novel therapeutic targets and functional imaging (e.g. with FDG-PET and dynamic MRI) will help to achieve this goal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors' contributions\nTS participated in medical treatment of patients, statistical analysis, and also prepared the manuscript. BL was in charge of surgical resection of tumors. BK participated in protocol design and medical treatment. MB supervised radiation therapy. FR reviewed imaging scans. SD performed the statistical analysis. ADS and LGS performed FDG-PET examens and analysis. GM served a reference pathologist, and graded postoperative tumor specimens according to Salzer-Kuntschik. PW and AH participated in medical treatment. GE supervised protocol design and medical treatment. All authors read and approved the final manuscript.\n\nPre-publication history\nThe pre-publication history for this paper can be accessed here:\n\nhttp://www.biomedcentral.com/1471-2407/11/510/prepub\n==== Refs\nJemal A Tiwari RC Murray T Ghafoor A Samuels A Ward E Feuer EJ Thun MJ Cancer statistics 2004 CA Cancer J Clin 2004 54 8 29 10.3322/canjclin.54.1.8 14974761 \nLawrence W Donegan WL Natarajan N Mettlin C Beart R Winchester D Adult soft tissue sarcomas. A pattern of care survey of the American College of Surgeons Ann Surg 1987 4 349 359 \nPisters PW Leung DH Woodruff J Shi W Brennan MF Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities J Clin Oncol 1996 14 1679 1689 8622088 \nStefanovski PD Bidoli E De Paoli A Buonadonna A Boz G Libra M Morassut S Rossi C Carbone A Frustaci S Prognostic factors in soft tissue sarcomas: A study of 395 patients Eur J Surg Oncol 2002 28 153 164 10.1053/ejso.2001.1242 11884051 \nZagars GK Ballo MT Pisters PW Pollock RE Patel SR Benjamin RS Evans HL Prognostic factors for patients with localized soft-tissue sarcoma treated with conservation surgery and radiation therapy: An analysis of 1225 patients Cancer 2003 97 2530 2543 10.1002/cncr.11365 12733153 \nWilson AN Davis A Bell RS O'Sullivan B Catton C Madadi F Kandel R Fornasier VL Local control of soft tissue sarcoma of the extremity: the experience of a multidisciplinary sarcoma group with definitive surgery and radiotherapy Eur J Cancer 1994 30 746 751 10.1016/0959-8049(94)90286-0 \nFein DA Lee WR Lanciano RM Corn BW Herbert SH Hanlon AL Hoffman JP Eisenberg BL Coia LR Management of extremity soft tissue sarcomas with limb-sparing surgery and postoperative irradiation: do total dose, overall treatment time, and the surgery-radiotherapy interval impact on local control? Int J Radiat Oncol Biol Phys 1995 32 969 976 10.1016/0360-3016(95)00105-8 7607971 \nO'Sullivan B Davis AM Turcotte R Bell R Catton C Chabot P Wunder J Kandel R Goddard K Sadura A Pater J Zee B Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial Lancet 2002 359 2235 2241 10.1016/S0140-6736(02)09292-9 12103287 \nSleijfer S Seynaeve C Verweij J Using single-agent therapy in adult patients with advanced soft tissue sarcoma can still be considered standard care Oncologist 2005 10 833 841 10.1634/theoncologist.10-10-833 16314294 \nEisenhauer EA Therasse P Bogaerts J Schwartz LH Sargent D Ford R Dancey J Arbuck S Gwyther S Mooney M Rubinstein L Shankar L Dodd L Kaplan R Lacombe D Verweij J New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer 2009 45 228 247 10.1016/j.ejca.2008.10.026 19097774 \nLorigan P Verweij J Papai Z Rodenhuis S Le Cesne A Leahy MG Radford JA Van Glabbeke MM Kirkpatrick A Hogendoorn PC Blay J Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study J Clin Oncol 2007 25 3144 3150 10.1200/JCO.2006.09.7717 17634494 \nReichardt P Tilgner J Hohenberger P Dörken B Dose-intensive chemotherapy with ifosfamide, epirubicin, and filgrastim for adult patients with metastatic or locally advanced soft tissue sarcoma: a phase II study J Clin Oncol 1998 16 1438 1443 9552049 \nKasper B Scharrenbroich I Schmitt T Wuchter P Dietrich S Ho AD Egerer G Consolidation with high-dose chemotherapy and stem cell support for responding patients with metastatic soft tissue sarcomas: prospective, single-institutional phase II study Bone Marrow Transplant 2010 45 1234 1238 10.1038/bmt.2009.333 19935728 \nIssels RD Abdel-Rahman S Wendtner C Falk MH Kurze V Sauer H Aydemir U Hiddemann W Neoadjuvant chemotherapy combined with regional hyperthermia (RHT) for locally advanced primary or recurrent high-risk adult soft-tissue sarcomas (STS) of adults: long-term results of a phase II study Eur J Cancer 2001 37 1599 1608 10.1016/S0959-8049(01)00183-6 11527684 \nIssels RD Lindner LH Verweij J Wust P Reichardt P Schem BC Abdel-Rahman S Daugaard S Salat C Wendtner CM Vujaskovic Z Wessalowski R Jauch KW Dürr HR Ploner F Baur-Melnyk A Mansmann U Hiddemann W Blay JY Hohenberger P European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) European Society for Hyperthermic Oncology (ESHO) Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study Lancet Oncol 2010 11 561 570 10.1016/S1470-2045(10)70071-1 20434400 \nSchlemmer M Reichardt P Verweij J Hartmann JT Judson I Thyss A Hogendoorn PC Marreaud S Van Glabbeke M Blay JY Paclitaxel in patients with advanced angiosarcomas of soft tissue: a retrospective study of the EORTC soft tissue and bone sarcoma group Eur J Cancer 2008 44 2433 2436 10.1016/j.ejca.2008.07.037 18771914 \nPenel N Bui BN Bay JO Cupissol D Ray-Coquard I Piperno-Neumann S Kerbrat P Fournier C Taieb S Jimenez M Isambert N Peyrade F Chevreau C Bompas E Brain EG Blay JY Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study J Clin Oncol 2008 26 5269 5274 10.1200/JCO.2008.17.3146 18809609 \nSalzer-Kuntschik M Delling G Beron G Sigmund R Morphological grades of regression in osteosarcoma after polychemotherapy - study COSS 80 J Cancer Res Clin Oncol 1983 106 Suppl 21 24 6577010 \nSchwarzbach MH Hinz U Dimitrakopoulou-Strauss A Willeke F Cardona S Mechtersheimer G Lehnert T Strauss LG Herfarth C Buchler MW Prognostic significance of preoperative [18-F] fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging in patients with resectable soft tissue sarcomas Ann Surg 2005 241 286 294 10.1097/01.sla.0000152663.61348.6f 15650639 \nTrotti A Colevas AD Setser A Rusch V Jaques D Budach V Langer C Murphy B Cumberlin R Coleman CN Rubin P CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment Semin Radiat Oncol 2003 13 176 181 10.1016/S1053-4296(03)00031-6 12903007 \nDimitrakopoulou-Strauss A Strauss LG Egerer G Vasamiliette J Mechtersheimer G Schmitt T Lehner B Haberkorn U Stroebel P Kasper B Impact of dynamic 18 F-FDG PET on the early prediction of therapy outcome in patients with high-risk soft-tissue sarcomas after neoadjuvant chemotherapy: a feasibility study J Nucl Med 2010 51 551 558 10.2967/jnumed.109.070862 20351350 \nCarneiro A Bendahl PO Engellau J Domanski HA Fletcher CD Rissler P Rydholm A Nilbert M A prognostic model for soft tissue sarcoma of the extremities and trunk wall based on size, vascular invasion, necrosis, and growth pattern Cancer 2011 117 1279 1287 10.1002/cncr.25621 21381015 \nKattan MW Leung DH Brennan MF Postoperative nomogram for 12-year sarcoma-specific death J Clin Oncol 2002 20 791 796 10.1200/JCO.20.3.791 11821462 \nGortzak E Azzarelli A Buesa J Bramwell VH van Coevorden F van Geel AN Ezzat A Santoro A Oosterhuis JW van Glabbeke M Kirkpatrick A Verweij J E.O.R.T.C. Soft Tissue Bone