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"abstract": "Mitochondrial disorder (MtD) is usually a multisystem disease due to impaired mitochondrial energy production. Severe hypokalemia resulting in muscle weakness and rhabdomyolysis has not been reported as a phenotypic feature of MtD. Here we describe a 60-year-old male patient who developed myalgias followed by generalized muscle weakness a few days before admission. Symptoms were attributed to severe hypokalemia that occurred after the patient had discontinued spironolactone, a competitive antagonist of the aldosterone receptor, four months earlier on his own judgment. Spironolactone was given for 10 years to treat suspected primary hyperaldosteronism (Conn's syndrome). He presented with myopathic face, bilateral ptosis, hypertelorism, brachydactylia, weakness of the axial and limb muscles, and bilateral leg edema. Hypertelorism and brachydactylia are known as physical traits of MtD. Laboratory investigations revealed hypokalemia of 1.7 mmol/l and elevated serum levels of creatine kinase (2,772 U/l). Electrocardiogram showed sinus rhythm, left bundle-branch-block, repolarization abnormalities, and prolonged QTc (571 ms), which is associated with a propensity to ventricular arrhythmias. Diagnostic work-up revealed bilateral adenomas of the suprarenal glands. Conn's syndrome was regarded as a manifestation of MtD, since MtDs are frequently associated with endocrine abnormalities. The patient also presented with occasional double vision, ptosis, renal insufficiency, bilateral renal cysts, hypertriglyceridemia, arterial hypertension, and hypertrophic cardiomyopathy. Taken together, we have made the diagnosis of MtD. In conclusion, MtD may be associated with adrenal adenomas, which may cause severe symptomatic hypokalemia, manifesting as generalized weakness and myalgias due to rhabdomyolysis. Endocrine involvement may be a phenotypic feature of MtD.",
"affiliations": "Krankenanstalt Rudolfstiftung, Vienna, Austria. fifigs1@yahoo.de",
"authors": "Finsterer|Josef|J|;Lässer|Stefan|S|",
"chemical_list": "D000450:Aldosterone; D012083:Renin; D006854:Hydrocortisone",
"country": "Japan",
"delete": false,
"doi": "10.1620/tjem.231.9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-8727",
"issue": "231(1)",
"journal": "The Tohoku journal of experimental medicine",
"keywords": null,
"medline_ta": "Tohoku J Exp Med",
"mesh_terms": "D000450:Aldosterone; D006801:Humans; D006854:Hydrocortisone; D007008:Hypokalemia; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases; D010243:Paralysis; D012083:Renin",
"nlm_unique_id": "0417355",
"other_id": null,
"pages": "9-12",
"pmc": null,
"pmid": "23985882",
"pubdate": "2013-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe hypokalemic paralysis as a manifestation of a mitochondrial disorder.",
"title_normalized": "severe hypokalemic paralysis as a manifestation of a mitochondrial disorder"
} | [
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"companynumb": "AT-MYLANLABS-2014M1013531",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SPIRONOLACTONE"
},
"drugadditional": null,
... |
{
"abstract": "The use of high-flow nasal cannula (HFNC) therapy as respiratory support for preterm infants has increased rapidly worldwide. The evidence available for the use of HFNC is as an alternative to nasal continuous positive airway pressure (CPAP) and in particular to prevent postextubation failure. We report a case of tension pneumocephalus in a preterm infant as a complication during HFNC ventilation. Significant neurological impairment was detected and support was eventually withdrawn. Few cases of pneumocephalus as a complication of positive airway pressure have been reported in the neonatal period, and they all have been related to CPAP. This report reinforces the need to be aware of this rare but possible complication during HFNC therapy, as timely diagnosis and treatment can prevent neurological sequelae. We also stress the importance of paying close attention to flow rate, nasal cannula size and insertion, and mouth position, and of regularly checking insertion depth.",
"affiliations": "Neonatal Unit, Department of Pediatrics, Hospital Clínico Universitario de Santiago, IDIS (Health Research Institute of Santiago de Compostela), Santiago de Compostela, Spain.;Neonatal Unit, Department of Pediatrics, Hospital Clínico Universitario de Santiago, IDIS (Health Research Institute of Santiago de Compostela), Santiago de Compostela, Spain.;Neonatal Unit, Department of Pediatrics, Hospital Clínico Universitario de Santiago, IDIS (Health Research Institute of Santiago de Compostela), Santiago de Compostela, Spain.;Neonatal Unit, Department of Pediatrics, Complejo Hospitalario Universitario de Pontevedra, Pontevedra, Spain.;Neonatal Unit, Department of Pediatrics, Hospital Clínico Universitario de Santiago, IDIS (Health Research Institute of Santiago de Compostela), Santiago de Compostela, Spain.",
"authors": "Iglesias-Deus|Alicia|A|;Pérez-Muñuzuri|Alejandro|A|;López-Suárez|Olalla|O|;Crespo|Pilar|P|;Couce|Maria-Luz|ML|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/archdischild-2015-309777",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1359-2998",
"issue": "102(2)",
"journal": "Archives of disease in childhood. Fetal and neonatal edition",
"keywords": "Air; Cranial cavity; Newborn; Non-invasive ventilation; Positive pressure ventilation",
"medline_ta": "Arch Dis Child Fetal Neonatal Ed",
"mesh_terms": "D000072601:Cannula; D045422:Continuous Positive Airway Pressure; D004867:Equipment Design; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D008279:Magnetic Resonance Imaging; D011007:Pneumocephalus; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9501297",
"other_id": null,
"pages": "F173-F175",
"pmc": null,
"pmid": "28213557",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tension pneumocephalus induced by high-flow nasal cannula ventilation in a neonate.",
"title_normalized": "tension pneumocephalus induced by high flow nasal cannula ventilation in a neonate"
} | [
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"companynumb": "ES-MLMSERVICE-20170412-0652489-1",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
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"activesubstance": {
"activesubstancename": "TEICOPLANIN"
},
"drugadditional": nul... |
{
"abstract": "Testicular tumours are the most common tumours in young men. Germ cell tumours (GCTs) account for 95% of all testicular cancers, and the non-seminomatous type (NSGCT) accounts for 50% of all GCTs. Cisplatin-based chemotherapy is curative in up to 90% of patients, but it is not without its inherent risks. Ischaemic stroke is a very uncommon, but severe complication of cisplatin-based chemotherapy. Strokes in young patients cause a disproportionately large economic impact by leaving victims disabled during their most productive years and strains the healthcare system with expensive hospital stays. We present a case of a young male patient with past medical history of metastatic NSGCT with the sudden onset of dysarthria, left hemiplegia and ipsilateral hemisensory loss 3 days after receiving cisplatin-based chemotherapy. Subsequent studies revealed a stroke involving the right middle cerebral artery territory secondary to an acute right internal carotid occlusion.",
"affiliations": "SBH Health System, Internal Medicine, Bronx, New York, USA.;SBH Health System, Internal Medicine, Bronx, New York, USA.;SBH Health System, Internal Medicine, Bronx, New York, USA.",
"authors": "Cerrud-Rodriguez|Roberto Christian|RC|;Quinteros|Maria Gabriela|MG|;Azam|Mohammed|M|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D002945:Cisplatin; D001241:Aspirin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-220084",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Cancer intervention; Contraindications and precautions; Drugs and medicines; Stroke",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000971:Antineoplastic Combined Chemotherapy Protocols; D001241:Aspirin; D002340:Carotid Artery Diseases; D002945:Cisplatin; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal; D010291:Paresis; D020521:Stroke; D013736:Testicular Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28630245",
"pubdate": "2017-06-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12715037;16412836;20016238;20435575;23429331;23512060;2413982;25750539;26425644",
"title": "Internal carotid artery occlusion and stroke as a complication of cisplatin-based chemotherapy for metastatic testicular germ cell tumour.",
"title_normalized": "internal carotid artery occlusion and stroke as a complication of cisplatin based chemotherapy for metastatic testicular germ cell tumour"
} | [
{
"companynumb": "US-MYLANLABS-2017M1045328",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
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"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nSo called \"mycotic\" aortic aneurysms account for only 0.7 to 1.3% of all aortic aneurysms and are commonly caused by Staphylococcus aureus and Salmonella species. Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, is part of the therapy of non-muscle-invasive bladder cancer (NMIBC).\n\n\nMETHODS\nWe report a case series of three patients with a mycobacterial graft infection related to BCG after surgical treatment of a presumed mycotic aortic aneurysm as an extremely rare complication after NMIBC treatment. All three patients developed aortic aneurysm after BCG instillation and subsequent mycobacterial graft infection.\n\n\nCONCLUSIONS\nDiagnosis requires a high degree of suspicion because of its nonspecific symptoms and imaging. The pathogen is not detected by standard microbiological testing. Treatment includes triple antimycobacterial therapy and radical surgical interventions. Graft preservation may be considered if no anastomosis is involved.",
"affiliations": "Department of Vascular and Endovascular Surgery, Charité - Universitätsmedizin Berlin, corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203, Berlin, Germany. matthias.buerger@charite.de.;Department of Vascular and Endovascular Surgery, Charité - Universitätsmedizin Berlin, corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203, Berlin, Germany.;Department of Vascular and Endovascular Surgery, Charité - Universitätsmedizin Berlin, corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203, Berlin, Germany.;Department of Vascular and Endovascular Surgery, Charité - Universitätsmedizin Berlin, corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203, Berlin, Germany.;Institute of Radiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Luisenstraße 10, 10117, Berlin, Germany.;Department of Vascular and Endovascular Surgery, Charité - Universitätsmedizin Berlin, corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203, Berlin, Germany.;Department of Vascular and Endovascular Surgery, Charité - Universitätsmedizin Berlin, corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203, Berlin, Germany.",
"authors": "Buerger|M|M|http://orcid.org/0000-0003-3403-4025;Kapahnke|S|S|;Omran|S|S|;Schomaker|M|M|;Rief|M|M|;Greiner|A|A|;Frese|J P|JP|",
"chemical_list": "D000900:Anti-Bacterial Agents; D001500:BCG Vaccine",
"country": "England",
"delete": false,
"doi": "10.1186/s12893-021-01142-1",
"fulltext": "\n==== Front\nBMC Surg\nBMC Surg\nBMC Surgery\n1471-2482\nBioMed Central London\n\n1142\n10.1186/s12893-021-01142-1\nCase Report\nAortic aneurysm and aortic graft infection related to Mycobacterium bovis after intravesical Bacille Calmette–Guérin therapy—a case series\nhttp://orcid.org/0000-0003-3403-4025\nBuerger M. matthias.buerger@charite.de\n\n1\nKapahnke S. 1\nOmran S. 1\nSchomaker M. 1\nRief M. 2\nGreiner A. 1\nFrese J. P. 1\n1 grid.6363.0 0000 0001 2218 4662 Department of Vascular and Endovascular Surgery, Charité – Universitätsmedizin Berlin, corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany\n2 grid.6363.0 0000 0001 2218 4662 Institute of Radiology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Luisenstraße 10, 10117 Berlin, Germany\n17 3 2021\n17 3 2021\n2021\n21 1381 5 2020\n9 3 2021\n© The Author(s) 2021\nOpen AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nSo called “mycotic” aortic aneurysms account for only 0.7 to 1.3% of all aortic aneurysms and are commonly caused by Staphylococcus aureus and Salmonella species. Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, is part of the therapy of non-muscle-invasive bladder cancer (NMIBC).\n\nCase presentation\n\nWe report a case series of three patients with a mycobacterial graft infection related to BCG after surgical treatment of a presumed mycotic aortic aneurysm as an extremely rare complication after NMIBC treatment. All three patients developed aortic aneurysm after BCG instillation and subsequent mycobacterial graft infection.\n\nConclusion\n\nDiagnosis requires a high degree of suspicion because of its nonspecific symptoms and imaging. The pathogen is not detected by standard microbiological testing. Treatment includes triple antimycobacterial therapy and radical surgical interventions. Graft preservation may be considered if no anastomosis is involved.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1186/s12893-021-01142-1.\n\nKeywords\n\nCase report\nAortic surgery\nMycotic aortic aneurysm\nGraft infection\nBladder cancer\nMycobacterium bovis\nCharité (3093)Open Access funding enabled and organized by Projekt DEAL.\n\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nInfectious or so called ‘mycotic’ aortic aneurysms represent merely 0.7 to 1.3% of all aortic aneurysms. Nevertheless, they constitute a life-threatening vascular complication associated with in-hospital mortality rates of up to 36% [1, 2]. Mycotic aortic aneurysms are usually caused by Staphylococcus aureus, followed by Salmonella spp., Streptococcus spp. and Escherichia coli. Mycotic aneurysms caused by mycobacterial infections are rare. Up to now, 44 cases in 42 case reports of mycotic aortic aneurysms caused by mycobacterial infection affecting the thoracoabdominal aorta after intravesical instillation of Bacillus Calmette–Guérin (BCG) have been reported (see Additional file 1: Table S1).\n\nIntravesical BCG applications are standard of care for treating non-muscle-invasive bladder cancer (NMIBC) [3]. The live attenuated strain of Mycobacterium bovis is administered to patients with NMIBC after transurethral resection of bladder tumors (TURBT) to avert recurrence and reduce progression rates of intermediate- and high-risk tumors [4]. The incidence of BCG-related systemic complications including spondylodiscitis, psoas abscess or vascular complications remains unclear. In this case series, we report three cases of mycobacterial aortic graft infection related to intravesical application of BCG for NMIBC. This represents the largest case series in the current literature. The particular challenges for the diagnosis and treatment of this infrequent complication are discussed in this report.\n\nCase presentations\n\nPatient A\n\nIn November 2010, a 63-year-old man was referred to our clinic because of persistent weakness, fever, night sweat and unspecific abdominal pain lasting for two weeks. Three months before this episode, the patient had undergone emergency surgery for a ruptured infrarenal abdominal aortic aneurysm, which was treated with implantation of an aortobiiliac graft at another clinic. In 2008, the patient had been treated for NMIBC by transurethral resection and had received three cycles of intravesical BCG instillations (see Table 1). At the time of presentation, clinical examination and blood tests were unremarkable for inflammation except for a temperature of 37.6 °C. Ultrasound revealed a retroperitoneal fluid collection. Computed tomography (CT) demonstrated an extensive low-density collection surrounding the aortic prosthesis. The retroperitoneal mass was surgically removed and tissue samples were collected for histologic and microbiological studies. A specimen of the necrotic mass indicated chronic inflammation but tested negative for acid-fast bacilli (AFB) in Ziehl–Neelsen stain (Artisan™ Acid-Fast Bacillus (AFB) Stain Kit, Agilent, Santa Clara, United States). As no evidence for mycobacterial infection was found, the patient was discharged home in good condition, without antitubercular medication. Another two years later in August 2012, he presented again to our clinic with fever (40.4 °C), elevated white blood cell count (17.92/nl) and increased C-reactive protein (14.4 mg/l). CT scan revealed recurrence of a large mass in the retroperitoneum (Fig. 1). The patient underwent CT-guided aspiration. A drain was placed and specimens were sent to the microbiological laboratory. Microscopic examination showed necrotizing granulomatous inflammation with multinucleated giant cells. Direct Polymerase-chain-reaction (PCR, cobas® 6800 MTB Test, Roche, Rotkreuz, Switzerland) tested positive for Mycobacterium tuberculosis complex. Growth of Mycobacterium bovis in solid (BBL Stonebrink TB Medium + PACT + BBL Löwenstein-Jensen; Becton Dickinson, Rungis, France) and liquid culture (MGIT BBL; Becton Dickinson, Rungis, France) confirmed the suspected diagnosis. Antitubercular therapy with Isoniazid (INH), Rifampicin (RFP) and Ethambutol (EB) was started and the fluid collection was removed surgically. Intraoperatively, a partial affection of the left leg of the bifurcated graft by the necrotic mass was detected. After extensive debridement, vacuum assisted wound therapy was initiated. The possibility of an aortic reconstruction using autologous deep femoral vein or cryo-preserved homograft was evaluated but declined by the patient. After four weeks of negative pressure wound therapy, the wound could be closed in secondary intention. CT- scan showed no signs of persistent graft infection or retroperitoneal abscess. The patient was discharged in good condition. The triple antitubercular treatment was continued for six month and reduced to RFH and INH for another six months. As the patient remained free of symptoms, and CT scan was unremarkable, antitubercular therapy was subsequently terminated. After a follow-up of 84 months, the patient is in excellent condition and there is no CT- morphologic sign of recurrence of retroperitoneal abscess or inflammation of vascular graft.Table 1 Patient characteristics\n\nPreliminary diagnoses\tPreliminary surgical procedures\t\nPatient A\t\n NMIBC in 2008\tAortobiiliac prosthesis in 2010\t\n Ruptured aortic aneurysm in 2010\t\t\n Chronic obstructive pulmonary disease\t\t\n Disc prolaps L5/L6\t\t\n Renal cysts\t\t\nPatient B\t\n NMIBC in 2014\tNone\t\n Disc prolaps L2/L3 and L3/L4\t\t\n Patient C\t\n NMIBC in 2008\tAortocoronary bypass operation in 2011\t\n Coronary artery disease\tInguinal hernia repair\t\n Cardial arrhythmia type II Wenckebach\tDacron tube graft in 2015\t\n Arterial hypertension\t\t\n Hyperlipidemia\t\t\nNMIBC Non-muscle-invasive bladder cancer\n\nFig. 1 CT- reconstruction showing massive retroperitoneal fluid mass affecting left branch of aortobiiliac graft\n\nPatient B\n\nIn January 2018, a 78-year-old man presented with acute abdominal pain after a six-week history of chronic back pain. CT scan revealed a small-sized saccular aneurysmatic formation suspicious for a penetrating aortic ulcer (PAU) with contained rupture in the infrarenal aorta. Bone lesions in the vertebral bodies L2/L3 were highly suspicious for concomitant spondylodiscitis. The PAU was too small in size and anatomically too remote to represent a likely cause. Retrospectively, CT scan from 2014 did not show an aortic or vertebral pathology. The patient’s medical history was significant for NMIBC treated with TURBT and multiple intravesical BCG applications in 2014 (Table 1). The patient was hemodynamically stable and showed no notable physical examination findings. Except for increased C-reactive protein (25.1 mg/l), laboratory parameters were within normal limits. Because of close proximity of the PAU to the renal arteries resulting in a short neck, endovascular treatment was rejected. Immediate aortic reconstruction was performed by implantation of a rifampicin-soaked Dacron tube graft. Pathological examination and microbiological testing showed no evidence of mycobacterial infection or other pathogens in intraoperative specimens of the infrarenal aorta. The patient had an uneventful recovery and was discharged after two weeks. After four months of persisting lower back pain, biopsy extraction and spondylodesis of the concomitant spondylodiscitis was performed. The microbiological analysis tested negative for AFB in Ziehl–Neelsen stain but the growth of Mycobacterium bovis in solid and liquid culture confirmed the diagnosis of mycobacterial infection. Antitubercular treatment consisting of RFP, INH, and EB was administered. One year later, follow-up CT scan revealed dislocation of the former implanted spondylodesis which was surgically removed and replaced. Intraoperative samples showed no evidence of persisting mycobacterial infection with acid fast medium culture and PCR. The patient was discharged after eight days. Antitubercular triple therapy was continued for another six months. During follow-up of 20 months, the patient presented free of symptoms. CT scan showed a shrinking psoas abscess. Three months later, the patient presented to the emergency room with increasing left lower abdominal pain. CT examination showed a false aneurysm near the proximal anastomosis of the Dacron tube graft and a retroperitoneal periprosthetic fluid collection (Fig. 2), indicating an imminent rupture. Graft explantation and replacement with homograft was performed. Intraoperative sample material did not show any evidence of Mycobacterium bovis nor other pathogens. Due to the earlier confirmation of BCG- related graft infection, the anti-mycobacterial therapy was continued for another 12 months with Doxycyclin, RFP and INH. After an uncomplicated course, the patient was discharged to a rehabilitation center two weeks after surgery. Follow-up imaging was performed five months later revealing no residual fluid collection. The patient remained in good clinical condition without any signs of re-infection.Fig. 2 Progress of periprosthetic fluid mass highly suspicious for mycobacterial graft infection and anastomotic pseudoaneurysm of the former implanted Dacron tube graft\n\nPatient C\n\nIn December 2017, a 79-year-old man presented as an outpatient to our clinic with night sweats and persisting weakness after treatment of a contained rupture of an infrarenal PAU with implantation of a Dacron tube graft at an external institution in 2015. Ultrasound examination and CT showed periprosthetic fluid collection. The patient’s medical history included NIMBC diagnosed in 2008 and treated with TURBT and a total of 36 intravesical BCG instillations (Table 1). Laboratory parameters were within normal limits (CRP: 4.7 mg/l; white blood cell count: 4.08/nl). Samples collected by CT-guided aspiration tested positive for AFB with Auramine-rhodamine stain (Wescor Aerospray TB 7722, ELITech Biomedical Systems, Logan, Utah, USA). PCR of the aspirated fluid was positive for Mycobacterium tuberculosis complex and incubation in solid and liquid culture showed growth of Mycobacterium bovis. Antimycobacterial treatment was initiated. Because of a critical interaction between Ranolexin (long-term medication), Rifampicin was replaced by Rifabutin in combination with INH and EB. After a follow-up period of six months, control CT scan revealed a false aneurysm in the infrarenal region near the proximal anastomosis of the Dacron tube graft and a progression of the fluid collection in the psoas muscle (Fig. 3). The Dacron tube graft was completely removed and replaced by deep femoral vein (Fig. S1 in Additional file 2). Despite a weak positive PCR for Mycobacterium complex, culture incubation showed no growth of Mycobacterium bovis. This was considered to be the result of an effective perioperative antimycotic therapy. After an uncomplicated postoperative course, the patient was discharged to an external rehabilitation center after 25 days. During routine outpatient follow-up 12 months after surgery, the patient was in good general condition. The CT scan showed no persistent prosthetic infection.Fig. 3 Anastomotic pseudoaneurysm and progression of both periprosthetic fluid mass and fluid collection in left psoas muscle\n\nDiscussion and conclusion\n\nIntravesical instillation of BCG is widely used for the treatment of NMIBC. First used as a vaccine against tuberculosis, intravesical instillation of the live attenuated strain of Mycobacterium bovis has become standard care for NMIBC. The exact mechanism of its antitumor efficacy is not clarified yet. Although BCG instillation is generally considered safe, severe side effects have been reported. The incidence of mycotic aortic aneurysms caused by disseminated tuberculosis after BCG instillation remains unclear. Three different mechanisms are described that could lead to a systemic dissemination of and vascular affection by Mycobacterium bovis: (1) hematogenous dissemination followed by direct intimal colonization favored by preexisting atherosclerosis, (2) metastatic implantation through the vasa vasorum, or (3) continuous dissemination of adjacent infected tissue such as contiguous lymphadenitis or psoas abscess [5].\n\nWe report three cases of graft infection after surgical treatment of suspected mycotic aortic aneurysms as an extremely rare complication after intravesical BCG application. Our therapy was based on two pillars: drug-based antitubercular therapy as well as the individually adapted surgical treatment consisting of radical surgical debridement, vacuum therapy, drainage and in case of anastomotic leakage, graft explantation and aortic reconstruction using deep femoral vein or homograft.\n\nSo far, 44 cases of mycotic aortic aneurysms caused by disseminated mycobacterial infection have been published. Foreign material was implanted in 28 patients [6–32]. Postoperative graft infection was diagnosed in 10 out of 28 cases (35.7%) [6, 12, 17, 19–22, 32–34]. Of these 10 patients, six were discharged resulting in a hospital survival rate of 60%. A long-term follow-up of more than 12 months is reported by only one author [33]. Treatment included medical therapy alone (n = 1) [6], invasive therapy including either CT-guided drainage or surgical debridement with graft preservation (n = 2) [12, 19] and radical surgical therapy with partial (n = 1) [17] or complete graft explantation (n = 6) [20–22, 32–34]. Antitubercular medication was administered in 8 out of 10 cases [6, 12, 17, 19–22, 33]. Apart from one case [33], graft explantation was performed combined with aortic stump ligation and implantation of an extraanatomic axillofemoral bypass. Similar to our patients B and C, Santbergen et al. (33) focused on aortic reconstruction with autologous replacement material with an excellent postoperative result. Eighteen months after completion of the antimycobacterial medication, there was no clinical and morphological evidence of a persistent infection.\n\nDiagnosis of mycotic aneurysms or vascular complications after intravesical BCG application is exceptionally challenging and a high level of suspicion is required. A thorough medical history with attention to past NMIBC and related BCG instillations is essential when a mycotic aneurysm or graft infection is suspected. Unspecific symptoms like night sweats, weight loss, malaise and persisting fever combined with an unremarkable clinical examination can draw suspicion to a chronic disease like disseminated BCG- infection. After obtaining sample material from affected regions, e.g. vertebral disc, fluid collection in psoas muscle, aortic wall, paraaortic lymph nodes, pathological and microbiological examination is required. Suspected diagnosis can only be confirmed by PCR and culture specific for mycobacterial pathogens. Standard microbiological testing is often negative.\n\nAll of our three patients had received BCG therapy several years before the primary intervention. Because of the slow replication rate of mycobacteria, symptomatic vascular disease will often occur with a long latency after BCG instillation. Delay in diagnosis will lead to a delay in starting antimycobacterial treatment, which may result in an increased risk of rupture and dissemination, further limiting surgical options.\n\nCurrently, no consensus guideline for optimal medical treatment options of graft infection secondary to BCG instillation is available. Given its rareness, a case by case decision has to be made. Antitubercular therapy should be administered immediately after confirmed diagnosis and should be continued for at least six to 12 months. This medical therapy should be supplemented by surgical treatment. Our first case was managed successfully without graft explantation, with repeated radical surgical debridement and vacuum therapy alone, as no anastomosis was involved in this case. In our two following cases, anastomotic aneurysm indicating imminent rupture was discovered during follow-up. In these cases, we decided to completely remove the infected graft and to reconstruct the aorta with deep femoral vein or homograft, respectively.\n\nIn conclusion, this three-case series represents our experience with this rare condition. We strongly suggest that in cases of aortic aneurysm or aortic graft infection in patients with previous BCG instillation, surgeons should be suspicious of BCG- infection and mycotic aneurysm and to initiate specific testing including PCR and culture for mycobacterial infection. In cases with involvement of any graft anastomosis, complete graft removal and replacement with biological material should be considered. In cases with no involvement of an anastomosis, graft preservation could be attempted. Adjuvant antimycobacterial treatment is essential and should be initiated as soon as diagnosis is confirmed.\n\nSupplementary Information\n\nAdditional file 1: Table S1. Publications reporting aortic aneurysm secondary to intravesical application of Bacillus Calmette Guérin\n\nAdditional file 2: Fig. S1. Intraoperative situs showing exit of purulent granular material from the aneurysmatic formation (A) surrounding former implanted Dacron tube graft (B) and aortic reconstruction after graft removal and reconstruction with deep femoral vein (C)\n\nAbbreviations\n\nBCG Bacille Calmette–Guérin\n\nNMIBC Non-muscle-invasive bladder cancer\n\nTURBT Transurethral resection of bladder tumors\n\nCT Computed tomography\n\nAFB Acid-fast bacilli\n\nPCR Polymerase-chain-reaction\n\nPZA Pyrazinamide\n\nINH Isoniazid\n\nRFP Rifampicin\n\nEB Ethambutol\n\nPAU Penetrating aortic ulcer\n\nMRI Magnetic resonance imaging\n\nAcknowledgements\n\nWe acknowledge support from the German Research Foundation (DFG) and the Open Access Publication Fund of Charité–Universitätsmedizin Berlin.\n\nAuthors' contributions\n\nThe idea and initial findings of this seldomly occurring disease were made by JPF. During writing and revising this paper by MB, SK, SO, MS, JPF and AG where involved in constant discussions and improvements of manuscript. All relevant surgeries were performed by JPF or AG. For visual support MR created images that are used. All authors read and approved the final manuscript.\n\nFunding\n\nOpen Access funding enabled and organized by Projekt DEAL.\n\nAvailability of data and materials\n\nThe data collection was done by reviewing the available literature and electronic health records at the Charité Universitätsmedizin Berlin. Relevant data was collected in Microsoft Excel and analysed descriptively. The data is stored on the Charité—server and, in order to avoid a violation of access rights, the data is encrypted using a password only known to the study physicians. The data that support the findings of this study is available, but restrictions apply to the availability of the data, which was used under license for the current study, and so is not publicly available. Data is however available from the authors upon reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe need for approval was waived by our institutional review board.\n\nConsent for publication\n\nWritten informed consent for publication of their clinical details and/or clinical images was obtained from all patients. A copy of the consent form is available for review by the Editor of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Muller BT Wegener OR Grabitz K Pillny M Thomas L Sandmann W Mycotic aneurysms of the thoracic and abdominal aorta and iliac arteries: experience with anatomic and extra-anatomic repair in 33 cases J Vasc Surg 2001 33 1 106 113 10.1067/mva.2001.110356 11137930\n2. Oderich GS Panneton JM Bower TC Cherry KJ Jr Rowland CM Noel AA Infected aortic aneurysms: aggressive presentation, complicated early outcome, but durable results J Vasc Surg 2001 34 5 900 908 10.1067/mva.2001.118084 11700493\n3. Morales A Eidinger D Bruce AW Intracavitary Bacillus Calmette–Guerin in the treatment of superficial bladder tumors J Urol 1976 116 2 180 183 10.1016/S0022-5347(17)58737-6 820877\n4. Babjuk M Bohle A Burger M Capoun O Cohen D Comperat EM EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016 Eur Urol 2017 71 3 447 461 10.1016/j.eururo.2016.05.041 27324428\n5. Long R Guzman R Greenberg H Safneck J Hershfield E Tuberculous mycotic aneurysm of the aorta: review of published medical and surgical experience Chest 1999 115 2 522 531 10.1378/chest.115.2.522 10027455\n6. Higashi Y Nakamura S Kidani K Matumoto K Kawago K Isobe J Mycobacterium bovis-induced aneurysm after intravesical Bacillus Calmette–Guerin therapy: a case study and literature review Intern Med 2018 57 3 429 435 10.2169/internalmedicine.9102-17 29093394\n7. Wadhwani A Moore RD Bakshi D Mirakhur A Mycotic aortic aneurysms post-Intravesical BCG treatment for early-stage bladder carcinoma CVIR Endovasc 2018 1 1 28 10.1186/s42155-018-0036-y 30652159\n8. Coddington ND Sandberg JK Yang C Sehn JK Kim EH Strope SA Mycotic aneurysm after Bacillus Calmette–Guerin treatment: case report and review of the literature Case Rep Urol 2017 2017 4508583 28316859\n9. Holmes BJ LaRue RW Black JH 3rd Dionne K Parrish NM Melia MT Mycotic aortic aneurysm due to intravesical BCG immunotherapy: clinical manifestations and diagnostic challenges Int J Mycobacteriol 2014 3 1 60 65 10.1016/j.ijmyco.2013.11.002 26786225\n10. Floros N Meletiadis K Kusenack U Zirngibl H Kamper L Haage P Ruptured Mycotic Aortic Aneurysm after Bacille Calmette-Guerin Therapy Ann Vasc Surg 2015 29 7 1450.e1 4 10.1016/j.avsg.2015.03.060\n11. Davis FM Miller DJ Newton D Arya S Escobar GA Successful treatment of a mycotic multifocal thoracoabdominal aortic aneurysm as a late sequelae of intravesical bacillus Calmette–Guerin therapy: case report and literature review Ann Vasc Surg 2015 29 4 840.e9 13 10.1016/j.avsg.2014.12.020\n12. Leo E Molinari AL Rossi G Ferrari SA Terzi A Lorenzi G Mycotic abdominal aortic aneurysm after adjuvant therapy with bacillus Calmette–Guerin in patients with urothelial bladder cancer: a rare but misinterpreted complication Ann Vasc Surg 2015 29 6 1318.e1 6 10.1016/j.avsg.2015.01.036\n13. Seastedt KP Ahmad U Lau C Ruggeri-Weigel P Tsang HC Hartman BJ Mycotic thoracic aortic aneurysm after intravesical Bacillus Calmette–Guerin treatment Ann Thorac Surg 2015 99 6 2210 2212 10.1016/j.athoracsur.2014.07.083 26046881\n14. Akita H Okamura T Nakane A Kobayashi T Yamada K Tanaka Y Infectious aortic aneurysms occurring 1 year after bacillus Calmette–Guerin bladder instillation therapy Int J Urol 2015 22 2 234 235 10.1111/iju.12635 25316101\n15. Nam EY Na SH Kim SY Yoon D Kim CJ Park KU Infected Aortic Aneurysm caused by Mycobacterium bovis after Intravesical Bacillus Calmette–Guerin treatment for bladder cancer Infect Chemother 2015 47 4 256 260 10.3947/ic.2015.47.4.256 26788410\n16. Roylance A Mosley J Jameel M Sylvan A Walker V Aorto-enteric fistula development secondary to mycotic abdominal aortic aneurysm following intravesical bacillus Calmette–Guerin (BCG) treatment for transitional cell carcinoma of the bladder Int J Surg Case Rep 2013 4 1 88 90 10.1016/j.ijscr.2012.09.009 23127864\n17. Mizoguchi H Iida O Dohi T Tomoda K Kimura H Inoue K Abdominal aortic aneurysmal and endovascular device infection with iliopsoas abscess caused by Mycobacterium bovis as a complication of intravesical bacillus Calmette–Guerin therapy Ann Vasc Surg 2013 27 8 1186.e1 5 10.1016/j.avsg.2012.12.004\n18. Harding GE Lawlor DK Ruptured mycotic abdominal aortic aneurysm secondary to Mycobacterium bovis after intravesical treatment with bacillus Calmette-Guerin J Vasc Surg 2007 46 1 131 134 10.1016/j.jvs.2007.01.054 17606130\n19. Roeke T Hovsibian S Schlejen PM Dinant S Koster T Waasdorp EJ A mycotic aneurysm of the abdominal aorta caused by Mycobacterium bovis after intravesical instillation with bacillus Calmette–Guerin J Vasc Surg Cases Innov Tech 2018 4 2 122 125 10.1016/j.jvscit.2018.01.008 29942898\n20. Costiniuk CT Sharapov AA Rose GW Veinot JP Desjardins M Brandys TM Mycobacterium bovis abdominal aortic and femoral artery aneurysms following intravesical bacillus Calmette–Guerin therapy for bladder cancer Cardiovasc Pathol 2010 19 2 e29 32 10.1016/j.carpath.2008.09.003 19026573\n21. Wolf YG Wolf DG Higginbottom PA Dilley RB Infection of a ruptured aortic aneurysm and an aortic graft with bacille Calmette-Guerin after intravesical administration for bladder cancer J Vasc Surg 1995 22 1 80 84 10.1016/S0741-5214(95)70092-7 7602717\n22. Lareyre F Reverso-Meinietti J Carboni J Gaudart A Hassen-Khodja R Raffort JM Mycotic aortic aneurysm and infected aortic graft after intravesical Bacillus Calmette–Guerin treatment for bladder cancer Vasc Endovascular Surg 2019 53 1 86 91 10.1177/1538574418800128 30213242\n23. Dahl T Lange C Odegard A Bergh K Osen SS Myhre HO Ruptured abdominal aortic aneurysm secondary to tuberculous spondylitis Int Angiol 2005 24 1 98 101 15877007\n24. Rozenblit A Wasserman E Marin ML Veith FJ Cynamon J Rozenblit G Infected aortic aneurysm and vertebral osteomyelitis after intravesical bacillus Calmette–Guerin therapy AJR Am J Roentgenol 1996 167 3 711 713 10.2214/ajr.167.3.8751686 8751686\n25. Woods JM Schellack J Stewart MT Murray DR Schwartzman SW Mycotic abdominal aortic aneurysm induced by immunotherapy with bacille Calmette–Guerin vaccine for malignancy J Vasc Surg. 1988 7 6 808 10 3286902\n26. Wada S Watanabe Y Shiono N Masuhara H Hamada S Ozawa T Tuberculous abdominal aortic pseudoaneurysm penetrating the left psoas muscle after BCG therapy for bladder cancer Cardiovasc Surg 2003 11 3 231 235 10.1016/S0967-2109(03)00002-4 12704335\n27. Damm O Briheim G Hagstrom T Jonsson B Skau T Ruptured mycotic aneurysm of the abdominal aorta: a serious complication of intravesical instillation bacillus Calmette–Guerin therapy J Urol 1998 159 3 984 10.1016/S0022-5347(01)63796-0 9474201\n28. Hellinger WC Oldenburg WA Alvarez S Vascular and other serious infections with Mycobacterium bovis after bacillus of Calmette–Guerin therapy for bladder cancer South Med J 1995 88 12 1212 1216 10.1097/00007611-199512000-00005 7502112\n29. Kusakabe T Endo K Nakamura I Suzuki H Nishimura H Fukushima S Bacille Calmette–Guerin (BCG) spondylitis with adjacent mycotic aortic aneurysm after intravesical BCG therapy: a case report and literature review BMC Infect Dis 2018 18 1 290 10.1186/s12879-018-3205-7 29954321\n30. Seelig MH Oldenburg WA Klingler PJ Blute ML Pairolero PC Mycotic vascular infections of large arteries with Mycobacterium bovis after intravesical bacillus Calmette–Guerin therapy: case report J Vasc Surg 1999 29 2 377 381 10.1016/S0741-5214(99)70391-5 9950996\n31. Smith DM BCG-osis following intravesical BCG treatment leading to miliary pulmonary nodules, penile granulomas and a mycotic aortic aneurysm BMJ Case Rep. 2016 2016 87\n32. Berchiolli R Mocellin DM Marconi M Tomei F Bargellini I Zanca R Ruptured mycotic aneurysm after intravesical instillation for bladder tumor Ann Vasc Surg. 2019 59 310.e7 e11 10.1016/j.avsg.2018.12.100\n33. Santbergen B Vriens PH de Lange WC Van Kasteren ME Combined infection of vertebroplasty and aortic graft after intravesical BCG treatment BMJ Case Rep. 2013 2013 22 10.1136/bcr-2012-008161\n34. LaBerge JM Kerlan RK Reilly LM Chuter TA Diagnosis please. Case 9: mycotic pseudoaneurysm of the abdominal aorta in association with mycobacterial psoas abscess–a complication of BCG therapy Radiology. 1999 211 1 81 5 10.1148/radiology.211.1.r99ap4081 10189456\n\n",
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"title": "Aortic aneurysm and aortic graft infection related to Mycobacterium bovis after intravesical Bacille Calmette-Guérin therapy-a case series.",
"title_normalized": "aortic aneurysm and aortic graft infection related to mycobacterium bovis after intravesical bacille calmette gu rin therapy a case series"
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"abstract": "A 67-year-old man with celiac disease developed recurrent diarrhea, profound weakness and weight loss, with evidence of marked protein depletion. His clinical course was refractory to a strict gluten-free diet and steroid therapy. Postmortem studies led to definition of unrecognized collagenous sprue that caused ulceration and small intestinal perforation. Although PCR showed identical monoclonal T-cell populations in antemortem duodenal biopsies and postmortem jejunum, careful pathological evaluation demonstrated no frank lymphoma. Rarely, overt or even cryptic T-cell lymphoma may complicate collagenous sprue, however, small intestinal ulcers and perforation may also develop independently. The dramatic findings here may reflect an underlying or early molecular event in the eventual clinical appearance of overt T-cell lymphoma.",
"affiliations": "Department of Medicine Gastroenterology, University of British Columbia Hospital, 2211 Wesbrook Mall, Vancouver, BC V6T 1W5, Canada. hugfree@shaw.ca",
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"title": "Free perforation of the small intestine in collagenous sprue.",
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"abstract": "We present the case of a 16-year-old girl who presented with severe refractory orthostatic hypotension secondary to pandysautonomia. Initially, she was treated for Guillain-Barré syndrome given clinical symptoms and increased protein on cerebrospinal fluid, but the severity of symptoms and lack of response to intravenous immunoglobulin prompted further evaluation for an autoimmune etiology. She was ultimately diagnosed with paraneoplastic neuropathy secondary to Hodgkin lymphoma. Paraneoplastic neurologic phenomena are rare, occurring in just 0.01% of cancers, and prompt recognition is crucial for initiating appropriate therapy. Rapid progression of severe disabling symptoms should raise suspicion for an underlying malignancy. The patient had limited response to splanchnic vasoconstrictors in addition to α-agonists, anticholinergics, and mineralocorticoids until initiation of modified Hodgkin lymphoma directed chemotherapy plus rituximab.",
"affiliations": "From the Department of Pediatrics, Hasbro Children's Hospital, Providence, RI.",
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"abstract": "Neuraxial analgesia has been established as the standard of care for labor analgesia. However, patients presenting with coagulopathy require anesthesiologists to explore alternate analgesic techniques. Systemic opioids may result in neonatal respiratory depression, and inhaled nitrous oxide may lead to nausea, vomiting, and over sedation and may not be readily available in all labor and delivery units. In this case report, we describe a case where posterior quadratus lumborum blocks provided effective analgesia in a parturient with Hemophilia A during the first stage of labor.",
"affiliations": "From the Department of Anesthesiology and Perioperative Medicine, McGovern School of Medicine, University of Texas Health Science Center at Houston, Houston, Texas.",
"authors": "de Haan|Johanna Blair|JB|;Tabba|Subhan|S|;Lee|Linden O|LO|;Ghebremichael|Semhar|S|;Sen|Sudipta|S|;Shoham|Daniel|D|;Hernandez|Nadia|N|",
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"title": "Posterior Quadratus Lumborum Block for Labor Analgesia: A Case Report.",
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"abstract": "The risk of reactivation of resolved hepatitis B virus (HBV) in hepatitis B surface antigen (HBsAg)-negative multiple myeloma patients after daratumumab has not been reported. Among 93 patients with daratumumab treatment, reactivation occurred in 6 patients (6.5%) with one hepatic failure. This is the first report demonstrating a considerable risk of reactivation of resolved HBV after daratumumab.",
"affiliations": "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.;Division of Hematology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.;Division of Hematology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.",
"authors": "Lee|Soon Kyu|SK|;Sung|Pil Soo|PS|0000-0002-5780-9607;Park|Sung-Soo|SS|0000-0002-8826-4136;Min|Chang-Ki|CK|;Nam|Heechul|H|;Jang|Jeong Won|JW|;Choi|Jong Young|JY|;Yoon|Seung Kew|SK|",
"chemical_list": "D000911:Antibodies, Monoclonal; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; C556306:daratumumab",
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"keywords": "Daratumumab; hepatitis B virus; multiple myeloma; reactivation",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000911:Antibodies, Monoclonal; D006509:Hepatitis B; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D006515:Hepatitis B virus; D006801:Humans; D009101:Multiple Myeloma; D014775:Virus Activation",
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"title": "Reactivation of Resolved Hepatitis B After Daratumumab for Multiple Myeloma.",
"title_normalized": "reactivation of resolved hepatitis b after daratumumab for multiple myeloma"
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"companynumb": "KR-JNJFOC-20210429659",
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{
"abstract": "BACKGROUND\nRaoultella are Gram-negative rod-shaped aerobic bacteria which grow in water and soil. They mostly cause nosocomial infections associated with surgical procedures. This case study is the first report of a Raoultella infection in Africa. Case presentation We report a case of a surgical site infection (SSI) caused by Raoultella planticola which developed after caesarean section (CS) and surgery for secondary small bowel obstruction. The patient became febrile with neutrophilia (19,157/µL) 4 days after laparotomy and started to develop clinical signs of a SSI on the 8th day after laparotomy. The patient continued to be febrile and became critically ill despite empirical treatment with ceftriaxone and vancomycin. Raoultella species with extended antimicrobial resistance (AMR) carrying the CTX-M-9 β-lactamase was isolated from the wound discharge. Considering the antimicrobial susceptibility test, ceftriaxone was replaced by ceftazidime. The patient recovered and could be discharged on day 29 after CS.\n\n\nCONCLUSIONS\nRaoultella planticola was isolated from an infected surgical site after repeated abdominal surgery. Due to the infection the patient's stay in the hospital was prolonged for a total of 4 weeks. It is noted that patients undergoing surgical and prolonged inpatient treatment are at risk for infections caused by Raoultella. The development of a SSI caused by Raoultella planticola with extended AMR has to be assumed to be a consequence of ineffective antibiotic utilization. The presented case advices that rare bacteria as Raoultella should be considered as potential cause of nosocomial SSI with challenging treatment due to high levels of AMR.",
"affiliations": "Asella Teaching and Referral Hospital, College of Health Sciences, Arsi University, P.O. Box 04, Asella, Ethiopia. tafeseb.tufa@yahoo.com.;Hirsch Institute of Tropical Medicine, P.O. Box 04, Asella, Ethiopia.;Hirsch Institute of Tropical Medicine, P.O. Box 04, Asella, Ethiopia.;Asella Teaching and Referral Hospital, College of Health Sciences, Arsi University, P.O. Box 04, Asella, Ethiopia.;Institute of Medical Microbiology and Hospital Hygiene, Düsseldorf University Hospital Centre, Universitätsstr. 1, 40225, Düsseldorf, Germany.;Institute of Medical Microbiology and Hospital Hygiene, Düsseldorf University Hospital Centre, Universitätsstr. 1, 40225, Düsseldorf, Germany.;Hirsch Institute of Tropical Medicine, P.O. Box 04, Asella, Ethiopia.",
"authors": "Tufa|Tafese Beyene|TB|http://orcid.org/0000-0002-9505-9341;Fuchs|Andre|A|;Feldt|Torsten|T|;Galata|Desalegn Tadesse|DT|;Mackenzie|Colin R|CR|;Pfeffer|Klaus|K|;Häussinger|Dieter|D|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002442:Ceftazidime; D001618:beta-Lactamases",
"country": "England",
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"doi": "10.1186/s12941-020-00380-0",
"fulltext": "\n==== Front\nAnn Clin Microbiol Antimicrob\nAnn. Clin. Microbiol. Antimicrob\nAnnals of Clinical Microbiology and Antimicrobials\n1476-0711 BioMed Central London \n\n380\n10.1186/s12941-020-00380-0\nCase Report\nCTX-M-9 group ESBL-producing Raoultella planticola nosocomial infection: first report from sub-Saharan Africa\nhttp://orcid.org/0000-0002-9505-9341Tufa Tafese Beyene tafeseb.tufa@yahoo.com 123 Fuchs Andre andre.fuchs@med.uni-duesseldorf.de 23 Feldt Torsten torsten.feldt@med.uni-duesseldorf.de 23 Galata Desalegn Tadesse jaalalasaan@gmail.com 1 Mackenzie Colin R. colin.mackenzie@med.uni-duesseldorf.de 4 Pfeffer Klaus klaus.pfeffer@med.uni-duesseldorf.de 4 Häussinger Dieter haeussinger@med.uni-duesseldorf.de 23 1 Asella Teaching and Referral Hospital, College of Health Sciences, Arsi University, P.O. Box 04, Asella, Ethiopia \n2 Hirsch Institute of Tropical Medicine, P.O. Box 04, Asella, Ethiopia \n3 grid.14778.3d0000 0000 8922 7789Department of Gastroenterology, Hepatology and Infectious Diseases, Düsseldorf University Hospital Center, Moorenstr. 5, 40225 Düsseldorf, Germany \n4 grid.14778.3d0000 0000 8922 7789Institute of Medical Microbiology and Hospital Hygiene, Düsseldorf University Hospital Centre, Universitätsstr. 1, 40225 Düsseldorf, Germany \n17 8 2020 \n17 8 2020 \n2020 \n19 3619 9 2019 11 8 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/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nRaoultella are Gram-negative rod-shaped aerobic bacteria which grow in water and soil. They mostly cause nosocomial infections associated with surgical procedures. This case study is the first report of a Raoultella infection in Africa.\n\nCase presentation\n\nWe report a case of a surgical site infection (SSI) caused by Raoultella planticola which developed after caesarean section (CS) and surgery for secondary small bowel obstruction. The patient became febrile with neutrophilia (19,157/µL) 4 days after laparotomy and started to develop clinical signs of a SSI on the 8th day after laparotomy. The patient continued to be febrile and became critically ill despite empirical treatment with ceftriaxone and vancomycin. Raoultella species with extended antimicrobial resistance (AMR) carrying the CTX-M-9 β-lactamase was isolated from the wound discharge. Considering the antimicrobial susceptibility test, ceftriaxone was replaced by ceftazidime. The patient recovered and could be discharged on day 29 after CS.\n\nConclusions\nRaoultella planticola was isolated from an infected surgical site after repeated abdominal surgery. Due to the infection the patient’s stay in the hospital was prolonged for a total of 4 weeks. It is noted that patients undergoing surgical and prolonged inpatient treatment are at risk for infections caused by Raoultella. The development of a SSI caused by Raoultella planticola with extended AMR has to be assumed to be a consequence of ineffective antibiotic utilization. The presented case advices that rare bacteria as Raoultella should be considered as potential cause of nosocomial SSI with challenging treatment due to high levels of AMR.\n\nKeywords\nRaoultella planticolaNosocomial infectionAntimicrobial resistanceExtended spectrum β-lactamasesESBLCTX-M-9 groupAfricaEthiopiaissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nRaoultella are Gram-negative rod-shaped aerobic bacteria growing in water and soil. They can also be detected in the human gastrointestinal tract (GIT) or upper respiratory tract (URT) and are a rare cause of mostly nosocomial infections in humans. They were defined as a new genus in the family of Enterobacteriaceae in 2001, based on gene sequences of its 16S rRNA and rpoB gene [1]. Raoultella can grow at wide range of temperature (4 °C to 44.5 °C) and do not produce gas from lactose at 44.5 °C. All Raoultella isolates are resistant to ampicillin due to the over expression of chromosomally encoded class-A β-lactamase [2].\n\nRaoultella planticola, R. ornithinolytica, R. terrigena, and R. electrica are medically relevant Raoultella species [3–6], with R. planticola and R. ornithinolytica currently being most commonly reported from clinical samples. Factors contributing to the pathogenesis of diseases caused by the genus of Raoultella share similarities with those of Klebsiella and include lipopolysaccharides, polysaccharide capsules, fimbriae, siderophores [7], toxins [8], hydrolytic enzymes, and bacteriocins [9]. Raoultella species are also able to form biofilms [10]. In contrast to Klebsiella species, Raoultella species harbour histidine decarboxylase, enabling the bacteria to produce histamine. This information might be used for species differentiation [11, 12].\n\nFollowing phenotypic and biochemical microbiological methods only, Raoultella species are most likely being underreported due to the difficult differentiation from Klebsiella species. Over recent years, the identification rate has improved by increased utilization of matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) [13].\n\nRaoultella planticola is not well known as human pathogen. Literature search revealed 87 reported cases of R. planticola-related infections. Here, bloodstream infections (32 cases), urinary tract infection (16 cases), and pneumonia (11 cases) are most frequent. Among abdominal foci of Raoultella-infections, 5 cases of cholangitis, 3 cases of pancreatitis, 3 cases of cholecystitis, 3 cases of surgical site infection (SSI), 2 cases of secondary bacterial peritonitis, and a single case of enterocolitis have been described. Antimicrobial resistance (AMR) of Raoultella causing human infections has not been analysed systematically. However, Raoultella species harbouring extended spectrum β-lactamase (ESBL) and carbapenemase genes have been reported [14–17]. Most of the cases were reported in Europe and the USA. To our best knowledge, this report is the first description of an SSI caused by R. planticola with multidrug resistance (MDR) in Africa.\n\nCase presentation\nInitial presentation\nA 17-year-old previously healthy pregnant woman presented to Asella Teaching and Referral Hospital (ATRH) delivery ward in Asella, Central Ethiopia. Upon admission she appeared healthy, without any signs of infection or life-threatening disease. Caesarean section (CS) was indicated due to posterior cephalic position of the child and large fetal size. Lower uterine transverse CS was performed and a healthy male neonate delivered.\n\nDevelopment of surgical site infection\nFor the first three days after delivery, the patient recovered well from her surgery. However, on the 4th day she developed cramping abdominal pain, constipation with clinical signs of ileus and an elevated body temperature (T) of 37.8 °C. After physical examination and abdominal X-ray revealed signs of small bowel obstruction, emergency laparotomy was performed. Intra-operative findings were a purulent peritonitis due to a volvulus of the cecum with formation of a gangrene. Peritoneal drainage and lavage and a right hemicolectomy with primary ileo-transverse anastomosis were performed. The postoperative course for the first days was uneventful.\n\nOn her 5th day after laparotomy (and 9th after CS) the patient developed shortness of breath with mild hypotension, tachycardia, tachypnea and fever (blood pressure (BP) 110/70 mmHg, pulse rate (PR) 108/min, RR 40/min, T 38.5 °C). Breath sounds were clear with good bilateral air entry. Abdominal examination revealed passage of faecal matter from the surgical site. Complete blood count (CBC) showed leucocytosis (21.5 × 103/µl) with an increased fraction of neutrophils (89.1%). Platelet count and haemoglobin level where within normal range. There was no growth in a blood culture for a total incubation period of 5 days (1 bottle, local production).\n\nFurther course and treatment\nThe patient was diagnosed with a suspected intestinal anastomotic leak and empiric parenteral antibiotic treatment was started according to local guidelines with 1 g ceftriaxone plus 1 g vancomycin daily. Re-laparotomy on the same day revealed intraperitoneal pus and faeces due to an anastomotic dehiscence with perforation of the distal ileum about 50 cm from the previous anastomosis. After dissection of the insufficient anastomosis, resection of necrotic intestine and peritoneal lavage, re-anastomosis and closure of the abdominal cavity were performed.\n\nOn the 6th day post re-laparotomy (11 days post first laparotomy and 15 days after CS), the patient was transferred to intensive care unit and she developed purulent discharge from the surgical site. At this time, a wound swab was taken for microbiological diagnostics. The culture revealed growth of Raoultella species and the previous antibiotic treatment was adjusted according to the drug susceptibility test result (see Table 1) by replacement of ceftriaxone with ceftazidime. After 7 days of parenteral antibiotic treatment with this new regimen (ceftazidime 1 g three times daily and vancomycin 1 g once daily) the patient developed frequent watery diarrhoea and bilateral lower extremity swelling. Because of suspected Clostridium difficile enteritis (diagnostic tests for Clostridium difficile are not available), intravenous antibiotics were discontinued and the patient was started on oral metronidazole. Along with easing of the diarrhoea, the patient recovered and could be discharged in good condition on the 29th day after CS. In general the case was summarized by (Fig. 1).Table 1 Results of antimicrobial susceptibility testing of Raoultella planticola isolated strain\n\nName of antimicrobial substance\tKirby–Bauer disc diffusion testa\tVITEK® 2 result\t\nDiameter (mm)\tEUCAST interpretation\tMIC\tEUCAST interpretation\t\nPiperacillin\t0\tR\t≥ 128\tR\t\nPiperacillin/tazobactam\t21\tS\t8\tS\t\nCefotaxime\t0\tR\t8\tR\t\nCeftazidime\t22\tS\t≤ 1\tS\t\nCefepime\t22\tI\t≤ 1\tS\t\nAztreonam\tNot tested\t\t2\tI\t\nImipenem\t26\tS\t0.5\tS\t\nMeropenem\t27\tS\t≤ 0.25\tS\t\nAmikacin\t20\tS\t≤ 2\tS\t\nGentamicin\t9\tR\t≥ 16\tR\t\nTobramycin\t12\tR\t8\tR\t\nMoxifloxacin\tNot tested\t\t2\tR\t\nTigecycline\tNot tested\t\t1\tS\t\nCiprofloxacin\t17\tR\t1\tR\t\nFosfomycin\tNot tested\t\t≤ 16\tS\t\nColistin\tNot tested\t\t≤ 0.5\tS\t\nTrimethoprim/sulfamethoxazole\tNot tested\t\t≥ 320\tR\t\nMIC minimum inhibitory concentration; R resistant, S sensitive, I intermediate\n\naResults of antimicrobial susceptibility testing (AST) was done by using disc diffusion method at Asella, Ethiopia whereas VITEK was performed at institute of Medical Microbiology and Hospital Hygiene, Düsseldorf, Germany. Both results were interpreted by using European Committee on Antimicrobial Susceptibility Testing (EUCAST) version: 08.01\n\nFig. 1 Timeline of the development and course of the surgical site infection\n\n\n\nMicrobiology results\nDuring the patient’s stay in the hospital, one blood culture and one wound swab from the surgical site were sent for microbiological culture. Despite the intraoperative finding of purulent peritonitis upon first laparotomy, no intraoperative swabs were ordered. The blood culture remained sterile after an incubation period of 5 days. The swab taken from the SSI 15 days after CS and before the 2nd laparotomy was positive for Gram-negative rod-shaped bacteria. According to biochemical identification tests performed on site in Ethiopia, the isolated bacteria were identified as Klebsiella oxytoca (oxidase and methyl red negative; lactose, urease, citrate and indole positive). The isolate was exported to the Institute of Medical Microbiology and Hospital Hygiene at Heinrich Heine University Düsseldorf, Germany for confirmation, further identification and antimicrobial susceptibility testing (AST)”. Using MALDI-TOF (VITEK®-MS, bioMérieux, Marcy-l’Étoile, France), the bacteria was re-classified as Raoultella planticola with a likelihood of 99.9%.\n\nThe AST was done using Kirby–Bauer disc diffusion and VITEK methods. The results of the disc diffusion test and the VITEK® 2 (bioMérieux) investigation are described in (Table 1). For molecular resistance gene detection, polymerase chain reactions with primers described in (Table 2) were performed [18].Table 2 Oligonucleotide sequences of the primer pairs for molecular resistant genes detection\n\nPrimer\tSequence (5ʹ–3ʹ)\tAmplicon size (bp)\t\nblaSHV (F)\tAGCCGCTTGAGCAAATTAAAC\t786\t\nblaSHV (R)\tGTTGCCAGTGCTCGATCAGC\t\nblaTEM (F)\tCATTTCCGTGTCGCCCTTATTC\t846\t\nblaTEM (R)\tCCAATGCTTAATCAGTGAGGC\t\nblaCTX-M-1 (F)\tCGTCACGCTGTTGTTAGGAA\t781\t\nblaCTX-M-1 (R)\tACGGCTTTCTGCCTTAGGTT\t\nblaCTX-M-2 (F)\tCTCAGAGCATTCGCCGCTCA\t843\t\nblaCTX-M-2 (R)\tCCGCCGCAGCCAGAATATCC\t\nblaCTX-M-9 (F)\tGCGCATGGTGACAAAGAGAGTGCAA\t876\t\nblaCTX-M-9 (R)\tGTTACAGCCCTTCGGCGATGATTC\t\nPossible extended spectrum β-lactamases (ESBLs) coding genes were screened by using conventional polymerase chain reaction (PCR)\n\nF forward, R reverse, bp base pairs\n\n\n\nCTX-M-9 group and TEM ESBL coding genes were detected and the isolated strain was identified as MDR (Fig. 2). However, ESBLs from the groups CTX-M-1, CTX-M-2 or the SHV β-lactamase were not detected.Fig. 2 Picture of blaCTX-M-9 ESBL positive result. blaCTX-M-9 ESBL gene detected in the isolated R. planticola strain (with M = DNA ladder; −K = negative control; + K = positive control; 285 = code given for patient’s sample\n\n\n\nDiscussion\nCases of infections caused by Raoultella planticola including infections with abdominal foci have been reported from different countries [19]. In addition, the isolation of Raoultella species as the causative agent of human infections containing ESBL and also carbapenemase genes have previously been reported. It is assumed that, to date, Raoultella species are often misdiagnosed as Klebsiella species in the context of restricted diagnostic capacities in many African laboratories. Therefore, and to our best knowledge, the described hospital-acquired SSI caused by an ESBL-producing strain of R. planticola is the first such case reported in Africa. The bacterial strain was isolated from a SSI after CS complicated by cecal volvulus with secondary peritonitis due to a breakdown of the primary anastomosis. Due to secondary infection the patient’s overall stay in the hospital was prolonged. It is noted that being immunocompromised, surgical procedures, long-term antibiotic therapy and prolonged stays in hospital have been described as risk factors to develop Raoultella infections [17, 20]. In our case report, the patient’s gastrointestinal tract has probably been colonized with R. planticola and the leakage of intestinal luminal contents and gut flora after anastomosis insufficiency was the likely route of the infection. It appears likely that, selection of resistant bacteria by the previous empirical antibiotic therapy with ceftriaxone, which was ineffective against identified R. planticola.\n\nCases of Raoultella infections can occur in many organ systems (e.g. urinary tract, gastrointestinal tract, respiratory tract) or at surgical sites. Bacteraemia, osteomyelitis, meningitis, cerebral abscess, mediastinitis, pericarditis, conjunctivitis, mandibular osteomyelitis and otitis caused by Raoultella have also been reported [20, 21]. In general, the most common microorganisms isolated from SSIs after small bowel surgery are aerobic Gram-negative enteric bacteria [14].\n\nRegarding the management of intra-abdominal infections, therapy should focus on adequate source control and appropriate adjustment of antimicrobial therapy to individual patient factors. Empiric antimicrobial therapy is essential [22], however inappropriate antibiotic therapy may result in unfavourable outcome and in the selection of bacterial AMR bacteria. As seen in the described case, health care-associated infections caused by multi-resistant bacteria have to be considered which lead to the necessity of complex multidrug regimens [23]. For the selection of empirical antibiotic treatment, a length of hospital stay of 5 days has moderate specificity and very high sensitivity for predicting the presence of MDR bacteria [24].\n\nDue to the high likelihood of infections caused by resistant bacteria, guidelines for empirical treatment of SSIs recommend utilization of broad spectrum antimicrobials (e.g. carbapenems) [25] which are frequently not available in resource-limited settings like Ethiopia. In the absence of carbapenems, piperacillin/tazobactam could be an option for the empiric treatment of high-risk intra-abdominal infections [26, 27], which lead to high rates of mortality [28].\n\nThe initial empirical treatment in the described case was a combination of vancomycin and ceftriaxone. It was shown to be ineffective according to the subsequently available AST results (see Table 1). The patient only recovered after the antibiotic treatment was adapted according to the AST, despite the local miss-identification of the causing pathogen as Klebsiella species. If AST results are not or not yet available, the initiation of antimicrobial treatment with substances active against most Enterobacteriaceae should be considered for critically-ill patients with secondary intra-abdominal infections [29]. In general, regional and local susceptibility profiles of common bacterial isolates should be available and considered before initiation of empiric antibiotic treatments. This becomes increasingly important because of rising resistance of Gram-negative bacteria circulating in the communities. Local guidelines considering common regional AMR patterns should be implemented and updated for the management of SSI and intra-abdominal infections.\n\nFrom both clinical and natural environment, MDR strains of R. planticola and R. ornithinolytica were reported [30, 31]. In recent years, infections with Raoultella strains producing ESBL from the families TEM, SHV, and CTX-M have been described [32]. The ability to produce ESBL was also detected in Raoultella strains isolated from the hospital environment. From different clinical samples, AmpC β-lactamase-producing R. ornithinolytica strains have been isolated [33]. Emerging organisms like Raoultella species are likely to escape routine identification or be disregarded as insignificant contaminants despite their potential to cause infections which are complicated to manage due to MDR [34]. Limitations in diagnostic microbiological capacities might lead to delayed identification of emerging pathogens and extended AMR patterns, resulting in suboptimal patient care. In the light of increasing AMR among pathogens worldwide but also in resource-limited settings, strengthening of microbiological facilities and thus improved infection surveillance and control will lead to better hospital hygiene and infection control practices, which are needed for optimal outcome and containment of spreading resistance genes.\n\nConclusions\nThis report shows evidence of an infection due to a MDR strain of R. planticola causing a SSI and intra-abdominal infection with the presence of the CTX-M-9 group ESBLs and is the first description of such an infection in Africa. Surgical treatment with intestinal leakage was the likely route of the infection caused by R. planticola. The source of the bacteria might be from gastrointestinal colonization as consequence of ineffective antibiotics utilization or from the hospital environmental. The absence of diagnostic facilities, limited awareness of treating physicians for the importance of microbiological culturing and AST, restricted availability of antibiotic substances for treatment of infections caused by MDR bacteria and lack of data for common local AMR patterns in resource limited settings is jeopardizing the success rate of empirical antibiotic treatment. These insufficiencies become more severe in patients with hospital-acquired infections and prolonged stay in a hospital. In general, the presented case serves to increase the awareness that rare bacterial species like Raoultella should be considered as a potential cause of nosocomial SSI with a high rate of AMR. This leads to the necessity of up-to-date guidelines for the management of intra-abdominal infections and for regular microbiological investigation of suitable clinical specimen in nosocomial infections.\n\nIn settings where colonization with MDR Enterobacteriaceae is common, surveillance and screening for colonization with MDR bacterial strains before invasive procedures and implementation or strengthening of antibiotic stewardship programs would contribute to successful patient care and should be considered.\n\nAbbreviations\nAMRAntimicrobial resistance\n\nASTAntimicrobial susceptibility testing\n\nATRHAsella Teaching and Referral Hospital\n\nBPBlood pressure\n\nCSCaesarean section\n\nESBLExtended spectrum β-lactamase\n\nMDRMulti-drug resistant\n\nPRPulse rate\n\nRRRespiratory rate\n\nSSISurgical site infection\n\nTBody temperature\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nTafese Beyene Tufa and Andre Fuchs contributed equally to this work\n\nThe authors thank the study and laboratory team from Hirsch Institute of Tropical Medicine in Asella, Ethiopia and the staff of the Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University, Düsseldorf, Germany for supporting this work. We also acknowledge the German ESTHER University and Hospital Partnership Program for endorsing microbiology facilities at the study site.\n\nAuthors’ contributions\nTBT: Design, Acquisition and interpretation of data, drafting of the manuscript. AF: Conception and design, acquisition and interpretation of data, drafting and revision of the manuscript. TF: Accountability for the published work, conception and design, interpretation of data, critical revision of the manuscript. DTG: Analysis and interpretation of data, drafting of the manuscript. Colin Mackenzie: Interpretation of data, accountability for microbiological results, critical revision of the manuscript. KP: Accountability for microbiological results, critical revision of the manuscript. DH: Critical revision of manuscript and approval of final version to be published. All authors read and approved the final manuscript.\n\nFunding\nFunding for the described microbiological investigations performed in Ethiopia were financed by the University and Hospital Partnership Programme (ESTHER Alliance for Global Health Partnerships, Germany, Federal Ministry for Economic Cooperation and Development). There was no influence of the funding organisation on analysis or interpretation of the described data.\n\nAvailability of data and materials\nAll data generated or analysed during this study are included in this published article [and its additional information files].\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nThe patient consented to participation and publication. The consent form (written in the patient’s mother tongue, Amharic) is available upon request.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. 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Sartelli M Chichom-Mefire A Labricciosa FM Hardcastle T Abu-Zidan FM Adesunkanmi AK Ansaloni L Bala M Balogh ZJ Beltran MA Ben-Ishay O Biffl WL Birindelli A Cainzos MA Catalini G Ceresoli M Che Jusoh A Chiara O Coccolini F Coimbra R Cortese F Demetrashvili Z Di Saverio S Diaz JJ Egiev VN Ferrada P Fraga GP Ghnnam WM Lee JG Gomes CA Hecker A Herzog T Kim JI Inaba K Isik A Karamarkovic A Kashuk J Khokha V Kirkpatrick AW Kluger Y Koike K Kong VY Leppaniemi A Machain GM Maier RV Marwah S McFarlane ME Montori G Moore EE Negoi I The management of intra-abdominal infections from a global perspective: 2017 WSES guidelines for management of intra-abdominal infections World J Emerg Surg 2017 12 29 10.1186/s13017-017-0141-6 28702076 \n23. Sartelli M A focus on intra-abdominal infections World J Emerg Surg 2010 5 9 10.1186/1749-7922-5-9 20302628 \n24. Seguin P Laviolle B Chanavaz C Donnio PY Gautier-Lerestif AL Campion JP Malledant Y Factors associated with multidrug-resistant bacteria in secondary peritonitis: impact on antibiotic therapy Clin Microbiol Infect 2006 12 980 985 10.1111/j.1469-0691.2006.01507.x 16961634 \n25. Solomkin JS Mazuski JE Bradley JS Rodvold KA Goldstein EJ Baron EJ O'Neill PJ Chow AW Dellinger EP Eachempati SR Gorbach S Hilfiker M May AK Nathens AB Sawyer RG Bartlett JG Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America Clin Infect Dis 2010 50 133 164 10.1086/649554 20034345 \n26. Gin A Dilay L Karlowsky JA Walkty A Rubinstein E Zhanel GG Piperacillin-tazobactam: a beta-lactam/beta-lactamase inhibitor combination Expert Rev Anti Infect Ther 2007 5 365 383 10.1586/14787210.5.3.365 17547502 \n27. Harris PNA Tambyah PA Paterson DL β-lactam and β-lactamase inhibitor combinations in the treatment of extended-spectrum β-lactamase producing Enterobacteriaceae: time for a reappraisal in the era of few antibiotic options? Lancet Infect Dis 2015 15 475 485 10.1016/S1473-3099(14)70950-8 25716293 \n28. Mulier S Penninckx F Verwaest C Filez L Aerts R Fieuws S Lauwers P Factors affecting mortality in generalized postoperative peritonitis: multivariate analysis in 96 patients World J Surg 2003 27 379 384 10.1007/s00268-002-6705-x 12658477 \n29. Mazuski JE Tessier JM May AK Sawyer RG Nadler EP Rosengart MR Chang PK O'Neill PJ Mollen KP Huston JM Diaz JJ Jr Prince JM The surgical infection society revised guidelines on the management of intra-abdominal infection Surg Infect (Larchmt) 2017 18 1 76 10.1089/sur.2016.261 28085573 \n30. Li J Lan R Xiong Y Ye C Yuan M Liu X Chen X Yu D Liu B Lin W Bai X Wang Y Sun Q Wang Y Zhao H Meng Q Chen Q Zhao A Xu J Sequential isolation in a patient of Raoultella planticola and Escherichia coli bearing a novel ISCR1 element carrying blaNDM-1 PLoS ONE 2014 9 e89893 10.1371/journal.pone.0089893 24594606 \n31. Koc S Kabatas B Icgen B Multidrug and heavy metal-resistant Raoultella planticola isolated from surface water Bull Environ Contam Toxicol 2013 91 177 183 10.1007/s00128-013-1031-6 23754693 \n32. Zurfluh K Hachler H Nuesch-Inderbinen M Stephan R Characteristics of extended-spectrum beta-lactamase- and carbapenemase-producing Enterobacteriaceae isolates from rivers and lakes in Switzerland Appl Environ Microbiol 2013 79 3021 3026 10.1128/AEM.00054-13 23455339 \n33. Sękowska A Raoultella spp.—clinical significance, infections and susceptibility to antibiotics Folia Microbiol 2017 62 221 227 10.1007/s12223-016-0490-7 28063019 \n34. Khan ID Sahni AK Bharadwaj R Lall M Jindal A Sashindran V Emerging organisms in a tertiary healthcare set up Med J Armed Forces India 2014 70 120 128 10.1016/j.mjafi.2013.09.005 24843199\n\n",
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"abstract": "Olfactory neuroblastoma (ONB) is an unusual malignant neoplasm originating from the olfactory neuroepithelium. Secretion of adrenocorticotropic hormone (ACTH) from this tumor has been exceptionally reported. We describe a young man with resistant hypertension and a cushingoid phenotype. After hormonal confirmation of an ACTH-dependent Cushing syndrome, non-invasive dynamic tests were carried out to evaluate the cause of the ACTH source. Plasma cortisol decrease after a high-dose dexamethasone suppression test and cortisol increase after a desmopressin (DDAVP) stimulation test suggested a Cushing disease. A magnetic resonance image (MRI) of the brain and an Indium-111 octreotide scan revealed a large mass centered in the sphenoid sinus with lateral and posterior extension. An ACTH secreting ONB was confirmed with a trasnasal biopsy. Patient was offered a combined therapy with surgical resection and radiotherapy but refused surgery. The neoplasm was treated with neoadjuvant cisplatin-based chemotherapy followed by fractionated radiotherapy. Hypercortisolism initially improved with metyrapone but normocortisolism was only achieved after local control of the tumor with radiotherapy. Clinical presentation of ONB is usually related to local symptoms (as nasal obstruction and epistaxis) dependent on its ubication and extension. Cushing syndrome from ACTH production is a rare manifestation of ONB. This case also underlies the difficulties related to the interpretation of dynamic endocrine tests in Cushing syndrome.",
"affiliations": "Department of Endocrinology, Hospital Clinico San Carlos, Madrid, Spain.;Department of Endocrinology, Hospital Clinico San Carlos, Madrid, Spain.",
"authors": "Familiar|Cristina|C|;Azcutia|Ane|A|",
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"fulltext": "\n==== Front\nClin Med Insights Endocrinol DiabetesClin Med Insights Endocrinol DiabetesENDspendClinical Medicine Insights. Endocrinology and Diabetes1179-5514SAGE Publications Sage UK: London, England 10.1177/117955141982583210.1177_1179551419825832Case ReportAdrenocorticotropic Hormone-Dependent Cushing Syndrome Caused by an Olfactory Neuroblastoma Familiar Cristina Azcutia Ane Department of Endocrinology, Hospital Clinico San Carlos, Madrid, SpainCristina Familiar, Department of Endocrinology, Hospital Clinico San Carlos, Calle Martin Lagos, s/n., 28040 Madrid, Spain. Email: cristinafamiliarcasado@gmail.com31 1 2019 2019 12 117955141982583221 12 2018 28 12 2018 © The Author(s) 20192019SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Olfactory neuroblastoma (ONB) is an unusual malignant neoplasm originating from the olfactory neuroepithelium. Secretion of adrenocorticotropic hormone (ACTH) from this tumor has been exceptionally reported. We describe a young man with resistant hypertension and a cushingoid phenotype. After hormonal confirmation of an ACTH-dependent Cushing syndrome, non-invasive dynamic tests were carried out to evaluate the cause of the ACTH source. Plasma cortisol decrease after a high-dose dexamethasone suppression test and cortisol increase after a desmopressin (DDAVP) stimulation test suggested a Cushing disease. A magnetic resonance image (MRI) of the brain and an Indium-111 octreotide scan revealed a large mass centered in the sphenoid sinus with lateral and posterior extension. An ACTH secreting ONB was confirmed with a trasnasal biopsy. Patient was offered a combined therapy with surgical resection and radiotherapy but refused surgery. The neoplasm was treated with neoadjuvant cisplatin-based chemotherapy followed by fractionated radiotherapy. Hypercortisolism initially improved with metyrapone but normocortisolism was only achieved after local control of the tumor with radiotherapy. Clinical presentation of ONB is usually related to local symptoms (as nasal obstruction and epistaxis) dependent on its ubication and extension. Cushing syndrome from ACTH production is a rare manifestation of ONB. This case also underlies the difficulties related to the interpretation of dynamic endocrine tests in Cushing syndrome.\n\nCushing syndromeectopic ACTH syndromeolfactory neuroblastomadexamethasone suppression testdesmopressin stimulation testcover-dateJanuary-December 2019\n==== Body\nIntroduction\nOlfactory neuroblastoma (ONB) is a rare neural crest-derived malignancy1 (accounting for less than 6% of all sinonasal malignant neoplasms) originating from the olfactory neuroepithelium. This neuroectodermal origin could explain certain morphologic features as well as the possibility of hormonal secretion. Adrenocorticotropic hormone (ACTH) ectopic Cushing syndrome attributable to ONB is exceptional with only 17 histologically confirmed cases reported in the literature to the best of our knowledge.2\n\nClinical Presentation\nIn February 2017, a 31-year-old Caucasian male presented with a 2-year history of resistant hypertension requiring 4 antihypertensive drugs. Typical Cushing appearance on physical examination (round face, dorsal fat pat, wide purple striae, proximal muscle weakness) and rapid weight gain lead to an endocrinologic evaluation. Routine laboratory tests are summarized in Table 1. Besides cushingoid phenotype, he did not complain of headaches or local symptoms. ACTH-dependent Cushing syndrome was confirmed with urinary free cortisol determinations above normal range on two occasions (230 μg/24 h and 301 μg/24 h, reference range below 200 μg/24 h), lack of plasma cortisol response to low-dose dexamethasone suppression test and high plasmatic ACTH levels (164 pg/mL; reference range: 10 to 60 pg/mL). To establish the etiology of the ACTH source (Cushing disease or an ectopic tumor),the patient underwent two non-invasive dynamic tests consistent in a DDAVP (desmopressin) stimulation test and a high-dose dexamethasone suppression test as shown in Table 2.Plasma cortisol increases after the DDAVP test and cortisol decreases after 8 mg of nocturnal dexamethasone suggested Cushing disease (Figure 1). A pituitary magnetic resonance image (MRI) was obtained revealing a large mass (36 × 46 × 46 mm) in the skull base centered in the sphenoid sinus with caudal extension in the nasopharynx and posterior extension in the clivus. The mass completely involved the sella (preventing pituitary gland identification) although without compromising the pituitary stalk and the optic chiasm (Figure 2). The mass was also identified with an Indium-111 octreotide scan confirming somatostatin receptor expression. A trasnasal biopsy of the lesion demonstrated an ACTH secreting ONB. Neoplastic cells showed a lobular architecture and were small with speckled nuclear chromatin and mild nuclear pleomorphism in a dense fibrillary stroma. Positive inmunoreactivity for synaptophysin, CD56, chromogranin, and neuron-specific enolase confirmed the neural tumor origin. Focal S100 staining was also found at the periphery and ACTH positivity was demonstrated in more than 50% of cells. The tumor was staged histologically as Hyams grade I (based on histological architecture and mitotic activity) and clinically as Kadish stage C (based on tumor extension). Patient refused surgery and was treated with neoadjuvant chemotherapy (etoposide and cisplatin for three cycles) followed by a full course of fractionated radiotherapy (50 Gy). Ketoconazole was started for hypercortisolism control but had to be discontinued after 6 weeks of therapy (800 mg daily) because of hepatotoxicity and was changed to metyrapone at increasing doses up to 3000 mg daily in divided doses. Despite the use of steroidogenesis enzyme inhibitors, eucortisolism (defined by normal free urinary cortisol level on two consecutive determinations) was not achieved until 1 month after radiotherapy. At that moment a dramatic clinical improvement was observed and antihypertensive drugs could be withdrawn. A new MRI revealed mass stability persisting in the last follow-up 1 year after radiotherapy (Figure 3).\n\nTable 1. Initial routine blood tests and hormonal values.\n\n\t\tNormal range\tPatient results\t\nComplete blood cell count\tWBC\t4000-10 500\t\n11 200\n\t\n\tNeutrophils\t1500-6600\t\n8400\n\t\n\tLymphocytes\t1500-3500\t1900\t\n\tHb\t13.5-18\t14.1\t\n\tHc\t42-55\t41.7\t\nLiver function tests\tALT (U/L)\t5-40\t27\t\n\tAST (U/L)\t5-40\t26\t\nRenal function tests\tCreatinine (mg/dL)\t0.6-1.1\t0.9\t\n\tUrea (mg/dL)\t0-50\t74\t\n\tCKD-EPI (mL/min)\t60-140\t79.3\t\nGlucose\tmg/dL\t60-100\t\n116\n\t\nSodium\tmmol/L\t135-145\t142\t\nPotassium\tmmol/L\t3.4-5.5\t3.9\t\nLDH\tU/L\t240-480\t\n813\n\t\nHormonal values\tLH (IU/L)\t1.2-8.6\t2\t\n\tFSH (IU/L)\t1.3-19.3\t5.1\t\n\tTestosterone (nmol/L)\t6-27\t8.2\t\n\tDHEAS (ng/mL)\t6.6-3.1\t\n5.1\n\t\n\tGH (ng/dL)\t0.05-3\t0.05\t\n\tIGF1 (ng/mL)\t41-246\t92.5\t\n\tTSH (uUI/mL)\t0.4-5.3\t\n0.22\n\t\n\tFree T4 (pg/mL)\t5.8-16.4\t7.2\t\nAbnormal values are marked in bold.\n\nAbbreviations: WBC, White Blood Cells count; ALT, Alanine Aminotransferase; AST, Apartate aminotransferase; CKD_EPI, chronic kidney disease epidemiology collaboration (ckd_epi) creatinine equation; LDH, Lactate dehydrogenase; LH, Luteinizing hormone; FSH, Follicule stimulating hormone; DHEAS, dehydroepiandrosterone sulfate; GH, Growth Hormone; IGF1, Insuline like factor1; TSH, Thyroid stimulating hormone.\n\nTable 2. Dynamic endocrine tests of ACTH-dependent Cushing syndrome.\n\nHigh-dose dexamethasone suppression test (8 mg given orally at 23 hPM the day before)\t\n\tBasal\t9 AM\t\t\t\t\t\t\nCortisol (μg/dL)\t25.2\t8.7a\t\t\t\t\t\t\nDDAVP stimulation test (10 μg of desmopressin given intravenously)\t\n\tBasal\t15 min\t30 min\t45 min\t60 min\t90 min\t120 min\t\nCortisol (μg/dL)\t25.2\t32.1\t36.1\t45.9b\t40.2\t38.6\t30.9\t\nACTH (pg/mL)\t141\t987c\t493\t305\t257\t144\t116\t\nAbbreviation: ACTH, adrenocorticotropic hormone.\n\na 75% of suppression.\n\nb 82% of increase.\n\nc 600% of increase.\n\nFigure 1. Changes in plasma cortisol after dynamic endocrine tests.\n\nFigure 2. A contrast-enhanced magnetic resonance image of the brain showing a large mass in the skull base involving the sella and extending in the nasopharynx the clivus.\n\nFigure 3. A magnetic resonance image of the brain 1 year after radiotherapy showing the stability of the tumor size.\n\nDiscussion\nONB is a rare malignancy3 with an annual incidence of 0.4-1 in 1 000 000 most commonly diagnosed during the second and sixth decade of life by local symptoms (nasal congestion, anosmia, epistaxis) with an equal sex distribution. Histologically, it shares morphologic features with other small round blue cells neoplasms and the differential diagnosis is not only based on morphologic cytology and architecture but also on inmunohistochemical stains.4 The optimal treatment has not been established due to the disease rarity but observational studies suggest that a combination of surgery and radiotherapy yields lower mortality and recurrence rates than using one modality alone5,6 (5 years survival rates of 65% for the combined treatment and below 50% with surgery or radiotherapy alone). Globally, recurrence disease occurs in almost half of the patients with a median time to recurrence of 7 years.7 Prognosis is also related to the initial mass extension with the best outcomes for tumors limited to the nasal fossa (Kadish Stage A)8 and higher recurrence and mortality rates for Kadish Stage B (extension to the paranasal sinus), Kadish Stage C (extension beyond the paranasal sinus and nasal cavity), and Kadish Stage D (lymph nodes or distant metastasis). Radiotherapy alone has been used in Kadish Stage A and in patients with irresectable neoplasms or who refused surgery as in our case.9 Expected results in Stage C are limited. Chemotherapy as part of a multimodality treatment is reserved for patients with advanced or metastatic disease10 with cisplatin-based regimens preferred at some institutions and is associated with few successful outcomes. Ectopic ACTH Cushing syndrome due to ONB is exceptional with 17 histologically confirmed cases found in the literature.3,11–20 The diagnosis of an ectopic ACTH syndrome requires the exclusion of the most prevalent ACTH-dependent Cushing from pituitary disease. For the distinction between the two entities, dynamic endocrine tests are recommended including suppressive tests (high-dose dexamethasone suppression tests) and stimulation tests (as corticotropin-releasing hormone [CRH] test or DDAVP). In this case, both tests incorrectly suggested an ACTH pituitary source highlighting the low specificity of these tests for the differential diagnosis of Cushing disease and ectopic ACTH syndrome.21,22 In some reported ectopic ACTH Cushing syndromes due to an ONB,12,16 plasma cortisol failed to suppress after high-dose dexamethasone test and did not rise after CRH test suggesting a true ectopic ACTH syndrome. Nevertheless, in other cases, where dynamic test was registered, a variety of responses have been observed. A publication of Kanno et al14 described a woman with non-suppressible hypercortisolism to dexamethasone but hyperresponsive to CRH leading to an inferior petrosal sinus sampling for ACTH whose result still falsely supported a pituitary disease. A hypothetical explanation in this case could be a cyclic Cushing syndrome with the dynamic tests done during an episode of low or absent ACTH neoplastic secretion so the responses could be similar to those expected with a normal hypothalamic-pituitary-adrenal axis. In the few cases reported in the literature, adrenalitic drugs (as ketoconazole and metyrapone) usually decreased cortisol but normocortisolism only was reached once local control tumor was achieved with surgery and/or radiotherapy.14,16-18 In one case,20 a bilateral adrenalectomy was necessary for hormonal improvement before a definitive tumor resection could be performed.\n\nConclusions\nEctopic ACTH production is a rare manifestation of ONB. We report another case of this uncommon tumor. This case also illustrates the difficulties related to the interpretation of dynamic endocrine tests in Cushing syndrome.\n\nFunding:The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nDeclaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nAuthor Contributions: CF wrote the first draft of the manuscript. AA and AA jointly developed the structure and arguments of the paper and made critical revisions and approved the final version of the manuscript. Both authors reviewed and approved the final manuscript.\n==== Refs\nReferences\n1 \nBroich G Pagliari A Ottaviani F. \nEsthesioneuroblastoma: a general review of the cases published since the discovery of the tumour in 1924 . Anticancer Res . 1996 ;17 :2683 –2706 .\n2 \nKunc M Gabrych A Czapiewski P Sworczak K. \nParaneoplastic syndromes in olfactory neuroblastoma . Contemp Oncol (Pozn) . 2015 ;19 :6 –16 .26199564 \n3 \nThompson LD. \nOlfactory neuroblastoma . Head Neck Pathol . 2009 ;3 :252 –259 .20596981 \n4 \nHirose T Scheithauer BW Lopes MB et al \nOlfactory neuroblastoma: an immunohistochemical, ultrastructural, and flow cytometric study . Cancer . 1995 ;76 :4 –19 .8630875 \n5 \nDulguerov P Allal AS Calcaterra TC. \nEsthesioneuroblastoma: a meta-analysis and review . Lancet Oncol . 2001 ;2 :683 –690 .11902539 \n6 \nOzsahin M Gruber G Olszyk O et al \nOutcome and prognostic factors in olfactory neuroblastoma: a rare cancer network study . Int J Radiat Oncol Biol Phys . 2010 ;78 :992 –997 .20231062 \n7 \nOw TJ Hanna EY Roberts DB et al \nOptimization of long-term outcomes for patients with esthesioneuroblastoma . Head Neck . 2014 ;36 :524 –530 .23780581 \n8 \nMorita A Ebersold MJ Olsen KD. \nEsthesioneuroblastoma: prognosis and management . Neurosurgery . 1993 ;32 :706 –714 .8492845 \n9 \nBenfari G Fusconi M Ciofalo A et al \nRadiotherapy alone for local tumour control in esthesioneuroblastoma . Acta Otorhinolaryngol Ital . 2008 ;28 :292 –297 .19205593 \n10 \nGupta S Husain N Sundar S. \nEsthesioneuroblastoma chemotherapy and radiotherapy for extensive disease: a case report . World J Surg Oncol . 2011 ;5 :118 .\n11 \nArnesen MA Scheithauer BW Freeman S. \nCushing’s syndrome secondary to olfactory neuroblastoma . Ultrastruct Pathol . 1994 ;18 :61 –68 .8191648 \n12 \nYu J Koch CA Patsalides A et al \nEctopic Cushing’s syndrome caused by an esthesioneuroblastoma . Endocr Pract . 2004 ;10 :119 –124 .15256328 \n13 \nFish S Harish S Tapino E. \nEctopic ACTH syndrome caused by olfactory neuroblastoma . Resid Staff Physician . 2005 ;51 :30 –33 .\n14 \nKanno K Morokuma Y Tateno T et al \nOlfactory neuroblastoma causing ectopic ACTH syndrome . Endocr J . 2005 ;52 :675 –681 .16410658 \n15 \nJosephs L Jones L Marenette L McKeever P. \nCushing’s syndrome: an unusual presentation of olfactory neuroblastoma . Skull Base . 2008 ;18 :73 –76 .18592016 \n16 \nKoo BK An JH Jeon KH et al \nTwo cases of ectopic adrenocorticotropic hormone syndrome with olfactory neuroblastoma and literature review . Endocr J . 2008 ;55 :469 –475 .18469486 \n17 \nHodish I Giordano TJ Starkman MN Schteingart DE. \nLocation of ectopic adrenocortical hormone-secreting tumors causing Cushing’s syndrome in the paranasal sinuses . Head Neck . 2009 ;31 :699 –706 .19031404 \n18 \nMintzer DM Zheng S Nagamine M Newman J Benito M. \nEsthesioneuroblastoma (Olfactory Neuroblastoma) with Ectopic ACTH Syndrome: a multidisciplinary case presentation from the Joan Karnell cancer center of Pennsylvania Hospital . Oncologist . 2010 ;15 :51 –58 .20053760 \n19 \nGalioto S Di Petrillo A Pastori M Arecchi A. \nMetastatic esthesioneuroblastoma secreting adrenocorticotropic hormone in pediatric patients . J Craniofac Surg . 2011 ;22 :1924 –1929 .21959469 \n20 \nHan JY Mirsadraei L Yeh MW et al \nBilateral adrenalectomy: lifesaving procedure in severe Cushing syndrome . Endocr Pract . 2012 ;18 : e85 –e90 .22441001 \n21 \nAron DC Raff H Findling JW. \nEffectiveness versus efficacy: the limited value in clinical practice of high dose dexamethasone suppression testing in the differential diagnosis of adrenocorticotropin-dependent Cushing’s syndrome . J Clin Endocrinol Metab . 1997 ;82 :1780 –1785 .9177382 \n22 \nPecori Giraldi F Invitti C Cavagnini F ; Study Group of the Italian Society of Endocrinology on the Pathophysiology of the Hypothalamic-Pituitary-Adrenal Axis . The corticotropin-releasing hormone test in the diagnosis of ACTH-dependent Cushing’s syndrome: a reappraisal . Clin Endocrinol (Oxf) . 2001 ;54 :601 –607 .11380490\n\n",