Sarcoma Group and the National Cancer Institute of Canada Clinical Trials Group/Canadian Sarcoma Group A randomised phase II study on neo-adjuvant chemotherapy for'high-risk' adult soft-tissue sarcoma Eur J Cancer 2001 37 1096 1103 10.1016/S0959-8049(01)00083-1 11378339 \nGrobmyer SR Maki RG Demetri GD Mazumdar M Riedel E Brennan MF Singer S Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma Ann Oncol 2004 15 1667 1672 10.1093/annonc/mdh431 15520069 \nPervaiz N Colterjohn N Farrokhyar F Tozer R Figueredo A Ghert M A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma Cancer 2008 113 573 581 10.1002/cncr.23592 18521899 \nItaliano A Delva F Mathoulin-Pelissier S Le Cesne A Bonvalot S Terrier P Trassard M Michels JJ Blay JY Coindre JM Bui B Effect of adjuvant chemotherapy on survival in FNCLCC grade 3 soft tissue sarcomas: a multivariate analysis of the French Sarcoma Group Database Ann Oncol 2010 21 2436 2441 10.1093/annonc/mdq238 20439343 \nLe Cesne A Van Glabbeke M Woll PJ Bramwell VH Casali PG Hoekstra HJ Reichardt P Hogendoorn PC Hohenberger P Blay JY The end of adjuvant chemotherapy era with doxorubicin-based regimen in resected high-grade soft tissue sarcoma: Pooled analysis of the two STBSG-EORTC phase III clinical trials [abstract] J Clin Oncol 2008 26 suppl 15 559s \nKraybill WG Harris J Spiro IJ Ettinger DS DeLaney TF Blum RH Lucas DR Harmon DC Letson GD Eisenberg B Long-term results of a phase 2 study of neoadjuvant chemotherapy and radiotherapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514 Cancer 2010 116 4613 4621 10.1002/cncr.25350 20572040 \nDonahue TR Kattan MW Nelson SD Tap WD Eilber FR Eilber FC Evaluation of neoadjuvant therapy and histopathologic response in primary, high-grade retroperitoneal sarcomas using the sarcoma nomogram Cancer 2010 116 3883 3891 10.1002/cncr.25271 20564145 \nMacDermed DM Miller LL Peabody TD Simon MA Luu HH Haydon RC Montag AG Undevia SD Connell PP Primary tumor necrosis predicts distant control in locally advanced soft-tissue sarcomas after preoperative concurrent chemoradiotherapy Int J Radiat Oncol Biol Phys 2010 76 1147 1153 10.1016/j.ijrobp.2009.03.015 19577863 \nLiu CY Yen CC Chen WM Chen TH Chen PC Wu HT Shiau CY Wu YC Liu CL Tzeng CH Soft tissue sarcoma of extremities: the prognostic significance of adequate surgical margins in primary operation and reoperation after recurrence Ann Surg Oncol 2010 17 2102 2111 10.1245/s10434-010-0997-0 20217247 \nTseng W Martinez SR Tamurian RM Borys D Canter RJ Histologic Type Predicts Survival in Patients with Retroperitoneal Soft Tissue Sarcoma J Surg Res 2010 in press \nSchuetze SM Baker LH Benjamin RS Canetta R Selection of response criteria for clinical trials of sarcoma treatment Oncologist 2008 13 suppl 2 32 40 18434637 \nJaffe CC Response assessment in clinical trials: implications for sarcoma clinical trial design Oncologist 2008 13 suppl 2 14 18 18434633 \nSchuetze SM Rubin BP Vernon C Hawkins DS Bruckner JD Conrad EU Eary JF Use of positron emission tomography in localized extremity soft tissue sarcoma treated with neoadjuvant chemotherapy Cancer 2005 103 339 348 10.1002/cncr.20769 15578712 \nBenz MR Czernin J Allen-Auerbach MS Tap WD Dry SM Elashoff D Chow K Evilevitch V Eckardt JJ Phelps ME Weber WA Eilber FC FDG-PET/CT imaging predicts histopathologic treatment responses after the initial cycle of neoadjuvant chemotherapy in high-grade soft-tissue sarcomas Clin Cancer Res 2009 15 2856 2863 10.1158/1078-0432.CCR-08-2537 19351756 \nDudeck O Zeile M Pink D Pech M Tunn PU Reichardt P Ludwig WD Hamm B Diffusion-weighted magnetic resonance imaging allows monitoring of anticancer treatment effects in patients with soft-tissue sarcomas J Magn Reson Imaging 2008 27 1109 1113 10.1002/jmri.21358 18425832 \nSleijfer S Ray-Coquard I Papai Z Le Cesne A Scurr M Schöffski P Collin F Pandite L Marreaud S De Brauwer A van Glabbeke M Verweij J Blay JY Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043) J Clin Oncol 2009 27 3126 3132 10.1200/JCO.2008.21.3223 19451427\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "11()",
"journal": "BMC cancer",
"keywords": null,
"medline_ta": "BMC Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D007069:Ifosfamide; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D011092:Polyethylene Glycols; D011446:Prospective Studies; D011994:Recombinant Proteins; D012509:Sarcoma; D012983:Soft Tissue Neoplasms; D055815:Young Adult",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "510",
"pmc": null,
"pmid": "22152120",
"pubdate": "2011-12-07",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "19097774;20217247;15650639;15520069;19451427;7917531;21381015;16314294;11884051;12103287;12903007;7607971;18425832;15578712;19351756;20434400;18521899;8622088;18809609;3566372;20564145;14974761;19935728;11527684;19577863;18771914;20351350;11821462;20869082;6577010;11378339;18434633;20572040;9552049;20439343;12733153;18434637;17634494",
"title": "A phase II study evaluating neo-/adjuvant EIA chemotherapy, surgical resection and radiotherapy in high-risk soft tissue sarcoma.",
"title_normalized": "a phase ii study evaluating neo adjuvant eia chemotherapy surgical resection and radiotherapy in high risk soft tissue sarcoma"
} | [
{
"companynumb": "DE-MYLANLABS-2017M1006168",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GRANISETRON"
},
"drugadditional": null,
... |
{
"abstract": "Haloperidol is widely prescribed as an antiemetic in patients receiving palliative care, but there is limited evidence to support and refine its use.\n\n\n\nTo explore the immediate and short-term net clinical effects of haloperidol when treating nausea and/or vomiting in palliative care patients.\n\n\n\nA prospective, multicenter, consecutive case series.\n\n\n\nTwenty-two sites, five countries: consultative, ambulatory, and inpatient services.\n\n\n\nWhen haloperidol was started in routine care as an antiemetic, data were collected at three time points: baseline; 48 hours (benefits); day seven (harms). Clinical effects were assessed using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE).\n\n\n\nData were collected (May 2014-March 2016) from 150 patients: 61% male; 86% with cancer; mean age 72 (standard deviation 11) years and median Australian-modified Karnofsky Performance Scale 50 (range 10-90). At baseline, nausea was moderate (88; 62%) or severe (11; 8%); 145 patients reported vomiting, with a baseline NCI CTCAE vomiting score of 1.0. The median (range) dose of haloperidol was 1.5 mg/24 hours (0.5-5 mg/24 hours) given orally or parenterally. Five patients (3%) died before further data collection. At 48 hours, 114 patients (79%) had complete resolution of their nausea and vomiting, with greater benefit seen in the resolution of nausea than vomiting. At day seven, 37 (26%) patients had a total of 62 mild/moderate harms including constipation 25 (40%); dry mouth 13 (21%); and somnolence 12 (19%).\n\n\n\nHaloperidol as an antiemetic provided rapid net clinical benefit with low-grade, short-term harms.",