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"keywords": "Cushing syndrome; desmopressin stimulation test; dexamethasone suppression test; ectopic ACTH syndrome; olfactory neuroblastoma",
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"title": "Adrenocorticotropic Hormone-Dependent Cushing Syndrome Caused by an Olfactory Neuroblastoma.",
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"abstract": "Midchildhood acne has been attributed to a number of causes in the literature, including adrenocortical tumor, hyperandrogenemia due to hypothalamic dysfunction, and contact with greasy topical skin care products. There are only a few case reports of inhaled steroids causing acneiform eruptions, all of which occurred in adults and with symptoms suggesting that the acne resulted from systemic absorption. We present two cases of comedonal and inflammatory midchildhood acne temporally associated with the use of inhaled corticosteroids administered through face masks, implicating a causative relationship between topical steroid exposure and midchildhood acne that does not necessitate systemic absorption.",
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"abstract": "BACKGROUND\nChronic liver disease often leads to amenorrhea in women of childbearing age. There are several reports of successful pregnancy after liver transplantation (LTx) with cyclosporine A immunosuppression. Tacrolimus has been increasingly used in solid-organ transplantation, and the effect of the drug on pregnancy is still of interest to clinicians. This study updates our single-center experience.\n\n\nMETHODS\nAll pregnancies after LTx with tacrolimus immunosuppression were followed prospectively. Patients' clinical courses during pregnancy and labor along with gestational period and birth weight were catalogued. Changes in liver function, renal function, and immunosuppression also were recorded. The birth weight percentile was calculated on the basis of the gestational period using a standard chart.\n\n\nRESULTS\nThirty-seven mothers delivered 49 babies. Three mothers delivered three times, and six mothers delivered two times. Thirty-six mothers (97%) survived the pregnancy, and 36 allografts (97%) survived. The one death and graft loss was in a patient who demonstrated infra-aortic arterial graft, which clotted by the gravid uterus during labor. The patient developed a gangrenous liver and died before she could undergo retransplantation. The mean gestational period was 36.4+/-3.2 weeks, excluding two premature deliveries at 23 and 24 weeks gestation. Twenty-two babies (46.9%) were delivered by cesarean section, and the other babies were delivered vaginally. In addition to the two premature babies, one baby, who was born to a mother with Alagille syndrome, died from congenital birth defects. The rest of the newborns survived. The mean birth weight was 2,797+/-775 g, with 38 babies (78%) weighing more than 2,000 g. The mean birth weight percentile to gestational period was 54+/-23. Four babies (8.5%) had a birth weight percentile of less than 25, and 28 babies (59.6%) had a birth weight percentile greater than 50. Twelve patients demonstrated an increase in hepatic enzymes without jaundice during the pregnancy. All of them responded to augmentation of immunosuppression.\n\n\nCONCLUSIONS\nThe present report reconfirms the safety of tacrolimus during pregnancy after LTx. Preterm delivery and low birth weight seem to be a persistent problem in all solid-organ transplantation under any form of immunosuppression. However, toxemia of pregnancy and new onset of hypertension seem to be have a low occurrence with the use of tacrolimus.",
"affiliations": "Thomas E. Starzl Transplantation Institute, Division of Transplantation, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. ashok_jain@urmc.rochester.edu",
"authors": "Jain|Ashokkumar B|AB|;Reyes|J|J|;Marcos|Amadeo|A|;Mazariegos|G|G|;Eghtesad|Bijan|B|;Fontes|Paulo A|PA|;Cacciarelli|Thomas V|TV|;Marsh|J Wallis|JW|;de Vera|Michael E|ME|;Rafail|Ann|A|;Starzl|Thomas E|TE|;Fung|John J|JJ|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D005438:Fludrocortisone; D011241:Prednisone; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1097/01.TP.0000084823.89528.89",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "76(5)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000015:Abnormalities, Multiple; D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents; D001724:Birth Weight; D003922:Diabetes Mellitus, Type 1; D005260:Female; D005438:Fludrocortisone; D006085:Graft Survival; D006801:Humans; D006973:Hypertension; D007166:Immunosuppressive Agents; D007231:Infant, Newborn; D007668:Kidney; D008099:Liver; D008107:Liver Diseases; D016031:Liver Transplantation; D011225:Pre-Eclampsia; D011241:Prednisone; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011256:Pregnancy Outcome; D011254:Pregnancy in Diabetics; D011446:Prospective Studies; D015996:Survival Rate; D016559:Tacrolimus; D014184:Transplantation, Homologous",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "827-32",
"pmc": null,
"pmid": "14501862",
"pubdate": "2003-09-15",
"publication_types": "D016428:Journal Article",
"references": "8116032;7520105;11112018;7940780;7878749;7475777;8696542;9293865;9500638;9787947;9787957;10493490;7008285;5906365;12091650;11933431;11844873;7506460;7506459;2234717;2305462;6380049;1703354;7523946",
"title": "Pregnancy after liver transplantation with tacrolimus immunosuppression: a single center's experience update at 13 years.",
"title_normalized": "pregnancy after liver transplantation with tacrolimus immunosuppression a single center s experience update at 13 years"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP015093",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional"... |
{
"abstract": "Obatoclax is a small molecule mimetic of the BH3 domain of BCL-2 family proteins. This phase 1 study combining obatoclax with FR was undertaken in chronic lymphocytic leukemia (CLL) patients relapsed after at least one prior therapy. Obatoclax was given as a 3-h infusion on days 1 and 3 and escalated through three dose levels, with standard dose FR days 1-5. Thirteen patients were enrolled, with a median of two prior therapies. One dose-limiting toxicity (DLT) of a 2-week treatment delay for persistent grade 2-3 neutropenia was observed at the highest obatoclax dose (20 mg/m2), but no maximum tolerated dose (MTD) was reached. The overall response rate (ORR) was 85%, with 15% complete responses (CRs) by NCI-96 criteria and 54% by IWCLL 2008 criteria. Median time to progression was 20 months. It is concluded that obatoclax can be safely administered to relapsed CLL patients in combination with FR and shows promising clinical activity.",
"affiliations": "a Department of Medical Oncology , Boston , MA , USA.;a Department of Medical Oncology , Boston , MA , USA.;a Department of Medical Oncology , Boston , MA , USA.;b Department of Biostatistics and Computational Biology , Dana-Farber Cancer Institute , Boston , MA , USA.;d Investigational Drug Branch, National Cancer Institute, National Institutes of Health , Bethesda , MD , USA.;a Department of Medical Oncology , Boston , MA , USA.;a Department of Medical Oncology , Boston , MA , USA.;a Department of Medical Oncology , Boston , MA , USA.;a Department of Medical Oncology , Boston , MA , USA.;b Department of Biostatistics and Computational Biology , Dana-Farber Cancer Institute , Boston , MA , USA.;a Department of Medical Oncology , Boston , MA , USA.",
"authors": "Brown|Jennifer R|JR|;Tesar|Bethany|B|;Yu|Lijian|L|;Werner|Lillian|L|;Takebe|Naoko|N|;Mikler|Evgeny|E|;Reynolds|Hazel M|HM|;Thompson|Christina|C|;Fisher|David C|DC|;Neuberg|Donna|D|;Freedman|A S|AS|",
"chemical_list": "D015415:Biomarkers; D007211:Indoles; D011758:Pyrroles; D000069283:Rituximab; D014740:Vidarabine; C024352:fludarabine; C520962:obatoclax",
"country": "United States",
"delete": false,
"doi": "10.3109/10428194.2015.1048441",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "56(12)",
"journal": "Leukemia & lymphoma",
"keywords": "BCL-2; Chronic lymphocytic leukemia; fludarabine; obatoclax; phase I–III trials; rituximab",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D002869:Chromosome Aberrations; D003131:Combined Modality Therapy; D018450:Disease Progression; D005260:Female; D006801:Humans; D007211:Indoles; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011758:Pyrroles; D012008:Recurrence; D019233:Retreatment; D000069283:Rituximab; D016896:Treatment Outcome; D014740:Vidarabine",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "3336-42",
"pmc": null,
"pmid": "25971907",
"pubdate": "2015",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Obatoclax in combination with fludarabine and rituximab is well-tolerated and shows promising clinical activity in relapsed chronic lymphocytic leukemia.",
"title_normalized": "obatoclax in combination with fludarabine and rituximab is well tolerated and shows promising clinical activity in relapsed chronic lymphocytic leukemia"
} | [
{
"companynumb": "US-ROCHE-1077360",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": null,
... |
{
"abstract": "This case report presents the unusual complication of bilateral temporomandibular joint dislocation following bronchoscopy, highlighting the importance of recognising it as a differential diagnosis in patients having jaw symptoms. The delayed diagnosis in this case resulted in multiple unsuccessful reduction attempts under sedation, which added to the distress of the patient. Notably, the procedure yielded a rare diagnosis for the patient that intrinsically changed the management of her breast cancer.",
"affiliations": "Respiratory, Flinders Medical Centre, Bedford Park, South Australia, Australia li.anna232@googlemail.com.;Respiratory, Flinders Medical Centre, Bedford Park, South Australia, Australia.;Respiratory, Flinders Medical Centre, Bedford Park, South Australia, Australia.",
"authors": "Li|Anna|A|;Mohammadi|Fadak|F|;Crocker|Helen|H|",
"chemical_list": "D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-240146",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(2)",
"journal": "BMJ case reports",
"keywords": "breast cancer; drugs: respiratory system; respiratory system; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001999:Bronchoscopy; D005260:Female; D006801:Humans; D004204:Joint Dislocations; D017239:Paclitaxel; D011014:Pneumonia; D013704:Temporomandibular Joint; D013705:Temporomandibular Joint Disorders",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33619143",
"pubdate": "2021-02-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bilateral temporomandibular joint dislocations post-bronchoscopy in a case of paclitaxel-induced pneumonitis.",
"title_normalized": "bilateral temporomandibular joint dislocations post bronchoscopy in a case of paclitaxel induced pneumonitis"
} | [
{
"companynumb": "AU-TEVA-2021-AU-1895597",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LIDOCAINE HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "Digoxin toxicity occurs more commonly in aged than younger individuals. Cardioactive drugs such as quinidine effect digoxin pharmacokinetics so as to increase the potential for digoxin toxicity. The calcium-channel antagonists have become extensively used for cardiac disorders and are often co-administered with digoxin. Despite documented calcium-channel antagonist interactions with digoxin, clinically significant digoxin toxicity associated with their concurrent use is apparently unusual. Two elderly patients receiving digoxin and verapamil simultaneously are presented to demonstrate the clinical importance and potential danger of the concomitant use of these drugs.",
"affiliations": null,
"authors": "Gordon|M|M|;Goldenberg|L M|LM|",
"chemical_list": "D004077:Digoxin; D014700:Verapamil; D011802:Quinidine",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1532-5415.1986.tb04908.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-8614",
"issue": "34(9)",
"journal": "Journal of the American Geriatrics Society",
"keywords": null,
"medline_ta": "J Am Geriatr Soc",
"mesh_terms": "D000368:Aged; D004077:Digoxin; D004347:Drug Interactions; D005260:Female; D006331:Heart Diseases; D006801:Humans; D007700:Kinetics; D011802:Quinidine; D014700:Verapamil",
"nlm_unique_id": "7503062",
"other_id": null,
"pages": "659-62",
"pmc": null,
"pmid": "3734315",
"pubdate": "1986-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clinical digoxin toxicity in the aged in association with co-administered verapamil. A report of two cases and review of the literature.",
"title_normalized": "clinical digoxin toxicity in the aged in association with co administered verapamil a report of two cases and review of the literature"
} | [
{
"companynumb": "CA-RECRO GAINESVILLE LLC-REPH-2019-000137",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugaddition... |
{
"abstract": "BACKGROUND\nDyskeratosis congenita (DC) is characterized by the clinical triad of reticular skin pigmentation, oral leukoplakia, and nail dystrophy associated with bone marrow failure (BMF) and an high risk to develop cancer and pulmonary complications. The only curative treatment for patients with DC and BMF is stem cell transplantation. Due to the rarity of the disease, the best transplant procedure is not yet known. The use of myeloablative procedures has been associated with high mortality. In the last 2 decades, encouraging results have been obtained with nonmyeloablative procedures. Heavily transfused patients have an additional risk of graft failure.\n\n\nMETHODS\nHerein we have reported a 4-year-old boy with DC and severe BMF at the time of transplantation, who had been transfused with nonleucodepleted blood products for 18 months. He experienced a favorable outcome after nonmyeloablative transplant conditioning using low-dose cyclophosphamide (40 mg/kg), fludarabine (180 mg/kg), and rabbit antithymocyte globulin (10 mg/kg). The patient received a peripheral stem cell graft containing 7.52 × 10(6) CD34/kg from an HLA identical sister. Graft versus host disease (GVHD) prophylaxis consisted of a short-term combination of cyclosporine and methotrexate.\n\n\nRESULTS\nWe observed rapid neutrophil engraftment on day +21 and for platelets on day +40. No early or late complications were recorded during 15 months follow-up. The patient developed only grade I skin GVHD. On day +30, chimerism assay showed 100% donor cells.\n\n\nCONCLUSIONS\nLong-term follow-up is essential to establish the efficacy and safety of this procedure.",
"affiliations": "Fundeni Clinical Institute, Bucharest, Romania; Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. Electronic address: ancacolita@yahoo.com.",
"authors": "Coliţă|A|A|;Tanase|A|A|;Varady|Z|Z|;Coliţă|A D|AD|;Arion|C|C|",
"chemical_list": "D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "45(7)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D064591:Allografts; D000971:Antineoplastic Combined Chemotherapy Protocols; D002675:Child, Preschool; D003520:Cyclophosphamide; D004305:Dose-Response Relationship, Drug; D006086:Graft vs Host Disease; D006801:Humans; D008297:Male; D033581:Stem Cell Transplantation; D016019:Survival Analysis; D016896:Treatment Outcome; D014740:Vidarabine",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2849-53",
"pmc": null,
"pmid": "24034063",
"pubdate": "2013-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Fludarabine, low-dose cyclophosphamide and rabbit antithymocyte globulin allowed stable engraftment after allogeneic peripheral blood stem cell transplantation for poly-transfused dyskeratosis congenita patient: case report.",
"title_normalized": "fludarabine low dose cyclophosphamide and rabbit antithymocyte globulin allowed stable engraftment after allogeneic peripheral blood stem cell transplantation for poly transfused dyskeratosis congenita patient case report"
} | [
{
"companynumb": "US-ROXANE LABORATORIES, INC.-2015-RO-01405RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
... |
{
"abstract": "BACKGROUND\nNocardia species are not commonly referred as primary infectious entities but rather as opportunistic pathogens. Infectious cases of Nocardia spp. in immunocompetent individuals are rare.\nAn immunocompetent 58-year-old patient presented with recurrent headaches.\n\n\nMETHODS\nA brain abscess was found and surgically drained. Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry and heat shock protein 65/16S-23S rRNA gene intergenic spacer genotyping from the sample revealed the etiological agent as Nocardia beijingensis.\n\n\nMETHODS\nMeropenem/amikacin/Trimethoprim-sulfamethoxazole were administered.\n\n\nRESULTS\nThe infection persisted leading to the patient's death.\n\n\nCONCLUSIONS\nHere we present the first case of N. beijingensis infection of the central nervous system in an immunocompetent patient from Latin America. Further inquiry is needed to establish whether this species is more virulent than other Nocardia isolates.",
"affiliations": "Hospital Universitario Mayor Méderi, Universidad del Rosario.;Hospital Universitario Mayor Méderi, Universidad del Rosario.;Molecular Biology and Immunology Department, Fundación Instituto de Inmunología de Colombia (FIDIC).;Hospital Universitario Mayor Méderi, Universidad del Rosario.;Hospital Universitario Mayor Méderi, Universidad del Rosario.;Clinical lab, Compensar.;Molecular Biology and Immunology Department, Fundación Instituto de Inmunología de Colombia (FIDIC).",
"authors": "Solano-Varela|David M|DM|;Barrios-Vidales|Edgar M|EM|;Plaza|David F|DF|;Riveros|William M|WM|;Guzmán|Julián|J|;Chica|Claudia E|CE|;Patarroyo|Manuel A|MA|",
"chemical_list": "D000900:Anti-Bacterial Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D000077731:Meropenem",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000014879",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30882696MD-D-18-0833710.1097/MD.0000000000014879148794900Research ArticleClinical Case ReportImmunocompetent patient with a brain abscess caused by Nocardia beijingensis in Latin America A case reportSolano-Varela David M. MDaBarrios-Vidales Edgar M. MDaPlaza David F. PhDbRiveros William M. MDaGuzmán Julián MDaChica Claudia E. MDcPatarroyo Manuel A. MD, DrScbd∗NA. a Hospital Universitario Mayor Méderi, Universidad del Rosariob Molecular Biology and Immunology Department, Fundación Instituto de Inmunología de Colombia (FIDIC)c Clinical lab, Compensard Basic Sciences Department, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia.∗ Correspondence: Manuel A. Patarroyo, Molecular Biology and Immunology Department, Fundación Instituto de Inmunología de Colombia (FIDIC), Carrera 50 # 26–20, Bogotá, Colombia (e-mail: mapatarr.fidic@gmail.com).3 2019 15 3 2019 98 11 e148798 11 2018 8 2 2019 20 2 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Supplemental Digital Content is available in the text\n\nAbstract\nRationale:\nNocardia species are not commonly referred as primary infectious entities but rather as opportunistic pathogens. Infectious cases of Nocardia spp. in immunocompetent individuals are rare.\n\nPatient concerns:\nAn immunocompetent 58-year-old patient presented with recurrent headaches.\n\nDiagnosis:\nA brain abscess was found and surgically drained. Matrix-assisted laser desorption ionization–time-of-flight mass spectrometry and heat shock protein 65/16S-23S rRNA gene intergenic spacer genotyping from the sample revealed the etiological agent as Nocardia beijingensis.\n\nInterventions:\nMeropenem/amikacin/Trimethoprim-sulfamethoxazole were administered.\n\nOutcomes:\nThe infection persisted leading to the patient's death.\n\nLessons:\nHere we present the first case of N. beijingensis infection of the central nervous system in an immunocompetent patient from Latin America. Further inquiry is needed to establish whether this species is more virulent than other Nocardia isolates.\n\nKeywords\nabscesscase reportcentral nervous systemimmunocompetenceLatin AmericaNocardia beijingensisOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nNocardia spp. infection is uncommon. It involves the lungs and spreads to the central nervous system (CNS) in rare cases,[1,2] affecting immunocompromised individuals primarily.[2,3] Nevertheless, one-third of the patients infected with Nocardia are immunocompetent.[4] It is uncommon to observe Nocardia beijingensis spreading into the CNS of immunocompetent individuals since this is a species that seldom infects humans. We report for the first time in Latin America, a patient with no signs of immunosenescence, HIV co-infection, cancer chemotherapy, or long-term use of immunomodulatory therapy, presenting a brain abscess caused by N. beijingensis as shown by matrix-assisted laser desorption ionization–time-of-flight mass spectrometry (VITEK MS) and heat shock protein 65 (hsp65) and 16S-23S rRNA gene intergenic spacer (ITS) genotyping. Mederi is a teaching hospital and, upon admission, all patients sign an informed consent authorizing the anonymous use of clinical and paraclinical data. The ethics committee at Hospital Universitario Mayor Méderi approved this study (Reference # DVO005 587-CV1021).\n\n2 Case report\nA 58-year-old male, with no history of concomitant disease, reported a 6-month headache with progressive right hemiparesis (more visible in the arm). Hyperreflexia and positive right Babinski reflex were also observed. A computed tomography (CT) scan showed a left thalamic lesion with ring-enhancement pattern (Fig. 1). Blood test showed leukocytosis (13,000 cell/mL) with negative detection of anti-HIV antibodies. VITEK MS analysis suggested that the infection was caused by N. beijingensis. This initial diagnosis led us to administer triple antibiotic therapy (1 g meropenem and 15 mg/kg trimethoprim/sulfamethoxazole/amikacin every 8 hours). The ventriculostomy system was shown to be closed; nevertheless, extensive swelling was still observed leading to the insertion of an Ommaya reservoir (Fig. 1).\n\nFigure 1 Pre and postsurgical CT scans. Presurgical intraparenchymatous lesion with inner septum, involving thalamus, mesencephalon, and left caudate nucleus. Lesion shows the adjacent edema in axial (A) and coronal (B) views. Postsurgical changes in the left frontal craniectomy showing the ventricular catheter in distal frontal horn and Ommaya reservoir, with intraparenchymatous infiltrative lesion in left thalamus (34 × 35 × 34 mm), ring-enhancement associated with multiple septum and cystic-necrotic content. Axial (C and D) and sagittal (E) views are shown. CT = computed tomography.\n\nBlood and cerebrospinal fluid cultures were negative. Thoracoabdominal CT scan did not show any mass or solid organ lesion. Transthoracic and transesophageal echocardiograms ruled out endocarditis. The patient showed clinical improvement in the following week but then he had a seizure episode with anisocoria. An emergency CT scan was taken and orotracheal intubation was performed.\n\nThe brain CT scan showed severe swelling and an increase in abscess size with supratentorial ventriculomegaly and cisternal obstruction. An emergency Ommaya puncture was performed, and a turbid-yellow liquid was retrieved. The patient required another surgical intervention where the abscess was drained, the capsule was partially resected, and a contralateral ventriculostomy system was attached. In the intensive care unit (ICU), the individual developed a systemic inflammatory response syndrome (SIRS) due to Pseudomonas aeruginosa and Klebsiella pneumoniae tracheitis that was managed with 500 mg intravenous vancomycin every 12 hours; however, fever and tachycardia persisted. Chest X-ray showed multilobed opacities and a blood culture revealed the presence of gram-positive bacilli. A septic shock with pulmonary foci was suspected so the patient was maintained under a multiple antibiotic regimen. Two days later, the patient required vasoactive support and anticonvulsive management for myoclonic movements. Two additional CT scans were performed during this period without new development at the abscess or hydrocephalus. Finally, the individual showed SIRS suggestive of multisystem infection, with significant increase of blood ureic nitrogen and creatinine, anuria, and an increase in ventilation requirements leading to his death after 14 days in the ICU.\n\nTo unambiguously identify the exact Nocardia species that caused the decease of the patient, the intraoperative sample collected was grown on 7H10 medium supplemented with oleic/albumin/dextrose/catalase (OADC). Two individual colonies (see Nc1 and Nc2 in Figure, Supplemental Digital Content 1, which illustrates the loci that were amplified and sequenced) were inoculated into 7H9-OADC broth and grown for 96 hours at 37°C under constant shaking. Cells were harvested by centrifugation at 3500 × g for 10 minutes and suspended in STET buffer (10 mM Tris-HCl, 0.1 M NaCl, 1 mM ethylenediaminetetraacetic acid, 5% [v/v] Triton X100, pH 8.0).[5] Bacteria were lysed at 100°C for 30 minutes and spinned-down at 10,000 × g for 10 minutes to collect the soluble fraction. In a separate microcentrifuge tube, DNA was precipitated from the soluble fraction with 95% ethanol at −20°C for 18 hours, resuspended in double-distilled water and quantified with a Thermo Scientific Multiskan GO (Vantaa, Finland). Degenerate oligos (hsp65F 5’-ACCAACGAYGGTGTBTCCAT-3’, hsp65R 5’-CTTGTCGAASCGCATRCCCT-3’) were used to amplify a 441 bp fragment from the hsp65 locus[6] with GoTaq Long PCR Master Mix (Promega, Madison, WI) following the manufacturer instructions. In brief, an initial 2 minutes denaturation step at 95°C was followed by 35 cycles of 95°C denaturation for 30 seconds, 55.4°C annealing for 30 seconds, and 72°C extension for 1 minute. A final 10 minutes extension step at 72°C was also programmed. The resulting product (see Figure, Supplemental Digital Content 1, which shows the amplification product for hsp65 as observed on an agarose gel) was cleaned-up using the Wizard SV Gel and PCR clean-up system (Promega, Madison, WI).\n\nIn addition, a 651 bp fragment corresponding to the ITS region[7] was amplified using the following oligos: 16Sf 5’-GAAGTTGGAGTCGCTAGTAATCGCAGATCAGC-3’ and 23Sr 5’-GACAGCTCCCCGAGGCTTATCGCA-3’. The PCR settings used for the hsp65 fragment were also used for the ITS region with a minor modification: 69.4°C as annealing temperature. A product of the expected size (see Figure, Supplemental Digital Content 1, which illustrates the loci that were amplified and sequenced) was purified from a 1% agarose gel with the Wizard SV Gel and PCR clean-up system (Promega). Finally, purified PCR products were sequenced by the Sanger method, trace files were manually curated with MEGA-X[8] and the resulting sequences were searched by blast against the NCBI nucleotide collection (nr) to identify the best hit corresponding to the isolate's genotype. Sequencing of these 2 loci revealed the identity of the etiologic agent as N. beijingensis (see Figure, Supplemental Digital Content 2, showing the sequences obtained).\n\n3 Discussion\nNocardia spp., are weak gram-positive, branching filamentous bacilli of the order Actinomycetales that frequently infect immunocompromised individuals.[1,3,4]Nocardia most frequently affects the lungs and the CNS is rarely involved,[1,4,9–12] mainly in the form of an abscess; however, it can also occur as meningitis, ventriculitis, or spinal cord infections.[13,14] The most common features of the CNS abscesses are supratentorial individual lesions leading to 57% mortality in immunocompromised individuals and 66% for patients with multiple lesions.[13,15]\n\nWorldwide, many Nocardia species cause abscesses in the CNS, being members of the Nocardia asteroides complex the most common causing agents.[12,15] Less common are the cases where N. beijingensis is the etiologic agent.[12] The first case of N. beijingensis infection in an immunocompetent patient from the United States was registered in 2014[4] and the case we present here corresponds to the first reported for Latin America, a region with twice the population of the United States and a fragile public health system, thus facilitating the unnoticed spread of infections like this.\n\nAbscesses caused by Nocardia develop a vascularized wall made of astrocytes and glial roots that can be seen in a CT scan or magnetic resonance imaging as a single or double ring enhancement depending of the capsular phase.[16] The late capsular phase shown in this case report corresponds to a multiloculated abscess.\n\nN. beijingensis was first isolated from a soil sample in China in 2001.[17] Since then, some clinical cases have been reported, targeting the lungs and spreading to the CNS in rare cases. Diagnosis of this condition requires a precise assessment of risk factors and epidemiology, as well as the isolation and culture of bacteria. For CNS episodes, the most common method to study the lesion is the less invasive stereotactical approach.[9,15,18]Nocardia genotyping involves the amplification and sequencing of multiple regions in the loci encoding rRNAs and the hsp65. We typified the isolate molecularly using a combined strategy of multi-loci sequencing and mass spectrometry analysis.\n\nMicroorganism isolation is crucial to promptly start the treatment with an effective antibiotic combination. Most Nocardia species are susceptible to trimethoprim/sulfamethoxazole,[4,19] that is the most commonly used therapy and our therapeutic choice for this patient.\n\nHere, we report the first case in Latin America of CNS infection with N. beijingensis causing a brain abscess in an immunocompetent patient. Further research is needed to establish whether this species is more virulent than other Nocardia isolates due to the absence of immunocompromise in the patient. Finally, we hope this case can provide a reference for incoming patients and their clinical management.\n\nAuthor contributions\nConceptualization: David M. Solano-Varela, Edgar M. Barrios-Vidales, David F. Plaza, Manuel A. Patarroyo.\n\nData curation: David M. Solano-Varela, Edgar M. Barrios-Vidales, David F. Plaza, Manuel A. Patarroyo.\n\nFormal analysis: David M. Solano-Varela, Edgar M. Barrios-Vidales, David F. Plaza, Manuel A. Patarroyo.\n\nFunding acquisition: Manuel A. Patarroyo.\n\nInvestigation: David M. Solano-Varela, Edgar M. Barrios-Vidales, David F. Plaza, William M. Riveros, Julián Guzmán, Claudia E. Chica, Manuel A. Patarroyo.\n\nMethodology: David M. Solano-Varela, Edgar M. Barrios-Vidales, David F. Plaza, William M. Riveros, Julián Guzmán, Claudia E. Chica, Manuel A. Patarroyo.\n\nProject administration: Manuel A. Patarroyo.\n\nResources: Manuel A. Patarroyo.\n\nSupervision: Manuel A. Patarroyo.\n\nWriting – original draft: David M. Solano-Varela, Edgar M. Barrios-Vidales, David F. Plaza, William M. Riveros, Julián Guzmán, Claudia E. Chica, Manuel A. Patarroyo.\n\nWriting – review & editing: David M. Solano-Varela, Edgar M. Barrios-Vidales, David F. Plaza, William M. Riveros, Julián Guzmán, Claudia E. Chica, Manuel A. Patarroyo.\n\nManuel A. Patarroyo orcid: 0000-0002-4751-2500.\n\nManuel Alfonso Patarroyo orcid: 0000-0002-4751-2500.\n\nSupplementary Material\nSupplemental Digital Content\n Abbreviations: CNS = central nervous system, CT = computed tomography, hsp65 = heat shock protein 65, ICU = intensive care unit, ITS = 16S-23S rRNA gene intergenic spacer, OADC = oleic/albumin/dextrose/catalase, SIRS = systemic inflammatory response syndrome, VITEK MS = matrix-assisted laser desorption ionization–time-of-flight mass spectrometry.\n\nDavid M. Solano-Varela, Edgar M. Barrios-Vidales, and David F. Plaza contributed equally to this work.\n\nThe authors have no conflicts of interest to disclose.\n\nSupplemental Digital Content is available for this article.\n==== Refs\nReferences\n[1] Anagnostou T Arvanitis M Kourkoumpetis TK \nNocardiosis of the central nervous system: experience from a general hospital and review of 84 cases from the literature . Medicine (Baltimore) \n2014 ;93 :19–32 .24378740 \n[2] Chow FC Marson A Liu C \nSuccessful medical management of a Nocardia farcinica multiloculated pontine abscess . BMJ Case Rep \n2013 ;2013 .\n[3] Phoompoung P Koomanachai P \nNocardia beijingensis brain abscess in an HIV infected patient: a first case report and literature review . Southeast Asian J Trop Med Public Health \n2016 ;47 :1020–5 .29620809 \n[4] Crozier JA Andhavarapu S Brumble LM \nFirst report of Nocardia beijingensis infection in an immunocompetent host in the United States . J Clin Microbiol \n2014 ;52 :2730–2 .24829230 \n[5] Bafghi MF Eshraghi SS Heidarieh P \nDNA extraction from Nocardia species for special genes analysis using PCR . N Am J Med Sci \n2014 ;6 :231–3 .24926450 \n[6] Schlaberg R Huard RC Della-Latta P \nNocardia cyriacigeorgica, an emerging pathogen in the United States . J Clin Microbiol \n2008 ;46 :265–73 .18003809 \n[7] Wang X Xiao M Kong F \nReverse line blot hybridization and DNA sequencing studies of the 16S-23S rRNA gene intergenic spacer regions of five emerging pathogenic Nocardia species . J Med Microbiol \n2010 ;59 (Pt 5) :548–55 .20110385 \n[8] Kumar S Stecher G Li M \nMEGA X: molecular evolutionary genetics analysis across computing platforms . Mol Biol Evol \n2018 ;35 :1547–9 .29722887 \n[9] Barnaud G Deschamps C Manceron V \nBrain abscess caused by Nocardia cyriacigeorgica in a patient with human immunodeficiency virus infection . J Clin Microbiol \n2005 ;43 :4895–7 .16145170 \n[10] Kageyama A Poonwan N Yazawa K \nNocardia beijingensis, is a pathogenic bacterium to humans: the first infectious cases in Thailand and Japan . Mycopathologia \n2004 ;157 :155–61 .15119850 \n[11] Kim S Lee KL Lee DM \nNocardia brain abscess in an immunocompetent patient . Infect Chemother \n2014 ;46 :45–9 .24693470 \n[12] Kumar VA Augustine D Panikar D \nNocardia farcinica brain abscess: epidemiology, pathophysiology, and literature review . Surg Infect (Larchmt) \n2014 ;15 :640–6 .25126828 \n[13] Uneda A Suzuki K Okubo S \nBrain abscess caused by Nocardia asiatica . Surg Neurol Int \n2016 ;7 :74.27563485 \n[14] Yamamoto F Yamashita S Kawano H \nMeningitis and ventriculitis due to Nocardia araoensis infection . Intern Med \n2017 ;56 :853–9 .28381755 \n[15] Keenan JG Mohapatra S \nNocardia beijingensis brain abscesses in an HIV-infected individual . IDCases \n2017 ;9 :65–9 .28706854 \n[16] Moorthy RK Rajshekhar V \nManagement of brain abscess: an overview . Neurosurg Focus \n2008 ;24 :E3.\n[17] Wang L Zhang Y Lu Z \nNocardia beijingensis sp. nov., a novel isolate from soil . Int J Syst Evol Microbiol \n2001 ;51 (Pt 5) :1783–8 .11594609 \n[18] Piau C Kerjouan M Le Mouel M \nFirst case of disseminated infection with Nocardia cerradoensis in a human . J Clin Microbiol \n2015 ;53 :1034–7 .25568436 \n[19] Wilson JW \nNocardiosis: updates and clinical overview . Mayo Clin Proc \n2012 ;87 :403–7 .22469352\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0025-7974",
"issue": "98(11)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001922:Brain Abscess; D006801:Humans; D007843:Latin America; D008297:Male; D000077731:Meropenem; D008875:Middle Aged; D009615:Nocardia; D009617:Nocardia Infections; D014057:Tomography, X-Ray Computed; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e14879",
"pmc": null,
"pmid": "30882696",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Immunocompetent patient with a brain abscess caused by Nocardia beijingensis in Latin America: A case report.",
"title_normalized": "immunocompetent patient with a brain abscess caused by nocardia beijingensis in latin america a case report"
} | [
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"companynumb": "CO-PFIZER INC-2019126893",
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"abstract": "The authors investigated whether computerized parameters quantifying ventricular repolarization delay, heterogeneity, and instability characterize individuals who developed drug-induced Torsades de Pointes. Assessing an individual's propensity to Torsades de Pointes when exposed to a QT-prolonging drug is challenging because baseline QT prolongation has limited predictive value. Five-minute digital 12-lead electrocardiograms were acquired at baseline and after a sotalol challenge in 16 patients who had a history of Torsades de Pointes in the context of a QT-prolonging drug and 17 patients who did not have such history. Computerized measurements of QTc, T peak to T end intervals (TpTe), TpTe/QTc, and QT variability were implemented, and novel quantifiers of ventricular repolarization heterogeneity from the early (ERD) and late (LRD) part of the T wave were investigated. Compared with electrocardiograms of patients without a history of Torsades de Pointes, the baseline electrocardiograms of patients with a history of Torsades de Pointes had a longer QTc and an increased repolarization heterogeneity of the early part of the T wave (ERD30%: 44 +/- 13 vs 35 +/- 8 ms, P = .02). On sotalol, the electrocardiograms from individuals with Torsades de Pointes revealed a delay of the terminal part of the T wave that was not present in patients without Torsades de Pointes (TpTe: 27 +/- 40 vs -2 +/- 21 ms, P = .02; LRD70%: 20 +/- 29 vs 2 +/- 4 ms, P = .04). Results suggest that the electrocardiogram abnormalities characterizing patients with a history of Torsades de Pointes are (1) an increased repolarization heterogeneity at baseline and (2) a sotalol-induced prolongation of the terminal part of the T wave.",
"affiliations": "Heart Research Follow-Up Program, Cardiology Department, University of Rochester Medical Center, Rochester, NY 14642, USA. jean-philippe.couderc@heart.rochester.edu",
"authors": "Couderc|Jean-Philippe|JP|;Kaab|Stefan|S|;Hinterseer|Martin|M|;McNitt|Scott|S|;Xia|Xiaojuan|X|;Fossa|Anthony|A|;Beckmann|Britt M|BM|;Polonsky|Slava|S|;Zareba|Wojciech|W|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D013015:Sotalol",
"country": "England",
"delete": false,
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"issn_linking": "0091-2700",
"issue": "49(1)",
"journal": "Journal of clinical pharmacology",
"keywords": null,
"medline_ta": "J Clin Pharmacol",
"mesh_terms": "D000889:Anti-Arrhythmia Agents; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013015:Sotalol; D016171:Torsades de Pointes; D018754:Ventricular Dysfunction",
"nlm_unique_id": "0366372",
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"pages": "6-16",
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"pmid": "18957528",
"pubdate": "2009-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Baseline values and sotalol-induced changes of ventricular repolarization duration, heterogeneity, and instability in patients with a history of drug-induced torsades de pointes.",
"title_normalized": "baseline values and sotalol induced changes of ventricular repolarization duration heterogeneity and instability in patients with a history of drug induced torsades de pointes"
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"abstract": "Evaluation of long-term tolerance to antiretroviral exposure during pregnancy is required. An increased risk of cancer has been suggested in children exposed in utero to didanosine.\n\n\n\nUpdated evaluation of cancer incidence in uninfected children exposed to nucleos(t)ide reverse transcriptase inhibitors (NRTIs) in the French perinatal study of children born to HIV+ mothers, by cross-checking with the National Cancer Registry. Associations between cancer risk and exposure to NRTIs were evaluated by univariate survival analysis and Cox proportional hazard models. Standardized incidence ratios (SIR) were used for comparison with the general population.\n\n\n\nA total of 21 cancers were identified in 15 163 children (median age: 9.9 years [interquartile range (IQR): 5.8-14.2]) exposed to at least one NRTI in utero, between 1990 and 2014. Five children were exposed to zidovudine monotherapy, and 16 to various combinations, seven including didanosine. Didanosine accounted for only 10% of prescriptions but was associated with one-third of cancers. In a multivariate analysis, didanosine exposure was significantly associated with higher risk [hazard ratio = 3.0 (0.9-9.8)]. The risk was specifically linked with first-trimester exposure [hazard ratio = 5.5 (2.1-14.4)]. Overall, the total number of cases was not significantly different from that expected for the general population [SIR = 0.8 (0.47-1.24)], but was twice that expected after didanosine exposure [SIR = 2.5 (1.01-5.19)].\n\n\n\nThere are strong arguments to suggest that didanosine displays transplacental oncogenicity. Although not extrapolable to other NRTIs, they stress the need for comprehensive evaluation of the transplacental genotoxicity of this antiretroviral class.",
"affiliations": "aEpidemiology and Population HealthCenter, Institut National de la Santé et de la Recherche Médicale (INSERM), Le Kremlin-Bicêtre bEpidemiology and Biostatistics, INSERM UMR1153, Sorbonne Paris Cité Research Center, Epidemiology of Childhood and Adolescent Cancers Team (EPICEA), Université Paris Descartes cFrench National Registry of Childhood Cancers, Villejuif dEast Center of Pathology and Neuropathology, Hospices Civils de Lyon, Bron eRadiology Unit, Pediatric Department, Hôpital Necker-Enfants Malades, AP-HP, Institut IMAGINE and Faculté Paris Descartes fPediatric Oncology Unit Centre Hospitalier Universitaire, Saint-Etienne gInfectious Diseases Department, Centre Hospitalier Universitaire, Nantes hPediatric Oncology Unit, Hôpital Universitaire Hautepierre, Strasbourg iInfectious Diseases Department, Hôpital Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris (AP-HP) jPediatric Department, Hôpital Trousseau, AP-HP kPediatric Department, Hôpital Robert Debré, AP-HP and Université Paris Diderot, Sorbonne Paris-Cité, Paris lGynecology and Obstetrics Department, Hôpital Louis Mourier, Hôpitaux Universitaires Paris Nord Val de Seine, AP-HP, Colombes mHôpital Bicêtre, AP-HP and Université Paris Sud, Le Kremlin-Bicêtre nImmunology Hematology Rhumatology Unit, Pediatric Department, Hôpital Necker-Enfants Malades AP-HP and Université Paris Descartes, Paris, France. *Members are listed in the Acknowledgements.",