"affiliations": "1 Discipline of Palliative Care, School of Medicine, Flinders University , Adelaide, South Australia, Australia .;1 Discipline of Palliative Care, School of Medicine, Flinders University , Adelaide, South Australia, Australia .;2 Hayward House Specialist Palliative Care Unit, School of Clinical Oncology, University of Nottingham , Nottingham, England.;3 Northern Adelaide Palliative Service , Northern Adelaide Local Health Network, Adelaide, South Australia, Australia .;5 Wolfson Palliative Care Research Centre, Hull York Medical School , University of Hull, Hull, England.;6 IMPACCT-Improving Palliative, Aged and Chronic Care through Clinical Research and Translation, Faculty of Health, University of Technology Sydney , Sydney, New South Wales, Australia .;7 Division of Palliative Medicine, Department of Oncology, Cumming School of Medicine, University of Calgary , Calgary, Alberta, Canada .;3 Northern Adelaide Palliative Service , Northern Adelaide Local Health Network, Adelaide, South Australia, Australia .;5 Wolfson Palliative Care Research Centre, Hull York Medical School , University of Hull, Hull, England.",
"authors": "Digges|Madeline|M|;Hussein|Akram|A|;Wilcock|Andrew|A|;Crawford|Gregory B|GB|;Boland|Jason W|JW|;Agar|Meera R|MR|;Sinnarajah|Aynharan|A|;Currow|David C|DC|;Johnson|Miriam J|MJ|",
"chemical_list": "D000932:Antiemetics; D006220:Haloperidol",
"country": "United States",
"delete": false,
"doi": "10.1089/jpm.2017.0159",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1557-7740",
"issue": "21(1)",
"journal": "Journal of palliative medicine",
"keywords": "haloperidol; nausea; palliative care; pharmacovigilance; symptom control; vomiting",
"medline_ta": "J Palliat Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000932:Antiemetics; D005260:Female; D006220:Haloperidol; D064946:Hospice and Palliative Care Nursing; D006801:Humans; D008297:Male; D008875:Middle Aged; D060735:Pharmacovigilance; D011446:Prospective Studies",
"nlm_unique_id": "9808462",
"other_id": null,
"pages": "37-43",
"pmc": null,
"pmid": "28772094",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pharmacovigilance in Hospice/Palliative Care: Net Effect of Haloperidol for Nausea or Vomiting.",
"title_normalized": "pharmacovigilance in hospice palliative care net effect of haloperidol for nausea or vomiting"
} | [
{
"companynumb": "AU-JNJFOC-20180208691",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": null,
... |
{
"abstract": "Multiple meningiomas growth in patients under cyproterone acetate (CPA) is now well known. However, time between initial CPA intake and diagnosis remains unclear. The exposure time differs in each reported case: from 2 to 10 years. We present the case of an old man with acute visual impairment caused by an unusual bilateral optic nerve compression by three likely planum sphenoidale meningiomas rapidly induced by the admistration of CPA for prostatic adenocarinoma. This case is the first reported with a short exposure time (7 months) to CPA treatment before diagnosis of multiple meningiomas and stabilization on clinical follow-up after CPA treatment discontinuation.",
"affiliations": "Department of Ophthalmology IV, Centre Hospitalier National d'Ophtalmologie (CHNO) des Quinze-Vingts, Faculty of Medicine Pierre et Marie Curie (Paris VI), 28 Rue de Charenton, 75 571 Paris, France;Department of Ophthalmology, Hôpital François Quesnay, 2 boulevard Sully, 78201 Mantes-la-Jolie CEDEX, France",
"authors": "Keilani|Chafik|C|;Abada|Samir|S|",
"chemical_list": null,
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574886312666170523154548",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1574-8863",
"issue": null,
"journal": "Current drug safety",
"keywords": "Bilateral papilledema; bilateral optic nerve compression; cyproterone acetate; exposure time\n\n; multiple\nmeningiomas; pharmacovigilance",
"medline_ta": "Curr Drug Saf",
"mesh_terms": null,
"nlm_unique_id": "101270895",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28545357",
"pubdate": "2017-05-23",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "An uncommon case of symptomatic multiple meningiomas with bilateral compressive optic neuropathy rapidly induced under cyproterone acetate treatment.",
"title_normalized": "an uncommon case of symptomatic multiple meningiomas with bilateral compressive optic neuropathy rapidly induced under cyproterone acetate treatment"
} | [
{
"companynumb": "ES-BAYER-2012-106552",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYPROTERONE ACETATE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nAs the aging rate in the traumatic brain injury population increases, the number of patients taking antithrombotic drugs is also expected to increase among the population with traumatic brain injury; however, the utility or risk of reversal of such drugs is unclear. Therefore, we performed a retrospective cohort study of the effect of reversal of antithrombotic drugs on geriatric traumatic brain injury at our hospital.\n\n\nMETHODS\nThe study subjects included 83 patients(65 years or older)with intracranial traumatic lesions or skull fractures who were admitted to our hospital during 2013-2018. According to the hospital's protocol, we performed platelet transfusion in patients taking antiplatelet drugs, prothrombin complex concentrate(PCC)administration in patients taking warfarin and direct oral anticoagulants except dabigatran: factor IX complex before January 2018 and four-factor PCC after February 2018. We administered idarucizumab in the case of dabigatran. Fresh frozen plasma transfusion was additionally performed in operative cases.\n\n\nRESULTS\nTwenty-six patients took antithrombotic drugs. There was no significant difference in the ratio of talk and deteriorate, favorable outcome(Glasgow Outcome Scale: good recovery+moderate disability), and hospitalization period between the non-antithrombotic and antithrombotic administration groups involving reversal. The timing of antithrombotic drug resumption varied, but no major embolic event occurred during the follow-up period.\n\n\nCONCLUSIONS\nThis study suggests that reversal of antithrombotic drugs in geriatric traumatic brain injury may contribute to suppression of talk and deteriorate and lead to more favorable outcomes. As there are also contradictory reports about the utility of reversal, additional studies should be performed for confirmation.",
"affiliations": "Department of Neurosurgery, Yamaguchi University School of Medicine.",
"authors": "Haji|Kohei|K|;Suehiro|Eiichi|E|;Kiyohira|Miwa|M|;Fujiyama|Yuichi|Y|;Suzuki|Michiyasu|M|",
"chemical_list": "D000925:Anticoagulants; D005343:Fibrinolytic Agents; D004364:Pharmaceutical Preparations",
"country": "Japan",
"delete": false,
"doi": "10.11477/mf.1436204218",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-2603",
"issue": "48(6)",
"journal": "No shinkei geka. Neurological surgery",
"keywords": null,
"medline_ta": "No Shinkei Geka",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D016913:Blood Component Transfusion; D000070642:Brain Injuries, Traumatic; D005343:Fibrinolytic Agents; D006801:Humans; D004364:Pharmaceutical Preparations; D010949:Plasma; D012189:Retrospective Studies",
"nlm_unique_id": "0377015",
"other_id": null,
"pages": "497-504",
"pmc": null,
"pmid": "32572000",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Effect of Antithrombotic Drugs Reversal on Geriatric Traumatic Brain Injury.",
"title_normalized": "effect of antithrombotic drugs reversal on geriatric traumatic brain injury"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-BI-033388",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "Epilepsy is an important health problem due to its high prevalence and potential for causing long-term morbidity. It is commonly treated in children with phenytoin sodium. It has wide pharmacokinetic variability and a narrow therapeutic range that leads to toxicity. Here, we report a case of phenytoin-induced cerebellar atrophy in a 16-year-old epileptic boy who presented to the hospital with a viral infection.",
"affiliations": "Department of Neurology, Vydehi Institute of Medical Sciences and Research Centre, Bangalore, Karnataka, India.;Department of Pharmacology, Vydehi Institute of Medical Sciences and Research Centre, Bangalore, Karnataka, India.;Department of Pharmacology, Vydehi Institute of Medical Sciences and Research Centre, Bangalore, Karnataka, India.;Department of Medicine, Vydehi Institute of Medical Sciences and Research Centre, Bangalore, Karnataka, India.;Department of Medicine, Vydehi Institute of Medical Sciences and Research Centre, Bangalore, Karnataka, India.",
"authors": "Kumar|Nithin|N|;Chakraborty|Ananya|A|;Suresh|Swaroop H|SH|;Basappaji|Sashidharan|S|;Betdur|Anand L|AL|",
"chemical_list": "D000927:Anticonvulsants; D010672:Phenytoin",
"country": "India",
"delete": false,
"doi": "10.4103/0253-7613.121388",
"fulltext": "\n==== Front\nIndian J PharmacolIndian J PharmacolIJPharmIndian Journal of Pharmacology0253-76131998-3751Medknow Publications & Media Pvt Ltd India IJPharm-45-63610.4103/0253-7613.121388Drug WatchPhenytoin-induced cerebellar atrophy in an epileptic boy Kumar Nithin Chakraborty Ananya 1Suresh Swaroop H. 1Basappaji Sashidharan 2Betdur Anand L 2Department of Neurology, Vydehi Institute of Medical Sciences and Research Centre, Bangalore, Karnataka, India1 Department of Pharmacology, Vydehi Institute of Medical Sciences and Research Centre, Bangalore, Karnataka, India2 Department of Medicine, Vydehi Institute of Medical Sciences and Research Centre, Bangalore, Karnataka, IndiaCorrespondence to: Dr. Ananya Chakraborty, E-mail: dr_ananya@yahoo.comNov-Dec 2013 45 6 636 637 16 4 2013 07 6 2013 06 8 2013 Copyright: © Indian Journal of Pharmacology2013This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Epilepsy is an important health problem due to its high prevalence and potential for causing long-term morbidity. It is commonly treated in children with phenytoin sodium. It has wide pharmacokinetic variability and a narrow therapeutic range that leads to toxicity. Here, we report a case of phenytoin-induced cerebellar atrophy in a 16-year-old epileptic boy who presented to the hospital with a viral infection.\n\nKEY WORDS\nAdverse drug reactionantiepileptic drugsantiseizure drugscerebellar atrophyphenytoin\n==== Body\nIntroduction\nChildren constitute approximately 40% of India's population but information on adverse drug reactions occurring in them is limited.[1] Phenytoin sodium (PHT) is one of the commonest antiepileptic drug (AED) used in children in India.[2] The drug has wide pharmacokinetic variability and has a narrow therapeutic range that leads to toxicity. There is some evidence of the association of long-term use of PHT and toxicity like cerebellar atrophy. Such cerebellar changes have been reported even with the long-term use of nontoxic levels of phenytoin.[3] However, such reporting is very scarce in pediatric population. Here, we report a case of reversible cerebellar atrophy induced by PHT in a 10-year-old boy.\n\nCase Report\nA 16-year-old boy was admitted to the hospital with fever and weakness. His systemic examination was normal. His past history included history of seizure for the last 10 years. He was on oral PHT, 5 mg/kg daily once daily. After initiating therapy with PHT 10 years back, he was seizure free for 2 years. Then he started getting seizures that required adjustment in his medication. Patient was also occasionally prescribed clobazam, 5 mg, oral, as and when required. The episodes used to last for a brief period of over 6-7 days. He would then be seizure free for the next 3-4 months. Seizures used to occur at every 3-4 months interval. The boy had history of birth asphyxia and delay in developmental milestones. His previous MRI scans of brain revealed no abnormality. There was no family history of seizure. The boy was managed conservatively for viral fever. After the patient recovered, he was evaluated again due to complaint of difficulty in walking. CNS examination revealed normal mentation with cerebellar signs including gaze-evoked nystagamus, truncal, and appendicular ataxia. MRI scan of the brain was advised and it showed cerebellar atrophy as shown in Figure 1. The patient had no other neurological and other systemic problems other than epilepsy. Serum phenytoin level was high (30 mcg/ml) and PHT was withdrawn immediately. Patient was started on valproic acid and followed up. The causality assessment was done using the Naranjo scale.[4] The causal analysis showed a probable association of the ADR with phenytoin.\n\nFigure 1 Axial T1 image of brain showing bilateral cerebellar atrophy in an epileptic boy on phenytoin\n\nDiscussion\nEpilepsy is a common neurological disorder that is managed with antiepileptic drugs. PHT is one of the commonest and the first line antiepileptic drug. PHT is used in both generalized and partial epilepsies and avoided in myoclonic epilepsy. This drug is generally safe and is commonly used throughout the world. However, a sizeable proportion of patients may develop drug induced adverse effects that include sedation, gum hypertrophy, lymphadenopathy, chorea, ataxia, etc.[56] There are a few reports on cerebellar atrophy after long-term use of PTH. These adverse effects are usually reported if the drug serum levels are above the therapeutic range. They have also been reported if the drug level is within the normal range.[78] These effects are, however, reversible on reducing the dose of PHT.[2] Our patient presented with severe cerebellar disorder and he was on the drug for 10 years. But he started recovering steadily after withdrawing the drug. Hence, a regular monitoring for adverse drug reaction should be considered in patients who are on drugs on long term basis. These reactions could be idiosyncratic or dose-dependent which again may be acute or chronic in nature. Since most of these effects are reversible, it is important to identify the clinical manifestations related to drug toxicity and to manage them appropriately. Also, it warns the need for regular monitoring of plasma concentration, accurate dosing, and identification of adherence issues in patients on phenytoin.\n\nSource of Support: Nil\n\nConflict of Interest: None declared\n==== Refs\n1 Kshirsagar NA Karande S Adverse drug reaction monitoring in pediatric practice Indian Pediatr 1996 33 993 8 9141798 \n2 Ahuja SR Karande S Kulkarni MV Cerebellar atrophy in an epileptic child: Is it due to phenytoin? J Postgrad Med 2000 46 278 9 11435657 \n3 Kuruvilla T Bharucha NE Cerebellar atrophy after acute phenytoin intoxication Epilepsia 1997 38 500 2 9118858 \n4 Adverse drug reaction probability scale (Naranjo) Last accessed on 2013, March 10 Available at:\nhttp://livertox.nih.gov/Narajo.html \n5 Longo DL Kasper DL Fauci AS Hauser LS Loscalzo J Jameson LJ Harrison's Principles of Internal Medicine 2012 18th ed New York, NY McGraw-Hill Publishing \n6 Barvaliya M Sanmukhani J Patel TK Tripathi CB Phenytoin induced chorea in a pediatric patient: An interaction between phenytoin, phenobarbital and clobazam Indian J Pharmacol 2011 43 731 2 22144787 \n7 Ghatak NR Santoso RA McKinney WM Cerebellar degeneration following long-term phenytoin therapy Neurol 1976 26 818 20 \n8 McLain LW Jr Martin JT Allen JH Cerebellar degeneration due to chronic phenytoin therapy Ann Neurol 1980 7 18 23 7362207\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-7613",