"authors": "Hleyhel|Mira|M|;Goujon|Stéphanie|S|;Delteil|Clémence|C|;Vasiljevic|Alexandre|A|;Luzi|Stéphanie|S|;Stephan|Jean-Louis|JL|;Reliquet|Véronique|V|;Jannier|Sarah|S|;Tubiana|Roland|R|;Dollfus|Catherine|C|;Faye|Albert|A|;Mandelbrot|Laurent|L|;Clavel|Jacqueline|J|;Warszawski|Josiane|J|;Blanche|Stéphane|S|;|||",
"chemical_list": "D019380:Anti-HIV Agents; D016049:Didanosine",
"country": "England",
"delete": false,
"doi": "10.1097/QAD.0000000000001051",
"fulltext": null,
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"issn_linking": "0269-9370",
"issue": "30(8)",
"journal": "AIDS (London, England)",
"keywords": null,
"medline_ta": "AIDS",
"mesh_terms": "D000293:Adolescent; D019380:Anti-HIV Agents; D002648:Child; D002675:Child, Preschool; D016049:Didanosine; D005260:Female; D005602:France; D015658:HIV Infections; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D008431:Maternal-Fetal Exchange; D009369:Neoplasms; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011297:Prenatal Exposure Delayed Effects; D011446:Prospective Studies; D018570:Risk Assessment; D011795:Surveys and Questionnaires",
"nlm_unique_id": "8710219",
"other_id": null,
"pages": "1245-56",
"pmc": null,
"pmid": "26854809",
"pubdate": "2016-05-15",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Risk of cancer in children exposed to didanosine in utero.",
"title_normalized": "risk of cancer in children exposed to didanosine in utero"
} | [
{
"companynumb": "FR-CIPLA LTD.-2016FR01574",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
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{
"abstract": "We report herein the usefulness of interventional radiological treatment( IVR) for hepatocellular carcinomas( HCCs), based on the results of transcatheter arterial chemoembolization( TACE) and transarterial infusion( TAI).\n\n\nMETHODS\nThe study included 256 cases of HCC. TACE and TAI were performed for durations permitted by the degree of liver damage. Results(: 1) TACE was performed in 224 cases( average: 4.5 times, range: 1-14 times), and TAI was performed in 32 cases( average: 2.3 times, range: 1-8 times).( 2) The 3- and 5-year survival rates for all cases were 45.5% and 31.6%, respectively.( 3) We classified all cases according to the number of HCCs, solitary, 2-4, and multiple HCCs, and found no significant differences in the survival rate between the 3 groups( p=0.207),( 4) TAI was followed by TACE in non-responsive cases, and the median survival time of the TAI group was 8.5 months.\n\n\nCONCLUSIONS\nWe can expect benefits from repeated TACE treatment in the multiple HCCs group, compared to the solitary HCC group. TAI followed by TACE might improve the prognosis of unresectable and recurrent HCCs. Therefore, we conclude that IVR has clinical benefit as local treatment for HCC.",
"affiliations": "Dept. of Surgery, Tokyo Women's Medical University, Medical Center East.",
"authors": "Shiozawa|Shunichi|S|;Usui|Takebumi|T|;Kuhara|Kotaro|K|;Tsuchiya|Akira|A|;Miyauchi|Tatsuomi|T|;Yamaguchi|Kentaro|K|;Yokomizo|Hajime|H|;Shimakawa|Takeshi|T|;Yoshimatsu|Kazuhiko|K|;Katsube|Takao|T|;Naritaka|Yoshihiko|Y|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "40(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D005260:Female; D006801:Humans; D007261:Infusions, Intra-Arterial; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012008:Recurrence",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1819-21",
"pmc": null,
"pmid": "24393933",
"pubdate": "2013-11",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Does interventional radiological treatment (transcatheter arterial chemoembolization/transarterial infusion) improve the prognosis of patients with unresectable and recurrent hepatocellular carcinomas?.",
"title_normalized": "does interventional radiological treatment transcatheter arterial chemoembolization transarterial infusion improve the prognosis of patients with unresectable and recurrent hepatocellular carcinomas"
} | [
{
"companynumb": "JP-20140318",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MITOMYCIN"
},
"drugadditional": null,
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{
"abstract": "OBJECTIVE\nVisual symptoms are common in patients with preeclampsia, and are caused by various underlying pathological changes in the retina. Blurred vision may be one of these symptoms. We describe three cases in which the underlying retinal pathology of blurred vision was clarified using optical coherence tomography (OCT), a novel, non-invasive ophthalmic imaging technique that provides micrometer-scale resolution images of the human retina.\n\n\nMETHODS\nThree patients with preeclampsia complained of blurred vision postpartum. In all cases, ophthalmoscopy was performed at the bedside, followed by the assessment of best corrected visual acuity, slit-lamp biomicroscopy, fluorescein angiography (FLA), and OCT. In all cases, the presence of central visual defects was examined by an Amsler-grid.\n\n\nRESULTS\nIn one case, the symptoms were bilateral. In all affected eyes, the patients complained of a relative central scotoma. Ophthalmoscopy showed edema in the affected maculae, while OCT examination clarified a serous neurosensory detachment of the macula. In one case, a neurosensory detachment was also detected in the papillomacular region of a fellow eye with no symptoms. In two cases, FLA was performed, but only in one case could we detect late leakage and subretinal exudates. The serous detachments observed showed total resolution in all cases within 5 to 10 weeks, with restoration of visual acuity.\n\n\nCONCLUSIONS\nIn patients with preeclampsia, OCT may provide a useful method for the precise assessment of retinal changes, distinguishing retinal edema from serous neurosensory detachments. This finding may help to clarify the pathophysiological circulatory changes seen in preeclampsia.",
"affiliations": "2nd Department of Ophthalmology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary. somfaigm@szem2.sote.hu",
"authors": "Somfai|Gábor Márk|GM|;Miháltz|Kata|K|;Tulassay|Eszter|E|;Rigó|János|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/10641950500543848",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1064-1955",
"issue": "25(1)",
"journal": "Hypertension in pregnancy",
"keywords": null,
"medline_ta": "Hypertens Pregnancy",
"mesh_terms": "D000328:Adult; D003937:Diagnosis, Differential; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D008266:Macula Lutea; D019095:Point-of-Care Systems; D049590:Postpartum Period; D011225:Pre-Eclampsia; D011247:Pregnancy; D012164:Retinal Diseases; D012720:Severity of Illness Index; D041623:Tomography, Optical Coherence",
"nlm_unique_id": "9421297",
"other_id": null,
"pages": "11-20",
"pmc": null,
"pmid": "16617539",
"pubdate": "2006",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diagnosis of serous neuroretinal detachments of the macula in severe preeclamptic patients with optical coherence tomography.",
"title_normalized": "diagnosis of serous neuroretinal detachments of the macula in severe preeclamptic patients with optical coherence tomography"
} | [
{
"companynumb": "PHHY2018HU014964",
"fulfillexpeditecriteria": "1",
"occurcountry": "HU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "(1) Background: We investigated survival outcomes following first-line chemotherapy before and after approval of bevacizumab (Bev) for ovarian cancer in Japan to evaluate the efficacy of Bev for advanced clear cell carcinoma (CCC). (2) Methods: We investigated 28 consecutive patients diagnosed with CCC (stages III/IV) at our hospital between 2008 and 2018. Bev was administered for treatment of advanced CCC after approval in Japan in November 2013. Progression-free survival (PFS) was compared between 10 patients treated before Bev approval (2008-2013, Bev- group) and 18 patients treated after Bev approval (2014-2018, Bev+ group) for first-line chemotherapy. (3) Results: No intergroup difference was observed in patient characteristics. The rate of completeness of resection was higher in the Bev - group (9/10, 90%) than in the Bev+ group (15/18, 83%) (p = 0.044). Eleven (61%) patients in the Bev + group received ≥ 21 cycles of Bev. The median PFS increased from 12.0 months before Bev approval to 29.8 months after Bev approval (Wilcoxon test, p = 0.026). Multivariate analysis showed that performance status (p = 0.049), Bev administration (p = 0.023) and completeness of resection (p = 0.023) were independent prognostic factors for PFS. (4) Conclusions: Bev incorporated into first-line chemotherapy might improve PFS in patients with advanced CCC. We hope that our findings will be confirmed in adequate clinical trials.",
"affiliations": "Department of Gynecology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan.;Department of Gynecology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan.;Department of Gynecology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan.;Department of Gynecology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan.;Biostatistics Section, Clinical Research Center, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan.;Biostatistics Section, Clinical Research Center, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan.;Biostatistics Section, Clinical Research Center, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan.;Department of Gynecology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan.",
"authors": "Tate|Shinichi|S|0000-0003-4013-5674;Nishikimi|Kyoko|K|;Matsuoka|Ayumu|A|;Otsuka|Satoyo|S|;Shiko|Yuki|Y|0000-0002-3959-9343;Ozawa|Yoshihito|Y|;Kawasaki|Yohei|Y|0000-0002-7474-7647;Shozu|Makio|M|0000-0002-7247-2205",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/cancers13133177",
"fulltext": "\n==== Front\nCancers (Basel)\nCancers (Basel)\ncancers\nCancers\n2072-6694\nMDPI\n\n34202220\n10.3390/cancers13133177\ncancers-13-03177\nArticle\nBevacizumab in First-Line Chemotherapy Improves Progression-Free Survival for Advanced Ovarian Clear Cell Carcinoma\nhttps://orcid.org/0000-0003-4013-5674\nTate Shinichi 1*\nNishikimi Kyoko 1\nMatsuoka Ayumu 1\nOtsuka Satoyo 1\nhttps://orcid.org/0000-0002-3959-9343\nShiko Yuki 2\nOzawa Yoshihito 2\nhttps://orcid.org/0000-0002-7474-7647\nKawasaki Yohei 2\nhttps://orcid.org/0000-0002-7247-2205\nShozu Makio 1\nOda Katsutoshi Academic Editor\n1 Department of Gynecology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan; knishikimi@hospital.chiba-u.jp (K.N.); a-matsuoka@chiba-u.jp (A.M.); caxa5597@chiba-u.jp (S.O.); shozu@faculty.chiba-u.jp (M.S.)\n2 Biostatistics Section, Clinical Research Center, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan; shiko_yuki@chiba-u.jp (Y.S.); yoshihito.ozawa@chiba-u.jp (Y.O.); ykawasaki@chiba-u.jp (Y.K.)\n* Correspondence: state@faculty.chiba-u.jp; Tel.: +81-43-226-2121\n25 6 2021\n7 2021\n13 13 317728 3 2021\n21 6 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nSimple Summary\n\nWe investigated survival outcomes following first-line chemotherapy before and after approval of bevacizumab for ovarian cancer in Japan to evaluate the efficacy of bevacizumab for advanced clear cell carcinoma. We investigated 28 consecutive patients diagnosed with clear cell carcinoma (stages III/IV) at our hospital between 2008 and 2018. Bevacizumab was administered for treatment after approval in Japan in November 2013. Progression-free survival was compared between 10 patients treated before bevacizumab approval (2008–2013,) and 18 patients treated after Bev approval (2014–2018) for first-line chemotherapy. The median progression-free survival increased from 12.0 months before bevacizumab approval to 29.8 months after bevacizumab approval (Wilcoxon test, p = 0.026). Multivariate analysis showed that performance status (p = 0.049), bevacizumab administration (p = 0.023) and completeness of resection (p = 0.023) were independent prognostic factors for progression-free survival. Bevacizumab incorporated into first-line chemotherapy might improve progression-free survival in patients with advanced clear cell carcinoma.\n\nAbstract\n\n(1) Background: We investigated survival outcomes following first-line chemotherapy before and after approval of bevacizumab (Bev) for ovarian cancer in Japan to evaluate the efficacy of Bev for advanced clear cell carcinoma (CCC). (2) Methods: We investigated 28 consecutive patients diagnosed with CCC (stages III/IV) at our hospital between 2008 and 2018. Bev was administered for treatment of advanced CCC after approval in Japan in November 2013. Progression-free survival (PFS) was compared between 10 patients treated before Bev approval (2008–2013, Bev- group) and 18 patients treated after Bev approval (2014–2018, Bev+ group) for first-line chemotherapy. (3) Results: No intergroup difference was observed in patient characteristics. The rate of completeness of resection was higher in the Bev − group (9/10, 90%) than in the Bev+ group (15/18, 83%) (p = 0.044). Eleven (61%) patients in the Bev + group received ≥ 21 cycles of Bev. The median PFS increased from 12.0 months before Bev approval to 29.8 months after Bev approval (Wilcoxon test, p = 0.026). Multivariate analysis showed that performance status (p = 0.049), Bev administration (p = 0.023) and completeness of resection (p = 0.023) were independent prognostic factors for PFS. (4) Conclusions: Bev incorporated into first-line chemotherapy might improve PFS in patients with advanced CCC. We hope that our findings will be confirmed in adequate clinical trials.\n\nbevacizumab\nchemotherapy\novarian cancer\nprogression-free survival\nsurgery\n==== Body\n1. Introduction\n\nClear cell carcinoma (CCC), a subtype of epithelial ovarian carcinoma, is rare in Europe and the United States [1]; however, it accounts for 20–30% of epithelial ovarian tumors in Asia, particularly in Japan [2,3]. Many CCCs are often diagnosed at an early stage, and advanced disease is uncommon. The Japanese Gynecologic Oncology Group (JGOG) 3017/Gynecologic Cancer Intergroup (GCIG) trial [4] reported that advanced CCC was diagnosed in only 156/667 patients (23.3%). CCC shows a poorer prognosis than high-grade serous carcinoma [1,3,5], particularly in patients with advanced-stage disease because it is less sensitive to conventional platinum-based chemotherapy [2,5,6,7]. Reportedly, paclitaxel-containing platinum chemotherapy was more effective than conventional platinum chemotherapy for advanced CCC [8]. However, no cytotoxic regimen more effective than paclitaxel and carboplatin has been reported in the available literature [4]. Therefore, therapeutic strategies for advanced CCC are urgently warranted.\n\nThe efficacy of bevacizumab (Bev) for CCC remains unknown because of the low incidence of this cancer. Two phase 3 trials have reported that the addition of Bev during and after carboplatin and paclitaxel chemotherapy prolonged progression-free survival (PFS) by approximately four months in patients with advanced epithelial ovarian cancer [9,10]. However, the exploratory subgroup analysis did not show any specific group of patients in whom Bev was particularly effective for treatment [11]. There are various mechanisms for induction of VEGF in CCC. The effectiveness of Bev in patients with CCC is attributable to Bev-induced AKT-mTOR pathway inhibition [12]. It has been reported that mTOR was more frequently activated in CCC than in serous adenocarcinoma [13]. In addition to activation of the mTOR pathway, endometriotic tumor microenvironment is closely associated with hypoxic condition in CCC [14]. Hypoxia-inducible factor (HIF) 1α expression levels are significantly higher in CCC than in other histologic subtypes of ovarian cancer [12]. This pathway is known to promote the expression of HIF 1α, which mediates the activation of vascular endothelial growth factor (VEGF), a potent pro-angiogenic factor necessary for tumor growth, invasion, and metastasis [15]. Although a few studies have reported the efficacy of Bev in patients with recurrent CCC [16,17] and high response rates of CCC to Bev during initial chemotherapy [18], no previous report has described the survival impact of Bev in first-line treatment.\n\nThe survival impact of Bev combined with aggressive surgery is also unknown in patients with advanced CCC. Aggressive surgery appears to be a more important treatment for advanced CCC than for serous carcinoma due to less chemo-sensitive [19]. Some retrospective studies have reported that complete resection without residual disease is the only determinant of improved survival outcomes in patients with advanced CCC [20]. Some gynecologic oncologists believe that aggressive surgery may be unnecessary during Bev administration, while others propose that aggressive surgery can obviate the need for Bev administration. Aggressive surgery, including gastrointestinal and upper abdominal procedures, was introduced for advanced ovarian cancer at our hospital in 2008. We observed that aggressive surgery performed mainly by gynecologic oncologists was safe and prolonged survival [21]. Moreover, Bev administration was initiated since it was approved for recurrent and advanced ovarian cancer in Japan in 2014 [22]. In this study, we retrospectively investigated the efficacy of Bev for advanced CCC and compared survival outcomes pre- and post-Bev approval after aggressive surgery was introduced at our hospital.\n\n2. Materials and Methods\n\n2.1. Patients\n\nThis retrospective, case-control study included 28 patients diagnosed with stage III/IV CCC (International Federation of Gynecology and Obstetrics [FIGO 2014] classification [23]), who were treated at Chiba University Hospital between January 2008 and December 2018. We performed cytoreductive surgery followed by first-line chemotherapy. Neoadjuvant chemotherapy was followed by interval debulking surgery in patients in whom primary debulking surgery was contraindicated. Aggressive surgery was introduced at our hospital for the treatment of advanced ovarian cancer in 2008, and gastrointestinal and upper abdominal surgeries were performed by gynecologic oncologists to achieve complete resection. Procedural details with regard to aggressive surgery are described in our previous report [21]. From a prospectively enrolled database of patients who underwent surgery and chemotherapy at our hospital, we obtained patients’ clinical data including age, FIGO stage, performance status (PS), peritoneal cancer index (PCI) [24], timing of debulking surgery, Bev administration, the number of Bev cycles administered, completeness of debulking surgery, the surgical complexity score [25], and adverse events associated with Bev-containing chemotherapy administered along with aggressive surgery. PCI is calculated as a sum of peritoneal tumor sizes in 13 different abdominopelvic regions [24]. The surgical complexity score rates each method used for ovarian cancer surgery, and the sum of this score represents the complexity of each procedure [25]. Bev (15 mg/kg every 3 weeks) was administered after it was approved in Japan in November 2013 for the treatment of FIGO III/IV ovarian cancer. The PFS and overall survival (OS) rates were compared between 10 patients treated before Bev approval (2008–2013, Bev- group) and 18 patients treated after Bev approval (2014–2018, Bev+ group). The study was approved by the Institutional Review Board (#3735) of Chiba University.\n\n2.2. Selection Criteria for Primary Debulking Surgery or Neoadjuvant Chemotherapy Followed by Interval Debulking Surgery in Our Institute\n\nWhen the surgical team (ST, KN, AM) deemed that complete resection was achievable by including upper abdominal surgery, the surgeon performed primary debulking surgery followed by six courses of adjuvant chemotherapy. If the surgeon deemed complete resection as impossible or life-threating, or that neoadjuvant chemotherapy would be preferable in terms of a trade-off between therapeutic efficacy and safety, the surgeon triaged the patient to a neoadjuvant chemotherapy followed by interval debulking surgery subgroup and performed a diagnostic biopsy with or without tumorectomy and/or partial omentectomy for symptom relief (e.g., for massive ascites).\n\n2.3. Diagnosis of Recurrence\n\nComputed tomography (CT) or positron emission tomography (PET) was used to diagnose recurrence. Serum cancer antigen 125 (CA125) levels were measured at 1–2-month intervals for the first 2 years and at 3-month intervals between the 3rd and 5th years after treatment completion. CT was performed at the end of initial treatment and every 6 months thereafter. CT was also performed in patients who showed increased serum CA125 levels or worsening of symptoms. Patients were closely followed-up and underwent PET/CT if CT failed to detect recurrence despite increased serum CA125 levels.\n\n2.4. Chemotherapy and Bevacizumab\n\nA combination of taxane-platinum was used as first-line chemotherapy in this study. Triweekly paclitaxel (175 mg/m2) plus carboplatin (area under the curve [AUC] 5–6) or triweekly docetaxel (75 mg/m2) plus carboplatin (AUC 5–6) was administered in 2008–2009. Weekly paclitaxel (80 mg/m2/week injected intravenously) and carboplatin (AUC 2–3/week injected intravenously) were administered between 2010 and 2018. Bev (15 mg/kg every 3 weeks) was administered to patients without any contraindication to its use after this drug was approved in November 2013 in Japan for the treatment of ovarian cancer. The Common Terminology Criteria for Adverse Events scale, version 4.0 published by the National Cancer Institute was used to grade toxicity.\n\n2.5. Statistical Analysis\n\nThe PFS and OS were the primary and secondary endpoints, respectively. The Kaplan–Meier method was used to estimate the PFS, OS, and the time until the first recurrence detected at intra- and extraperitoneal sites. The log-rank and Wilcoxon tests were used to compare statistically significant differences. PFS was defined as the time interval between the date of treatment initiation and the date of diagnosis of the first recurrence. OS was defined as the time interval between treatment initiation and the date of death or the last follow-up. Patient characteristics were compared between the Bev- and Bev+ groups using the Fisher exact test or the Chi-square test. The variables included the multivariate analysis were selected using backward stepwise selection based on the corrected Akaike’s information criterion. Performance status, bevacizumab use, and completeness of resection were selected. Using three variables, Cox proportional hazards regression analysis was performed to analyze the prognostic factors associated with PFS and OS. All statistical analyses were two-sided, and a p value < 0.05 was considered statistically significant. All statistical analyses were performed using the JMP statistical software, version 11.0 (SAS, Cary, NC, USA).\n\n3. Results\n\n3.1. Patient Characteristics\n\nTable 1 shows patient characteristics; no statistically significant intergroup difference was observed in patient characteristics. The median age was 54 years and 53 years in the Bev− and Bev+ groups (p = 0.810), respectively. Stage IV disease was diagnosed in 3 (30%) and 4 (22%) patients in the Bev− and Bev+ groups, respectively (p = 0.674). The PS was ≥ 2 in 1 (10%) and 5 (28%) patients in the Bev– and Bev+ groups, respectively (p = 0.375). The peritoneal cancer index was 5.5 in both groups (p = 0.727). Primary debulking surgery was performed in 10 (100%) and 11 (61%) patients in the Bev− and Bev+ groups, respectively. The median surgical complexity score was 9 in both groups (p = 0.700). The rate of completeness of resection was higher in the Bev− group (9/10, 90%) than in the Bev+ group (15/18, 83%) (p = 0.044). One patient in the Bev+ group could not complete first-line chemotherapy because of disease progression.\n\n3.2. Bevacizumab Administration\n\nWe administered a median of 21 cycles (interquartile range (IQR) 7.5–21) of Bev, and 12 of 18 patients (67%) completed Bev maintenance therapy. Notably, 12 of 18 patients in the Bev+ group showed recurrence, and 6 of these patients underwent Bev re-administration after disease progression. The remaining six patients did not receive Bev because of poor PS or development of adverse events. In the Bev- group, relapse occurred in 7 of 10 patients; 4 of these patients received Bev for relapse.\n\n3.3. Survival Analysis\n\nFigure 1 shows the PFS and OS rates. The median follow-up period was 36.8 months (IQR 22.4–49.9). The median PFS in the Bev+ and Bev- groups was 29.8 months (95% confidence interval [CI] 17.2–infinity) and 12.0 months (95% CI 1.9–infinity) (log-rank test p = 0.156 and Wilcoxon test p = 0.036), respectively. The median OS in the Bev+ and Bev− groups was 49.6 months (95% CI 34.3–infinity) and 30.0 months (95% CI 15.6–infinity) (log-rank test p = 0.530 and Wilcoxon test p = 0.464), respectively.\n\n3.4. Bevacizumab-Induced Adverse Events\n\nTable 2 shows the Bev-induced adverse events observed in this study. Adverse events included grade 2 and 3 hypertension (33% and 22%, respectively), grade 2 and 3 proteinuria (6% and 22%, respectively), and grade 3 bleeding (6%). No patient developed thromboembolic events, gastrointestinal perforation, or fistula.\n\n3.5. Perioperative Complications\n\nSevere perioperative complications (Clavien-Dindo grade ≥ IIIb [26]) occurred in 2 patients (7.1%, grade IIIb: lymphorrhea and intra-abdominal bleeding in 1 patient each).\n\n3.6. Multivariate Analysis of Prognostic Factors Associated with Progression-Free Survival\n\nCox proportional hazards regression analysis was performed to analyze the prognostic factors associated with PFS and OS (Table 3). Performance status (hazard ratio [HR] 0.28, 95% CI 0.09–0.94, p = 0.049), Bev administration (HR 0.26, 95% CI 0.08–0.82, p = 0.022) and completeness of resection (HR 0.20, 95% CI 0.06–0.70, p = 0.013) were independently associated with the PFS, and completeness of resection (HR 0.19, 95% CI 0.05–0.78, p = 0.021) was independently associated with OS.\n\n4. Discussion\n\n4.1. Key Findings of This Study\n\nIn this study, we observed that the addition of Bev to the chemotherapeutic regimen and completeness of resection were associated with successful initial treatment of advanced CCC. Despite its small sample size, this study highlights the effectiveness of an important treatment strategy for the initial treatment of advanced CCC. To date, even large-scale clinical studies have not conclusively established the efficacy of Bev for the treatment of advanced CCC owing to the low incidence of this cancer. In this study, we confirmed that anti-angiogenic therapy that targets the VEGF pathway as well as aggressive surgery could effectively treat advanced CCC. Our results are consistent with exploratory subgroup analyses performed in large clinical trials, which prove that Bev had consistently better effects on any factors [9].\n\n4.2. Efficacy of Bev in First-Line Chemotherapy\n\nWe observed that the addition of Bev to the chemotherapeutic regimen prolonged the PFS of patients with advanced CCC. Several large randomized controlled trials have reported the efficacy of Bev addition to first-line chemotherapy for advanced ovarian cancer [9,10]. However, these trials enrolled a small number of patients with CCC because these studies included patients from Western countries, and exploratory subgroup analyses could not establish the efficacy of Bev in non-serous ovarian cancer [9]. The ICON-7 trial could prove the efficacy of Bev with regard to the PFS and OS in the high-risk group; however, the role of Bev in patients with CCC, including in those with stage I–IV disease could not be definitively established primarily because >50% of patients with CCC included in this trial were diagnosed with early-stage ovarian cancer (stages I and II) [27]. A prospective observational study that investigated first-line chemotherapy showed that paclitaxel-carboplatin combination chemotherapy with the addition of Bev for CCC was associated with a response rate of 63.6% (n = 11), suggesting that the addition of Bev could play a key role in the optimization of treatment for CCC [18]. Our study is the first to highlight that the addition of Bev to the initial chemotherapeutic regimen prolonged PFS in patients with advanced CCC.\n\n4.3. Efficacy of Bev in Salvage Chemotherapy\n\nIn addition to its role in first-line chemotherapy, a few reports have described the effects of Bev added to salvage chemotherapy regimens for the treatment of CCC. In clinical trials that investigated patients with recurrent ovarian cancer (both platinum-sensitive [28,29] and resistant disease [30]), CCC was diagnosed in ≤10% of the study population. Retrospective studies that investigated the effects of Bev on CCC observed that Bev added to salvage chemotherapy regimens for recurrent CCC was associated with high response rates and prolonged PFS [31]. Similarly, Bev monotherapy was also associated with high response rates and prolonged PFS [16]. A case report in the available literature has described that Bev administered to a patient with CCC and pericardial and pleural effusion improved the patient’s symptoms and quality of life [17].\n\n4.4. Efficacy of Aggressive Surgery in CCC\n\nSeveral gynecologic oncologists are of the view that novel molecularly targeted therapy using agents such as Bev could obviate the need for aggressive surgery as initial treatment because secondary debulking surgery did not result in longer PFS and OS than chemotherapy with Bev in GOG-213 trial [32]. However, CCC is less sensitive to chemotherapy; therefore, aggressive surgery may be warranted for the initial treatment of CCC. Aggressive surgery was shown to be effective in advanced CCC [20], similar to its role in other histopathological cancer types [33,34,35]. The ICON-7 [10] trial confirmed a 2-month prolongation in PFS, and the GOG-218 trial [9] confirmed a 3.8-month prolongation in PFS, following Bev administration. We observed a 17-month prolongation in PFS in our study. Although it is difficult to compare the results of the two clinical trials, which primarily enrolled patients with serous carcinoma, the significant prolongation in PFS observed in our study cannot be attributed exclusively to the addition of Bev to the therapeutic regimen of patients with CCC, who showed a >85% complete resection rate. The ICON 7 trial reported that the addition of Bev was effective in patients with advanced ovarian cancer, who underwent complete resection or even in patients with residual disease. Therefore, it is reasonable to conclude that the addition of Bev and aggressive surgery may have synergistic effects on PFS, while the completeness of surgical resection was the only independent factor associated with OS.\n\n4.5. Strengths and Limitation\n\nFollowing are the limitations of the current study: (A) The retrospective design of this small-scale case-control study is a drawback. However, this was a single-center study; therefore, in contrast to previous studies, we could maintain uniformity in treatment policies and operative and other procedural details. Considering the proportion of advanced CCC of all ovarian cancers, 28 patients in our study may not be small. (B) Potential histopathological misclassification cannot be excluded. However, CCC was diagnosed in the study population at our hospital by histopathologists familiar with gynecologic oncology. (C) Bev is contraindicated in patients with thromboembolic conditions. CCC is associated with thromboembolic diseases. However, we administered Bev without active thromboembolic events after adequate heparin prophylaxis against thromboembolic events. (D) We did not show the efficacy of Bev in overall survival. In the Bev− group, relapse occurred in 7 of 10 patients; 4 of these patients received Bev for relapse. Overall survival was not different between the groups in this retrospective study due to crossover to Bev. This result was similar to those of GOG 218 [9], which was a prospective study.\n\n5. Conclusions\n\nSince the introduction of Bev as a therapeutic option in patients with ovarian cancers, many studies have reported the use of biomarkers to evaluate the efficacy of Bev; however, no valid biomarkers are available in real-world practice. Advanced ovarian CCC is rare; therefore, it is difficult to determine the efficacy of Bev for this cancer. However, our study shows that CCC itself can serve as a biomarker for Bev. In this study, treatment for advanced CCC, as well as other histopathological types, included aggressive surgery to achieve complete resection without residual disease followed by paclitaxel and carboplatin chemotherapy concomitant with Bev administration to target the VEGF pathway. This approach might be an effective therapeutic strategy that prolonged PFS. We hope that our findings will be proven in adequate clinical trials. It would be interesting to find biomarkers to select the patients who may benefit from the treatment, in future studies.\n\nAuthor Contributions\n\nConceptualization, S.T. and M.S.; methodology, S.T.; formal analysis, S.T., Y.S., Y.O. and Y.K.; investigation, S.T.; data curation, S.T. and K.N.; writing—original draft preparation, S.T.; writing—review and editing, S.T., K.N., A.M. and S.O.; visualization, S.T.; supervision, M.S.; project administration, S.T. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board at Chiba University on 30 June 2020 (protocol code #3735).\n\nInformed Consent Statement\n\nPatient consent was waived due to the retrospective design of this study. An opt-out system was used instead.\n\nData Availability Statement\n\nAll datasets analyzed during the current study are available from the corresponding author upon reasonable request.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 Progression-free survival and overall survival following the addition of bevacizumab to the chemotherapeutic regimen.\n\ncancers-13-03177-t001_Table 1 Table 1 Patient Characteristics.\n\nCharacteristic\tBev− Group (n = 10)\tBev+ Group (n = 18)\tp Value\t\nAge\t\t\t\nMedian age, years (IQR)\t54 (48–59)\t53 (46–63)\t0.81\t\nFIGO Stage, No. (%)\t\t\t\nIII\t7\t70%\t14\t78%\t0.674\t\nIV\t3\t30%\t4\t22%\t\t\nPerformance status, No. (%)\t\t\t\t\t\t\n0–1\t9\t90%\t13\t72%\t0.375\t\n2–4\t1\t10%\t5\t28%\t\t\nCA 125, IU/mL, (median, IQR)\t419 (247–924)\t271 (121–607)\t0.179\t\nPeritoneal Cancer Index (median, IQR)\t5.5 (3–11.25)\t5.5 (3–17.25)\t0.727\t\nTiming of debulking surgery\t\t\t\t\t\t\nPrimary\t10\t100%\t11\t61%\t\t\nInterval\t0\t0%\t6\t33%\t0.075\t\nNo debulking surgery\t0\t0%\t1\t6%\t\t\nSurgical complexity score, No. (%)\t\t\t\nMedian, IQR\t9 (4.8–11)\t9 (4–14)\t0.7\t\nLow (0–3)\t1\t10%\t2\t11%\t\t\nModerate (4–7)\t3\t30%\t7\t39%\t0.874\t\nHigh (8–18)\t6\t60%\t9\t50%\t\t\nCompleteness of resection, No. (%)\t\t\t\n0 cm\t9\t90%\t15\t83%\t\t\n>0 cm\t1\t10%\t2\t11%\t0.742\t\n>1 cm\t0\t\t1\t6%\t\t\nFirstline chemotherapy regimen\t\t\t\nTri-weekly paclitaxel (or docetaxel) carboplatin\t4\t40%\t0\t0%\t0.01\t\nWeekly paclitaxel carboplatin\t6\t60%\t18\t100%\t\t\nCompleteness of firstline chemotherapy, No. (%)\t\t\t\nCompleteness\t10\t100%\t17\t94%\t1\t\nNo-completeness\t0\t\t1\t6%\t\t\nAbbreviations: FIGO, International Federation of Gynecology and Obstetrics; IQR, interquartile range: NACT, neoadjuvant chemotherapy.\n\ncancers-13-03177-t002_Table 2 Table 2 Adverse events induced by bevacizumab in bevacizumab+ group (n = 18).\n\nAdverse Events\tGrade\t\n0\t\t1\t\t2\t\t3\t\t4\t\t\nHypertension\t4\t22%\t4\t22%\t6\t33%\t4\t22%\t0\t\t\nProteinuria\t8\t44%\t5\t28%\t1\t6%\t4\t22%\t0\t\t\nBleeding\t12\t67%\t5 a\t28%\t0\t\t1 b\t6%\t0\t\t\nColonic obstruction\t16\t89%\t0\t0%\t0\t\t2\t11%\t0\t\t\nThromboemboic events\t18\t\t0\t\t0\t\t0\t\t0\t\t\nGastrointestinal perforation\t18\t\t0\t\t0\t\t0\t\t0\t\t\nWound dehiscence\t18\t\t0\t\t0\t\t0\t\t0\t\t\nFistula\t18\t\t0\t\t0\t\t0\t\t0\t\t\na: nasal bleeding, b: anal hemorrhage.\n\ncancers-13-03177-t003_Table 3 Table 3 Multivariable Cox proportional analysis of risk factors for progression-free survival and overall survival for advanced clear cell carcinoma.\n\nVariable\tPFS\tOS\t\nHazard Ratio\t95% CI\tp Value\tHazard Ratio\t95% CI\tp Value\t\nPerformance Status\t0–1/≥2\t0.28\t0.09–0.94\t0.049\t0.33\t0.10–1.03\t0.058\t\nBevacizumab use\tBev +/−\t0.26\t0.08–0.82\t0.022\t0.52\t0.18–1.46\t0.216\t\nCompleteness of resection\tComplete/Others\t0.20\t0.06–0.70\t0.013\t0.19\t0.05–0.78\t0.021\t\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Winter W.E. 3rd Maxwell G.L. Tian C. Carlson J.W. Ozols R.F. Rose P.G. Markman M. Armstrong D.K. Muggia F. McGuire W.P. Prognostic factors for stage III epithelial ovarian cancer: A Gynecologic Oncology Group Study J. Clin. Oncol. 2007 25 3621 3627 10.1200/JCO.2006.10.2517 17704411\n2. Sugiyama T. Kamura T. Kigawa J. Terakawa N. Kikuchi Y. Kita T. Suzuki M. Sato I. Taguchi K. Clinical characteristics of clear cell carcinoma of the ovary: A distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy Cancer 2000 88 2584 2589 10.1002/1097-0142(20000601)88:11<2584::AID-CNCR22>3.0.CO;2-5 10861437\n3. del Carmen M.G. Birrer M. Schorge J.O. Clear cell carcinoma of the ovary: A review of the literature Gynecol. Oncol. 2012 126 481 490 10.1016/j.ygyno.2012.04.021 22525820\n4. Sugiyama T. Okamoto A. Enomoto T. Hamano T. Aotani E. Terao Y. Suzuki N. Mikami M. Yaegashi N. Kato K. Randomized Phase III Trial of Irinotecan Plus Cisplatin Compared With Paclitaxel Plus Carboplatin As First-Line Chemotherapy for Ovarian Clear Cell Carcinoma: JGOG3017/GCIG Trial J. Clin. Oncol. 2016 34 2881 2887 10.1200/JCO.2016.66.9010 27400948\n5. Goff B.A. Sainz de la Cuesta R. Muntz H.G. Fleischhacker D. Ek M. Rice L.W. Nikrui N. Tamimi H.K. Cain J.M. Greer B.E. Clear cell carcinoma of the ovary: A distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy in stage III disease Gynecol. Oncol. 1996 60 412 417 10.1006/gyno.1996.0065 8774649\n6. Takano M. Sugiyama T. Yaegashi N. Sagae S. Kuzuya K. Udagawa Y. Tsuda H. Suzuki M. Kigawa J. Goto T. Less impact of adjuvant chemotherapy for stage I clear cell carcinoma of the ovary: A retrospective Japan Clear Cell Carcinoma Study Int. J. Gynecol. Cancer 2010 20 1506 1510 10.1111/IGC.0b013e3181fcd089 21119366\n7. Kajiyama H. Suzuki S. Yoshihara M. Nishino K. Yoshikawa N. Utsumi F. Niimi K. Mizuno M. Kawai M. Oguchi H. The possible existence of occult metastasis in patients with ovarian clear-cell carcinoma who underwent complete resection without any residual tumours Oncotarget 2018 9 6298 6307 10.18632/oncotarget.23921 29464073\n8. Ho C.M. Huang Y.J. Chen T.C. Huang S.H. Liu F.S. Chang Chien C.C. Yu M.H. Mao T.L. Wang T.Y. Hsieh C.Y. Pure-type clear cell carcinoma of the ovary as a distinct histological type and improved survival in patients treated with paclitaxel-platinum-based chemotherapy in pure-type advanced disease Gynecol. Oncol. 2004 94 197 203 10.1016/j.ygyno.2004.04.004 15262142\n9. Burger R.A. Brady M.F. Bookman M.A. Fleming G.F. Monk B.J. Huang H. Mannel R.S. Homesley H.D. Fowler J. Greer B.E. Incorporation of bevacizumab in the primary treatment of ovarian cancer N. Engl. J. Med. 2011 365 2473 2483 10.1056/NEJMoa1104390 22204724\n10. Perren T.J. Swart A.M. Pfisterer J. Ledermann J.A. Pujade-Lauraine E. Kristensen G. Carey M.S. Beale P. Cervantes A. Kurzeder C. A phase 3 trial of bevacizumab in ovarian cancer N. Engl. J. Med. 2011 365 2484 2496 10.1056/NEJMoa1103799 22204725\n11. Gonzalez Martin A. Oza A.M. Embleton A.C. Pfisterer J. Ledermann J.A. Pujade-Lauraine E. Kristensen G. Bertrand M.A. Beale P. Cervantes A. Exploratory outcome analyses according to stage and/or residual disease in the ICON7 trial of carboplatin and paclitaxel with or without bevacizumab for newly diagnosed ovarian cancer Gynecol. Oncol. 2019 152 53 60 10.1016/j.ygyno.2018.08.036 30449719\n12. Yagyu T. Tsuji Y. Haruta S. Kitanaka T. Yamada Y. Kawaguchi R. Kanayama S. Tanase Y. Kurita N. Kobayashi H. Activation of mammalian target of rapamycin in postmenopausal ovarian endometriosis Int. J. Gynecol. Cancer 2006 16 1545 1551 10.1111/j.1525-1438.2006.00625.x 16884363\n13. Mabuchi S. Kawase C. Altomare D.A. Morishige K. Sawada K. Hayashi M. Tsujimoto M. Yamoto M. Klein-Szanto A.J. Schilder R.J. mTOR is a promising therapeutic target both in cisplatin-sensitive and cisplatin-resistant clear cell carcinoma of the ovary Clin. Cancer Res. 2009 15 5404 5413 10.1158/1078-0432.CCR-09-0365 19690197\n14. Wendel J.R.H. Wang X. Hawkins S.M. The Endometriotic Tumor Microenvironment in Ovarian Cancer Cancers 2018 10 261 10.3390/cancers10080261\n15. Mabuchi S. Kawase C. Altomare D.A. Morishige K. Hayashi M. Sawada K. Ito K. Terai Y. Nishio Y. Klein-Szanto A.J. Vascular endothelial growth factor is a promising therapeutic target for the treatment of clear cell carcinoma of the ovary Mol. Cancer Ther. 2010 9 2411 2422 10.1158/1535-7163.MCT-10-0169 20663925\n16. Bai H. Sha G. Cao D. Yang J. Chen J. Wang Y. Lang J. Shen K. Zhang Z. Salvage Chemotherapy for Patients With Recurrent or Persistent Ovarian Clear Cell Carcinoma: A Retrospective Study of 164 Cases Medicine 2015 94 e1121 10.1097/MD.0000000000001121 26166110\n17. Ueda T. Tsubamoto H. Eguchi A. Terada T. Shibahara H. Bevacizumab helped resolve pericardial and pleural effusion that was associated with malignant ovarian clear cell carcinoma Gynecol. Oncol. Rep. 2016 16 11 13 10.1016/j.gore.2016.01.006 27331128\n18. Komiyama S. Kato K. Inokuchi Y. Takano H. Matsumoto T. Hongo A. Asai-Sato M. Arakawa A. Kamiura S. Tabata T. Bevacizumab combined with platinum-taxane chemotherapy as first-line treatment for advanced ovarian cancer: A prospective observational study of safety and efficacy in Japanese patients (JGOG3022 trial) Int. J. Clin. Oncol. 2019 24 103 114 10.1007/s10147-018-1319-y 30030657\n19. Itamochi H. Kigawa J. Terakawa N. Mechanisms of chemoresistance and poor prognosis in ovarian clear cell carcinoma Cancer Sci. 2008 99 653 658 10.1111/j.1349-7006.2008.00747.x 18377417\n20. Takano M. Kikuchi Y. Yaegashi N. Kuzuya K. Ueki M. Tsuda H. Suzuki M. Kigawa J. Takeuchi S. Tsuda H. Clear cell carcinoma of the ovary: A retrospective multicentre experience of 254 patients with complete surgical staging Br. J. Cancer 2006 94 1369 1374 10.1038/sj.bjc.6603116 16641903\n21. Tate S. Kato K. Nishikimi K. Matsuoka A. Shozu M. Survival and safety associated with aggressive surgery for stage III/IV epithelial ovarian cancer: A single institution observation study Gynecol. Oncol. 2017 147 73 80 10.1016/j.ygyno.2017.07.136 28800941\n22. Tate S. Nishikimi K. Matsuoka A. Shozu M. Aggressive surgery for advanced ovarian cancer decreases the risk of intraperitoneal recurrence Int. J. Clin. Oncol. 2020 25 1726 1735 10.1007/s10147-020-01714-w 32500467\n23. Berek J.S. Crum C. Friedlander M. Cancer of the ovary, fallopian tube, and peritoneum Int. J. Gynaecol. Obstet 2015 131 Suppl. S2 S111 S122 10.1016/j.ijgo.2015.06.007 26433667\n24. Jacquet P. Sugarbaker P.H. Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis Cancer Treat. Res. 1996 82 359 374 8849962\n25. Aletti G.D. Eisenhauer E.L. Santillan A. Axtell A. Aletti G. Holschneider C. Chi D.S. Bristow R.E. Cliby W.A. Identification of patient groups at highest risk from traditional approach to ovarian cancer treatment Gynecol. Oncol. 2011 120 23 28 10.1016/j.ygyno.2010.09.010 20933255\n26. Dindo D. Demartines N. Clavien P.A. Classification of surgical complications: A new proposal with evaluation in a cohort of 6336 patients and results of a survey Ann. Surg. 2004 240 205 213 10.1097/01.sla.0000133083.54934.ae 15273542\n27. Oza A.M. Cook A.D. Pfisterer J. Embleton A. Ledermann J.A. Pujade-Lauraine E. Kristensen G. Carey M.S. Beale P. Cervantes A. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): Overall survival results of a phase 3 randomised trial Lancet Oncol. 2015 16 928 936 10.1016/S1470-2045(15)00086-8 26115797\n28. Aghajanian C. Blank S.V. Goff B.A. Judson P.L. Teneriello M.G. Husain A. Sovak M.A. Yi J. Nycum L.R. OCEANS: A randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer J. Clin. Oncol. 2012 30 2039 2045 10.1200/JCO.2012.42.0505 22529265\n29. Coleman R.L. Brady M.F. Herzog T.J. Sabbatini P. Armstrong D.K. Walker J.L. Kim B.G. Fujiwara K. Tewari K.S. O’Malley D.M. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): A multicentre, open-label, randomised, phase 3 trial Lancet Oncol. 2017 18 779 791 10.1016/S1470-2045(17)30279-6 28438473\n30. Pujade-Lauraine E. Hilpert F. Weber B. Reuss A. Poveda A. Kristensen G. Sorio R. Vergote I. Witteveen P. Bamias A. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial J. Clin. Oncol. 2014 32 1302 1308 10.1200/JCO.2013.51.4489 24637997\n31. Gallego A. Ramon-Patino J. Brenes J. Mendiola M. Berjon A. Casado G. Castelo B. Espinosa E. Hernandez A. Hardisson D. Bevacizumab in recurrent ovarian cancer: Could it be particularly effective in patients with clear cell carcinoma? Clin. Transl. Oncol. 2020 10.1007/s12094-020-02446-z 32651885\n32. Coleman R.L. Spirtos N.M. Enserro D. Herzog T.J. Sabbatini P. Armstrong D.K. Kim J.W. Park S.Y. Kim B.G. Nam J.H. Secondary Surgical Cytoreduction for Recurrent Ovarian Cancer N. Engl. J. Med. 2019 381 1929 1939 10.1056/NEJMoa1902626 31722153\n33. Chi D.S. Eisenhauer E.L. Lang J. Huh J. Haddad L. Abu-Rustum N.R. Sonoda Y. Levine D.A. Hensley M. Barakat R.R. What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)? Gynecol. Oncol. 2006 103 559 564 10.1016/j.ygyno.2006.03.051 16714056\n34. Wimberger P. Lehmann N. Kimmig R. Burges A. Meier W. Du Bois A. Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group Prognostic factors for complete debulking in advanced ovarian cancer and its impact on survival. An exploratory analysis of a prospectively randomized phase III study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR) Gynecol. Oncol. 2007 106 69 74 10.1016/j.ygyno.2007.02.026 17397910\n35. Chang S.J. Bristow R.E. Ryu H.S. Impact of complete cytoreduction leaving no gross residual disease associated with radical cytoreductive surgical procedures on survival in advanced ovarian cancer Ann. Surg. Oncol. 2012 19 4059 4067 10.1245/s10434-012-2446-8 22766983\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2072-6694",