"issue": "45(6)",
"journal": "Indian journal of pharmacology",
"keywords": "Adverse drug reaction; antiepileptic drugs; antiseizure drugs; cerebellar atrophy; phenytoin",
"medline_ta": "Indian J Pharmacol",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D002531:Cerebellum; D004827:Epilepsy; D006801:Humans; D008297:Male; D010672:Phenytoin",
"nlm_unique_id": "7902477",
"other_id": null,
"pages": "636-7",
"pmc": null,
"pmid": "24347780",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9141798;7362207;11435657;22144787;821007;9118858",
"title": "Phenytoin-induced cerebellar atrophy in an epileptic boy.",
"title_normalized": "phenytoin induced cerebellar atrophy in an epileptic boy"
} | [
{
"companynumb": "IN-ACTAVIS-2014-21278",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nWe examined the relationship between location of residence at the time of diagnosis of diffuse large B-cell lymphoma (DLBCL) and health outcomes in a geographically large Canadian province with publicly funded, universally available medical care.\n\n\nMETHODS\nThe British Columbia Cancer Registry was used to identify all patients 18-80 years of age diagnosed with DLBCL between January 2003 and December 2008. Home and treatment center postal codes were used to determine urban versus rural status and driving distance to access treatment.\n\n\nRESULTS\nWe identified 1,357 patients. The median age was 64 years (range: 18-80 years), 59% were male, 50% were stage III/IV, 84% received chemotherapy with curative intent, and 32% received radiotherapy. There were 186 (14%) who resided in rural areas, 141 (10%) in small urban areas, 183 (14%) in medium urban areas, and 847 (62%) in large urban areas. Patient and treatment characteristics were similar regardless of location. Five-year overall survival (OS) was 62% for patients in rural areas, 44% in small urban areas, 53% in medium urban areas, and 60% in large urban areas (p = .018). In multivariate analysis, there was no difference in OS between rural and large urban area patients (hazard ratio [HR]: 1.0; 95% confidence interval [CI]: 0.7-1.4), although patients in small urban areas (HR: 1.4; 95% CI: 1.0-2.0) and medium urban areas (HR: 1.4; 95% CI: 1.0-1.9) had worse OS than those in large urban areas.\n\n\nCONCLUSIONS\nPlace of residence at diagnosis is associated with survival of patients with DLBCL in British Columbia, Canada. Rural patients have similar survival to those in large urban areas, whereas patients living in small and medium urban areas experience worse outcomes.",
"affiliations": "Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; Leukemia/Bone Marrow Transplantation Program of British Columbia, Vancouver, British Columbia, Canada.",
"authors": "Lee|Benny|B|;Goktepe|Ozge|O|;Hay|Kevin|K|;Connors|Joseph M|JM|;Sehn|Laurie H|LH|;Savage|Kerry J|KJ|;Shenkier|Tamara|T|;Klasa|Richard|R|;Gerrie|Alina|A|;Villa|Diego|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2013-0343",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "19(3)",
"journal": "The oncologist",
"keywords": "Access to care; Cancer care quality; Disparities; Lymphoma",
"medline_ta": "Oncologist",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001955:British Columbia; D005260:Female; D054625:Healthcare Disparities; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D012111:Residence Characteristics; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "283-90",
"pmc": null,
"pmid": "24569946",
"pubdate": "2014-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "22338328;17054549;20010868;20452216;19752339;18189295;8622041;15698354;22591230;19879951;15598815;22757954;20594811;21426283;15495877;18022581;16835910",
"title": "Effect of place of residence and treatment on survival outcomes in patients with diffuse large B-cell lymphoma in British Columbia.",
"title_normalized": "effect of place of residence and treatment on survival outcomes in patients with diffuse large b cell lymphoma in british columbia"
} | [
{
"companynumb": "CA-JNJFOC-20150214156",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Multisystem inflammatory syndrome in adults, MIS-A, is a rare but severe post-covid-19 immunologic complication. The presentation is similar to Multisystem inflammatory syndrome in children, MIS-C. Both MIS-A/C are life-threatening immunologic syndromes characterized by hypotension, skin rashes, myocardial affection, coagulopathy and GI symptoms. Here we describe a case of MIS-A in a 35-year-old previously healthy female who, five weeks after a mild covid-19 infection, presented with a life-threatening immunological reaction. The patient made a swift recovery upon treatment with immunoglobulins, corticosteroids and an interleukin-1 receptor antagonist. We want to highlight the importance of immunological derangements following covid-19 infections in adults. We also present a treatment suggestion for MIS-A based on the management routine for MIS-C, which has been developed from international discussions and collaborations by pediatric rheumatologists in Sweden and around the world.",
"affiliations": ".;med dr, överläkare, intensivvårdssektionen, ANOPIVA, Akademiska sjukhuset, Uppsala.;doktorand, specialistläkare, , intensivvårdssektionen, ANOPIVA, Akademiska sjukhuset, Uppsala.;med dr, ST-läkare, kirurgkliniken, Akademiska sjukhuset, Uppsala.;doktorand, bitr överläkare, infektionskliniken; samtliga Akademiska sjukhuset, UppsalaSiri Kurland, doktorand, bitr överläkare, infektionskliniken, Akademiska sjukhuset, Uppsala.",
"authors": "Berntson|Lillemor|L|;von Seth|Magnus|M|;Bülow Anderberg|Sara|S|;Åkerström|Tobias|T|;Kurland|Siri|S|",
"chemical_list": null,
"country": "Sweden",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0023-7205",
"issue": "118()",
"journal": "Lakartidningen",
"keywords": null,
"medline_ta": "Lakartidningen",
"mesh_terms": "D000328:Adult; D000086382:COVID-19; D002648:Child; D005260:Female; D006801:Humans; D000086402:SARS-CoV-2; D013548:Sweden; D013577:Syndrome; D018746:Systemic Inflammatory Response Syndrome",
"nlm_unique_id": "0027707",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33999400",
"pubdate": "2021-05-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rare but potentially life-threatening - Multisystem inflammatory syndrome in adults - a case description.",
"title_normalized": "rare but potentially life threatening multisystem inflammatory syndrome in adults a case description"
} | [
{
"companynumb": "SE-LUPIN PHARMACEUTICALS INC.-2021-18073",
"fulfillexpeditecriteria": "2",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugad... |
{
"abstract": "Objectives: To contribute to a precise and thorough knowledge of immune-related adverse events (irAE) induced by immune checkpoint inhibitors (ICI) and to emphasize the importance of this specific form of toxicity in terms of potential predictive value and long-term effects. Materials and Methods: We report the first case of granulomatosis with polyangiitis (GPA) in a patient treated with an anti-Programmed Death protein-1 (PD-1) antibody for advanced non-small-cell lung cancer (NSCLC). Results: After a single dose of this drug the patient showed severe myositis associated with a high anti-PR3 anti-neutrophil cytoplasmic antibody titer. Discontinuation of the anti-PD-1 and introduction of corticoids led to a remission of the irAE. Regarding tumor a partial response was noted. A year later a neutrophilic, sterile pleural exudate and cutaneous lesions appeared with the pathological findings of neutrophilic vasculitis. Retreatment with corticoids induced a new remission of symptoms. It remains unclear whether GPA was preexisting and clinically silent but revealed by the use of ICI or primarily induced by this treatment. Conclusions: irAE are rare when anti-PD-1 antibodies are used in monotherapy. They present with a distinct clinical picture and temporal course and require specific treatment. Patients with irAE usually have a favorable oncological outcome.",
"affiliations": "Department of Pulmonology, University Hospital of Liège, Liège, Belgium.;Department of Internal Medicine, University Hospital of Liège, Liège, Belgium.;Department of Rhumatology, University Hospital of Liège, Liège, Belgium.;Department of Pathology, University Hospital of Liège, Liège, Belgium.;Department of Internal Medicine, University Hospital of Liège, Liège, Belgium.;Department of Pulmonology, University Hospital of Liège, Liège, Belgium.;Department of Pulmonology, University Hospital of Liège, Liège, Belgium.",
"authors": "Sibille|Anne|A|;Alfieri|Romain|R|;Malaise|Olivier|O|;Detrembleur|Nancy|N|;Pirotte|Michelle|M|;Louis|Renaud|R|;Duysinx|Bernard|B|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2019.00478",
"fulltext": "\n==== Front\nFront OncolFront OncolFront. Oncol.Frontiers in Oncology2234-943XFrontiers Media S.A. 10.3389/fonc.2019.00478OncologyCase ReportGranulomatosis With Polyangiitis in a Patient on Programmed Death-1 Inhibitor for Advanced Non-small-cell Lung Cancer Sibille Anne 1*Alfieri Romain 2Malaise Olivier 3Detrembleur Nancy 4Pirotte Michelle 2Louis Renaud 1Duysinx Bernard 11Department of Pulmonology, University Hospital of Liège, Liège, Belgium2Department of Internal Medicine, University Hospital of Liège, Liège, Belgium3Department of Rhumatology, University Hospital of Liège, Liège, Belgium4Department of Pathology, University Hospital of Liège, Liège, BelgiumEdited by: Antonio Calles, Gregorio Marañón Hospital, Spain\n\nReviewed by: Elena Levantini, Beth Israel Deaconess Medical Center and Harvard Medical School, United States; Matteo Giaj Levra, Centre Hospitalier Universitaire de Grenoble, France\n\n*Correspondence: Anne Sibille Anne.sibille@chuliege.beThis article was submitted to Thoracic Oncology, a section of the journal Frontiers in Oncology\n\n06 6 2019 2019 9 47801 4 2019 20 5 2019 Copyright © 2019 Sibille, Alfieri, Malaise, Detrembleur, Pirotte, Louis and Duysinx.2019Sibille, Alfieri, Malaise, Detrembleur, Pirotte, Louis and DuysinxThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Objectives: To contribute to a precise and thorough knowledge of immune-related adverse events (irAE) induced by immune checkpoint inhibitors (ICI) and to emphasize the importance of this specific form of toxicity in terms of potential predictive value and long-term effects.\n\nMaterials and Methods: We report the first case of granulomatosis with polyangiitis (GPA) in a patient treated with an anti-Programmed Death protein-1 (PD-1) antibody for advanced non-small-cell lung cancer (NSCLC).\n\nResults: After a single dose of this drug the patient showed severe myositis associated with a high anti-PR3 anti-neutrophil cytoplasmic antibody titer. Discontinuation of the anti-PD-1 and introduction of corticoids led to a remission of the irAE. Regarding tumor a partial response was noted. A year later a neutrophilic, sterile pleural exudate and cutaneous lesions appeared with the pathological findings of neutrophilic vasculitis. Retreatment with corticoids induced a new remission of symptoms. It remains unclear whether GPA was preexisting and clinically silent but revealed by the use of ICI or primarily induced by this treatment. Conclusions: irAE are rare when anti-PD-1 antibodies are used in monotherapy. They present with a distinct clinical picture and temporal course and require specific treatment. Patients with irAE usually have a favorable oncological outcome.\n\nimmune checkpoint inhibitornon-small-cell lung cancergranulomatosis with polyangiitisimmune-related adverse eventsanti-PD-1 antibody\n==== Body\nIntroduction\nImmune-checkpoint inhibitors (ICI) have become widely used in advanced non-small-cell lung cancer (NSCLC). Classically, patients with preexisting autoimmune disorder (PAID) have been excluded from clinical trials using ICI. Real-life experience, however, shows that physicians sometimes do prescribe ICI to those patients (1, 2). Although mostly well-tolerated, ICI can cause severe and irreversible immune-related adverse events (irAE), affecting the quality of life and further lines of treatment. Timely recognition of irAE is paramount in order to control them.\n\nWe report the case of a patient with advanced NSCLC in whom treatment with pembrolizumab revealed a granulomatosis with polyangiitis (GPA). We then discuss the predictive value of irAE and safety of ICI in patients with PAID.\n\nCase Presentation\nA 64-years old male patient was diagnosed with stage IVB poorly differentiated NSCLC favoring adenocarcinoma of the right upper lobe with several bone lesions (cT4N2M1c). His medical history included a cerebrovascular accident and ischemic heart disease with subacute myocardial infarction in 2003. His chronic medication included acetylsalicylate acid 100 mg once daily (OD) and simvastatin 40 mg 0D, both since 2003. Regarding the tumor no driver mutation was identified by next-generation sequencing analysis. The Programmed Death Ligand-1 (PD-L1) expression level was assessed by immunohistochemistry using a monoclonal antibody to PD-L1 (clone 22C3, Dako) and a Benchmark Ultra (Roche) automated scope with subsequent evaluation by a certified pathologist, revealing 100% staining of a section including at least 100 evaluable tumor cells. Hence, pembrolizumab 200 mg every 3 weeks was started. Ten days after the first dose the patient was admitted to the hospital due to severe myalgia in both lower limbs with severe functional loss. Biochemistry showed creatine kinase (CK) of 1265 IU/L (upper limit of normal (ULN) = 190) and myoglobin of 2361 μg/L (ULN = 72) with normal renal function. Autoimmune serology showed a normal anti-nuclear factor (ANF) titer (1/80) without any characterization (especially for primary immune-mediated myositis with no anti-JO1, PL-7, PL-12, EJ, SRP, Mi-2, MDA-5, HMGCoA reductase) and anti-neutrophil cytoplasmic antibodies (ANCA) with a high titer of anti-PR3 (178 U/mL, ULN = 2); the infectious serology was negative. The statin was taken for several years prior to these symptoms and CK level before the start of the anti-PD-1 was normal. The electroneuromyography before corticoids