"issue": "13(13)",
"journal": "Cancers",
"keywords": "bevacizumab; chemotherapy; ovarian cancer; progression-free survival; surgery",
"medline_ta": "Cancers (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101526829",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34202220",
"pubdate": "2021-06-25",
"publication_types": "D016428:Journal Article",
"references": "32651885;24637997;16884363;26433667;31722153;30449719;10861437;27331128;29464073;22766983;17397910;21119366;16714056;32500467;18377417;17704411;19690197;22525820;27400948;20663925;26115797;28438473;16641903;22204724;22204725;30030657;15262142;15273542;20933255;26166110;8849962;22529265;30087267;28800941;8774649",
"title": "Bevacizumab in First-Line Chemotherapy Improves Progression-Free Survival for Advanced Ovarian Clear Cell Carcinoma.",
"title_normalized": "bevacizumab in first line chemotherapy improves progression free survival for advanced ovarian clear cell carcinoma"
} | [
{
"companynumb": "JP-ROCHE-2863920",
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"activesubstancename": "BEVACIZUMAB"
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"abstract": "BACKGROUND\nLymphatic malformations (LMs) can be effectively treated by percutaneous intralesional injection of a variety of sclerosant drugs. This study aims to evaluate the efficacy of doxycycline in the treatment of LMs.\n\n\nRESULTS\nWe reviewed the medical records of all patients with LMs who underwent sclerotherapy with doxycycline between January 1, 2003 and September 1, 2004 at Children's Hospital Boston. Follow-up imaging was performed to assess for change in lesion size. Surveys were sent to all study patients, to assess perceived improvements in symptoms and satisfaction with the results. Sixty sclerotherapy procedures were performed on 41 patients in the 20-month study period. The median age was 6.9 years (3 mo-31 y). The most common location was cervicofacial (66%), followed by truncal (19%) and extremity (15%). The most common lesion type was macrocystic (49%), followed by combined (44%) and microcystic (7%). The major and minor complication rates were 2% and 10%, respectively. The mean outcome score by imaging was 4.41/5 with a 95% CI of [4.13-4.68] corresponding to about an 83% reduction in lesion size, and by patient survey was 4.47/5 with a 95% CI of [4.15-4.79] corresponding to between a good to complete response. Higher complication rates were associated with microcystic and combined lesions (p = 0.03), and greater doxycycline dose (p = 0.05).\n\n\nCONCLUSIONS\nDoxycycline is a safe and effective sclerosant for LMs. Greater follow-up is necessary to quantify long-term outcomes and assess the risks of lesion recurrence.",
"affiliations": "Vascular Anomalies Center, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA. pburrows@chpnet.org",
"authors": "Burrows|Patricia E|PE|;Mitri|Ragheed K|RK|;Alomari|Ahmad|A|;Padua|Horacio M|HM|;Lord|David J|DJ|;Sylvia|Mary Beth|MB|;Fishman|Steven J|SJ|;Mulliken|John B|JB|",
"chemical_list": "D012597:Sclerosing Solutions; D004318:Doxycycline",
"country": "United States",
"delete": false,
"doi": "10.1089/lrb.2008.1004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1539-6851",
"issue": "6(3-4)",
"journal": "Lymphatic research and biology",
"keywords": null,
"medline_ta": "Lymphat Res Biol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004318:Doxycycline; D005260:Female; D006801:Humans; D007223:Infant; D044148:Lymphatic Abnormalities; D008208:Lymphatic System; D008297:Male; D012189:Retrospective Studies; D012597:Sclerosing Solutions; D015911:Sclerotherapy; D016896:Treatment Outcome",
"nlm_unique_id": "101163587",
"other_id": null,
"pages": "209-16",
"pmc": null,
"pmid": "19093794",
"pubdate": "2008",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Percutaneous sclerotherapy of lymphatic malformations with doxycycline.",
"title_normalized": "percutaneous sclerotherapy of lymphatic malformations with doxycycline"
} | [
{
"companynumb": "US-PFIZER INC-2019445627",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BUPIVACAINE"
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{
"abstract": "Intraperitoneal chemotherapy using paclitaxel is considered an experimental approach for treating peritoneal carcinomatosis. This study aimed to determine the recommended dose, and to evaluate the clinical efficacy and safety, of the combination of intravenous gemcitabine, intravenous nab-paclitaxel and intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis.\n\n\n\nThe frequencies of dose-limiting toxicities were evaluated, and the recommended dose was determined in phase I. The primary endpoint of the phase II analysis was overall survival rate at 1 year. Secondary endpoints were antitumour effects, symptom-relieving effects, safety and overall survival.\n\n\n\nThe recommended doses of intravenous gemcitabine, intravenous nab-paclitaxel and intraperitoneal paclitaxel were 800, 75 and 20 mg/m2 respectively. Among 46 patients enrolled in phase II, the median time to treatment failure was 6·0 (range 0-22·6) months. The response and disease control rates were 21 of 43 and 41 of 43 respectively. Ascites disappeared in 12 of 30 patients, and cytology became negative in 18 of 46. The median survival time was 14·5 months, and the 1-year overall survival rate was 61 per cent. Conversion surgery was performed in eight of 46 patients, and those who underwent resection survived significantly longer than those who were not treated surgically (median survival not reached versus 12·4 months). Grade 3-4 haematological toxicities developed in 35 of 46 patients, whereas non-haematological adverse events occurred in seven patients.\n\n\n\nAdding intraperitoneal paclitaxel had clinical efficacy with acceptable tolerability.",
"affiliations": "Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Surgery and Science Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan.;Department of Surgery, Kansai Medical University, Hirakata, Japan.;Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Surgery and Science Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan.;Department of Surgery, Kansai Medical University, Hirakata, Japan.;Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Surgery and Science Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan.;Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.;Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, Sapporo, Japan.;Department of Hepatobiliary-pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Ehime, Fukuoka, Japan.;Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Biostatistics Centre, Graduate School of Medicine, Kurume University, Fukuoka, Japan.;Department of Gastrointestinal Surgery, Jichi Medical University, Tochigi, Japan.;Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Surgery, Kansai Medical University, Hirakata, Japan.;Department of Surgery, Kansai Medical University, Hirakata, Japan.",
"authors": "Yamada|S|S|0000-0001-9912-9119;Fujii|T|T|;Yamamoto|T|T|0000-0002-7951-7429;Takami|H|H|;Yoshioka|I|I|;Yamaki|S|S|;Sonohara|F|F|;Shibuya|K|K|;Motoi|F|F|;Hirano|S|S|;Murakami|Y|Y|0000-0001-6208-3081;Inoue|H|H|;Hayashi|M|M|;Murotani|K|K|;Kitayama|J|J|;Ishikawa|H|H|;Kodera|Y|Y|;Sekimoto|M|M|;Satoi|S|S|0000-0001-6527-5409",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1002/bjs.11792",
"fulltext": "\n==== Front\nBr J Surg\nBr J Surg\n10.1002/(ISSN)1365-2168\nBJS\nThe British Journal of Surgery\n0007-1323 1365-2168 John Wiley & Sons, Ltd. Chichester, UK \n\n32638367\n10.1002/bjs.11792\nBJS11792\nHPB\nOriginal Article\nOriginal Articles\nPhase I/II study of adding intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis\nIntraperitoneal therapy for metastatic pancreatic ductal adenocarcinomaS. Yamada, T. Fujii, T. Yamamoto, H. Takami, I. Yoshioka, S. Yamaki et al.Yamada S. https://orcid.org/0000-0001-9912-9119\n1\n Fujii T. \n2\n Yamamoto T. https://orcid.org/0000-0002-7951-7429\n3\n Takami H. \n1\n Yoshioka I. \n2\n Yamaki S. \n3\n Sonohara F. \n1\n Shibuya K. \n2\n Motoi F. \n4\n Hirano S. \n5\n Murakami Y. https://orcid.org/0000-0001-6208-3081\n6\n Inoue H. \n7\n Hayashi M. \n1\n Murotani K. \n8\n Kitayama J. \n9\n Ishikawa H. \n10\n Kodera Y. \n1\n Sekimoto M. \n3\n Satoi S. https://orcid.org/0000-0001-6527-5409\n3\nsatoi@hirakata.kmu.ac.jp \n1 \nGastroenterological Surgery\nNagoya University Graduate School of Medicine\nNagoya\nJapan\n\n\n2 \nDepartment of Surgery and Science Faculty of Medicine, Academic Assembly\nUniversity of Toyama\nToyama\nJapan\n\n\n3 \nDepartment of Surgery\nKansai Medical University\nHirakata\nJapan\n\n\n4 \nDepartment of Surgery\nTohoku University Graduate School of Medicine\nSendai\nJapan\n\n\n5 \nDepartment of Surgery, Institute of Biomedical and Health Sciences\nHiroshima University\nHiroshima\nJapan\n\n\n6 \nDepartment of Gastroenterological Surgery II, Faculty of Medicine\nHokkaido University\nSapporo\nJapan\n\n\n7 \nDepartment of Hepatobiliary–pancreatic and Breast Surgery\nEhime University Graduate School of Medicine, Ehime\nFukuoka\nJapan\n\n\n8 \nBiostatistics Centre, Graduate School of Medicine\nKurume University\nFukuoka\nJapan\n\n\n9 \nDepartment of Gastrointestinal Surgery\nJichi Medical University\nTochigi\nJapan\n\n\n10 \nDepartment of Molecular‐Targeting Cancer Prevention, Graduate School of Medical Science\nKyoto Prefectural University of Medicine\nKyoto\nJapan\n\n* Correspondence to: Professor S. Satoi, Department of Surgery, Kansai Medical University, 2‐5‐1, Shin‐machi, Hirakata 573‐1010, Japan (e‐mail: satoi@hirakata.kmu.ac.jp)\n07 7 2020 \n12 2020 \n107 13 10.1002/bjs.v107.131811 1817\n23 2 2020 27 4 2020 19 5 2020 © 2020 The Authors. British Journal of Surgery published by John Wiley & Sons Ltd on behalf of BJS Society 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.Background\nIntraperitoneal chemotherapy using paclitaxel is considered an experimental approach for treating peritoneal carcinomatosis. This study aimed to determine the recommended dose, and to evaluate the clinical efficacy and safety, of the combination of intravenous gemcitabine, intravenous nab‐paclitaxel and intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis.\n\nMethods\nThe frequencies of dose‐limiting toxicities were evaluated, and the recommended dose was determined in phase I. The primary endpoint of the phase II analysis was overall survival rate at 1 year. Secondary endpoints were antitumour effects, symptom‐relieving effects, safety and overall survival.\n\nResults\nThe recommended doses of intravenous gemcitabine, intravenous nab‐paclitaxel and intraperitoneal paclitaxel were 800, 75 and 20 mg/m2 respectively. Among 46 patients enrolled in phase II, the median time to treatment failure was 6·0 (range 0–22·6) months. The response and disease control rates were 21 of 43 and 41 of 43 respectively. Ascites disappeared in 12 of 30 patients, and cytology became negative in 18 of 46. The median survival time was 14·5 months, and the 1‐year overall survival rate was 61 per cent. Conversion surgery was performed in eight of 46 patients, and those who underwent resection survived significantly longer than those who were not treated surgically (median survival not reached versus 12·4 months). Grade 3–4 haematological toxicities developed in 35 of 46 patients, whereas non‐haematological adverse events occurred in seven patients.\n\nConclusion\nAdding intraperitoneal paclitaxel had clinical efficacy with acceptable tolerability.\n\nThis multicentre phase I/II study was undertaken to determine the recommended dose of the combination of intravenous gemcitabine, intravenous nab‐paclitaxel and intraperitoneal paclitaxel in patients with pancreatic ductal adenocarcinoma and peritoneal metastasis, and to evaluate its clinical efficacy and safety. This regimen exhibited promising clinical efficacy, with acceptable tolerability.\n\n\n\nEffective and safe in pancreatic cancer\n\nAntecedentes\nLa quimioterapia intraperitoneal con paclitaxel se considera una terapia experimental para el tratamiento de la carcinomatosis peritoneal. Este estudio tuvo como objetivo determinar la dosis recomendada y evaluar la eficacia clínica y la seguridad de la combinación de gemcitabina intravenosa, nab‐paclitaxel intravenoso y paclitaxel intraperitoneal en pacientes con cáncer de páncreas y metástasis peritoneales.\n\nMétodos\nSe evaluaron las frecuencias de las toxicidades limitantes de la dosis, y la dosis recomendada se determinó en la fase I. El objetivo principal de la fase II fue la tasa de supervivencia global a 1 año. Los objetivos secundarios fueron los efectos antitumorales, los efectos de alivio de los síntomas, la seguridad y la supervivencia global.\n\nResultados\nLas dosis recomendadas de gemcitabina intravenosa, nab‐paclitaxel intravenoso y paclitaxel intraperitoneal fueron de 800, 75 y 20 mg/m2, respectivamente. De los 46 pacientes incluidos en la fase II del estudio, la mediana de tiempo hasta el fracaso del tratamiento fue de 6,0 meses (rango, 0‐22,6). Las tasas de respuesta y de control de la enfermedad fueron del 45% y 95%, respectivamente. La ascitis desapareció en el 40% de los pacientes, y la citología se negativizó en el 39% de los pacientes. La mediana del tiempo de supervivencia fue de 14,5 meses y la tasa de supervivencia global a 1 año del 60,9%. La cirugía de rescate se realizó en ocho (17%) pacientes, y los que se sometieron a cirugía sobrevivieron significativamente más tiempo que los que no fueron tratados quirúrgicamente (mediana de supervivencia no alcanzada versus 12,4 meses). Las toxicidades hematológicas de grado 3/4 ocurrieron en el 76% de los pacientes, mientras que los eventos adversos no hematológicos se presentaron en el 15% de los pacientes.\n\nConclusión\nAgregar paclitaxel intraperitoneal tuvo eficacia clínica con una tolerabilidad aceptable. (UMIN000018878)\n\n source-schema-version-number2.0cover-dateDecember 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.4 mode:remove_FC converted:26.11.2020\n==== Body\nIntroduction\nPancreatic cancer has a poor prognosis, particularly for disseminated disease\n1\n. The presence of peritoneal metastasis is often associated with ascites and intestinal obstruction, leading to malnutrition and poor performance status, which could deprive patients of the opportunity to receive chemotherapy\n2\n. Intraperitoneal chemotherapy appears advantageous owing to higher drug concentrations achieved in the peritoneal cavity, compared with systemic chemotherapy\n3\n, \n4\n, \n5\n, \n6\n.\n\nFavourable clinical effects of intraperitoneal paclitaxel have been reported in clinical trials of patients with peritoneal metastasis, including those with ovarian\n3\n, \n4\n, gastric\n5\n, \n6\n and pancreatic\n7\n cancer. A previous phase II study\n8\n of intravenous and intraperitoneal paclitaxel combined with S‐1 for patients with pancreatic cancer and peritoneal metastasis demonstrated good outcomes, with favourable response and disease control rates. The median survival time and 1‐year overall survival rate were 16·3 months and 62 per cent, and conversion surgery was performed in one‐quarter of the enrolled patients\n8\n. Recently, nab‐paclitaxel combined with gemcitabine was shown to be the standard treatment option for patients with pancreatic cancer and distant metastasis\n9\n.\n\nThe aims of this phase I/II study were to determine the recommended dose for the combination of intravenous nab‐paclitaxel with gemcitabine and intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis, and to evaluate its clinical efficacy and safety.\n\nMethods\nThe eligibility and exclusion criteria are shown in Fig. \n1\n. This study was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by the institutional review board of the affiliated hospital. The registration number for this clinical trial is UMIN000018878. The last follow‐up date was 31 December 2019.\n\nTable 1 Clinical responses to treatment\n\n\tNo. of patients* (n = 46)\t\n\nTumour shrinkage (%)\n\n†\n\n\t20 (0–100)\t\n\nCA19‐9\n\t\t\nMinimum (units/ml)†\n\t72 (4–23 700)\t\nDecreased ratio (%)†\n\t84·4 (16·9–99·1)\t\nNormalization\t12\t\n\nObjective tumour responses\n\t\nn = 43\t\nBest RECIST category\t\t\nComplete response\t2\t\nPartial response\t19\t\nStable disease\t20\t\nProgressive disease\t2\t\nResponse\t21\t\nDisease control\t41\t\n\nPeritoneal cytology turned negative\n\t18\t\n\nDisappearance of ascites\n\t12 of 30\t\n\nConversion surgery\n\t8\t\n* Unless indicated otherwise;\n\n† values are median (range). CA19‐9, carbohydrate antigen 19‐9; RECIST, Response Evaluation Criteria in Solid Tumours.\n\nTreatment\nIf peritoneal dissemination or positive peritoneal cytology was detected during staging laparoscopy or open laparotomy, a peritoneal access port was implanted in the lower abdomen. Intravenous nab‐paclitaxel combined with gemcitabine was administered along with intraperitoneal paclitaxel on days 1, 8 and 15, followed by 1 week of rest. The treatment course was repeated every 4 weeks until unacceptable toxicity had developed, disease progression or surgery (Fig. \n1\n). The criteria for surgical resection (conversion surgery) were: an Eastern Cooperative Oncology Group performance status of 0 or 1; marked tumour shrinkage; decrease or normalization of tumour marker levels; washing cytology via peritoneal access port turned negative (twice in a row); and disappearance of peritoneal deposits on staging laparoscopy\n8\n. To obtain a sufficient clinical effect with this regimen and avoid early peritoneal recurrence, the decision to proceed to conversion surgery was based on an interval exceeding 8 months between the initial treatment and surgical resection, which was associated with favourable prognosis in patients with initially unresectable pancreatic cancer in a previous study\n10\n.\n\nFig. 1 Study protocol and flow chart\nGEM, gemcitabine; PAX, paclitaxel.\n\n\nBJS-11792-FIG-0001-cPrimary and secondary endpoints\nThe primary endpoint of phase II of the study was the 1‐year overall survival rate. The secondary endpoints were antitumour effects, symptom‐relieving effects, safety and overall survival.\n\nObjective tumour responses were classified according to Response Evaluation Criteria in Solid Tumours (RECIST) guidelines version 1.1\n11\n. To evaluate antitumour effects on peritoneal metastases, peritoneal washing cytology specimens were examined every 2 months.\n\nToxicity was monitored weekly and graded according to the National Cancer Institute–Common Terminology Criteria for Adverse Events (CTCAE) version 4.0\n12\n.\n\nDefinition of dose‐limiting toxicities and determination of recommended dose\nThe frequencies of dose‐limiting toxicities were evaluated, and the recommended dose was determined during phase I of the study. Dose‐limiting toxicities were determined during the first two cycles of chemotherapy. Dose‐limiting toxicities were defined according to CTCAE version 4.0\n12\n based on the presence of one or more of the following events: grade 4 leucopenia or neutropenia; grade 3 neutropenia complicated by fever of at least 38°C; grade 3–4 anaemia, thrombocytopenia or non‐haematological toxicities; and more than 2 weeks of drug withdrawal within one cycle. The maximum tolerated dose was determined, and the previous level was set as the recommended dose\n13\n.\n\nStatistical analysis\nThe sample size was calculated for an estimated overall survival rate at 1 year after treatment initiation for patients with metastatic pancreatic cancer of 25 per cent. Assuming a null hypothesis of 25 per cent and an alternative hypothesis of 45 per cent with a one‐sided type I error of 0·05 and power of 0·8, enrolment of 24 patients was required.\n\nContinuous variables are expressed as median (range). Overall survival was defined as the interval from the start of treatment to death from any cause. Survival analysis was based on the Kaplan–Meier method, with evaluation of differences using the log rank test. A binary logistic regression model using the backward method was employed to predict the use of conversion surgery. The level of statistical significance was set at P < 0·050. All statistical analyses were done using JMP® Pro version 14.2.0 (SAS Institute, Cary, North Carolina, USA).\n\nResults\nA total of 50 patients diagnosed with pancreatic cancer and peritoneal metastasis were enrolled in this phase I/II study from seven Japanese centres; ten patients participated in phase I and 46 (including 6 patients from phase I) in phase II (Fig. \n1\n).\n\nDetermination of recommended dose\nDose levels and dose‐limiting toxicities in phase I are shown in \nTable S1\n (supporting information). At dose level 1, three of four patients experienced dose‐limiting toxicities. Therefore, the next six patients were enrolled at level 0; only one patient experienced a dose‐limiting toxicity (grade 4 neutropenia) at this level. Based on these results, the recommended doses for intravenous gemcitabine, intravenous nab‐paclitaxel and intraperitoneal paclitaxel were 800, 75 and 20 mg/m\n2\n respectively.\n\nPatient characteristics\nA total of 46 patients were enrolled in phase II, and drugs were administered at the recommended dose (level 0). The tumour was located in the pancreatic head in 13 patients and the body/tail in 33. Median tumour diameter was 36 (range 18–64) mm. Primary tumours were categorized as resectable in 12 patients, borderline resectable in 11, and unresectable and locally advanced in 23 patients\n14\n. Malignant ascites was observed in 30 of the 46 patients on laparoscopy or laparotomy. All patients had positive intraperitoneal cytology, and 29 had pathological confirmation of peritoneal dissemination. The median duration of treatment was 6·0 (range 0–22·6) months (\nTable S2\n, supporting information).\n\nClinical responses and survival by treatment type\nDuring treatment, median primary tumour shrinkage was 20 (range 0–100) per cent (Fig. \n2a,b\n). CA19‐9 levels decreased by a median of 84·4 (range 16·9–99·1) per cent, and normalized in 12 patients. The response and disease control rates were 21 of 43 and 41 of 43 respectively. Peritoneal washing cytology turned negative in 18 of 46 patients, and malignant ascites disappeared in 12 of 30 (Table \n1\n).\n\nFig. 2 Tumour response and survival\na Waterfall plot of tumour shrinkage response. Median primary tumour shrinkage was 20 per cent (red line). b Spider plot showing tumour response over time. The dotted line indicates no change. c Overall survival of 46 patients with pancreatic ductal adenocarcinoma and peritoneal metastasis. The shaded area represents the 95 per cent confidence interval. d Comparison of survival between patients who underwent conversion surgery and those who did not. P = 0·004 (log rank test). OS, overall survival.\n\n\nBJS-11792-FIG-0002-cTable 2 Clinical characteristics of patients who underwent conversion surgery\n\nPatient no.\tAge (years)\tSex\tTumour size (mm)*\n\tBest RECIST category\tCA19‐9, (units/l)*\n\tOperative procedure\tR\tEvans grade\tTumour stage\tOS (months)\tStatus\t\n1\t74\tF\t46 → 18\tPR\t232 → 14\tPD + PVR\tR0\tIIB\tT1 N0 M0\t13·5\tDead\t\n2\t67\tF\t25 → 10\tPR\t837 → 48\tDP\tR0\tIIA\tT3 N1 M0\t32·7\tAlive\t\n3\t75\tM\t38 → 25\tPR\t1127 → 43\tDP‐CAR\tR0\tIIA\tT3 N0 M0\t15·1\tDead\t\n4\t73\tF\t41 → 40\tSD\t59 → 47\tPD + PVR\tR1\tIIA\tT3 N1 M0\t23·4\tAlive\t\n5\t77\tM\t30 → 30\tSD\t246 → 23\tDP\tR0\tIIB\tT2 N1 M0\t23·4\tAlive\t\n6\t54\tF\t25 → 0\tCR\t167 → 12\tDP\tR0\tIV\tT3 N1 M0\t17·7\tAlive\t\n7\t74\tM\t52 → 10\tPR\t162 → 37\tPD + PVR\tR0\tIII\tT3 N0 M0\t15·4\tAlive\t\n8\t77\tF\t46 → 23\tPR\t703 → 17\tDP\tR0\tIII\tT1 N0 M0\t14·2\tAlive\t\n* Change from before treatment to before surgery. RECIST, Response Evaluation Criteria in Solid Tumours; CA19‐9, carbohydrate antigen 19‐9; OS, overall survival; PR, partial response; PD, pancreatoduodenectomy; PVR, portal vein resection; DP, distal pancreatectomy; DP‐CAR, distal pancreatectomy with coeliac artery resection; SD, stable disease; CR, complete response.\n\nAll eligible patients were followed up for at least 12 months. Median overall survival was 14·5 (range 11·5–19·2) months, and 1‐ and 2‐year overall survival rates were 61 and 32 per cent respectively (Fig. \n2c\n).\n\nConversion surgery\nEight of the 46 patients underwent conversion surgery (Table \n2\n). The tumour was located in the pancreatic body and tail in seven patients. Six patients had peritoneal dissemination at diagnosis, and two patients had positive peritoneal washing cytology plus unresectable locally advanced cancer before surgery. The median time to surgery was 8·8 (range 4·1–12·2) months after the initiation of chemotherapy. Seven patients underwent R0 resection. The Evans (tumour regression) grade was IIA in three patients, IIB and III in two patients each, and IV in one patient.\n\nConcerning overall survival, patients who underwent conversion surgery survived significantly longer than those who did not (median survival not reached versus 12·4 (range 11·0–18·1) months; P = 0·004) (Fig. \n2d\n).\n\nAdverse event profile\nThe adverse events data are summarized in \nTable S3\n (supporting information). Grade 3–4 haematological adverse events occurred in 35 of 46 patients, including leucocytopenia (22), neutropenia (32), febrile neutropenia (4), anaemia (8) and thrombocytopenia (6). Grade 3–4 non‐haematological adverse events occurred in seven patients, including appetite loss (4) and nausea (2). A grade 3–4 peritoneal port problem was observed in one patient.\n\nPrediction of conversion surgery in patients with peritoneal dissemination\nUnivariable analysis identified a shift to negative peritoneal cytology and normalization of CA19‐9 levels as significant predictors of survival. In multivariable analysis, age (odds ratio 1·29, 95 per cent c.i. 1·04 to 1·59; P = 0·020) and a shift to negative peritoneal cytology (odds ratio 32·73, 2·71 to 395·30; P = 0·006) were significant predictors of eligibility for conversion surgery (\nTable S4\n, supporting information).\n\nDiscussion\nThis trial demonstrated the clinical efficacy of a chemotherapy regimen comprising intravenous gemcitabine, intravenous nab‐paclitaxel and intraperitoneal paclitaxel, with acceptable tolerability, in patients with peritoneal metastasis from pancreatic cancer. Although the clinical response and survival data did not exceed those of an S‐1‐based regimen in a previous study\n8\n, this strategy represents an option for treating peritoneal disease in countries where S‐1 is not available.\n\nIntraperitoneal chemotherapy enables peritoneal deposits to be exposed to high concentrations of drugs without increasing the systemic concentration to toxic levels\n15\n. The duration of effectiveness after intraperitoneal administration is determined by the molecular characteristics of the drug. In this regard, paclitaxel is a large‐molecule lipophilic drug that is absorbed slowly\n3\n. In addition to this pharmacokinetic advantage, combination with systemic chemotherapy is a key variable in intraperitoneal chemotherapy. Ishigami and colleagues\n16\n established the use of intravenous/intraperitoneal paclitaxel combined with S‐1 therapy in patients with gastric cancer, and conducted the phase III PHOENIX‐GC trial to compare this regimen with standard therapy. The present authors\n8\n also reported the promising clinical efficacy and acceptable tolerability of intravenous/intraperitoneal paclitaxel combined with S‐1 therapy in patients with pancreatic cancer and peritoneal metastasis. In the present study, intraperitoneal paclitaxel was added to the combination of intravenous gemcitabine and intravenous nab‐paclitaxel, which has been established as a standard therapy for metastatic disease\n9\n, and its efficacy was confirmed to be similar to that reported previously for intravenous/intraperitoneal paclitaxel and S‐1 therapy.\n\nA previous study\n17\n reported poor overall survival following weekly paclitaxel in patients with pancreatic cancer and malignant ascites. Another study\n2\n revealed median survival times of 8 months in patients with pancreatic cancer and peritoneal dissemination, and 13 months in those with locally advanced disease and positive peritoneal washing cytology. Considering that patients with peritoneal metastasis generally have a poor prognosis, the results of the present study may be considered encouraging. Conversely, no significant improvement was noted compared with the effects of a previous S‐1‐based regimen\n8\n, despite the use of state‐of‐the‐art systemic therapy in combination with intraperitoneal paclitaxel.\n\nRecently, multidisciplinary treatment combining chemotherapy and surgery has been used widely and regarded as a promising strategy. In particular, conversion surgery for metastatic disease has an advantage in that chemotherapy is administered to patients with a better performance status. The combination therapy used in the present study enabled eight of 46 patients to be eligible for conversion surgery. The median survival time was not reached in patients who underwent conversion surgery, which is a considerable achievement given the generally poor outcomes of patients with pancreatic cancer and peritoneal disease. Median survival time after conversion surgery for pancreatic cancer has generally been reported in the range 30–52 months\n10\n, \n18\n, \n19\n, \n20\n. The present combination therapy has performed remarkably in terms of both conversion rate and survival outcome, and its potential to control both peritoneal metastasis and the primary tumour was proven. However, this investigation was conducted as a phase I/II study with a single‐arm design; the bias in its clinical implications must be recognized. A phase III study is being planned to compare survival outcomes between the intraperitoneal therapy used here and standard chemotherapy.\n\nRegarding adverse events, grade 3–4 haematological toxicities occurred in 35 of 46 patients and non‐haematological adverse events in seven. In particular, the rate of haematological toxicities was high, but the incidence and severity were comparable to those of standard chemotherapy regimens\n9\n, \n21\n and previous findings\n8\n. In the phase II analysis, grade 4 neutropenia was noted in seven of 40 patients (18 per cent); however, these events were well managed and tolerable. Intraperitoneal port‐related adverse events were less frequent than in the authors' initial experience\n8\n, which was a meaningful result for this intraperitoneal therapy.\n\nSupporting information\n\nAppendix S1: Supporting information\n\nClick here for additional data file.\n\n Acknowledgements\nS. Yamada and T. Yamamoto are joint first authors of this article. The authors thank S. Hirooka, H. Ryota, N. Kondo, K. Uemura, Y. Nagakawa, A. Tsuchida, A. Matsushita, Y. Nakamura, K. Asai, M. Watanabe, T. Asano, K. Wada, M. Yasunaga, Y. Takada, G. Honda, H. Shinchi, Y. Mataki, S. Shimizu, F. Miura and N. 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Ann Surg \n2016 ; 265 : 397 –401\n.\n9 \n\nVon Hoff \nDD \n, \nErvin \nT \n, \nArena \nFP \n, \nChiorean \nEG \n, \nInfante \nJ \n, \nMoore \nM \n\net al\nIncreased survival in pancreatic cancer with nab‐paclitaxel plus gemcitabine\n. N Engl J Med \n2013 ; 369 : 1691 –1703\n.24131140 \n10 \n\nSatoi \nS \n, \nYamaue \nH \n, \nKato \nK \n, \nTakahashi \nS \n, \nHirono \nS \n, \nTakeda \nS \n\net al\nRole of adjuvant surgery for patients with initially unresectable pancreatic cancer with a long‐term favorable response to non‐surgical anti‐cancer treatments: results of a project study for pancreatic surgery by the Japanese Society of Hepato‐Biliary‐Pancreatic Surgery\n. J Hepatobiliary Pancreat Sci \n2013 ; 20 : 590 –600\n.23660962 \n11 \n\nEisenhauer \nEA \n, \nTherasse \nP \n, \nBogaerts \nJ \n, \nSchwartz \nLH \n, \nSargent \nD \n, \nFord \nR \n\net al\nNew response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)\n. 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Oncology \n2009 ; 76 : 311 –314\n.19299904 \n16 \n\nIshigami \nH \n, \nFujiwara \nY \n, \nFukushima \nR \n, \nNashimoto \nA \n, \nYabusaki \nH \n, \nImano \nM \n\net al\nPhase III trial comparing intraperitoneal and intravenous paclitaxel plus S‐1 versus cisplatin Plus S‐1 in patients with gastric cancer with peritoneal metastasis: PHOENIX‐GC trial\n. J Clin Oncol \n2018 ; 36 : 1922 –1929\n.29746229 \n17 \n\nShukuya \nT \n, \nYasui \nH \n, \nBoku \nN \n, \nOnozawa \nY \n, \nFukutomi \nA \n, \nYamazaki \nK \n\net al\nWeekly paclitaxel after failure of gemcitabine in pancreatic cancer patients with malignant ascites: a retrospective study\n. Jpn J Clin Oncol \n2010 ; 40 : 1135 –1138\n.20656694 \n18 \n\nDonahue \nTR \n, \nIsacoff \nWH \n, \nHines \nOJ \n, \nTomlinson \nJS \n, \nFarrell \nJJ \n, \nBhat \nYM \n\net al\nDownstaging chemotherapy and alteration in the classic computed tomography/magnetic resonance imaging signs of vascular involvement in patients with pancreaticobiliary malignant tumors: influence on patient selection for surgery\n. Arch Surg \n2011 ; 146 : 836 –843\n.21768431 \n19 \n\nKatz \nMH \n, \nFleming \nJB \n, \nBhosale \nP \n, \nVaradhachary \nG \n, \nLee \nJE \n, \nWolff \nR \n\net al\nResponse of borderline resectable pancreatic cancer to neoadjuvant therapy is not reflected by radiographic indicators\n. Cancer \n2012 ; 118 : 5749 –5756\n.22605518 \n20 \n\nSatoi \nS \n, \nYamamoto \nT \n, \nYamaki \nS \n, \nSakaguchi \nT \n, \nSekimoto \nM \n. Surgical indication for and desirable outcomes of conversion surgery in patients with initially unresectable pancreatic ductal adenocarcinoma\n. Ann Gastroenterol Surg \n2019 ; 4 : 6 –13\n.32021953 \n21 \n\nUeno \nH \n, \nIkeda \nM \n, \nUeno \nM \n, \nMizuno \nN \n, \nIoka \nT \n, \nOmuro \nY \n\net al\nPhase I/II study of nab‐paclitaxel plus gemcitabine for chemotherapy‐naive Japanese patients with metastatic pancreatic cancer\n. Cancer Chemother Pharmacol \n2016 ; 77 : 595 –603\n.26842789\n\n",
"fulltext_license": "CC BY",
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"issue": "107(13)",
"journal": "The British journal of surgery",
"keywords": null,
"medline_ta": "Br J Surg",
"mesh_terms": "D000368:Aged; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D021441:Carcinoma, Pancreatic Ductal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007274:Injections, Intraperitoneal; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel; D010190:Pancreatic Neoplasms; D010534:Peritoneal Neoplasms; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "0372553",
"other_id": null,
"pages": "1811-1817",
"pmc": null,
"pmid": "32638367",
"pubdate": "2020-12",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": "19097774;26842789;23660962;20656694;24676891;19605503;22605518;26791083;28059968;24131140;29502139;29746229;22850624;32021953;9704711;19299904;16394300;20947926;21768431",
"title": "Phase I/II study of adding intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis.",
"title_normalized": "phase i ii study of adding intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis"
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"companynumb": "JP-PFIZER INC-2020274522",
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"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
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"abstract": "OBJECTIVE\nTo report on a case of acute transient myopia associated with ciliochoroidal detachment induced by indapamide.\n\n\nMETHODS\nCase report. Clinical examination, ultrasonography, and fluorescein angiography were performed during the acute phase of disease and convalescence.\n\n\nRESULTS\nAfter indapamide was discontinued, acute bilateral myopia, which was associated with anterior chamber shallowing and diffuse choroidal thickening, resolved spontaneously 8 days after onset. The initial angiography showed scattered islands of delayed fluorescein filling that disappeared without any permanent change by day 30.\n\n\nCONCLUSIONS\nIndapamide can induce spontaneously resolving transient myopia associated with diffuse choroidal thickening.",
"affiliations": "Department of Ophthalmology, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Université Paris 7, Paris, France.",
"authors": "Blain|P|P|;Paques|M|M|;Massin|P|P|;Erginay|A|A|;Santiago|P|P|;Gaudric|A|A|",
"chemical_list": "D000959:Antihypertensive Agents; D007190:Indapamide",
"country": "United States",
"delete": false,
"doi": "10.1016/s0002-9394(99)00402-x",
"fulltext": null,
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"issn_linking": "0002-9394",
"issue": "129(4)",
"journal": "American journal of ophthalmology",
"keywords": null,
"medline_ta": "Am J Ophthalmol",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000959:Antihypertensive Agents; D015862:Choroid Diseases; D005451:Fluorescein Angiography; D006801:Humans; D007190:Indapamide; D008297:Male; D009216:Myopia",
"nlm_unique_id": "0370500",
"other_id": null,
"pages": "538-40",
"pmc": null,
"pmid": "10764870",
"pubdate": "2000-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute transient myopia induced by indapamide.",
"title_normalized": "acute transient myopia induced by indapamide"
} | [
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"companynumb": "FR-SA-2019SA325209",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
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"actiondrug": "1",
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"activesubstancename": "INDAPAMIDE"
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{
"abstract": "The aim of our study was to assess the utility of next generation sequencing (NGS) for predicting toxicity and clinical response to thiopurine drugs in paediatric patients with inflammatory bowel disease. Exome data for 100 patients were assessed against biochemically measured TPMT enzyme activity, clinical response and adverse effects. The TPMT gene and a panel of 15 other genes implicated in thiopurine toxicity were analysed using a gene based statistical test (SKAT-O test). Nine patients out of 100 (Crohn's disease- 67, ulcerative colitis- 23 and IBDU-10) had known TPMT mutations associated with deficient enzyme activity. A novel and a highly pathogenic TPMT variant not detectable through standard genotyping, was identified through NGS in an individual intolerant to thiopurines. Of the 14 patients intolerant to thiopurines, NGS identified deleterious TPMT variants in 5 individuals whereas the biochemical test identified 8 individuals as intolerant (sensitivity 35.7% and 57.14%; specificity 93.75% and 50% respectively). SKAT-O test identified a significant association between MOCOS gene and TPMT activity (p = 0.0015), not previously reported. Although NGS has the ability to detect rare or novel variants not otherwise identified through standard genotyping, it demonstrates no clear advantage over the biochemical test in predicting toxicity in our modest cohort.",
"affiliations": "Human Genetics and Genomic medicine, University of Southampton, Southampton, UK.;Human Genetics and Genomic medicine, University of Southampton, Southampton, UK.;Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, UK.;Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, UK.;Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, UK.;Cancer Sciences Division, Faculty of Medicine, University Hospital Southampton, Southampton, UK.;Cancer Sciences Division, Faculty of Medicine, University Hospital Southampton, Southampton, UK.;Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, UK.;Human Genetics and Genomic medicine, University of Southampton, Southampton, UK.",
"authors": "Coelho|Tracy|T|;Andreoletti|Gaia|G|;Ashton|James J|JJ|;Batra|Akshay|A|;Afzal|Nadeem Ahmad|NA|;Gao|Yifang|Y|;Williams|Anthony P|AP|;Beattie|Robert M|RM|;Ennis|Sarah|S|",
"chemical_list": "D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; C425823:MOCOS protein, human; D013466:Sulfurtransferases; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.1038/srep34658",