showed proximal myopathy of moderate intensity without signs of necrosis. The quadriceps biopsy before corticotherapy was normal. He was treated with analgesics, intravenous fluids, and high-dose methylprednisolone (1 mg/kg/day) with favorable evolution. The diagnosis of immune-mediated myositis associated to granulomatosis with polyangiitis (GPA), former Wegener's disease, was established. The anti-PD-1 remained discontinued. Eight months after an initial partial response (PR) to pembrolizumab, progressive disease was noted and second-line doublet chemotherapy was started after antalgic irradiation of a metastatic pelvic mass. Subsequently, PR was noted. A year after the initial presentation of myositis the patient's condition worsened due to dyspnea and arthritis. Evaluation showed a new left-sided pleural effusion and a new lung consolidation. Based on a strong inflammatory syndrome (C-reactive protein (CRP) 116 mg/dL) and a neutrophilic exudate without evidence for empyema the patient was treated with amoxicilline-clavulanate for 14 days. In total, three pleural fluid cultures remained sterile. Due to persistence of the effusion and lack of clinical improvement a pleuroscopy was performed. The fluid appeared unclear and a few non-specific lesions were biopsied on the parietal pleura. They revealed a subacute pleuritis without tumor infiltration, granuloma or vasculitis. The arthritis was symmetrical and located in the wrists, metacarpophalangeal (MCP) joints and knees, without any evidence for infection or crystal-associated disease. A few days later, skin lesions appeared on the MCP and knees (Figure 1). Biopsy there showed a neutrophilic vasculitis, as can be seen in cutaneous forms of GPA (3) (Figure 2). The new lung consolidation was biopsied and showed only necrosis with no specific features of GPA-related lung involvement. Along with this clinical deterioration the autoimmune serology showed a rise in anti-PR3 titer (352.1 U/mL). The CRP dropped dramatically after initiation of corticoids (methylprednisolone at 1 mg/kg/day) along with clear clinical improvement. Recent clinical and radiological evaluation showed that the patient was in good overall condition with no signs of oncological progression despite discontinuation of the chemotherapy. We noted a progression-free survival (PFS) of 10 months after the second line chemotherapy and an overall survival (OS) of 18 months.\n\nFigure 1 Dark red, necrotic, slightly tender lesions developed symmetrically on MCP joints and knees.\n\nFigure 2 Hematoxylin and eosin (HE) staining shows blood vessels (white areas) with surrounding neutrophilic inflammatory aggregates (arrows), establishing the diagnosis of neutrophilic vasculitis. Picture magnification: 20x; scale bar: 50 μ.\n\nDiscussion\nWith this case we report a unique and rare but severe side effect of pembrolizumab with long-lasting consequences in a NSCLC patient. It remains uncertain whether GPA was preexisting and clinically silent but revealed by the use of the anti-PD-1 or primarily induced by this treatment. Indeed, no autoimmune serology was available from before the start of treatment. Retrospectively, the patient mentioned mild myalgia with normal CK values prior to diagnosis and treatment, responding to corticoids. We therefore think they were possibly signs of a low active GPA.\n\nImmune-related adverse events (irAE) are a kind of adverse events specific to immune checkpoint inhibitors (ICI). Virtually all organs can be affected depicting a wide variety of symptoms. They mostly appear early during treatment but can also appear long after drug discontinuation. Relapses are possible, also in the long term, as seen in our patient (4). Severe irAE occur at a low frequency (~10%) for anti-PD-1/-PD-L1 used in monotherapy (5–9). The general consensus for their management is high-dose corticoids and interruption of the ICI. In the absence of response, adding immunomodulators (mycophenolate mofetyl, anti-TNFα) is recommended (4, 10).\n\nBeside their impact on patients' quality of life and treatment plan, irAE are of specific interest for the clinician. They are considered potential predictors of response to treatment. In NSCLC, several studies showed superior PFS, response rates (RR) and/or OS in patients treated with anti-PD-1/anti-PD-L1 and showing irAE of various types and severity (11–13). The responses were independent of corticoids when needed. These series are, however, small-sized and retrospective. Our patient's tumor showed a PR according to the REsponse Criteria in Solid Tumors (RECIST) version 1.1 with a 50% reduction in the sum of target lesions and a PFS of 8 months after a single dose of pembrolizumab.\n\nMechanisms of irAE are not yet fully understood. In melanoma, it is argued that there exists a similarity between self-antigens and tumor neoantigens (14). Due to checkpoint inhibition, reactivated and expanding T-cells can interact with both tumor and healthy cells. Preexisting autoimmunity can also explain irAE: preexisting inactivated T-cells directed at self-antigens get reactivated by ICI, clinically translating into irAE (15). ICI might also impact B-cells, either directly via the PD-1 receptor or via the action of T-cells. These effects, however, are not yet fully understood (16).\n\nNew onset granulomatous diseases have been described in cancer patients treated with ICI (17, 18). These cases were involving the lungs and/or lymph nodes and pathologically identified as sarcoid-like reactions. To our knowledge, only one case of ICI-induced GPA has been reported in a melanoma patient first treated with ipilimumab, then with pembrolizumab (19). As CD4+ T-cells driven disease, it is understandable that sarcoidosis may be revealed by ICI that will increase the CD4+ T lymphocyte population although the precise mechanisms of this have not been ascertained so far. Wilde et al. suggested the role of the negative coregulatory factor PD-1 in GPA by demonstrating a high level of PD-1 expression in a series of 32 patients as compared to healthy controls and the lack of PD-1 on CD4+ lymphocytes in GPA lesions (20). The IL-17 pathway, known to induce inflammatory and autoimmune phenomena, is also suspected to play a role in GPA as levels of IL-17 producing T cells (Th17) were found to be increased, irrespective of disease activity (21).\n\nClassically, patients known to have an autoimmune disorder have been excluded from clinical trials with ICI. Daily practice, however, shows that this restriction is not always followed. Small-sized studies of such (mainly melanoma) patients treated with an anti-PD-1 are available (1, 2). Reporting on mostly stable PAID, both studies show an increased risk of (new) autoimmune symptoms in ~40% of patients, mainly with low-grade severity. The permanent discontinuation rate due to irAE was 8% (1) vs. 9% (2) which is similar to patients with no PAID (5–9). The type of PAID might also indicate a higher vs. lower risk of flare on anti-PD-1 treatment, as is the case for rheumatologic disorders, closely linked to the PD-1/PD-L1 axis (1). Danlos et al. found an earlier onset of irAE in patients with PAID compared to patients without PAID (2). Both studies found a similar efficacy of ICI in patients with and without PAID on anti-PD-1 in terms of OS and RR. As a consequence, both authors conclude that ICI treatment in patients with PAID is feasible, albeit requiring adequate follow-up and multidisciplinary management. Systematic autoimmune screening before the start of ICI might reinforce the awareness for irAE.