"fulltext": "\n==== Front\nSci RepSci RepScientific Reports2045-2322Nature Publishing Group srep3465810.1038/srep34658ArticleGenes implicated in thiopurine-induced toxicity: Comparing TPMT enzyme activity with clinical phenotype and exome data in a paediatric IBD cohort Coelho Tracy a12*Andreoletti Gaia 1*Ashton James J. 2Batra Akshay 2Afzal Nadeem Ahmad 2Gao Yifang 3Williams Anthony P. 3Beattie Robert M. 2Ennis Sarah 11 Human Genetics and Genomic medicine, University of Southampton, Southampton, UK2 Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, UK3 Cancer Sciences Division, Faculty of Medicine, University Hospital Southampton, Southampton, UKa T.F.Coelho@soton.ac.uk* These authors contributed equally to this work.\n\n05 10 2016 2016 6 3465806 06 2016 13 09 2016 Copyright © 2016, The Author(s)2016The Author(s)This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/The aim of our study was to assess the utility of next generation sequencing (NGS) for predicting toxicity and clinical response to thiopurine drugs in paediatric patients with inflammatory bowel disease. Exome data for 100 patients were assessed against biochemically measured TPMT enzyme activity, clinical response and adverse effects. The TPMT gene and a panel of 15 other genes implicated in thiopurine toxicity were analysed using a gene based statistical test (SKAT-O test). Nine patients out of 100 (Crohn’s disease- 67, ulcerative colitis- 23 and IBDU-10) had known TPMT mutations associated with deficient enzyme activity. A novel and a highly pathogenic TPMT variant not detectable through standard genotyping, was identified through NGS in an individual intolerant to thiopurines. Of the 14 patients intolerant to thiopurines, NGS identified deleterious TPMT variants in 5 individuals whereas the biochemical test identified 8 individuals as intolerant (sensitivity 35.7% and 57.14%; specificity 93.75% and 50% respectively). SKAT-O test identified a significant association between MOCOS gene and TPMT activity (p = 0.0015), not previously reported. Although NGS has the ability to detect rare or novel variants not otherwise identified through standard genotyping, it demonstrates no clear advantage over the biochemical test in predicting toxicity in our modest cohort.\n==== Body\nThiopurine drugs, which include azathioprine and 6-mercaptopurine (6-MP) have been effectively used in inflammatory bowel disease for more than 30 years. They are also widely used in the treatment of patients with neoplastic conditions, post-organ transplantation and a wide range of autoimmune and inflammatory conditions. However concerns over toxicity and adverse reactions frequently result in discontinuation of treatment and a switch to alternative therapies12. Known adverse reactions include bone marrow suppression, severe gastric intolerance, pancreatitis, hepatotoxicity, skin reactions, susceptibility to infections, risk of malignancy and flu-like symptoms23.\n\nThiopurine S-methyl transferase (TPMT) is a key enzyme involved in the metabolism of thiopurine drugs and functions by catalysing the S-methylation of aromatic and heterocyclic sulfhydryl groups4. TPMT is encoded by a gene located on chromosome 6p22, consisting of 10 exons, encoding one protein domain5. Although the precise mode of action of thiopurines is still unclear, the most important mechanism is thought to be the incorporation of 6-TGNs (thioguanine nucleotides) into the cell DNA, resulting in an impaired DNA synthesis and cell death26 (Fig. 1). The TPMT gene is known to exhibit genetic heterogeneity resulting in wide inter-individual differences, both in terms of clinical efficacy and toxicity profiles based on the enzyme activity27. Approximately 4–11% of individuals of Caucasian origin are heterozygous for a mutant TPMT allele with intermediate enzyme activity, whereas approximately 1 in 300 individuals are homozygous or compound heterozygous with a consequent low or absent TPMT activity37. Current clinical guidelines recommend determining TPMT status in a given patient before commencement of thiopurine therapy; this is achieved by measuring TPMT enzyme activity in the circulating red blood cells or through genotyping known TPMT variants associated with enzyme deficiency289.\n\nThe rationale for assessing the TPMT status before commencement of thiopurine therapy is to minimise the risk of adverse effects whilst aiming for an optimal clinical response. Thiopurines are best avoided in individuals who are deficient or have extremely low TPMT activity and administered at a reduced dose if TPMT activity is intermediate or low normal2910.\n\nAlthough TPMT is the most crucial pharmaco-gene involved in the metabolism of thiopurines, previous studies have highlighted the role of other genes, whose products substantially alter drug metabolism and consequently impact clinical efficacy or toxicity1112131415161718. It is plausible that some proportion of adverse effects observed whilst on treatment in the context of a normal TPMT status (genotype or phenotype), could be explained by variation in genes encoding the other enzymes involved in thiopurine metabolism.\n\nIn this study, we identify genes known to be involved in thiopurine metabolism and determine all coding mutations in these genes in a cohort of 100 children with IBD.\n\nWe assess the joint effect of rare and common variants within the TPMT gene and other genes implicated in thiopurine toxicity on TPMT enzyme activity through the application of a gene based statistical test (SKAT-O). The test was also conducted to investigate the association of these variants with thiopurine tolerance and clinical response.\n\nMaterials and Methods\nStudy Population\nPatients were identified through the paediatric gastroenterology service database based at the University Hospital Southampton (UHS), recruited from outpatient clinics and followed through their treatment. All children were diagnosed using the Porto diagnostic criteria19 and treated according to British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) published guidelines9. Data for one hundred paediatric patients with TPMT phenotype defined as red blood cell enzyme activity and concurrent exome data were analysed.\n\nEthical Approval\nThe study was ethically approved by Southampton and South West Hampshire Research Ethics Committee (09/H0504/125). Informed consent was obtained from all participants before recruitment to the study. All methods were carried out in accordance with the approved and published guidelines.\n\nTPMT Phenotype Determination\nTPMT enzyme activity was measured using standard high performance liquid chromatographic technique20. TPMT enzyme activity level groups were defined as previously described (Fig. 2)2021.\n\nUse of Thiopurines and Monitoring for Adverse Effects\nBritish Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) recommend initiation of treatment with thiopurines for maintenance of remission in individuals who relapse in less than 6 months, have 2 or more relapses per year following initial successful therapy and in all steroid-dependent patients. Practice with regards to initiation of treatment varies among clinicians, but is usually commenced and monitored as per the BSPGHAN guidelines919, with regular blood tests to monitor adverse effects such as bone marrow suppression, pancreatitis, hepatotoxicity and patients are clinically followed up to assess progress through treatment. For this study, bone marrow suppression was defined as leucopoenia (WBC < 3000 mm−3) and/or thrombocytopenia (platelets < 100,000 mm−3); liver toxicity was alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT) or alkaline phosphatase more than twice their normal levels; acute pancreatitis was defined as significant abdominal pain within 3 months of starting thiopurines, accompanied by a serum amylase or lipase level of greater than twice their normal levels as per our local laboratory values22.\n\nEvaluation of response to therapy\nAssessment of clinical poor response or non-response was based on one of the following: (1) Inability to achieve clinical improvement as assessed by global clinical assessment after at least 6 months of thiopurine therapy; (2) Corticosteroid dependence after at least 3 months of thiopurine therapy; (3) Relapse within 6 months of therapy; (4) Use of biologics within 6 months of therapy with thiopurines and; (5) Disease progression needing surgery within 6 months of thiopurine therapy commencement.\n\nIntolerance to treatment was based on all of the following: (1) Occurrence of adverse side effects (including bone marrow suppression, severe gastric intolerance, pancreatitis, hepatotoxicity, skin reactions, flu-like symptoms); (2) Adverse effects unexplained by disease course or other concomitant co-morbidities; and (3) Partial or complete resolution of the observed adverse effects following discontinuation of therapy.\n\nGenes Implicated in Thiopurine Toxicity\nA systematic search was conducted through ovidsp using MEDLINE and EMBASE from inception to the end of March 2015. Only studies in humans describing TPMT genetic variants and other genes involved in thiopurine metabolism and toxicity were included. We applied the TPMT nomenclature committee website (http://www.imh.liu.se/tpmtalleles) that outlines all reported TPMT variants23, to cross-reference against variants identified in this study.\n\nWhole Exome Sequencing and Data Analysis\nDNA Extraction\nGenomic DNA was extracted from peripheral venous blood samples collected in EDTA, using the salting out method as previously described2425.\n\nExome Sequencing\nWhole-exome capture was performed using Agilent SureSelect Human all Exon 51 Mb (versions 4 and 5) capture kit as previously described25. A bespoke script was used to assign individual variants as “novel” if they were not previously reported in the dbSNP137 databases26, 1000 Genomes Project (1 KG)27, the Exome Variant Server (EVS) of European Americans of the NHLI-ESP project with 6500 exomes [http://evs.gs.washington.edu/EVS/], in 46 unrelated human subjects sequenced by Complete Genomics28 or in the Southampton database of reference exomes.\n\nBurden of Mutation Testing\nThe burden of genetic variations within the genes was conducted using a gene-based statistical test (the sequence kernel association optimal unified test- SKAT-O)29. To conduct the test, a group file of non-synonymous, synonymous, splicing, frameshifts and non-frameshift, stop gain and stop loss mutations was created for each of the genes analysed. SKAT-O was executed with the small sample adjustment, by applying MAF threshold of 0.05 to define rare variations within the whole cohort, and using default weights. The EPACTS software package30 was use to perform this test. The test was conducted to assess the impact of variations on TPMT enzyme activity, drug tolerance and clinical response.\n\nResults\nClinical Data\nOf the 100 patients, 78 initiated thiopurines as part of their clinical management while 22 maintained remission without recourse to this therapy. The median duration of follow up for the 78 patients commenced on thiopurines was 46 months (7–156) from diagnosis and 43 months (6–119) from starting therapy with thiopurines (Table 1).\n\nGenes identified in TMPT metabolism and toxicity\nA systematic search of genes implicated in TPMT metabolism and toxicity identified 15 genes with robust evidence from a review of over 3,000 articles (Fig. 1 and Supplementary Table S1) for which we could ascertain variation from exome data. Variation in TMPT and these genes was included in downstream analysis of: (1) biochemically assessed TMPT activity; (2) tolerance to thiopurines and; (3) response to treatment.\n\nBiochemically measured TPMT activity in red blood cells\nThe TPMT enzyme activity was unexpectedly bimodal in distribution across the 100 patients examined in this study. We compared the distribution in our pIBD cohort against the same measure for an independent control group of individuals with various clinical diagnoses, aged ≤18 years from the Wessex region for whom TPMT activity was assessed by the same laboratory over the same period and observed a statistically significant distribution between the groups (P = 7.69 × 10−12) (Fig. 2). While approximately half of our cohort samples had biochemical activity levels within the normal range and half in the intermediate range, almost 80% of control samples had biochemical activity levels falling within the normal range. We believe this may reflect an ascertainment bias in our study cohort due to the fact that exome sequencing was preferentially conducted on children with most severe disease at earliest onset. This will have enriched for children with poor response to first-line treatments.\n\nTPMT gene variants - their correlation with biochemically measured TPMT enzyme activity, thiopurine tolerance and response\nWe identified five TPMT variants across our cohort (Table 2). These included two non-synonymous variants (A154T and Y240C) previously known to impact TMPT function that were found to co-segregate in 9 individuals. The mean biochemical measurement of TMPT activity for this group was 36 mU/L (range 16–56), which is significantly different (p = 0.003) from that found in the 91 individuals without these mutations (mean = 68.1 mU/L). Although exome data are insufficient to resolve haplotypes, we postulate these two variants occur on a single haplotype in all nine individuals, consistent with the complex TPMT allele referred to as TPMT*3A, previously described as the most prevalent TPMT deficiency allele in Caucasians31. Of these 9 patients, 8 were commenced on thiopurine treatment and four were later identified as intolerant to this therapy. All four patients that tolerated thiopurine drugs showed therapeutic response.\n\nOne novel non-synonymous variant (p.A73V) was identified in a female patient with Crohn’s disease and a biochemical activity level of 55 mU/L. In silico tools indicate this variant is strongly conserved (Phylop = 0.99) and likely to have a deleterious impact on enzyme function (GERP = 4.98). The patient was initiated on thiopurine treatment at a reduced dose (1 mg/kg) but developed severe persistent nausea and treatment was discontinued. This variant has since been catalogued as a functionally significant allele by the TPMT nomenclature committee (http://www.imh.liu.se/tpmtalleles) with a unique allele number TPMT*39.\n\nOne UC patient harboured a rare intronic variant (in heterozygote form) proximal to the exon 7 splice junction (c.420-4G > A), this patient had a biochemical activity level of 32 mU/L, was administered thiopurine treatment which was tolerated and subsequently demonstrated therapeutic response. The MaxEnt score (0.95) for this splice junction variant predicts minimal impact on splicing within the gene. While this is positively consistent with drug tolerance, it does not explain the relatively low biochemical activity level observed in this patient.\n\nFinally, we observed a common synonymous variant (I158I) at high frequency (37 heterozygotes and 57 homozygotes). Mean biochemical activity level is 67.1 mU/L (32–99) and 66 mU/L (152-145) across the subgroup of individuals carrying the variant in heterozygous and homozygous state respectively. The very common frequency of this variant and the fact it does not alter amino acid composition is consistent with silent variation having no impact on function.\n\nBurden of mutation testing within TPMT and additional genes implicated in thiopurine toxicity\nWe interrogated exome data across fifteen additional genes implicated in thiopurine metabolism and toxicity. We observed mutations across 11 genes (no variation in HPRT1, GSTM1, FSLT5 and MTHFR).\n\nSKAT-O test was applied to investigate the joint effect of rare, low frequency and common variations within these genes on TPMT enzyme activity, thiopurine tolerance and response.\n\nSignificant evidence for association was observed within MOCOS (p = 0.0015) and TPMT (p = 0.0017) gene with TPMT biochemical activity levels. The test also detected a nominal association between GMPS and drug tolerance (p = 0.0212) as well as variations within IL6ST (p = 0.0084) and ABBC4 (p = 0.0452) and drug response (Table 3, Supplementary Tables S2 and S3).\n\nIndividual tolerance and intolerance\nThiopurine drugs were discontinued in 14 individuals due to adverse effects. Eight of these patients had TPMT enzyme activity in the intermediate category and the rest had TPMT activity in the normal range.\n\nFour of the eight individuals with TPMT enzyme activity in the intermediate range had known TPMT mutations associated with deficient enzyme activity and one individual had a novel TPMT mutation described in the previous section. In the rest of the nine individuals, there was enrichment for deleterious variants within the MOCOS gene and the AOX1 gene (Table 4).\n\nPrediction of thiopurine toxicity showed a specificity of 93.75% through detection of TPMT risk variants compared to 50% for the biochemical test. Both tests had a low sensitivity of 37% and 57% respectively for predicting toxicity (Table 5). However, all the five patients with deleterious variants within the TPMT gene detected through NGS were also identified as potentially intolerant through the biochemical test. Although the biochemical test identified a higher number of individuals intolerant to thiopurines, the difference between the two approaches in predicting toxicity was not statistically significant (P value 0.45, Fisher’s exact test). The clinical data of individuals intolerant to thiopurines, is shown in Table 6 and of the entire cohort in Supplementary Table S4.\n\nDiscussion\nIt is well established that in a small percentage of patients, TPMT genotyping alone or in combination with TPMT phenotype is insufficient to predict tolerance to thiopurine drugs2. Several TPMT variants associated with deficient enzyme activity have been described23, however an appreciable subset of patients with intermediate to low activity do not harbour known risk alleles32. Our study identified nine individuals with the known TPMT mutations (9% compared to 11% reported in previous studies)31. All nine individuals had TPMT enzyme activity levels in the intermediate range in line with expectations; mean TPMT value across this group was significantly different compared to individuals without these mutations (36.6 mU/L compared to 68.1 mU/L, p = 0.003). However 43% of individuals with TPMT activity in the intermediate range did not have the known TPMT mutations. Our results indicate that although prediction of thiopurine toxicity through NGS has a higher specificity compared to the biochemical test, the sensitivity of both methods is clinically suboptimal (35.7% and 57.14% respectively). Among the 14 individuals intolerant to thiopurines, all the 5 patients who harboured deleterious TPMT variants would also have been predicted as potentially intolerant to thiopurines through the biochemical test. Furthermore, all the nine individuals with deleterious variants within the TPMT gene across the cohort of 100 patients would also have been identified as potentially intolerant as all these nine individuals had TPMT enzyme activity levels within the intermediate range. Hence based on first principles, NGS did not have a clear advantage over the biochemical test in predicting thiopurine toxicity.\n\nWe identified a highly pathogenic novel variant in TPMT in an individual who had TPMT enzyme activity level of 55 mU/L, but developed severe gastrointestinal toxicity despite a reduced dose. This suggests that thiopurine toxicity can develop in individuals harbouring rare or yet unknown variants, not detected through standard genotyping. As a widely used practical approach, TPMT genotyping of known variants is considered only when biochemical tests suggest a deficiency or if a patient has recently been transfused. However, a normal genotype for known variants cannot exclude the possibility of rare variation causing TPMT deficiency and development of adverse effects2. Exome sequencing therefore can be a powerful tool in identifying individuals at risk of toxicity who could have been missed through standard TPMT genotyping.\n\nThe SKAT-O test identified a significant association between variations within the MOCOS gene and TPMT enzyme activity (p = 0.0015). Molybdenum cofactor sulfurase (MOCOS) is a protein-coding gene located on 18q12, which sulfurates the molybdenum cofactor in XDH and AOX1, key enzymes involved in the degradation of thiopurines33. Previous studies have suggested a role for MOCOS gene in thiopurine metabolism with possible impact on clinical outcomes in patients with mutations, however an association between MOCOS and TPMT enzyme activity has not been explored. This is the first study to identify a significant role for this gene with variations causing alterations in biochemical enzyme activity. Further work is required to determine how MOCOS influences TPMT function.\n\nWe also detected a nominal association between GMPS and drug tolerance (p = 0.0212). GMPS is involved in the phosphorylation of 6-TIMP (6-thioinosine monophosphate) to thioguanine nucleotides, which is an important step for thiopurines to exert their cytotoxic effects. Further mechanistic studies will be required to elucidate the molecular mechanisms and clearly define the role of these genes involved in the thiopurine metabolic pathway.\n\nA limitation of this study is that only children who had undergone exome analysis with concurrent TPMT values were selected for the study. While approximately half of our cohort patients had TPMT activity in the intermediate range, only 20% of control samples had TPMT activity in the intermediate category. Exome sequencing was preferentially conducted on children with the most severe disease phenotype, which would have enriched for patients with poor response to first-line treatments. Secondly, the selected population is predominantly Caucasian and a relatively small cohort, thereby limiting the general applicability of the results. Following a systematic search of literature to identify genes implicated in thiopurine toxicity, a panel of 15 genes was prioritised for assessment. It is it is possible that potentially pathogenic variants in other genes may have been missed through this approach. However extension of the list of genes examined would compromise power in the highest priority candidate genes.\n\nAlthough there is no clear advantage of NGS over the biochemical test in predicting toxicity, our study demonstrates the strength of NGS as a powerful tool in identifying pathogenic variants in patients not detected through standard genotyping. As high throughput sequencing becomes more accessible and affordable, a more objective approach to assessing pharmaco-genomic variation in all genes involved in the drug metabolism pathway may be indicated in selected patients to guide treatment strategies. Replication in larger studies would be required for a comprehensive curation of candidate genes, possibly paving the way for a targeted gene panel as a reliable predictor of toxicity.\n\nAdditional Information\nHow to cite this article: Coelho, T. et al. Genes implicated in thiopurine-induced toxicity: Comparing TPMT enzyme activity with clinical phenotype and exome data in a paediatric IBD cohort. Sci. Rep.\n6, 34658; doi: 10.1038/srep34658 (2016).\n\nSupplementary Material\nSupplementary Information\n The authors are grateful to all patients and their families. We thank Rachel Haggarty, senior research nurse for recruitment of patients; Nikki J Graham and Sylvia J Diaper for technical assistance in the DNA laboratory; Eleanor G Seaby for assistance with diagrams and Olivia Kaye for help with biochemical data extraction. The work presented here, was financially supported by The Crohn’s in Childhood Research Association (CICRA) and The Gerald Kerkut Charitable Trust.\n\nAuthor Contributions T.C. and G.A. contributed equally to the paper; wrote the main manuscript text. J.J.A. prepared figures and helped with clinical data extraction. A.B. and N.A.A. helped with clinical data extraction. Y.G. and A.P.W. contributed to the outline of the paper, helped with the interpretation of findings. R.M.B. supervised the work, helped with clinical data extraction, contributed to the outline of the paper. S.E. supervised the work throughout, scrutinised every detail of the paper, designed the overall structure of the paper. All authors reviewed the manuscript.\n\nFigure 1 Schematic diagram showing thiopurine drug metabolism and genes implicated in thiopurine-induced toxicity.\nThere are three main catabolic pathways for thiopurine drugs, following conversion of AZA to 6-MP: (1) Phosphorylation to 6-thioguanines (6-TGN) which are active metabolites; 6-MP is first converted by hypoxanthine guanine phosphoribosyl-transferase (HGPRT) to 6-thioinosine monophosphate (6-TIMP), which is then phophorylated to 6-TGN with inosine 5-monophosphate dehydrogenase (IMPDH1 and IMPDH2) and guanosine monophosphate synthetase (GMPS) (2) Methylation by of 6-MP by TPMT to form 6-methyl-MP (6-MMP) which is an inactive metabolite and not a substrate for IMPDH) (3) Catabolism of 6-MP to 6-thiouracil (6-TU) via xanthine dehydrogenase (XDH, synonym- Xanthine oxidase) or aldehyde oxidase 1 (AOX1). TPMT competes with IMPDH for their common substrate 6-TIMP to form 6- methylmercaptopurine nucleotides (6-MMPN). 6-TIMP can be phosphorylated by kinases to 6-thioinosine triphosphate (6-TITP), which can get dephosphorylated by inosine triphosphatase (ITPase) to form 6-TIMP again. Although the precise mode of action of thiopurines is still unclear, the most important mechanism is thought to be the incorporation of 6-TGNs into the cell DNA, resulting in an impaired DNA synthesis and cell death26. Abbreviations: ABCC4- ATP-binding cassette, sub-family C (CFTR/MRP), member 4; AZA- azathioprine; FSLT5- Follistatin-Like 5; GST- glutathione s-transferase; HGPRT- hypoxanthine phosphoribosyltransferase;IL6ST- Interleukin 6 signal transducer; 6-MP- 6- mercaptopurine; 6-MMPN- 6- methyl mercaptopurine nucleotides; MOCOS- Molybdenum cofactor sulfurase; MTHFR- Methyl-enetetrahydrofolate reductase ;NUDT15- Nudix (nucleoside diphosphate linked moiety X)-type motif 15; PACSIN2- Protein kinase C and casein kinase substrate in neurons 2; 6-TXMP- 6-thioxanthosine monophosphate)\n\nFigure 2 TPMT phenotype frequency distribution for the Wessex paediatric population and the research cohort.\nFigure shows the TPMT phenotype frequency distribution for 524 paediatric patients, in the Wessex region (524 patients ≤ 18 years, between Dec 2010–April 2015, includes patients with/without IBD) and the TPMT phenotype distribution in our research cohort. Within our cohort we observe a statistically significant difference between the sub-category with TPMT values between 21–40 units (p = 0.001) compared to the Wessex paediatric population. This difference is not observed between the sub-categories with TPMT values between 41 to161 (p = 0.90)\n\nTable 1 A summary of the key clinical and biochemical (TPMT) features of the cohort.\nClinical Category\tNumber of patients within each group\tMedian duration of follow-up in months\tMales (%)\tDisease\tTPMT biochemical activity Number of patients across groups (%)\t\n \t \tCD (%)\tUC (%)\tIBDU (%)\tLow activity (<10 mU/L)\tIntermediate activity (10–67 mU/L)\tNormal activity (68–150 mU/L)\tHigh activity (>150 mU/L)\t\nNot Treated with thiopurines\t22\t60 (10–156)\t15 (68)\t13 (59)\t6 (27)\t3 (14)\t0 (0)\t12 (54)\t10 (46)\t0\t\nIntolerant\t14\t42 (9–82)\t10(71)\t12 (86)\t2 (14)\t0\t0 (0)\t8 (57)\t6(43)\t0\t\nTolerant\tResponders\t51\t52 (7–124)\t24 (47)\t31 (60)\t13 (26)\t7 (14)\t0 (0)\t22 (43)\t28 (55)\t1 (2)\t\n \tNon-responders\t13\t63 (13–126)\t7 (54)\t11 (85)\t2 (15)\t0\t0 (0)\t10 (77)\t3 (23)\t0\t\n \tTotal\t100\t54 (7–156)\t56 (56)\t67 (67)\t23 (23)\t10 (10)\t0 (0)\t52 (52)\t47 (47)\t1 (1)\t\nOf the 100 patients within the cohort, 67 individuals had Crohn’s disease (CD), 23 had ulcerative colitis (UC) and 10 had inflammatory bowel disease unclassified (IBDU). The proportion of males was 56% and the median duration of follow up was 54 months.\n\nTable 2 TPMT variants in our cohort.\nposition in hg19\tvariant\tCoding change\tProtein change\tPhylop\tgerp\tMaxEnt\tdbSNP\tFrequency in 1000 genome\tGenotypes in whole cohort (n = 100)\tGenotypes in intolerant (n = 14)\tGenotypes in tolerant (n = 64)\tMean TPMT biochemical value (n=100)\t\n18148069\tns\tc.218C > T\tp.A73V\t0.99\t4.98\t.\t.\t.\t99,1,0\t13;1;0\t64;0;0\t55\t\n18139272\tsp\tc.420–4G > A\t.\t.\t.\t0.95\t.\t0.0005\t99,1,0\t14;0;0\t63;1;0\t32\t\n18139228\tns\tc.460G > A\tp.A154T\t0.22\t0.93\t.\trs1800460\t0.02\t91,9,0\t10;4;0†\t60;4;0†\t36.6\t\n18130918\tns\tc.719A > G\tp.Y240C\t0.99\t5.13\t.\trs1142345\t0.05\t91,9,0\t10;4;0†\t60;4;0†\t36.6\t\n18139214\tsn\tc.474C > T\tp.I158I\t.\t.\t.\trs2842934\t0.77\t6,37,57\t1;5;8\t3;25;36\t67.4\t\nFive TPMT variants were identified across the cohort. These included two non-synonymous variants (A154T and Y240C) previously known to impact TMPT function and were found to co-segregate in 9 individuals. A highly pathogenic novel variant was identified in an individual intolerant to thiopurines. The other two included a splicing variant and a common synonymous variant. For all groups, genotypes are listed as homozygous reference allele, heterozygous and homozygous alternative allele. Variants associated with intermediate or low TPMT enzyme activity levels are shown in bold. Novel variants are in grey.\n\n†One out of the nine individuals harbouring p.A154T and p. Y240C was not commenced on thiopurine drugs. (Abbreviations: ns- non-synonymous; sn- synonymous; sp- splicing).\n\nTable 3 SKAT-O test association analysis across TPMPT and other genes involved in thiopurine toxicity.\nChr\tLbp\tRbp\tGene\tTotal number of samples\tFraction of individuals who carry rare variants under the MAF thresholds (MAF < 0.05)\tNumber of all variants defined in the group file\tNumber of variants defined as rare (MAF < 0.05)*\t\nBiochemical activity (52 with TPMT value <67 and 48 with TPMT value >67)\t\n 18\t33767568\t33848581\tMOCOS\t100\t0.12000\t12\t5\t\n 6\t18130918\t18148069\tTPMT\t100\t0.10000\t5\t2\t\nTolerance (14 intolerant and 64 tolerant)\t\n 3\t155588592\t155654236\tGMPS\t78\t0.12821\t5\t5\t\n 6\t18130918\t18148069\tTPMT\t78\t0.01282\t5\t1\t\nResponses (51 Responders and 13 non-responders)\t\n 5\t55231311\t55272085\tIL6ST\t64\t0.10937\t8\t3\t\n 13\t95696540\t95953517\tABCC4\t64\t0.31250\t22\t9\t\nThe SKAT-O test was applied to assess the joint effect of common, rare and low frequency variants within the genes implicated in thiopurine toxicity (only significant genes are shown) on TPMT enzyme activity, tolerance and response to the drug.\n\n*These variants received different weights in the SKAT-O joint test. Genes are ordered by p-value.\n\nTable 4 Deleterious variants occurring within the group of individuals with intolerance to thiopurines.\nGene\tChr\tPosition on hg19\tVariant type\tCoding change\tProtein change\tNovel\tPhylop,\t1- sift\tPolyphen 2\tMutationtaster\tGerp++\tdbSNP\tFrequency in 1000 genome\tFrequency in EVS\tTPMT biochemical activity\tint\tint\tint\tint\tint\tint\tint\tint\tNormal\tNormal\tNormal\tNormal\tNormal\tNormal\t\nTPMT activity\t16\t21\t47\t52\t55\t18\t26\t30\t80\t83\t93\t113\t114\t128\t\nDiagnosis\tCD\tCD\tCD\tCD\tCD\tCD\tUC\tCD\tCD\tCD\tCD\tCD\tUC\tCD\t\nGender\tM\tM\tM\tM\tF\tF\tM\tF\tF\tM\tM\tM\tM\tM\t\nIDs\t1\t3\t6\t7\t8\t2\t4\t5\t9\t10\t11\t12\t13\t14\t\nTPMT\t6\t18130918\tns\tc.719A >G\tp.Y240C\t.\t0.998258\t0.94\t0.94\t0.999973\t5.13\trs1142345\t0.05\t0.041715\t \t1\t1\t1\t1\t0\t0\t0\t0\t0\t0\t0\t0\t0\t0\t\nTPMT\t6\t18148069\tns\tc.218C > T\tp.A73V\tNOVEL\t0.999474\t0.95\t0.898\t0.999898\t4.98\t.\t.\t.\t \t0\t0\t0\t0\t1\t0\t0\t0\t0\t0\t0\t0\t0\t0\t\nMOCOS\t18\t33779705\tns\tc.G359A\tp.S120N\t.\t0.961984\t0.98\t0.284\t0.013289\t2.79\trs3744900\t0.06\t0.047093\t \t0\t0\t0\t0\t1\t0\t0\t0\t0\t0\t1\t0\t0\t0\t\nMOCOS\t18\t33831189\tns\tc.C2107A\tp.H703N\t.\t0.998524\t0.58\t0.706\t0.010571\t4.98\trs594445\t0.25\t0.283953\t \t1\t0\t0\t0\t0\t1\t2\t0\t1\t0\t1\t2\t1\t0\t\nMOCOS\t18\t33848581\tns\tc.T2600C\tp.V867A\t.\t0.998597\t1\t0.063\t0.006647\t5.69\trs1057251\t0.08\t0.116279\t \t1\t0\t1\t0\t0\t1\t0\t1\t0\t0\t0\t0\t0\t0\t\nXDH\t2\t31572983\tns\tc.G2738A\tp.R913Q\tNOVEL\t0.999016\t1\t1\t1\t5.38\t.\t.\t.\t \t0\t0\t0\t0\t0\t1\t0\t0\t0\t0\t0\t0\t0\t0\t\nXDH\t2\t31590917\tns\tc.A2107G\tp.I703V\t.\t0.998578\t1\t0.336\t0.999913\t4.52\trs17011368\t0.05\t0.034186\t \t0\t0\t0\t0\t1\t0\t0\t0\t0\t0\t0\t0\t0\t0\t\nXDH\t2\t31611143\tns\tc.G514A\tp.G172R\t.\t0.998995\t0.99\t0.004\t0.99994\t5.35\trs45523133\t0.04\t0.026047\t \t0\t1\t0\t0\t0\t0\t0\t0\t0\t0\t0\t0\t0\t0\t\nXDH\t2\t31621523\tns\tc.A349T\tp.T117S\t.\t0.998756\t0.96\t0.997\t0.999999\t5.81\t.\t.\t.\t \t0\t0\t0\t0\t0\t0\t0\t0\t0\t0\t0\t2\t0\t0\t\nAOX1\t2\t2.02E+08\tns\tc.A3404G\tp.N1135S\t.\t0.996285\t0\t0\t2.70E-05\t5.3\trs55754655\t0.11\t0.129767\t \t0\t0\t0\t1\t0\t1\t0\t0\t1\t1\t0\t0\t0\t1\t\nIL6ST\t5\t55264153\tns\tc.G442C\tp.G148R\t.\t0.995114\t0.98\t0\t2.70E-05\t5.6\trs2228044\t0.19\t0.119535\t \t0\t0\t1\t1\t0\t0\t0\t0\t0\t1\t0\t0\t0\t0\t\nNUDT15\t13\t48619855\tns\tc.C415T\tp.R139C\t.\t0.998597\t0.92\t0.057\t0.937718\t5.04\trs116855232\t0.04\t0.002442\t \t0\t0\t1\t0\t0\t0\t0\t0\t0\t0\t0\t0\t0\t0\t\nITPA\t20\t3193842\tns\tc.C94A\tp.P32T\t.\t0.998747\t0.87\t0.131\t0.996149\t5.14\trs1127354\t0.08\t0.067674\t \t0\t0\t0\t0\t0\t0\t0\t1\t0\t0\t0\t2\t0\t0\t\nPACSIN2\t22\t43280404\tns\tc.C773A\tp.S258Y\t.\t0.999724\t1\t0.998\t0.999962\t5.16\trs200427054\t0.0005\t0.00314\t \t0\t0\t0\t0\t0\t0\t0\t1\t0\t0\t0\t0\t0\t0\t\nFourteen out of the 100 patients were intolerant to thiopurines. Five of the fourteen individuals had deleterious TPMT variants; there was enrichment for deleterious variants within the MOCOS gene and the AOX1 gene in the other 9 individuals. Deleterious variants included: frameshift indels, stopgain/loss, splicing with Maxent score >3 and nonsynonymous variants with a gerp score >2. (ns- non-synonymous; 1 and 2 indicate heterozygous and homozygous genotype respectively).\n\nTable 5 Specificity and sensitivity for drug intolerance and tolerance.\n \tIntolerant\tTolerant\tSensitivity\tSpecificity\t\nBiochemical test\t+\t8\t32\t57.14%\t50%\t\n−\t6\t32\t\nDeleterious TPMT variants\t+\t5\t4\t35.7\t93.75%\t\nNon-deleterious variants\t−\t9\t60\t\nThe specificity for predicting toxicity through the biochemical test and through application of TPMT genetic variants was 50% and 93.75% respectively. The sensitivity obtained through both methods was sub-optimal.\n\nTable 6 The group of individuals with intolerance to thiopurines.\nPatient ID\tDiagnosis\tAge at Diagnosis (years)\tGender\tTPMT Gene Deleterious Variants\tTPMT Biochemical Activity\tTPMT Value (mU/L)\tUndergoing treatment with 5-aminosalicylic drugs at time of test\tFollow up (months)\tThiopurine Drug\tMedian Dose (mg/Kg)\tAdverse Effects\t\n6\tCD\t15\tM\tYes\tIntermediate\t21\tNo\t14\tAZA\t1.5\tLeuco-encephalopathy\t\n10\tCD\t13.5\tF\tNo\tIntermediate\t18\tNo\t42\tAZA\t1.5\tNeutropenia\t\n22\tUC\t10.5\tM\tNo\tIntermediate\t26\tYes\t82\tAZA\t2\tElevated amylase\t\n23\tCD\t14.5\tF\tNo\tIntermediate\t30\tYes\t63\tAZA\t2\tPersistent Nausea\t\n28\tCD\t5\tM\tNo\tNormal\t93\tYes\t32\tAZA\t1\tPersistent Nausea\t\n39\tCD\t10.9\tM\tYes\tIntermediate\t16\tNo\t75\tAZA\t1.5\tPancytopenia\t\n40\tCD\t9.5\tM\tYes\tIntermediate\t52\tNo\t75\t6-MP\t1\tPersistent Nausea\t\n41\tUC\t11.7\tM\tNo\tNormal\t114\tYes\t47\tAZA\t1\tAbnormal ALT\t\n69\tCD\t16\tF\tNo\tNormal\t80\tNo\t32\tAZA\t2.5\tPersistent Nausea\t\n73\tCD\t14\tM\tNo\tNormal\t128\tNo\t23\tAZA\t2\tPersistent Nausea\t\n74\tCD\t13.5\tF\tYes\tIntermediate\t55\tNo\t45\tAZA\t1\tPersistent Nausea\t\n88\tCD\t11\tM\tNo\tNormal\t83\tNo\t25\tAZA\t2\tPersistent Nausea\t\n92\tCD\t12\tM\tYes\tIntermediate\t47\tNo\t27\tAZA\t1.5\tAbnormal ALT\t\n95\tCD\t15.5\tM\tNo\tNormal\t113\tNo\t9\t6-MP\t1.5\tPancreatitis\t\nThe drugs used were azathioprine (AZA) in 12 patients (dose range 1–2.5 mg/kg/day) and 6-mercaptopurine (6-MP) in 2 patients (dose range 1–1.5 mg/kg/day). 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L. \net al.\nNomenclature for alleles of the thiopurine methyltransferase gene . Pharmacogenetics and genomics \n23 , 242 –248 , doi: 10.1097/FPC.0b013e32835f1cc0 (2013 ).23407052 \nMiller S. A. , Dykes D. D. & Polesky H. F. \nA simple salting out procedure for extracting DNA from human nucleated cells . Nucleic acids research \n16 , 1215 (1988 ).3344216 \nAndreoletti G. \net al.\nExome analysis of patients with concurrent pediatric inflammatory bowel disease and autoimmune disease . Inflammatory bowel diseases \n21 , 1229 –1236 , doi: 10.1097/MIB.0000000000000381 (2015 ).25895113 \nSherry S. T. \net al.\ndbSNP: the NCBI database of genetic variation . Nucleic acids research \n29 , 308 –311 (2001 ).11125122 \nGenomes Project C. \net al.\nAn integrated map of genetic variation from 1,092 human genomes . Nature \n491 , 56 –65 , doi: 10.1038/nature11632 (2012 ).23128226 \nDrmanac R. \net al.\nHuman genome sequencing using unchained base reads on self-assembling DNA nanoarrays . Science \n327 , 78 –81 , doi: 10.1126/science.1181498 (2010 ).19892942 \nIonita-Laza I. e. a. “Sequence Kernel Association Tests for the Combined Effect of Rare and Common Variants.” American journal of human genetics 92.6 (2013): 841–53. Web. 13 Jan. 2014.\nKang H. M. , Z X. , Sim X. & Ma C. Biostatistics Dept, Univ Michigan, Ann Arbor, Ann Arbor, MI. “EPACTS (Efficient and Parallelizable Association Container Toolbox)”. N. p., n.d.\nSchaeffeler E. \net al.\nComprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants . Pharmacogenetics \n14 , 407 –417 (2004 ).15226673 \nColombel J. F. \net al.\nGenotypic analysis of thiopurine S-methyltransferase in patients with Crohn’s disease and severe myelosuppression during azathioprine therapy . Gastroenterology \n118 , 1025 –1030 (2000 ).10833476 \nIchida K. , Matsumura T. , Sakuma R. , Hosoya T. & Nishino T. \nMutation of human molybdenum cofactor sulfurase gene is responsible for classical xanthinuria type II . Biochemical and biophysical research communications \n282 , 1194 –1200 , doi: 10.1006/bbrc.2001.4719 (2001 ).11302742\n\n",
"fulltext_license": "CC BY",
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"mesh_terms": "D000293:Adolescent; D001379:Azathioprine; D002648:Child; D002675:Child, Preschool; D003093:Colitis, Ulcerative; D003424:Crohn Disease; D059472:Exome; D005260:Female; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D015122:Mercaptopurine; D008780:Methyltransferases; D009154:Mutation; D013466:Sulfurtransferases",
"nlm_unique_id": "101563288",
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"pmid": "27703193",
"pubdate": "2016-10-05",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Genes implicated in thiopurine-induced toxicity: Comparing TPMT enzyme activity with clinical phenotype and exome data in a paediatric IBD cohort.",
"title_normalized": "genes implicated in thiopurine induced toxicity comparing tpmt enzyme activity with clinical phenotype and exome data in a paediatric ibd cohort"
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"abstract": "BACKGROUND\nAlthough propranolol can be an effective primary medical therapy for infantile hemangiomas of the head and neck, the duration of treatment and time to discontinue propranolol is unclear.\n\n\nOBJECTIVE\nThe objective of this study is to determine the duration of treatment and age at which propranolol may be successfully discontinued in children with infantile hemangiomas of the head and neck.\n\n\nMETHODS\nA review of all patients presenting to a pediatric vascular anomalies clinic from January 2008 to December 2011 was performed. Those with head and neck infantile hemangiomas who completed propranolol therapy were included. Each patient's records were reviewed for demographics, clinical response to propranolol, age at discontinuation of propranolol, and adverse events.\n\n\nRESULTS\nForty-five patients were included for review (mean age at presentation, 3.5 months) with all demonstrating positive responses. The mean age at discontinuation of propranolol was 11.8 months of age (range, 8-15 months) with a mean treatment duration of 6.5 months (range, 3-11 months). No recurrences were noted over a mean follow-up period of 19.9 months (range, 10-28 months).\n\n\nCONCLUSIONS\nDiscontinuation of propranolol at approximately 12 months of age was found to be appropriate in our study population.",
"affiliations": "IWK Health Centre, Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, Dalhousie University, Halifax, NS, Canada. Paul.Hong@iwk.nshealth.ca",
"authors": "Hong|Paul|P|;Tammareddi|Neelima|N|;Walvekar|Rohan|R|;Chiu|Ernest S|ES|;Poole|Jeffrey C|JC|;Kluka|Evelyn A|EA|;Simon|Lawrence M|LM|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D011433:Propranolol",
"country": "Ireland",
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"issue": "77(7)",
"journal": "International journal of pediatric otorhinolaryngology",
"keywords": null,
"medline_ta": "Int J Pediatr Otorhinolaryngol",
"mesh_terms": "D000319:Adrenergic beta-Antagonists; D000367:Age Factors; D005260:Female; D005500:Follow-Up Studies; D006258:Head and Neck Neoplasms; D006391:Hemangioma; D006801:Humans; D007223:Infant; D008297:Male; D011433:Propranolol; D013997:Time Factors; D016896:Treatment Outcome; D028761:Withholding Treatment",
"nlm_unique_id": "8003603",
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"pubdate": "2013-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Successful discontinuation of propranolol for infantile hemangiomas of the head and neck at 12 months of age.",
"title_normalized": "successful discontinuation of propranolol for infantile hemangiomas of the head and neck at 12 months of age"
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"abstract": "BACKGROUND\nNon-Hodgkin Lymphomas (NHL) appear with the malign transformation of mature lymphocytes. Intestinal perforations are one of the most well-known complications of NHLs. In this review, a 29-year-old male patient who was diagnosed with NHL with gastrointestinal involvement that developed intestinal perforation after chemotherapy is presented.\n\n\nMETHODS\nA 29-year-old male patient who received systemic chemotherapy in another healthcare center due to Major B-Cell Lymphoma was examined because he had stomachache after the treatment. The patient was urgently taken to operation. In the exploration, there were partly mass lesions in all small intestine segments. It was determined that one of the lesion was perforated. Small intestine resection was applied. The pathology report on resection material was reported as High Grade Major B-Cell Lymphoma.\n\n\nCONCLUSIONS\nIn the treatment of Lymphoma with intestinal B-Cells, there is no consensus because this disease is rarely observed. Perforation may appear as a complication of the chemotherapy. Depending on the steroids given to the patient, perforation may develop, and the clinical symptoms may be masked.\n\n\nCONCLUSIONS\nIt must be born in mind that there may be intestinal involvement in patients diagnosed with NHL, and intestinal perforation may develop due to chemotherapy.",
"affiliations": "Istanbul Training and Research Hospital, Department of General Surgery, Istanbul, Turkey. Electronic address: tatarcihad@gmail.com.;Istanbul Training and Research Hospital, Department of General Surgery, Istanbul, Turkey. Electronic address: mmazzllumm@gmail.com.;Istanbul Training and Research Hospital, Department of General Surgery, Istanbul, Turkey. Electronic address: dronderakkus@hotmail.com.;Istanbul Training and Research Hospital, Department of General Surgery, Istanbul, Turkey. Electronic address: btapkan79@hotmail.com.;Istanbul Training and Research Hospital, Department of General Surgery, Istanbul, Turkey. Electronic address: okb991@hotmail.com.;Istanbul Training and Research Hospital, Department of General Surgery, Istanbul, Turkey. Electronic address: savasbayrak74@gmail.com.;Istanbul Training and Research Hospital, Department of General Surgery, Istanbul, Turkey. Electronic address: ctatargs@yahoo.com.",
"authors": "Tatar|Cihad|C|;Yavas|Mazlum|M|;Akkus|Onder|O|;Tapkan|Bahaeddin|B|;Batikan|Oguz Kagan|OK|;Bayrak|Savas|S|;Arikan|Soykan|S|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijscr.2017.08.058",
"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(17)30450-910.1016/j.ijscr.2017.08.058ArticleIntestinal perforation that developed after chemotherapy in a patient diagnosed with non-Hodgkin lymphoma: A case report and review of literature Tatar Cihad tatarcihad@gmail.com⁎Yavas Mazlum mmazzllumm@gmail.comAkkus Onder dronderakkus@hotmail.comTapkan Bahaeddin btapkan79@hotmail.comBatikan Oguz Kagan okb991@hotmail.comBayrak Savas savasbayrak74@gmail.comArikan Soykan ctatargs@yahoo.comIstanbul Training and Research Hospital, Department of General Surgery, Istanbul, Turkey⁎ Corresponding author. tatarcihad@gmail.com02 9 2017 2017 02 9 2017 39 321 323 8 8 2017 28 8 2017 28 8 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Intestinal perforations are one of the most well-known complications of NHLs.\n\n• The reasons of perforation in patients who receive chemotherapy were fast tumor necrosis, tumor lysis, and tissue impairment.\n\n• Depending on the steroids given to the patient, perforation may develop, and the clinical symptoms may be masked.\n\n\n\nIntroduction\nNon-Hodgkin Lymphomas (NHL) appear with the malign transformation of mature lymphocytes. Intestinal perforations are one of the most well-known complications of NHLs. In this review, a 29-year-old male patient who was diagnosed with NHL with gastrointestinal involvement that developed intestinal perforation after chemotherapy is presented.\n\nPresentation of case\nA 29-year-old male patient who received systemic chemotherapy in another healthcare center due to Major B-Cell Lymphoma was examined because he had stomachache after the treatment. The patient was urgently taken to operation. In the exploration, there were partly mass lesions in all small intestine segments. It was determined that one of the lesion was perforated. Small intestine resection was applied. The pathology report on resection material was reported as High Grade Major B-Cell Lymphoma.\n\nDiscussion\nIn the treatment of Lymphoma with intestinal B-Cells, there is no consensus because this disease is rarely observed. Perforation may appear as a complication of the chemotherapy. Depending on the steroids given to the patient, perforation may develop, and the clinical symptoms may be masked.\n\nConclusion\nIt must be born in mind that there may be intestinal involvement in patients diagnosed with NHL, and intestinal perforation may develop due to chemotherapy.\n\nKeywords\nChemotherapyIntestinalLymphomaNon-HodgkinPerforation\n==== Body\n1 Introduction\nNon-Hodgkin Lymphomas (NHL) appear with the malign transformation of mature lymphocytes. Gastrointestinal NHLs are the most frequent extranodal lymphomas. B-Cell lymphoma is more frequent than T-cell lymphoma, and Diffused Large-Cell B-Cell Lymphoma is the most frequent sub-type [1]. Intestinal perforations are one of the most well-known complications of NHLs. Ono et al. [2] reported that the reasons of perforation in patients who receive chemotherapy treatment were fast tumor necrosis, tumor lysis, and tissue impairment due to excessive granulation based on chemotherapy. Vaidya et al. [3] reported that the most widespread perforation area is the small intestines, and the most frequent perforation is observed in Diffused Major B-Cell sub-type. In this review, a patient who was diagnosed with NHL with gastrointestinal involvement that developed intestinal perforation after chemotherapy is presented. This work is reported in line with the SCARE criteria [4].\n\n2 Presentation of case\nA 29-year-old male patient who received systemic chemotherapy in another healthcare center due to Major B-Cell Lymphoma was examined because he had stomach ache after the treatment. In the follow-ups, the stomach-ache continued and increased, and therefore, the patient was sent to us on his 3rd day of hospitalization. The patient was taken to Emergency Service. In his medical history, it was observed that the patient was diagnosed with NHL diagnosis 6 months ago, and received R-COP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) treatment whose 4th Session was completed 2 weeks ago. Aside from these, there were no additional background data in his family and resume. In physical examination, there was widespread sensitivity and defense in the stomach. The WBC was 7000 × 103/μL, and small intestine-type air-liquid leveling was observed in standing direct abdominal graphics. In the CT on the abdomen, it was observed that there was widespread liquid and air in the stomach. For this reason, the patient was urgently taken to operation by general surgery specialist. In the exploration, it was observed that there was widespread intestinal content in the abdomen. There were partly mass lesions in all small intestine segments. It was determined that one of the lesions was perforated in a distance of 75 cm to ileocecal valve (Fig. 1). Small intestine resection to include these two lesions was applied. The patient was observed as stable in terms of clinical and laboratory values in the postoperative period, and was discharged with recommendations on the postoperative 5th day. The follow-up and treatment of the patient is still continued by us including a hematology specialist without any problems. The pathology report on the resection material was reported as High Grade Major B-Cell Lymphoma. Written informed consent was obtained from the patient and from his first degree relatives for publication of this case and involving images.Fig. 1 Intestinal perforation site.\n\nFig. 1\n\n3 Discussion\nIn the treatment of Lymphoma with intestinal B-Cells, there is no consensus because this disease is rarely observed. The majority of patients with intestinal lymphoma generally respond well to medical treatment. However, several complications like obstruction, perforation, fistula or bleeding may require that surgical treatment is added [5], [6]. Most of the time, chemotherapy, surgery and in some cases, radio-therapy combinations are applied. The frequency of perforation due to intestinal lymphoma was reported as 1–25%. There might appear small intestine perforation spontaneously or as a chemotherapy complication [7], [8], [9], [10], [11], [12]. In aprevious study, a period of 37 years was investigated, and it was determined that perforation developed in 9% of the patients with gastrointestinal lymphoma, and perforation developed after chemotherapy in 55% of these patients [3]. Depending on the steroids given to the patient, perforation may develop, and the clinical symptoms may be masked [13]. In our case, the patient was followed-up in another healthcare center for 3 days due to stomachache; however, since there were no acute abdomen symptoms in the patient, perforation was not suspected. When the patient was sent to our clinic, perforation was suspected, and the pre-diagnosis was confirmed with Computerized Tomography. Although perforation is a well-known complication of chemotherapy, delays in the diagnosis have opened the road to debates on the role of the elective surgery before chemotherapy in patients with NHL, which is known as intestine involvement. Zinzani et al. [14] applied surgical resection before chemotherapy to 32 patients with intestinal lymphoma, and reported better results in terms of survival. Ibrahim et al. [15] applied surgical resection before chemotherapy in 66 patients, and reported that there were no significant differences in terms of survival rates.\n\nConsidering that mortality and morbidity may increase in patients who develop perforation, and longer hospitalization durations may be required, and assessing the results like the decrease in the comfort of the patient and possible ostomy after urgent surgery, we believe that applying elective surgery in selected patients in localized diseases will be proper in terms of event-free survival and cost-effective results although there are no significant differences in terms of survival rates. More clinical studies are needed in this field.\n\n4 Conclusion\nIt must be born in mind that there may be intestinal involvement in patients diagnosed with NHL, and intestinal perforation may develop due to chemotherapy. In order to decrease mortality and morbidity, the required tests and treatment must be applied in an urgent manner in case there is clinical suspicion. On the other hand, we believe that it will be more beneficial to consider elective surgery for each patient separately before chemotherapy and apply it on selected patients.\n\nConflicts of interest\nNo.\n\nFunding\nNo.\n\nEthical approval\nNone.\n\nConsent\nWritten informed consent was obtained from the patient's and his first degree relatives for publication of this case and involving images.\n\nAuthor contribution\nCT, BT, OKB, contributed in the study concept, data acquisition and data analysis. CT and OA contributed in the data analysis. CT, MY, SA, SB wrote the paper. All authors read and approved the final version of the submitted manuscript.\n\nGuarantor\nCihad Tatar.\n==== Refs\nReferences\n1 Kim S.J. Choi C.W. Mun Y.C. Oh S.Y. Kang H.J. Lee S.I. Multicenter retrospective analysis of 581 patients with primary intestinal non-hodgkin lymphoma from the Consortium for Improving Survival of Lymphoma (CISL) BMC Cancer 11 2011 321 333 21798075 \n2 Ono K. Matsumura S. Sakamoto K. Kobayashi S. Kamano T. Iwasaki R. A case of gastric malignant lymphoma with perforation during chemotherapy Gan To Kagaku Ryoho 24 1997 105 108 9020954 \n3 Vaidya R. Habermann T.M. Donohue J.H. Bowel perforation in intestinal lymphoma: incidence and clinical features Ann. Oncol. 24 2013 2439 2443 23704194 \n4 Agha R.A. Fowler A.J. Saetta A. Barai I. Rajmohan S. Orgill D.P. The SCARE Group The SCARE Statement: consensus-based surgical case report guidelines Int. J. Surg. 34 2016 180 –186 27613565 \n5 Navarra G. Adani G.L. Bardella E. Ascanelli S. Turini A. Pozza E. Primary rectal lymphoma as a cause of bowel obstruction. Report of a case Tumori 89 2003 88 90 12729370 \n6 Sakakibara T. Kurasawa T. Narumi K. Kamano T. Tsurumaru M. T-cell malignant lymphoma of the ileum causing ileac fistulas: report of a case Surg. Today 32 2002 536 540 12107782 \n7 Wada M. Onda M. Tokunaga A. Kiyama T. Yoshiyuki T. Matsukura N. Spontaneous gastrointestinal perforation in patients with lymphoma receiving chemotherapy and steroids. Report of three cases Nippon Ika Daigaku Zasshi 66 1999 37 40 10097589 \n8 Aydin I. Baskent A. Celik G. Aren A. Eren M.Z. Ayar E. A case of primary intestinal lymphoma associated with intestinal perforation Ulus Travma Derg. 7 2001 74 76 11705180 \n9 Sakakura C. Hagiwara A. Nakanishi M. Yasuoka R. Shirasu M. Togawa T. Bowel perforation during chemotherapy for non-Hodgkin’s lymphoma Hepatogastroenterology 46 1999 3175 3177 10626181 \n10 Yokota T. Yamada Y. Murakami Y. Yasuda M. Kunii Y. Yamauchi H. Abdominal crisis caused by perforation of ileal lymphoma Am. J. Emerg. Med. 20 2002 136 137 11880888 \n11 Hata S. Pietsch J. Shankar S. Intestinal complications in children undergoing chemotherapy for mediastinal non-Hodgkin’s lymphoma Pediatr. Hematol. Oncol. 21 2004 707 710 15739625 \n12 Ara C. Coban S. Kayaalp C. Yilmaz S. Kirimlioglu V. Spontaneous intestinal perforation due to non-Hodgkin’s lymphoma: evaluation of eight cases Dig. Dis. Sci. 52 2007 1752 1756 17420936 \n13 Abbott S. Nikolousis E. Badger I. Intestinal lymphoma-a review of the management of emergency presentations to the general surgeon Int. J. Colorectal Dis. 30 2015 151 157 25374417 \n14 Zinzani P.L. Magagnoli M. Pagliani G. Primary intestinal lymphoma: clinical and therapeutic features of 32 patients Haematologica 82 1997 305 308 9234576 \n15 Ibrahim E.M. Ezzat A.A. El-Weshi A.N. Primary intestinal diffuse large B-cell non-Hodgkin’s lymphoma: clinical features, management and prognosis of 66 patients Ann. Oncol. 12 2001 53 58 11249049\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "39()",
"journal": "International journal of surgery case reports",
"keywords": "Chemotherapy; Intestinal; Lymphoma; Non-Hodgkin; Perforation",
"medline_ta": "Int J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101529872",
"other_id": null,
"pages": "321-323",
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"pmid": "28898795",
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"title": "Intestinal perforation that developed after chemotherapy in a patient diagnosed with non-Hodgkin lymphoma: A case report and review of literature.",
"title_normalized": "intestinal perforation that developed after chemotherapy in a patient diagnosed with non hodgkin lymphoma a case report and review of literature"
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"abstract": "The number of trauma patients on prehospital novel oral anticoagulants (NOACs) is increasing. After an initial negative computed tomography of the head (CTH), practice patterns are variable for obtaining repeat CTH to evaluate for delayed intracranial hemorrhage (ICH-d). However, the risks and outcomes of ICH-d for patients on NOACs are unclear. We hypothesized that, for these patients, the incidence of ICH-d is low, similar to that of warfarin, and when it occurs, it does not result in clinically significant worse outcomes.\n\n\n\nFive level 1 trauma centers in Northern California participated in a retrospective review of anticoagulated trauma patients. Patients were included if their initial CTH was negative. Primary outcomes were incidence of ICH-d, neurosurgical intervention, and death. Patient factors associated with the outcome of ICH-d were determined by multivariable regression.\n\n\n\nFrom 2016 to 2018, 777 patients met the inclusion criteria (NOAC, n = 346; warfarin, n = 431), 54% of whom received a repeat CTH. Delayed intracranial hemorrhage incidence was 2.3% in the NOAC group and 4% in the warfarin group (p = 0.31). No NOAC patient with ICH-d required neurosurgical intervention or died because of their head injury. Two warfarin patients received neurosurgical intervention, and three died from their head injury. Head Abbreviated Injury Scale ≥3 was associated with increased odds of developing ICH-d (adjusted odds ratio, 32.70; p < 0.01).\n\n\n\nThe incidence of ICH-d in patients taking NOAC is low. In this study, patients on NOACs who developed ICH-d after an initial negative CTH did not need neurosurgical intervention or die from their head injury. Repeat CTH in this patient population does not appear necessary.\n\n\n\nPrognostic/epidemiologic study, level III.Therapeutic, level IV.",
"affiliations": "From the Department of Surgery (C.M.C., G.B., G.P.V.), University of California, San Francisco-East Bay, Oakland, CA; Department of Surgery (J.A.B., J.M.G.), University of California, Davis, Sacramento, CA; Department of Surgery (A.M.K., R.C.D.), University of California, San Francisco, Fresno, CA; Department of Surgery (L.Z.K., R.P.), Zuckerberg San Francisco General Hospital, University of California, San Francisco, San Francisco, CA; and Department of Surgery (T.D.B.), Stanford University, Stanford, CA.",
"authors": "Cohan|Caitlin M|CM|;Beattie|Genna|G|;Bowman|Jessica A|JA|;Galante|Joseph M|JM|;Kwok|Amy M|AM|;Dirks|Rachel C|RC|;Kornblith|Lucy Z|LZ|;Plevin|Rebecca|R|;Browder|Timothy D|TD|;Victorino|Gregory P|GP|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
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"mesh_terms": "D000284:Administration, Oral; D000925:Anticoagulants; D002140:California; D006259:Craniocerebral Trauma; D006801:Humans; D015994:Incidence; D020300:Intracranial Hemorrhages; D010818:Practice Patterns, Physicians'; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D014057:Tomography, X-Ray Computed; D019564:Unnecessary Procedures; D014859:Warfarin",
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"pubdate": "2020-08",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Repeat computed tomography head scan is not indicated in trauma patients taking novel anticoagulation: A multicenter study.",
"title_normalized": "repeat computed tomography head scan is not indicated in trauma patients taking novel anticoagulation a multicenter study"
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"abstract": "Direct current cardioversion (DCCV) is a common rhythm control strategy in patients with symptomatic atrial fibrillation or flutter. There is no long-term data regarding the safety of DCCV in patients with endocardial left atrial appendage occlusion (LAAO) devices.\n\n\n\nThe purpose of this study was to assess the feasibility and safety of DCCV in patients with an LAAO device.\n\n\n\nThis multicenter retrospective study included 148 patients with an LAAO device who underwent DCCV for symptomatic atrial fibrillation or atrial flutter.\n\n\n\nThe average age of the included patients was 72 ± 7 years and 59% were men. All patients (100%) had a transesophageal echocardiogram prior to DCCV. Device-related thrombus was seen in 2.7%. They were all successfully treated with oral anticoagulation (OAC) and were able to undergo DCCV after 6 to 8 weeks. DCCV restored sinus rhythm in all patients. None of the patients had DCCV-related thromboembolic complications. A total of 22% of patients were newly started on OAC after DCCV. There was no difference in DCCV-related complications between patients treated with or without OAC post-DCCV. Patients receiving OAC post-DCCV were found to undergo cardioversion at an earlier time after implantation (3.6 months [interquartile range (IQR): 0.7 to 8.6 months] vs. 8.6 months [IQR: 2.5 to 13.3 months]; p = 0.003). Three transient ischemic attacks, unrelated to DCCV, were found during follow-up. During a median follow-up of 12.8 months (IQR: 11.8 to 14.2 months), no device or left atrial thrombosis, device dislodgement, or a new device leak were observed. One patient died during follow-up due to noncardiac cause.\n\n\n\nDCCV is feasible in high-risk AF patients with an LAAO device without the need for oral anticoagulation if pre-procedural transesophageal echocardiography shows good device position, absence of device-related thrombus, and peridevice leak of ≤5 mm. The preliminary results are encouraging, but further large studies are warranted to establish safety.",
"affiliations": "Kansas City Heart Rhythm Institute and Research Foundation, Overland Park, Kansas.;Icahn School of Medicine at Mount Sinai, New York, New York.;Kansas City Heart Rhythm Institute and Research Foundation, Overland Park, Kansas.;Icahn School of Medicine at Mount Sinai, New York, New York.;Cedars-Sinai Medical Center, Los Angeles, California.;Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin, Texas.;Texas Heart Institute, St. Luke's Hospital, Houston, Texas.;Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.;The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.;Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin, Texas.;Kansas City Heart Rhythm Institute and Research Foundation, Overland Park, Kansas. Electronic address: dlakkireddy@gmail.com.",
"authors": "Sharma|Sharan Prakash|SP|;Turagam|Mohit K|MK|;Gopinathannair|Rakesh|R|;Reddy|Vivek|V|;Kar|Saibal|S|;Mohanty|Sangamitra|S|;Cheng|Jie|J|;Holmes|David R|DR|;Sondergaard|Lars|L|;Natale|Andrea|A|;Lakkireddy|Dhanunjaya|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jacc.2019.08.1045",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-1097",
"issue": "74(18)",
"journal": "Journal of the American College of Cardiology",
"keywords": "Watchman; direct current cardioversion; left atrial appendage occlusion; oral anticoagulation",
"medline_ta": "J Am Coll Cardiol",
"mesh_terms": "D000368:Aged; D020517:Atrial Appendage; D001281:Atrial Fibrillation; D004554:Electric Countershock; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D055989:Septal Occluder Device; D016896:Treatment Outcome",
"nlm_unique_id": "8301365",
"other_id": null,
"pages": "2267-2274",
"pmc": null,
"pmid": "31672183",
"pubdate": "2019-11-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Direct Current Cardioversion of Atrial Fibrillation in Patients With Left Atrial Appendage Occlusion Devices.",
"title_normalized": "direct current cardioversion of atrial fibrillation in patients with left atrial appendage occlusion devices"
} | [
{
"companynumb": "US-BAYER-2019-205009",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"activesubstancename": "ASPIRIN"
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"abstract": "A 48-year-old woman attended to discuss a dilemma. She had suffered a cardiac arrest immediately following microsclerotherapy of leg telangiectasia with 0.3% aethoxysklerol. She had successful defibrillation and been transferred to hospital. In hospital, despite normal cardiac tests, she was diagnosed as having idiopathic cardiac arrest. The exposure to aethoxysklerol was discounted by her cardiologists as a cause of her arrest. Following the hospital protocol, she was strongly advised to have an implantable defibrillator. Cardiac arrest and myocardial infarction are documented after aethoxysklerol injection with proposed mechanisms being anaphylaxis, direct cardiotoxicity or endothelin-1 release. Before consenting to an implantable defibrillator, which may have its own complications in the long term, doctors and the patient need to be certain that this arrest was not due to a reaction to aethoxysklerol.",
"affiliations": "The Whiteley Clinic, Guildford, UK.;The Whiteley Clinic, Guildford, UK.;The Whiteley Clinic, Guildford, UK.;The Whiteley Clinic, Guildford, UK.",
"authors": "Whiteley|Mark S|MS|https://orcid.org/0000-0001-6727-6245;Taylor|Laura K|LK|;King|Julie C|JC|;Hughes|Brittany E|BE|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2050313X211000866",
"fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X\nSAGE Publications Sage UK: London, England\n\n10.1177/2050313X211000866\n10.1177_2050313X211000866\nCase Report\nClinical dilemma of management: Cardiac arrest after microsclerotherapy for lower limb telangiectasia with liquid 0.3% aethoxysklerol or idiopathic cardiac arrest?\nhttps://orcid.org/0000-0001-6727-6245\nWhiteley Mark S 12\nTaylor Laura K 1\nKing Julie C 1\nHughes Brittany E 1\n1 The Whiteley Clinic, Guildford, UK\n2 Faculty of Health and Biomedical Sciences, University of Surrey, Guildford, UK\nMark S Whiteley, The Whiteley Clinic, Stirling House, Stirling Road, Guildford GU2 7RF, Surrey, UK. Email: mark@thewhiteleyclinic.co.uk\n9 3 2021\n2021\n9 2050313X2110008661 2 2021\n17 2 2021\n© The Author(s) 2021\n2021\nSAGE Publications\nThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nA 48-year-old woman attended to discuss a dilemma. She had suffered a cardiac arrest immediately following microsclerotherapy of leg telangiectasia with 0.3% aethoxysklerol. She had successful defibrillation and been transferred to hospital. In hospital, despite normal cardiac tests, she was diagnosed as having idiopathic cardiac arrest. The exposure to aethoxysklerol was discounted by her cardiologists as a cause of her arrest. Following the hospital protocol, she was strongly advised to have an implantable defibrillator. Cardiac arrest and myocardial infarction are documented after aethoxysklerol injection with proposed mechanisms being anaphylaxis, direct cardiotoxicity or endothelin-1 release. Before consenting to an implantable defibrillator, which may have its own complications in the long term, doctors and the patient need to be certain that this arrest was not due to a reaction to aethoxysklerol.\n\nCardiac arrest\nsclerotherapy\naethoxysklerol\nanaphylaxis\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nAethoxysklerol is one of two widely used detergent sclerosants by doctors treating telangiectasia and varicose veins. Injected directly into the target vein, its mechanism of action is to insert itself into the predominantly phospholipid cell membrane of the endothelial cells lining the venous wall.1\n\nAs concentration increases, the cell wall disrupts, killing the endothelial cell. This stimulates cellular inflammation and apoptosis in the adjacent media cells, resulting in immediate inflammation and then healing by fibrosis and occlusion.2 Serious complications are rare.\n\nImplantable cardiac devices (implantable defibrillators) can be lifesaving. However, like any medical device, they can malfunction, and as with any implantable foreign body, they can be associated with complications. Such malfunctions and complications occur in 4%–11% of patients in the early post-implantation period (i.e. haematoma, device malfunction and lead problems) and in the longer term, 10 per 100 patient years have been reported in a registry of patients over 65 years old followed for a median of 2.7 years.3 Such longer-term problems include failure to shock, inappropriate shocks and infections. Hence, although risks are relatively low and are acceptable if the indication for an implantable defibrillator is strong, they become more of a concern if there is only a very weak case for recommending one in the first place.\n\nThis case has been reported as it leads to a dilemma of future management, depending on whether the cardiac arrest was due to a reaction to aethoxysklerol or was an unrelated factor.\n\nCase report\n\nA 48-year-old female presented seeking advice, having had a cardiac arrest immediately following microsclerotherapy for lower limb telangiectasia performed elsewhere. The patient had undergone microsclerotherapy treatment of her lower limb telangiectasia (CEAP C1), on the lower leg front and back and behind her knee, with 0.3% aethoxysklerol, made up by diluting 2% lauromacrogol. She had not had a duplex ultrasound as this was not the practice of her aesthetic doctor at the time.\n\nShe had suffered from an upper respiratory tract infection for the week preceding the microsclerotherapy but was otherwise well. Her only known allergy was to sodium lauryl sulphate. She had never had any previous cardiac history. The patient had had the same treatment annually for approximately the last decade. Subsequently, she reported that after previous treatments she had often felt that she had a ‘heavy feeling’ in her chest and blackspots before her eyes, sometimes accompanied by a headache.\n\nOn this occasion, she felt strange approximately 15 min after the start of the injections. She was prone with chin resting on her hands. After standing for 1–3 min, she felt dizzy, and a feeling of ‘heat rushing up her body from her legs to her chest and neck’. She felt faint and collapsed. She was found to be in cardiac arrest and cardiopulmonary resuscitation (CPR) was commenced. She underwent immediate defibrillation (one shock) with an automatic defibrillation device that was within the clinic.\n\nAn ambulance attended within 3 min and the crew confirmed ventricular fibrillation. They performed one defibrillation putting the patient into atrial fibrillation and then one more shock, into sinus rhythm. They then took her to hospital. On arrival at the hospital, photographs taken by her friend showed that her face was swollen, her eyelids were puffy and a red rash extended down her neck. The swelling resolved quite quickly in hospital, but the rash remained for several hours. She was given morphine which made her vomit violently.\n\nShe was admitted under the cardiologists and underwent cardiac magnetic resonance imaging (MRI), coronary angiography, chest x-ray, 24 h electrocardiogram (ECG), cardiac stress and ajmaline tests. All were normal, and no patent foramen ovale found. No cardiac cause was found for her cardiac arrest.\n\nIn the patient’s family, her mother gets anaphylaxis to iodine, shellfish and paracetamol. One sister is allergic to aspartame sweetener, developed eczema after ibuprofen and is gluten-sensitive, although a biopsy was negative for coeliac disease. Another sister has Hashimoto’s thyroiditis and eczema.\n\nThe dilemma for this patient is that her cardiac team has diagnosed idiopathic cardiac arrest and is advising that following their protocol, she needs an implantable defibrillator. However, the patient is understandably concerned that if her arrest is related to the injection of aethoxysklerol, she would be accepting a lifelong implant with all the risks associated with that, for no advantage.\n\nDiscussion\n\nSclerotherapy is a recognised treatment for unwanted leg veins. Aethoxysklerol (aka polidocanol or Lauromacrogol 400) is a detergent sclerosant. It is chemically very similar to sodium lauryl sulphate and other surfactants used in soap, shampoos and other personal cleaning products. The patient was known to have an allergy to this surfactant.\n\nLow concentrations of liquid solution 0.25% and 0.5% aethoxysklerol are used to treat telangiectasia and small reticular veins. Larger varicose veins or incompetent truncal veins are usually treated with higher concentrations between 1% and 3%, and often made into a foam with air or gas. The foam displaces blood, allowing interaction between sclerosant and vein wall.\n\nAethoxysklerol has been reported to have caused cardiac arrest and myocardial ischaemia previously,4 with anaphylaxis or direct cardiac toxicity having been suggested. Another reported the death of a 35-year-old woman following varicose veins treatment with aethoxysklerol.5 Post-mortem showed no sign of anaphylaxis but direct action of the sclerosant on the heart muscle was suggested as the cause of death.\n\nReports of cardiac arrest in children where high doses of aethoxysklerol were injected into venous malformations also seem to point towards a direct cardiotoxicity of the drug,6,7 as does a report of a 48-year-old lady who underwent cardiac arrest following the injection of ‘7-mL foam polidocanol injection’.8\n\nPolidocanol foam sclerotherapy has also been reported to cause myocardial infarction in a 78-year-old patient,9 but myocardial infarction with foam sclerotherapy has been reported with foam made from both aethoxysklerol and sodium tetradecyl sulphate.10,11\n\nFurther cases have been reported of myocardial infarction after foam sclerotherapy with aethoxysklerol or sodium tetradecylsulphate.9–11 The difficulty of assessing these latter cases as to whether they constitute a reaction to the sclerosant or the gas bubbles in the foam is the inconsistency of reporting which detergent was used and in what concentration, what gas was used to make the foam and the total dose injected into which veins.\n\nA further possible mechanism of cardiac toxicity is the potential release of endothelin-1 from the action of the sclerosant on the endothelium. Endothelin-1 was suggested to be a cause of visual disturbance after foam sclerotherapy12 and a study in rats showed endothelin-1 release with aethoxysklerol injection, although only with foam and not liquid sclerotherapy.13\n\nThis finding was confirmed in humans14 and endothelin-1 release after foam sclerotherapy treatment was suggested as the cause of a non-ST elevation myocardial infarction in one case, although this was sodium tetradecyl sulphate foam rather than aethoxysklerol.15\n\nConclusion\n\nIn conclusion, sclerotherapy with aethoxysklerol can cause cardiac arrest due to anaphylaxis, direct cardiotoxicity or maybe endothelin-1 release. In the presented case, a very low concentration and volume of aethoxysklerol was used. In addition, the patient had a swollen face and red rash on admission and a family history of allergy, suggesting anaphylaxis is the most likely mechanism for her cardiac arrest. The previous history of heaviness in the chest, blackspots in front of the eyes and occasional headache after previous treatments raise the possibility of sensitivity to endothelin-1 release, although the two mechanisms might not be mutually exclusive. Direct cardiotoxicity is possible but less likely.\n\nHowever, with regards to the patient dilemma, there would appear to be relatively good evidence to suspect a direct causal relationship between the intravenous aethoxysklerol injections and subsequent cardiac arrest. As such, it is difficult for her to accept an implantable defibrillator, with the inherent risks of a long-term device implanted within her body, with the sole justification being that it is the protocol to do so.\n\nAuthor contributions: Conception and design – M.S.W. Analysis and interpretation – not relevant. Data collection – L.K.T., J.C.K., B.E.H. Writing the manuscript – M.S.W. Critical revision of the manuscript – M.S.W., L.K.T., J.C.K., B.E.H. Statistical analysis – not relevant. Obtaining funding – not relevant.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship and/or publication of this article.\n\nGuarantor: Mark S Whiteley\n\nEthical approval: Patient has given her written consent for reporting her case.\n\nInformed consent: Written informed consent was obtained from the patient(s) for their anonymised information to be published in this article.\n\nORCID iD: Mark S Whiteley https://orcid.org/0000-0001-6727-6245\n==== Refs\nReferences\n\n1 Parsi K. Interaction of detergent sclerosants with cell membranes. Phlebology 2015; 30 (5 ): 306–315. DOI: 10.1177/0268355514534648. 24827732\n2 Whiteley MS Dos Santos SJ Fernandez-Hart TJ , et al . Media damage following detergent sclerotherapy appears to be secondary to the induction of inflammation and apoptosis: an immunohistochemical study elucidating previous histological observations. Eur J Vasc Endovasc Surg 2016; 51 (3 ): 421–428. DOI: 10.1016/j.ejvs.2015.11.011. 26790396\n3 Ranasinghe I Parzynski CS Freeman JV , et al . Long-term risk for device-related complications and reoperations after implantable cardioverter-defibrillator implantation: an observational cohort study. Ann Intern Med 2016; 165 (1 ): 20–29. DOI: 10.7326/M15-2732. 27135392\n4 Stricker BH van Oijen JA Kroon C , et al . Anafylaxie na gebruik van polidocanol [Anaphylaxis following use of polidocanol]. Ned Tijdschr Geneeskd 1990; 134 (5 ): 240–242.2304580\n5 Paysant F Baert A Morel I , et al . L’aetoxisclerol accusé à tort d’entraîner une mort subite [Case of death occurred after an injection of aetoxisclerol. The responsibility of the product should be discussed]. Acta Clin Belg 2006; 61 (Suppl. 1 ): 51–53.16700152\n6 Marrocco-Trischitta MM Guerrini P Abeni D , et al . Reversible cardiac arrest after polidocanol sclerotherapy of peripheral venous malformation. Dermatol Surg 2002; 28 (2 ): 153–155. DOI: 10.1046/j.1524-4725.2002.00344.x. 11860427\n7 Shimo T Hidaka K Yanagawa S , et al . [Two episodes of cardiac arrest in a boy receiving sclerotherapy with polidocanol: a case report]. Masui 2005; 54 (1 ): 57–59.15717471\n8 Sylvoz N Villier C Blaise S , et al . Toxicité cardiaque du polidocanol: rapport d’un cas et revue de la littérature [Polidocanol induced cardiotoxicity: a case report and review of the literature]. J Mal Vasc 2008; 33 (4–5 ): 234–238. DOI: 10.1016/j.jmv.2008.09.004. 19019599\n9 Engelberger RP Ney B Clair M , et al . Myocardial infarction after ultrasoundguided foam sclerotherapy for varicose veins: a case report and review of the literature of a rare but serious adverse event. Vasa 2016; 45 (3 ): 255–258. DOI: 10.1024/0301-1526/a000534. 27129073\n10 Timothy AC Snow Julian P McEntee Sally C , et al . Myocardial infarction following sclerotherapy in a patient with a patent foramen ovale. N Z Med J 2012; 125 : 64–67, http://www.nzma.org.nz/journal/125-1366/5447/\n11 Jia X Mowatt G Burr JM , et al . Systematic review of foam sclerotherapy for varicose veins. Br J Surg 2007; 94 (8 ): 925–936. DOI: 10.1002/bjs.5891. 17636511\n12 Gillet JL Donnet A Lausecker M , et al . Pathophysiology of visual disturbances occurring after foam sclerotherapy. Phlebology 2010; 25 (5 ): 261–266. DOI: 10.1258/phleb.2009.009068. 20870875\n13 Frullini A Felice F Burchielli S , et al . High production of endothelin after foam sclerotherapy: a new pathogenetic hypothesis for neurological and visual disturbances after sclerotherapy. Phlebology 2011; 26 (5 ): 203–208. DOI: 10.1258/phleb.2010.010029. 21478144\n14 Frullini A Barsotti MC Santoni T , et al . Significant endothelin release in patients treated with foam sclerotherapy. Dermatol Surg 2012; 38 (5 ): 741–747. DOI: 10.1111/j.1524-4725.2012.02390.x. 22540861\n15 Stephens R Dunn S. Non-ST-elevation myocardial infarction following foam ultrasound-guided sclerotherapy. Phlebology 2014; 29 (7 ): 488–490. DOI: 10.1177/0268355513481765. 23563647\n\n",
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"nlm_unique_id": "101638686",
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"pages": "2050313X211000866",
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"title": "Clinical dilemma of management: Cardiac arrest after microsclerotherapy for lower limb telangiectasia with liquid 0.3% aethoxysklerol or idiopathic cardiac arrest?",
"title_normalized": "clinical dilemma of management cardiac arrest after microsclerotherapy for lower limb telangiectasia with liquid 0 3 aethoxysklerol or idiopathic cardiac arrest"
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"abstract": "► Young women with hypercalcemic type small cell ovarian cancer face a poor prognosis. ► Tumors respond to multi-agent chemotherapy, although rapid recurrence is typical. ► Using updated immunohistochemical staining patterns, this tumor can be identified.",
"affiliations": "Division of Gynecologic Oncology, Orlando Health - MD Anderson Cancer Center - Orlando, USA ; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Michigan Medical Center, USA.;Division of Gynecologic Oncology, Orlando Health - MD Anderson Cancer Center - Orlando, USA.;Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Michigan Medical Center, USA ; Department of Pathology, University of Michigan Medical Center, USA.",
"authors": "Bakhru|Arvind|A|;Liu|J Rebecca|JR|;Lagstein|Amir|A|",
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"title": "A case of small cell carcinoma of the ovary hypercalcemic variant in a teenager.",
"title_normalized": "a case of small cell carcinoma of the ovary hypercalcemic variant in a teenager"
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"abstract": "Herpes simplex virus encephalitis (HSVE) usually presents as a monophasic disease. Symptomatic HSVE relapsing with seizures, encephalopathy, or involuntary movements associated with anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis have been recently reported. We report 2 cases of adult post-HSVE anti-NMDAR encephalitis from Portugal. Two female patients aged 50 years and 30 years were diagnosed with herpes simplex virus type 2 and type 1 encephalitis, respectively. After the initial improvement with specific treatment and despite virologic negativization, both patients suffered clinical, electroencephalographic, and imaging deterioration. The autoimmune encephalitis hypothesis was confirmed with the demonstration of anti-NMDAR antibodies in both cerebrospinal fluid and serum. Both responded to human immunoglobulin and methylprednisolone, with progressive gain of autonomy along the follow-up period. Thymectomy for thymic hyperplasia diagnosed during follow-up was performed in 1 patient. Although being rare, post-HSVE anti-NMDAR encephalitis should be considered in all cases of symptomatic recrudescence after HSVE, since adequate immune-modulating treatment improves the outcome. The role of thyme hyperplasia in autoimmune encephalitis pathogenesis needs better understanding.",
"affiliations": "Neurology Department, University and Hospital Center of Coimbra, Coimbra, Portugal.;Neurology Department, Algarve Hospital University Center, Faro, Portugal.;Infectious Disease Department, Algarve Hospital University Center, Faro, Portugal.;Neurology Department, University and Hospital Center of Coimbra, Coimbra, Portugal.;Neurology Department, University and Hospital Center of Coimbra, Coimbra, Portugal.;Neurology Department, University and Hospital Center of Coimbra, Coimbra, Portugal.;Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal.",
"authors": "Brás|Ana|A|;André|Ana|A|https://orcid.org/0000-0003-1921-4095;Sá|Laura|L|;Carvalho|João|J|;Matos|Anabela|A|;Gens|Helena|H|;Nzwalo|Hipólito|H|",
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"issue": "10(2)",
"journal": "The Neurohospitalist",
"keywords": "autoimmune NMDA-R-receptor antibody encephalitis; encephalitis relapse; herpes simplex type 2; herpes virus simplex encephalitis; thyme hyperplasia",
"medline_ta": "Neurohospitalist",
"mesh_terms": null,
"nlm_unique_id": "101558199",
"other_id": null,
"pages": "133-138",
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"title": "Anti-NMDAR Encephalitis Following Herpes Simplex Virus Encephalitis: 2 Cases From Portugal.",
"title_normalized": "anti nmdar encephalitis following herpes simplex virus encephalitis 2 cases from portugal"
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"abstract": "A patient presented with sudden, unexplained lower abdominal pain without peritonism or signs of infection or inflammatory reaction, but with recent bloody stools and a history of radiation therapy, diabetes and immunosuppression. Plain abdominal x-ray showed only air-fluid levels and air distention of the colon, but a later abdominal CT scan revealed extensive gas gangrene of the colon. The patient's clinical status rapidly worsened. Elective surgical rectosigmoid debridement did not prevent the patient's death. In conclusion, the diagnosis of 'spontaneous' life-threatening gas gangrene requires a high degree of clinical suspicion and allows life-saving surgical intervention.\nSudden and rapidly worsening lower abdominal pain without peritonitis or ileus can indicate gas gangrene from distal bowel perforation.Bloody stools or other symptoms and/or procedures reported previously and apparently resolved could indicate hidden perforation.Diagnostic gas detection, clinically or radiologically, occurs too late to prevent fatal consequences, so early signs of infection and inflammation should be sought for and evaluated as early surgery is life saving.",
"affiliations": "Unit of Internal Medicine 2, University Hospital Policlinico of Modena, University of Modena and Reggio Emilia, Modena, Italy.;Unit of Internal Medicine 2, University Hospital Policlinico of Modena, University of Modena and Reggio Emilia, Modena, Italy.;Unit of Internal Medicine 2, University Hospital Policlinico of Modena, University of Modena and Reggio Emilia, Modena, Italy.",
"authors": "Scarlini|Stefania|S|;Gandolfo|Marco|M|;Pietrangelo|Antonello|A|",
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"fulltext": "\n==== Front\nEur J Case Rep Intern MedEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2016_000444444-1-3069-1-10-20160914ArticlesSudden Onset of Lower Abdominal Pain Without Peritonitis or Ileus Scarlini Stefania Gandolfo Marco Pietrangelo Antonello Unit of Internal Medicine 2, University Hospital Policlinico of Modena, University of Modena and Reggio Emilia, Modena, Italy2016 14 9 2016 3 7 00044410 8 2016 22 8 2016 © EFIM 20162016This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseA patient presented with sudden, unexplained lower abdominal pain without peritonism or signs of infection or inflammatory reaction, but with recent bloody stools and a history of radiation therapy, diabetes and immunosuppression. Plain abdominal x-ray showed only air-fluid levels and air distention of the colon, but a later abdominal CT scan revealed extensive gas gangrene of the colon. The patient’s clinical status rapidly worsened. Elective surgical rectosigmoid debridement did not prevent the patient’s death. In conclusion, the diagnosis of ‘spontaneous’ life-threatening gas gangrene requires a high degree of clinical suspicion and allows life-saving surgical intervention.\n\nLEARNING POINTS\nSudden and rapidly worsening lower abdominal pain without peritonitis or ileus can indicate gas gangrene from distal bowel perforation.\n\nBloody stools or other symptoms and/or procedures reported previously and apparently resolved could indicate hidden perforation.\n\nDiagnostic gas detection, clinically or radiologically, occurs too late to prevent fatal consequences, so early signs of infection and inflammation should be sought for and evaluated as early surgery is life saving.\n\nGas gangreneClostridium septicumacute abdominal pain\n==== Body\nINTRODUCTION\nGas gangrene is associated with perforating trauma. However, the lower bowel can perforate spontaneously and anaerobes from the intestinal flora can cause life-threatening soft tissue gangrene. Spontaneous perforation, often due to a weakened intestinal wall, is a rare and severe occurrence with high mortality due to the lack of obvious clinical manifestations and rapid development of systemic toxicity. A high level of suspicion is essential for early diagnosis and immediate treatment.\n\nCASE PRESENTATION\nA 60-year-old man with a history of diabetes, pulmonary small cell carcinoma being treated with carboplatin-etoposide and previous radiotherapy for prostate cancer, complained of the onset of stabbing and diffuse, non-irradiated, abdominal pain. He mentioned having bloody stools 3 days previously that had spontaneously resolved. When he visited his doctor 2 days before hospitalization, he was asymptomatic except for slight haemorrhoidal congestion. On admission he was febrile (38.5°C) and haemodynamically stable but with acute pain in the lower abdominal quadrants without peritonism.\n\nPeristalsis was torpid but the bowel was open. Abdominal x-ray showed a colon distended with air and fluid. Laboratory tests showed haemoglobin 9 g/dl, leukocytes 2860/μl (55% neutrophil granulocytes), platelets 89,000/μl, C-reactive protein (CRP) 12 mg/dl (normal values <0.5 mg/dl), CPK 470 U/l (normal values <350 U/l) and plasma creatinine 2.3 mg/dl. Due to the suspicion of infection, empirical therapy with piperacillin-tazobactam was started after sample collection for blood cultures. Pain sedation required the use of morphine. After 6 h the patient developed hypotension, tachycardia and chest pain. The ECG and troponin levels were diagnostic for non-ST elevation myocardial infarction (NSTEMI). Hemogasanalysis showed pH 7.19, HCO3 17 and lactate 30, indicating severe metabolic acidosis. Intravenous fluid resuscitation and teicoplanin infusion were started. The patient was transferred to the ICU where he became unconscious. A total body CT scan was performed and showed a diffuse gas gangrene starting from the rectum and extending to the thoracic muscles (Fig. 1). A surgical rectosigmoid resection was immediately performed but the patient died 8 h after surgery. Blood and intestinal tissue cultures were positive for Clostridium septicum.\n\nDISCUSSION\nGas gangrene, usually caused by Clostridium septicum, is a severe infection leading to muscular and soft tissue necrosis. It is generally associated with perforating trauma but, in rare cases (e.g. patients with bowel malignancy, radiation therapy, leukaemia, diabetes and immunosuppression) can occur without apparent perforation. Signs of systemic toxicity develop rapidly, followed by shock and multiple organ failure. Death usually occurs within 24–48 h after symptom onset. Early diagnosis is essential but difficult: the lower intestinal perforation is not readily apparent, while gas in tissues, detectable clinically as crepitus, or radiologically, develops late, although a history of previous procedures, like enemas etc., can give rise to suspicion[1–2]. The most important alert sign is acute and unexplained abdominal pain that should immediately call for appropriate imaging (CT or MRI). After diagnosis, early antibiotic treatment with clindamycin 600–900 mg/kg every 8 h plus penicillin 2–4 million units every 4–6 h and aggressive surgical debridement are essential[3].\n\nIn our case, the bloody stools seen a few days previously, which apparently did not cause concern and were unexplained (although initially attributed to haemorrhoids), may well have been an early sign of rectal wall perforation. In fact, a number of factors, in particular radiation treatment for prostate cancer and immunosuppression therapy, may have weakened and fissured the distal intestinal wall, favouring access of Gram-negative bacteria and anaerobes to peri-rectal fat and leading to soft tissue gangrene. The sudden lower abdominal pain is the second key diagnostic element. In our case, lack of peritonism, due to the extra-peritoneal site of intestinal perforation, and immediate and aggressive pain treatment with morphine that rapidly reduced the key alarming symptom, affected our clinical judgement and delayed further imaging evaluation. In this context, a sharp pain could also suggest a dissecting aortic aneurism and prompt abdominal ultrasound evaluation. The third important clinical element of this case was the impending septic shock. Neutropenia, renal failure and a generalized inflammatory reaction (which may have also caused troponin elevation, initially attributed to NSTEMI) may all be signs of Gram-negative sepsis or anaerobic infection. The empirical antibiotic therapy was clearly ineffective for controlling the infection sustained by the Clostridium in our immunodepressed patient who died shortly after surgery due to severe sepsis.\n\nCONCLUSION\nAcute and unexplained abdominal pain can be the only early manifestation of spontaneous gas gangrene. Lack of peritonism should not mean surgical evaluation is postponed and the patient should be immediately investigated with a diagnostic radiological work-up (CT or MRI). Aggressive surgical debridement remains the only life-saving strategy.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nFigure 1 (a) Sagittal and (b,c) transversal full-body CT scans showing rectal perforation with gas in the pelvis (arrows in a and c) with microbubbles in the abdominal wall (arrowheads)\n==== Refs\nREFERENCES\n1 Stevens DL Bisno AL Chambers HF Everett ED Dellinger P Goldstein EJC Practice guidelines for the diagnosis and management of skin and soft-tissue infections Clin Infect Dis 2005 41 1373 1406 16231249 \n2 Mishra SP Singh S Gupta SK Necrotizing soft tissue infections: surgeon’s prospective J Inflamm 2013 2013 1 7 \n3 Hartel M Kutup A Gehl A Zustin J Grossterlinden LG Rueger JM Foudroyant course of an extensive Clostridium septicum gas gangrene in a diabetic patient with occult carcinoma of the colon Orthopedics 2013 2013 1 5\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2284-2594",
"issue": "3(7)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Clostridium septicum; Gas gangrene; acute abdominal pain",
"medline_ta": "Eur J Case Rep Intern Med",
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"nlm_unique_id": "101648453",
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"title": "Sudden Onset of Lower Abdominal Pain Without Peritonitis or Ileus.",
"title_normalized": "sudden onset of lower abdominal pain without peritonitis or ileus"