\n\nConclusion\nICI are commonly used in the treatment of advanced NSCLC. They can, although rarely, induce severe irAE that can cause a major morbidity with potentially long-term effects and that can impact further treatment plan. We describe the first case of GPA in a patient treated with an anti-PD-1 antibody for advanced NSCLC. Although stable PAID does not seem an absolute contraindication to the use of ICI, close monitoring for side effects in these patients seems warranted. Patients presenting an irAE seem to have a favorable oncological outcome. The exact mechanisms of irAE remain unclear.\n\nPatient Informed Consent\nWritten informed consent was obtained from the participant for the publication of this case report and any potentially identifying images/information.\n\nAuthor Contributions\nAS reviewed the literature and wrote the paper. RA and MP followed the patient and collected clinical and biological data. OM analyzed the autoimmune serology data and contributed to the redaction of the manuscript. ND gave the pathology input of this case. RL and BD reviewed and contributed to the final version of the paper. All authors read and approved the final manuscript.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nFunding. This research did not receive any specific grant from funding agencies in the public, commercial, or non-profit sector.\n==== Refs\nReferences\n1. Menzies AM Johnson DB Ramanujam S Atkinson VG Wong ANM Park JJ . Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab . Ann Oncol. (2017 ) 28 :368 –76 . 10.1093/annonc/mdw443 27687304 \n2. Danlos FX Voisin AL Dyevre V Michot JM Routier E Taillade L \nSafety and efficacy of anti-programmed death 1 antibodies in patients with cancer and pre-existing autoimmune or inflammatory disease . Eur J Cancer. (2018 ) 91 :21 –9 . 10.1016/j.ejca.2017.12.008 29331748 \n3. Comfere NI Macaron NC Gibson LE . Cutaneous manifestations of Wegener's granulomatosis: a clinicopathologic study of 17 patients and correlation to antineutrophil cytoplasmic antibody status . J Cutan Pathol. (2007 ) 34 :739 –47 . 10.1111/j.1600-0560.2006.00699.x 17880578 \n4. Postow MA Hellmann MD \nAdverse events associated with immune checkpoint blockade . N Engl J Med. (2018 ) 378 :1165 \n10.1056/NEJMc1801663 29562154 \n5. Brahmer J Reckamp KL Baas P Crinò L Eberhardt WE Poddubskaya E . Nivolumab versus Docetaxel in advanced squamous-cell non-small-cell lung cancer . N Engl J Med. (2015 ) 373 :123 –35 . 10.1056/NEJMoa1504627 26028407 \n6. Borghaei H Paz-Ares L Horn L Spigel DR Steins M Ready NE . Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer . N Engl J Med. (2015 ) 373 :1627 –39 . 10.1056/NEJMoa1507643 26412456 \n7. Herbst RS Baas P Kim DW Felip E Pérez-Gracia JL Han JY . Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial . Lancet. (2016 ) 387 :1540 –50 . 10.1016/S0140-6736(15)01281-7 26712084 \n8. Rittmeyer A Barlesi F Waterkamp D Park K Ciardiello F von Pawel J . Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial . Lancet. (2017 ) 389 :255 –65 . 10.1016/S0140-6736(16)32517-X 27979383 \n9. Reck M Rodríguez-Abreu D Robinson AG Hui R Csoszi T Fülöp A . Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer . N Engl J Med. (2016 ) 375 :1823 –33 . 10.1056/NEJMoa1606774 27718847 \n10. Haanen JBAG Carbonnel F Robert C Kerr KM Peters S Larkin J . Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up . Ann Oncol. (2017 ) 28 (Suppl_4 ):iv119 –42 . 10.1093/annonc/mdx225 28881921 \n11. Haratani K Hayashi H Chiba Y Kudo K Yonesaka K Kato R . Association of immune-related adverse events with nivolumab efficacy in non-small cell lung cancer . JAMA Oncol. (2018 ) 4 :374 –8 . 10.1001/jamaoncol.2017.2925 28975219 \n12. Hasan Ali O Diem S Markert E Jochum W Kerl K French LE . Characterization of nivolumab-associated skin reactions in patients with metastatic non-small cell lung cancer . Oncoimmunology. (2016 ) 5 :e1231292 . 10.1080/2162402X.2016.1231292 27999741 \n13. Osorio JC Ni A Chaft JE Pollina R Kasler MK Stephens D . Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer . Ann Oncol. (2017 ) 28 :583 –9 . 10.1093/annonc/mdw640 27998967 \n14. Cui J Bystryn JC . Melanoma and vitiligo are associated with antibody responses to similar antigens on pigment cells . Arch Dermatol. (1995 ) 131 :314 –8 . 10.1001/archderm.131.3.314 7887661 \n15. Yoest JM . Clinical features, predictive correlates, and pathophysiology of immune-related adverse events in immune checkpoint inhibitor treatments in cancer: a short review . Immunotar Ther. (2017 ) 6 :73 –82 . 10.2147/ITT.S126227 29067284 \n16. Zhang M Xia L Yang Y Liu S Ji P Wang S . PD-1 blockade augments humoral immunity through ICOS-mediated CD4 . Int Immunopharmacol. (2019 ) 66 :127 –38 . 10.1016/j.intimp.2018.10.045 30448635 \n17. Nishino M Sholl LM Awad MM Hatabu H Armand P Hodi FS . Sarcoid-like granulomatosis of the lung related to immune-checkpoint inhibitors: distinct clinical and imaging features of a unique immune-related adverse event . Cancer Immunol Res. (2018 ) 6 :630 –5 . 10.1158/2326-6066.CIR-17-0715 29622582 \n18. Faviez G Bousquet E Rabeau A Rouquette I Collot S Goumarre C . Sarcoid-like granulomatosis in cancer patients treated with immune checkpoints inhibitors . Rev Mal Respir. (2018 ) 35 :963 –7 . 10.1016/j.rmr.2018.08.003 30220489 \n19. van den Brom RR Abdulahad WH Rutgers A Kroesen BJ Roozendaal C de Groot DJ . Rapid granulomatosis with polyangiitis induced by immune checkpoint inhibition . Rheumatology. (2016 ) 55 :1143 –5 . 10.1093/rheumatology/kew063 27069016 \n20. Wilde B Hua F Dolff S Jun C Cai X Specker C . Aberrant expression of the negative costimulator PD-1 on T cells in granulomatosis with polyangiitis . Rheumatology. (2012 ) 51 :1188 –97 . 10.1093/rheumatology/kes034 22447882 \n21. von Euw E Chodon T Attar N Jalil J Koya RC Comin-Anduix B . CTLA4 blockade increases Th17 cells in patients with metastatic melanoma . J Transl Med. (2009 ) 7 :35 . 10.1186/1479-5876-7-35 19457253\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "9()",
"journal": "Frontiers in oncology",
"keywords": "anti-PD-1 antibody; granulomatosis with polyangiitis; immune checkpoint inhibitor; immune-related adverse events; non-small-cell lung cancer",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "478",
"pmc": null,
"pmid": "31245290",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "17880578;19457253;22447882;26028407;26412456;26712084;27069016;27687304;27718847;27979383;27998967;27999741;28881921;28975219;29067284;29331748;29562154;29622582;30220489;30448635;7887661",
"title": "Granulomatosis With Polyangiitis in a Patient on Programmed Death-1 Inhibitor for Advanced Non-small-cell Lung Cancer.",
"title_normalized": "granulomatosis with polyangiitis in a patient on programmed death 1 inhibitor for advanced non small cell lung cancer"
} | [
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"fulfillexpeditecriteria": "1",
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"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
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