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"abstract": "Capecitabine (CAP) is an antineoplastic agent that is known to cause mild hepatotoxicity. However, severe and late acute liver injury was not reported previously as an adverse reaction of CAP. This report discusses the case of a 63-year-old man with colon cancer who was receiving the fifth cycle of CAP as a monotherapy and presented with fatigue and jaundice during the fifth cycle of CAP. Laboratory tests showed markedly elevated transaminases (aspartate transaminase: 2,448 U/L; alanine transaminase: 1,984 U/L). Eventually, discontinuation of CAP was enough to reverse the delayed CAP-induced acute hepatic injury in clinical and laboratory terms.",
"affiliations": "Internal Medicine, Hamad Medical Corporation, Doha, QAT.;Internal Medicine, Faculty of Medicine, Damascus University, Damascus, SYR.;Internal Medicine, Faculty of Medicine, Damascus University, Damascus, SYR.;Internal Medicine, Faculty of Medicine, Damascus University, Damascus, SYR.;Hematology, Hamad Medical Corporation, Doha, QAT.",
"authors": "Habib|Mhd Baraa|MB|;Hanafi|Ibrahem|I|;Al Zoubi|Maya|M|;Bdeir|Zeina|Z|;Yassin|Mohamed A|MA|",
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"doi": "10.7759/cureus.12477",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.12477\nInternal Medicine\nGastroenterology\nOncology\nSevere and Late Acute Liver Injury Induced by Capecitabine\nMuacevic Alexander Adler John R Habib Mhd Baraa 1 Hanafi Ibrahem 2 Al Zoubi Maya 2 Bdeir Zeina 2 Yassin Mohamed A 3 \n1 \nInternal Medicine, Hamad Medical Corporation, Doha, QAT \n\n2 \nInternal Medicine, Faculty of Medicine, Damascus University, Damascus, SYR \n\n3 \nHematology, Hamad Medical Corporation, Doha, QAT \n\nMhd Baraa Habib mhabib2@hamad.qa\n4 1 2021 \n1 2021 \n13 1 e124774 1 2021 Copyright © 2021, Habib et al.2021Habib et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/47288-severe-and-late-acute-liver-injury-induced-by-capecitabineCapecitabine (CAP) is an antineoplastic agent that is known to cause mild hepatotoxicity. However, severe and late acute liver injury was not reported previously as an adverse reaction of CAP. This report discusses the case of a 63-year-old man with colon cancer who was receiving the fifth cycle of CAP as a monotherapy and presented with fatigue and jaundice during the fifth cycle of CAP. Laboratory tests showed markedly elevated transaminases (aspartate transaminase: 2,448 U/L; alanine transaminase: 1,984 U/L). Eventually, discontinuation of CAP was enough to reverse the delayed CAP-induced acute hepatic injury in clinical and laboratory terms.\n\ncapecitabinesevere hepatotoxicitylate acute liver injurycolon cancerreversible adverse effectThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nDrug-induced liver injuries can be categorized into five patterns: cholestatic hepatitis, acute hepatitis, chronic hepatitis, chronic cholestasis, and acute cholestasis [1]. The American DILI Network reported that antibiotics, herbal agents, cardiovascular agents, anti-neoplastic agents, analgesics, and many other classes are implicated in drug-induced liver injury [2]. Colorectal cancer is one of the most common and fatal malignancies worldwide [3]. Capecitabine (CAP), an oral prodrug of 5-fluorouracil, is a pyrimidine analogue that has been used since 1998 to treat advanced colon cancer [4]. The recommended regimen of CAP is 850-1,250 mg/m2 orally twice daily for 14 days. The cycle needs to be repeated every three weeks for total eight cycles [5]. The most common adverse reactions are diarrhea, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia [6]. Drug-induced liver injury is a known side effect of CAP therapy, which usually manifests with a high bilirubin level. The suggested mechanism is thought to be direct hepatotoxicity. CAP is mainly metabolized in the liver through the microsomal enzyme system, and production of toxic substances may induce liver injury [4]. Serum aminotransaminase rarely may increase in some patients receiving CAP; however, it is unusual to result in high levels more than five times of upper limit of the reference range [4].\n\nIn this case report, we present the case of an elderly man who was treated with CAP for colon cancer and presented to our center in the fifth cycle of CAP because of acute liver injury with elevated transaminase in thousands.\n\nCase presentation\nA 63-year-old male patient was diagnosed with colorectal cancer accidentally after urgent surgery for bowel obstruction. He was referred to the oncology center and received four cycles of adjuvant chemotherapy with a conventional dose of CAP at 1,250 mg/m2. He was on the 10th day of the fifth cycle when he presented to our hospital complaining of fatigue and yellowish color of his eyes for one week. The patient denied any fever or abdominal pain but mentioned clay-colored stool and dark-colored urine without any changes in defecation or urination habits. Except for the mentioned cancer, his medical history was unremarkable. He also denied any recent intake of alcohol or regular medications or herbals.\n\nOn admission, he was afebrile, with a blood pressure of 135/84 mmHg, heart rate of 76 beats per minute, respiratory rate of 17 breaths per minute, and BMI of 26. Physical examination was positive for jaundice noted in sclera and skin. Abdominal examination was unremarkable with no organomegaly. Laboratory findings were significant for markedly elevated serum transaminases and bilirubin (Table 1). Viral hepatitis was ruled out by negative serology for hepatitis A, B, C, and E, Epstein-Barr virus, cytomegalovirus, and herpes simplex virus. Autoimmune panel including ANA, ANCA, and AMA was negative. Ultrasound of the abdomen was unremarkable. CT of the abdomen revealed no hepatic metastases. One month before the presentation, the patient’s baseline liver enzymes and bilirubin were normal (Table 1). The multidisciplinary team decided to discontinue CAP as it was the likely implicated reason behind this severe hepatotoxicity. Two weeks later, the patient’s transaminase level went down with clinical improvement as well. Therefore, the diagnosis of CAP-induced acute liver injury was established. Laboratory tests after six-month follow-up revealed normal serum transaminase and bilirubin levels. At that point, the patient was not taking any chemotherapy and he refused to resume chemotherapy afterward.\n\nTable 1 Blood tests\nALT, alanine transaminase; AST, aspartate transaminase; INR, international normalized ratio\n\n\nDetail\n\t\nOne month before the presentation\n\t\nOn admission\n\t\nTwo weeks after hospitalization\n\t\nNormal range\n\t\n\nALT\n\t\n16\n\t\n1,984\n\t\n110\n\t\n1-43 U/L\n\t\n\nAST\n\t\n21\n\t\n2,448\n\t\n68\n\t\n1-43 U/L\n\t\n\nTotal bilirubin\n\t\n0.97\n\t\n23.03\n\t\n3.96\n\t\n0.5-1.2 mg/dL\n\t\n\nDirect bilirubin\n\t\nNA\n\t\n20.8\n\t\n2.10\n\t\n0.00-0.30 mg/dL\n\t\n\nAlkaline phosphatase\n\t\n \n\t\n523\n\t\n \n\t\n90-290 U/L\n\t\n\nINR\n\t\n \n\t\n1.25\n\t\n \n\t\n0.9-1.2\n\t\n\nUrea\n\t\n \n\t\n34\n\t\n \n\t\n10-40 mg/dL\n\t\n\nCreatinine\n\t\n \n\t\n1.09\n\t\n \n\t\n0.5-1.4 mg/dL\n\t\n\nSodium\n\t\n \n\t\n141\n\t\n \n\t\n136-145 mmol/L\n\t\n\nPotassium\n\t\n \n\t\n4.1\n\t\n \n\t\n3.5-5.1 mmol/L\n\t\nDiscussion\nSevere hepatotoxicity (high alanine transaminase [ALT] and aspartate transaminase [AST] > 1,000 U/L) is usually related to a few etiologies including viral hepatitis, ischemic liver injury, and toxin- or drug-induced liver injury [7]. Drug-induced liver injury is a common cause of acute liver injury in general population. A detailed history taking should focus on the possible hepatotoxic medications along with other potential etiologies [8]. Although CAP is mainly metabolized by the liver, hepatopathy due to CAP is not a frequent manifestation due to its rapid metabolism and short half-life [9]. Mild hyperbilirubinemia is a well-known side effect of CAP. However, it is often reversible and isolated without other abnormal liver tests [4]. In addition, one article reported a mild serum enzyme elevation that was accompanied by steatosis and inflammation in a patient treated with CAP. This pathology resolved after holding the chemotherapy [10]. Hence, even though several hepatic adverse effects were reported, the severely elevated transaminase was not noticed.\n\nIn our case, the patient developed a late elevation of AST and ALT (while he was receiving the fifth course of CAP), which was not noticed in the previous cycles. Furthermore, it was a very severe increment in transaminase (in thousands), which was not reported previously in association with CAP as the patient was vitally stable and the viral hepatitis and autoimmune panels were negative; ischemic and viral etiologies of severe transaminitis were excluded. Therefore, drug-induced hepatotoxicity emerged as the principal diagnosis. A liver biopsy for histological confirmation was not performed in our patient due to the complete recovery of liver enzyme abnormalities after discontinuation of CAP. These unique associated findings were not reported previously as an adverse reaction of CAP.\n\nConclusions\nCAP-induced acute liver injury with very high transaminase can be a serious and late side effect, and it should be considered anytime during the course of treatment. Monitoring liver enzymes for possible hepatotoxicity of CAP and the immediate cessation of treatment might be advisable to mitigate the toxic effects and possible complications.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n\nAuthors acknowledge the esteemed contributions of Mohamed Alkayyal, MD, Asaad Alkoht, MD, Dana Abo Samra, MD, and Mohammad Sakkal, MD.\n==== Refs\nReferences\n1 Hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical associations Hepatology Kleiner DE Chalasani NP Lee WM 661 670 59 2014 24037963 \n2 Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study Gastroenterology Chalasani N Bonkovsky HL Fontana R 1340 1352 148 2015 25754159 \n3 Cancer incidence in five continents: inclusion criteria, highlights from Volume X and the global status of cancer registration Int J Cancer Bray F Ferlay J Laversanne M 2060 2071 137 2015 26135522 \n4 LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet] National Institute of Diabetes and Digestive and Kidney Diseases Bethesda, MD National Institute of Diabetes and Digestive and Kidney Diseases 2012 https://www.ncbi.nlm.nih.gov/books/NBK547986/. \n5 Capecitabine in the management of colorectal cancer Cancer Manag Res Hirsch BR Yousuf Zafar S 79 89 3 2011 21629830 \n6 XELODA (capecitabine) tablets, for oral use 8 2020 0 3 31 2019 https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020896s037lbl.pdf \n7 Liver enzyme alteration: a guide for clinicians CMAJ Giannini EG Testa R Savarino V 367 379 172 2005 15684121 \n8 Hepatotoxicity by drugs: the most common implicated agents Int J Mol Sci Björnsson ES 224 17 2016 26861310 \n9 Capecitabine: an overview of the side effects and their management Anticancer Drugs Saif MW Katirtzoglou NA Syrigos KN 447 464 19 2008 https://pubmed.ncbi.nlm.nih.gov/18418212/ 18418212 \n10 Hepatic steatosis secondary to capecitabine: a case report J Med Case Rep Chin S Kim T Siu L 227 4 2010 24576340\n\n",
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"keywords": "capecitabine; colon cancer; late acute liver injury; reversible adverse effect; severe hepatotoxicity",
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"nlm_unique_id": "101596737",
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"pages": "e12477",
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"pmid": "33552791",
"pubdate": "2021-01-04",
"publication_types": "D002363:Case Reports",
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"title": "Severe and Late Acute Liver Injury Induced by Capecitabine.",
"title_normalized": "severe and late acute liver injury induced by capecitabine"
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"abstract": "Antiepileptic drugs (AEDs) are commonly prescribed to women of childbearing age. As 0.3%-0.7% of all pregnancies occur in women with epilepsy (WWE), the effect of recurrent seizures and teratogenicity on pregnancy outcome and the fetus have been widely studied. Most of these studies have focused on live births. A significant number of terminated pregnancies in WWE were ignored in past studies, thus reducing the calculated incidence of congenital malformations and possible influence of AED exposure. We scrutinized the medical records at our medical center for termination of pregnancy (TOP) in WWE for the years 2004-2016. Fifty-eight TOPs occurred in WWE during these years. Reasons for TOP included spontaneous abortions necessitating medical intervention (46.6%), patient's request (31.0%), medically recommended (10.3%), and unknown (12.1%).",
"affiliations": "Department of Neurology, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.;Department of Neurology, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.;Department of Neurology, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.;Department of Neurology, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: felixbenninger@gmail.com.",
"authors": "Goldstein|Lilach|L|;Shihman|Boris|B|;Amiel|Noam|N|;Benninger|Felix|F|",
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"keywords": "Abortion; Antiepileptic drugs (AEDs); Teratogenicity; Termination of pregnancy (TOP); Women with epilepsy (WWE)",
"medline_ta": "Epilepsy Behav",
"mesh_terms": "D000028:Abortion, Induced; D000022:Abortion, Spontaneous; D000328:Adult; D000927:Anticonvulsants; D004827:Epilepsy; D005260:Female; D006801:Humans; D008875:Middle Aged; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012189:Retrospective Studies",
"nlm_unique_id": "100892858",
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"title": "Termination of pregnancy in women with epilepsy - A retrospective single center study.",
"title_normalized": "termination of pregnancy in women with epilepsy a retrospective single center study"
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"abstract": "A 60-year-old man was found to have anemia and leukocytosis from a health examination, and diagnosed with primary myelofibrosis (PMF). He was treated with low-dose melphalan but required frequent transfusions of red blood cells, and his splenomegaly enlarged. He received reduced-intensity stem cell transplantation (RIST)from an HLA-identical unrelated donor. The recovery of hematopoiesis was delayed due to the small number of transplanted cells (0.4 x 10(8)/kg). Splenomegaly and myelofibrosis gradually improved, and transfusion was not necessary 6 months later. He died of pneumonia about 1 year after transplantation. However, this case suggests that RIST is an effective treatment for PMF with giant splenomegaly.",
"affiliations": "Dept. of Hematology, Kanagawa Cancer Center, Yokohama City University Graduate School of Medicine.",
"authors": "Ito|Satomi|S|;Hagihara|Maki|M|;Motohashi|Kenji|K|;Maruta|Atsuo|A|;Ishigatsubo|Yoshiaki|Y|;Gomi|Seiji|S|;Kanamori|Heiwa|H|",
"chemical_list": "D019653:Myeloablative Agonists; D008558:Melphalan",
"country": "Japan",
"delete": false,
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"issue": "37(2)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
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"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D017809:Fatal Outcome; D006801:Humans; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D019653:Myeloablative Agonists; D055728:Primary Myelofibrosis; D033581:Stem Cell Transplantation; D014057:Tomography, X-Ray Computed",
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"other_id": null,
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment with reduced-intensity stem cell transplantation for primary myelofibrosis.",
"title_normalized": "successful treatment with reduced intensity stem cell transplantation for primary myelofibrosis"
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"companynumb": "JP-MYLANLABS-2016M1016523",
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"abstract": "BACKGROUND\nChronic pulmonary aspergillosis (CPA) has substantial impact on quality of life. A subset of patients develops significant pulmonary fibrosis, identified either on biopsy or radiologically. The term chronic fibrosing pulmonary aspergillosis (CFPA) has been suggested.\n\n\nMETHODS\nWe describe 11 patients with CFPA referred to our centre.\n\n\nRESULTS\nMean age was 58.5 years and five were male. In nine, fibrosis was already evident on presentation, while in two it developed 3 and 6 years later. The predominant radiological feature was extensive or complete involvement of the entire lung, with minimal contralateral involvement. All patients received prolonged antifungal treatment. Two patients had surgical treatment; both developed post-operative complications. The contralateral lung remained free of significant disease in all but three patients.\n\n\nCONCLUSIONS\nCFPA is a rare complication of CPA that is usually evident on presentation, but may develop after years in patients not on antifungals. Fibrosis resembles the 'destroyed lung' syndrome described after treated tuberculosis.",
"affiliations": "a National Aspergillosis Centre, Manchester Academic Health Science Centre , University Hospital of South Manchester, University of Manchester , Manchester , UK.;a National Aspergillosis Centre, Manchester Academic Health Science Centre , University Hospital of South Manchester, University of Manchester , Manchester , UK.;a National Aspergillosis Centre, Manchester Academic Health Science Centre , University Hospital of South Manchester, University of Manchester , Manchester , UK.;a National Aspergillosis Centre, Manchester Academic Health Science Centre , University Hospital of South Manchester, University of Manchester , Manchester , UK.",
"authors": "Kosmidis|Chris|C|;Newton|Pippa|P|;Muldoon|Eavan G|EG|;Denning|David W|DW|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/23744235.2016.1232861",
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"issn_linking": "2374-4243",
"issue": "49(4)",
"journal": "Infectious diseases (London, England)",
"keywords": "Chronic pulmonary aspergillosis; case series; destroyed lung; fibrosis; outcome; radiology",
"medline_ta": "Infect Dis (Lond)",
"mesh_terms": "D000328:Adult; D000368:Aged; D002908:Chronic Disease; D005260:Female; D005355:Fibrosis; D006801:Humans; D008168:Lung; D008297:Male; D008875:Middle Aged; D055732:Pulmonary Aspergillosis; D013902:Radiography, Thoracic; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101650235",
"other_id": null,
"pages": "296-301",
"pmc": null,
"pmid": "27658458",
"pubdate": "2017-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Chronic fibrosing pulmonary aspergillosis: a cause of 'destroyed lung' syndrome.",
"title_normalized": "chronic fibrosing pulmonary aspergillosis a cause of destroyed lung syndrome"
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"companynumb": "GB-PFIZER INC-2017074396",
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"abstract": "BACKGROUND\nAnti-glomerular basement membrane disease (anti-GBM disease) is an autoimmune glomerulonephritis disease that is characterized by IgG linear deposition along the non-collagen domain of a3 chains of type IV collagen on the GBM. Although anti-GBM disease accompanied with IgA linear deposition along GBMs was discussed previously in some papers, anti-GBM disease combined with IgA granular deposition in the mesangial area, especially complicated with reversible posterior leukoencephalopathy syndrome (RPLS), was rarely reported. RPLS is usually caused by hypertensive encephalopathy, renal decompensation, fluid retention, and adverse effects of immunosuppressive drugs.\n\n\nMETHODS\nA male patient with the chief complaints of headache, gross hematuria, and nocturia was referred to our hospital. Based on renal biopsy, the diagnosis was finally confirmed as anti-GBM disease combined with IgA nephropathy and, the patient received comprehensive treatment, including cyclophosphamide (CTX), which led to symptom improvement. Two days after the third impulse CTX was given, he suddenly experienced headache and dizziness, which eventually developed into a tonic-clonic seizure. RPLS was identified by cranial magnetic resonance imaging (MRI) with reversible neuroimaging. After diazepam and antihypertension management, seizures were controlled. RPLS, a neurological complication, was found in anti-GBM disease with IgA nephropathy during our immunosuppressants therapy for the first time.\n\n\nCONCLUSIONS\nIt is worth paying more attention to patients with rapidly progressive glomerulonephritis (RPGN), as they might be complicated with RPLS during intravenous administration of CTX and methylprednisolone. We suggest the neuroimaging be examined as soon as the seizure happens.",
"affiliations": "Department of Nephrology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China (mainland).;Department of Nephrology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China (mainland).;Department of Nephrology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China (mainland).;Department of Nephrology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China (mainland).",
"authors": "Ge|Ya-ting|YT|;Liao|Jin-lan|JL|;Liang|Wei|W|;Xiong|Zu-ying|ZY|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/ajcr.894619",
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"issn_linking": "1941-5923",
"issue": "16()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D019867:Anti-Glomerular Basement Membrane Disease; D001706:Biopsy; D001921:Brain; D003937:Diagnosis, Differential; D005922:Glomerulonephritis, IGA; D006801:Humans; D007668:Kidney; D008279:Magnetic Resonance Imaging; D008297:Male; D054038:Posterior Leukoencephalopathy Syndrome; D055815:Young Adult",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "849-53",
"pmc": null,
"pmid": "26621456",
"pubdate": "2015-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21124085;20693857;22366925;24411012;21659781;22401499;24292045;12063238;12213946;8559202;9469509;18356474;18403560;18708970;21318395",
"title": "Anti-Glomerular Basement Membrane Disease Combined with IgA Nephropathy Complicated with Reversible Posterior Leukoencephalopathy Syndrome: An Unusual Case.",
"title_normalized": "anti glomerular basement membrane disease combined with iga nephropathy complicated with reversible posterior leukoencephalopathy syndrome an unusual case"
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"activesubstancename": "CYCLOPHOSPHAMIDE"
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"abstract": "Established doxorubicin cardiomyopathy is a lethal disease. When congestive heart failure develops, mortality is approximately 50%. Extensive research has been done to understand the mechanism and pathophysiology of doxorubicin cardiomyopathy, and considerable knowledge and experience has been gained. Unfortunately, no effective treatment for established doxorubicin cardiomyopathy is presently available. Extensive research has been done and is being done to discover preventive treatments. However an effective and clinically applicable preventive treatment is yet to be discovered.",
"affiliations": "Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242-1081, USA. kanu-chatterjee @ uiowa.edu",
"authors": "Chatterjee|Kanu|K|;Zhang|Jianqing|J|;Honbo|Norman|N|;Karliner|Joel S|JS|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000265166",
"fulltext": null,
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"issn_linking": "0008-6312",
"issue": "115(2)",
"journal": "Cardiology",
"keywords": null,
"medline_ta": "Cardiology",
"mesh_terms": "D000903:Antibiotics, Antineoplastic; D009202:Cardiomyopathies; D004317:Doxorubicin; D006801:Humans; D009206:Myocardium",
"nlm_unique_id": "1266406",
"other_id": null,
"pages": "155-62",
"pmc": null,
"pmid": "20016174",
"pubdate": "2010",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "1462166;4353012;3320376;15100413;8355075;7817916;9734474;7733633;15247354;2266394;6157945;10075079;18590705;11549349;18209766;1540237;2000986;667860;8068938;17329180;6248123;574979;15772336;11579094;6262301;10899161;17161256;9333325;4270890;12373350;17974986;11767415;1451268;9704703;15811867;10942736;15169927;11535996;7441509;9744975;3931886;6293697;7563102;3456345;1929498;12767102;18660728;12628736;12527808;3655914;10766158;10922372;496103;16157314;10024299;17662302;582782;9388241;34156",
"title": "Doxorubicin cardiomyopathy.",
"title_normalized": "doxorubicin cardiomyopathy"
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"abstract": "OBJECTIVE\nTo assess alterations in the composition of peripheral immune cells in acute progressive multifocal leukoencephalopathy (PML).\n\n\nMETHODS\nFresh blood samples from 5 patients with acute PML and 10 healthy controls were analyzed by flow cytometry for naive, central memory and effector memory CD4 and CD8 T cells, B lymphocytes, plasma cells, memory B cells, plasma blasts, and natural killer (NK) cells. The frequency of central memory CD4 T cells was determined longitudinally during the course of PML in 2 patients.\n\n\nRESULTS\nThe frequencies of naive, central memory and effector memory CD8 T cells, B cells, plasma cells, and NK cells were not altered in patients with PML. In contrast, the frequencies of naive CD4 T cells (p = 0.04) and central memory CD4 T cells (p < 0.00001) were reduced and the frequencies of effector memory CD4 T cells were increased (p = 0.01). Longitudinal analysis showed that this pattern was preserved in a patient with fatal PML outcome and restored in one patient who recovered from PML.\n\n\nCONCLUSIONS\nThese data indicate that PML is associated with reduced frequencies of peripheral central memory helper T cells but not with alterations in the frequencies of cytotoxic T cell populations, B lymphocytes, plasma cells, or NK cells.",
"affiliations": "Center of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Germany.;Center of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Germany.;Center of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Germany.",
"authors": "Dubois|Evelyn|E|;Ruschil|Christoph|C|;Bischof|Felix|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1212/NXI.0000000000000177",
"fulltext": "\n==== Front\nNeurol Neuroimmunol NeuroinflammNeurol Neuroimmunol NeuroinflammnnnNEURIMMINFLNeurology® Neuroimmunology & Neuroinflammation2332-7812Lippincott Williams & Wilkins Hagerstown, MD NEURIMMINFL201500565210.1212/NXI.000000000000017741137142144ArticleLow frequencies of central memory CD4 T cells in progressive multifocal leukoencephalopathy Dubois Evelyn Scientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nRuschil Christoph MDScientific Advisory Boards:\n(1) Novartis Pharma GmbH\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nBischof Felix MDScientific Advisory Boards:\nFB received compensation for serving on Scientific Advisory Boards for Genzyme, Novartis and Roche. The other authors declare that they have no competing interests.\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nFB received speaker honoraria and travel support from Biogen Idec, Genzyme and Novartis.\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nFB received research support from Novartis.\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nFrom the Center of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Germany.Correspondence to Dr. Bischof: felix.bischof@uni-tuebingen.deFunding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was paid by the authors.\n\n29 10 2015 12 2015 29 10 2015 2 6 e17704 4 2015 23 9 2015 © 2015 American Academy of Neurology2015American Academy of NeurologyThis is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.Objectives:\nTo assess alterations in the composition of peripheral immune cells in acute progressive multifocal leukoencephalopathy (PML).\n\nMethods:\nFresh blood samples from 5 patients with acute PML and 10 healthy controls were analyzed by flow cytometry for naive, central memory and effector memory CD4 and CD8 T cells, B lymphocytes, plasma cells, memory B cells, plasma blasts, and natural killer (NK) cells. The frequency of central memory CD4 T cells was determined longitudinally during the course of PML in 2 patients.\n\nResults:\nThe frequencies of naive, central memory and effector memory CD8 T cells, B cells, plasma cells, and NK cells were not altered in patients with PML. In contrast, the frequencies of naive CD4 T cells (p = 0.04) and central memory CD4 T cells (p < 0.00001) were reduced and the frequencies of effector memory CD4 T cells were increased (p = 0.01). Longitudinal analysis showed that this pattern was preserved in a patient with fatal PML outcome and restored in one patient who recovered from PML.\n\nConclusions:\nThese data indicate that PML is associated with reduced frequencies of peripheral central memory helper T cells but not with alterations in the frequencies of cytotoxic T cell populations, B lymphocytes, plasma cells, or NK cells.\n\nOPEN-ACCESSTRUE\n==== Body\nLatent infection with the human polyomavirus John Cunningham virus (JCV) is common in healthy individuals. Under circumstances of reduced immunocompetence within the CNS, JCV, which was kept in a quiescent state, is reactivated and causes progressive multifocal leukoencephalopathy (PML).1 PML is a lytic infection of the brain that often leads to severe neurologic deficits or death. The immunologic characteristics that predispose to the development of PML are poorly defined.2\n\nHIV infection accounts for about 85% of all PML cases,1 and up to 5% of patients with AIDS develop PML.3 In patients with HIV infection, PML typically develops before initiation of antiretroviral therapy, at a time when CD4 helper T cell numbers are low and their function is impaired. PML also develops in 3.7–5.2 in 1,000 patients with relapsing-remitting multiple sclerosis treated for more than 24 months with the VLA-4 antibody natalizumab, which prevents lymphocytes from entering the CNS. In addition, PML has been reported in patients treated with fumaric acid for psoriasis who were lymphopenic for at least several months.4 These combined observations indicate that persistent alterations in lymphocyte populations or their ability to enter the brain predispose to PML.\n\nHerein, we provide direct evidence that a reduced frequency of peripheral central memory CD4 T cells is associated with the development of PML.\n\nMETHODS\nStandard protocol approvals, registrations, and patient consents.\nPatients were recruited at the Department of Neurology, University of Tübingen, Germany. All patients gave written informed consent for the provision of blood for the purpose of this research. The protocol under which these samples were obtained was approved by the ethics committee of the University of Tübingen, Germany. Baseline characteristics of the patients are depicted in the table.\n\nTable Patient characteristics\n\nFlow cytometric analysis.\nWhite blood cell counts were determined by routine testing at the central laboratory of our hospital. Flow cytometric analysis was performed with fresh whole blood specimens after staining with fluorochrome-labeled antibodies. The following antibodies were used: anti-human CD3-APC (1/100) clone UCHT1, anti-human CD4-FITC (1/100) clone SK3, anti-human CD8-PerCP (1/100) clone SK1, anti-human CD19-FITC (1/100) clone HIB19, anti-human CD27-PE (1/50) clone L128, anti-human CD38-APC (1/50) clone HIT2, anti-human CD56-PE (1/50) clone B159, anti-human CD197(CCR7)-PE (1/50) clone 3D12, all from BD Biosciences, and anti-human CD45RA-APC (1/50) clone HI100 from BioLegend. As a reference, these analyses were performed in 10 healthy controls. The mean age of healthy controls was 45 years. Absolute numbers of CD4 and CD8 T cells were calculated by multiplying lymphocyte numbers obtained from the white blood cell count with the frequency of CD4 and CD8 cells in flow cytometric analysis.\n\nQuantitative JCV-PCR.\nJCV copy numbers were determined by quantitative PCR at the Institute for Virology, Heinrich Heine University, Düsseldorf, Germany. This assay is able to detect less then 10 viral copies/mL CSF.\n\nStatistical analysis.\nStatistical analysis was performed by unpaired t test using SPSS 22 (IBM Corp., Armonk, NY).\n\nRESULTS\nPatient characteristics.\nThree female and 2 male patients between 39 and 56 years of age were recruited at our institution at the initial presentation of PML between 2012 and 2015 (table). Two patients had HIV-associated PML, 2 patients were on treatment with fumaric acid (Fumaderm) for psoriasis for more than 6 months, and one patient with relapsing-remitting multiple sclerosis was on natalizumab for more than 24 months. PML outcome was related to the JCV copy numbers within the CSF at the time of PML diagnosis. In one patient with negative JCV-PCR, PML diagnosis was established by brain biopsy. This patient was completely free of neurologic deficits after resolution of PML. An immune reconstitution inflammatory syndrome (IRIS) developed in both patients with HIV-PML following initiation of combined antiretroviral therapy and in the natalizumab-treated patient with multiple sclerosis following plasma exchange. IRIS was characterized by the development of new neurologic symptoms and new contrast-enhancing lesions on cerebral MRI. Two patients with less than 500 JCV copies per mL CSF had only moderate residual symptoms and 2 patients who displayed >10,000 copies of the JCV DNA per mL of CSF died of PML within 44 and 61 days, respectively. All patients had reduced lymphocyte numbers at the initial diagnosis of PML (table).\n\nReduced frequency of central memory CD4 T cells in patients with PML.\nAt the initial diagnosis of PML, peripheral blood samples were obtained from all patients and cells were directly analyzed by flow cytometry after staining with the indicated fluorochrome-labeled antibodies (figure 1). As compared with healthy controls, the frequency of central memory CD4 T cells was highly significantly reduced (figure 2; p < 0.00001), as was the frequency of naive CD4 T cells (p = 0.04). The proportion of effector memory CD4 T cells was increased (p = 0.01). In contrast, the frequencies of naive, central memory and effector memory CD8+ T cells (figure 2), CD19+ B lymphocytes, CD19+CD38+ plasma cells, CD19+CD27+ memory B cells, and CD56+ natural killer cells (figure 3) were not significantly different from healthy controls.\n\nFigure 1 Schematic overview of flow cytometry\nSchematic overview on the analysis of peripheral immune cells by flow cytometry. Expression of CCR7 and CD45RA was determined on live CD4 and CD8 cells, and expression of CD38 and CD27 was determined on live CD19 cells as indicated. NK = natural killer cells; NKT = natural killer T cells.\n\nFigure 2 Reduced frequency of central memory CD4 T cells in patients with PML\nReduced frequency of central memory CD4 T cells (CD4Tcm) (p < 0.00001), naive CD4 T cells (p = 0.04), and effector memory CD4 T cells (CD4Tem) (p = 0.01) in patients with PML. Healthy controls (HC) are depicted in the first column of each dotplot, patients with PML in the second. PML = progressive multifocal leukoencephalopathy.\n\nFigure 3 Frequency of B lymphocytes, plasma cells, and NK cells\nFrequency of CD19+ B lymphocytes, CD19+CD38+ plasma cells, CD19+CD27+ memory B cells, and CD56+ NK cells does not significantly differ from healthy controls (HC). Healthy controls are depicted in the first column of each dotplot, patients with PML in the second. NK = natural killer; PML = progressive multifocal leukoencephalopathy.\n\nLongitudinal analysis of peripheral immune cell composition.\nLongitudinal analysis of peripheral immune cells was performed during the course of PML in patients 1 and 2. Patient 1 displayed a high JCV viral load within the CSF (27,300 copies/mL CSF) and died 61 days after initial PML diagnosis. He displayed highly reduced frequencies of naive CD4 T cells and central memory CD4 T cells and an increased proportion of effector memory CD4 T cells throughout the progressive course of the disease (figure 4). In patient 2, the reduced frequencies of naive CD4 T cells and central memory CD4 T cells returned almost to normal levels after initiation of combined antiretroviral therapy and during subsequent resolution of PML. Patient 1 neither clinically nor radiologically showed signs of IRIS whereas patient 2 already showed radiologic signs (edema, gadolinium enhancement) when diagnosed with PML.\n\nFigure 4 Longitudinal analysis of peripheral immune cell composition\nFrequency of naive, central memory (Tcm), and effector memory (Tem) CD4 T cells over the course of PML in patient 1 (open circles) and patient 2 (closed triangles). Gray areas indicate normal values (mean values ± 2 SDs of healthy controls). Timeline indicates days after diagnosis of PML. PML = progressive multifocal leukoencephalopathy.\n\nDISCUSSION\nHerein, we provide data indicating that alterations in the composition of peripheral CD4 helper T cell subpopulations are associated with development of PML. CD4 T cells have a pivotal role in the defense against viral infections as has been shown in numerous human diseases including HIV, hepatitis C virus, and JCV.5–8 The development of PML is known to be associated with low total numbers of CD4 T cells in patients with late-stage HIV infections and patients with idiopathic CD4 T cell lymphopenia.9 Our patients with PML did not display any significant alterations in the frequencies of naive, central memory and effector memory CD8 T cells, B lymphocyte populations, and natural killer cells. In contrast, the proportions of CD4 central memory and naive T cells were highly significantly decreased and the proportion of effector memory CD4 T cells was increased. Central memory T cells express the chemokine receptor CRR7 and CD62L and recirculate through secondary lymphoid organs. Effector memory CD4 T cells do not express CCR7 and CD62L, molecules required for entry into lymph nodes, but express chemokine receptors such as CCR5, which direct their migration to the sites of inflammation. They are preferentially located within nonlymphoid tissues or remain within the blood and rapidly exhibit effector functions after a new antigen encounter.10,11 The fact that the proportion of CD4 effector memory T cells was high in the peripheral blood of patients with PML thus indicates that a large proportion of peripheral CD4 T cells is actively engaged in viral defense. This is consistent with the previously observed prominent infiltration of CD4 T cells into inflammatory CNS lesions in PML12 and further supports the central role of CD4 rather than CD8 T cells in immune defense against JCV.\n\nBefore the diagnosis of PML, 2 patients had been on immunomodulatory treatment with fumaric acid and one patient with natalizumab. These treatments are known to induce alterations in peripheral immune cells and may thus have influenced our results. Dimethyl fumarate has been shown to both reduce the frequency of lymphocytes in peripheral blood and to disproportionally reduce the frequency of CD8 T cells,13 while natalizumab increases peripheral lymphocyte counts and the proportion of peripheral B lymphocytes.14\n\nThe fact that the reduction of naive and central memory CD4 T cells was partially restored in patient 2 after resolution of PML and not in patient 1 who displayed a fatal course of PML may further indicate that the frequencies of these cells negatively correlate to PML disease activity. Collectively, these observations are in line with previous reports that found reduced frequencies of CD62L-expressing CD4 T cells in natalizumab-treated patients with relapsing-remitting multiple sclerosis who developed PML.15 In our cohort, the frequency of central memory CD4 T cells was reduced in patients with HIV-associated PML as well as in patients who developed PML under immunomodulatory treatment. This further supports the notion that the reduced frequency of central memory CD4 T cells represents a state of the immune system with reduced immunocompetence against JCV. Furthermore, these data indicate that additional in-depth analysis of the role of CD4 helper T cell populations during the course of PML could provide important insights into the immune conditions that predispose to this disease. Reconstitution of CD4 T cells in longitudinal analysis might be a predictor for clinical outcome.\n\nObviously, this investigation is limited by the small number of patients, by the different conditions and medications under which PML developed, and the different courses of disease (i.e., with and without development of IRIS). If confirmed, the observed alterations in CD4 T cell subpopulations could provide new insights into the pathogenesis of PML and may ultimately represent a biomarker for PML disease activity or to detect patients at risk of PML development. This would be urgently needed as JCV infections of the nervous system including PML, JCV meningitis,16 and cerebellar granule cell neuronopathy17 become more clinically prominent.\n\nACKNOWLEDGMENT\nThe authors are grateful to the patients and their relatives for agreeing to participate in this study.\n\nAUTHOR CONTRIBUTIONS\nStudy concept and design: F.B. Acquisition of data: E.D. Analysis and interpretation: E.D., C.R., F.B. Critical revision of the manuscript for important intellectual content: E.D., C.R., F.B. Study supervision: F.B. Statistical analysis: F.B.\n\nSTUDY FUNDING\nNo targeted funding.\n\nDISCLOSURE\nE. Dubois reports no disclosures. C. Ruschil is on the scientific advisory board for Novartis Pharma GmbH. F. Bischof served on the scientific advisory board for Genzyme, Novartis, and Roche, received speaker honoraria and travel funding from Biogen Idec, Genzyme, and Novartis, and received research support from Novartis. Go to Neurology.org/nn for full disclosure forms.\n\nGLOSSARY\nIRISimmune reconstitution inflammatory syndrome\n\nJCVJohn Cunningham virus\n\nNKnatural killer\n\nPMLprogressive multifocal leukoencephalopathy\n==== Refs\nREFERENCES\n1. Brew BJ Davies NW Cinque P Clifford DB Nath A \nProgressive multifocal leukoencephalopathy and other forms of JC virus disease . Nat Rev Neurol \n2010 ;6 :667 –679 .21131916 \n2. Jelcic I Jelcic I Faigle W Sospedra M Martin R \nImmunology of progressive multifocal leukoencephalopathy . J Neurovirol \nEpub 2015 Mar 5 .\n3. Power C Gladden JG Halliday W \nAIDS- and non-AIDS-related PML association with distinct p53 polymorphism . Neurology \n2000 ;54 :743 –746 .10680816 \n4. Ermis U Weis J Schulz JB \nPML in a patient treated with fumaric acid . N Engl J Med \n2013 ;368 :1657 –1658 .23614603 \n5. Day CL Lauer GM Robbins GK \nBroad specificity of virus-specific CD4+ T-helper-cell responses in resolved hepatitis C virus infection . J Virol \n2002 ;76 :12584 –12595 .12438584 \n6. Gasnault J Kahraman M de Goer de Herve MG Durali D Delfraissy JF Taoufik Y \nCritical role of JC virus-specific CD4 T-cell responses in preventing progressive multifocal leukoencephalopathy . AIDS \n2003 ;17 :1443 –1449 .12824781 \n7. McNeil AC Shupert WL Iyasere CA \nHigh-level HIV-1 viremia suppresses viral antigen-specific CD4(+) T cell proliferation . Proc Natl Acad Sci USA \n2001 ;98 :13878 –13883 .11717444 \n8. Rosenberg ES Altfeld M Poon SH \nImmune control of HIV-1 after early treatment of acute infection . Nature \n2000 ;407 :523 –526 .11029005 \n9. Puri V Chaudhry N Gulati P Patel N Tatke M Sinha S \nProgressive multifocal leukoencephalopathy in a patient with idiopathic CD4+T lymphocytopenia . Neurol India \n2010 ;58 :118 –121 .20228479 \n10. Masopust D Picker LJ \nHidden memories: frontline memory T cells and early pathogen interception . J Immunol \n2012 ;188 :5811 –5817 .22675215 \n11. Pepper M Jenkins MK \nOrigins of CD4(+) effector and central memory T cells . Nat Immunol \n2011 ;12 :467 –471 .21739668 \n12. Yousef S Planas R Chakroun K \nTCR bias and HLA cross-restriction are strategies of human brain-infiltrating JC virus-specific CD4+ T cells during viral infection . J Immunol \n2012 ;189 :3618 –3630 .22942431 \n13. Spencer CM Crabtree-Hartman EC Lehmann-Horn K Cree BA Zamvil SS \nReduction of CD8(+) T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate . Neurol Neuroimmunol Neuroinflamm \n2015 ;2 :e76 .25738172 \n14. Krumbholz M Meinl I Kumpfel T Hohlfeld R Meinl E \nNatalizumab disproportionately increases circulating pre-B and B cells in multiple sclerosis . Neurology \n2008 ;71 :1350 –1354 .18936427 \n15. Schwab N Schneider-Hohendorf T Posevitz V \nL-selectin is a possible biomarker for individual PML risk in natalizumab-treated MS patients . Neurology \n2013 ;81 :865 –871 .23925765 \n16. Agnihotri SP Wuthrich C Dang X \nA fatal case of JC virus meningitis presenting with hydrocephalus in a human immunodeficiency virus-seronegative patient . Ann Neurol \n2014 ;76 :140 –147 .24895208 \n17. Agnihotri SP Dang X Carter JL \nJCV GCN in a natalizumab-treated MS patient is associated with mutations of the VP1 capsid gene . Neurology \n2014 ;83 :727 –732 .25037207\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2332-7812",
"issue": "2(6)",
"journal": "Neurology(R) neuroimmunology & neuroinflammation",
"keywords": null,
"medline_ta": "Neurol Neuroimmunol Neuroinflamm",
"mesh_terms": null,
"nlm_unique_id": "101636388",
"other_id": null,
"pages": "e177",
"pmc": null,
"pmid": "26568972",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": "24895208;20228479;23614603;25037207;11717444;18936427;10680816;23925765;21739668;12438584;21131916;22675215;11029005;22942431;12824781;25740538;25738172",
"title": "Low frequencies of central memory CD4 T cells in progressive multifocal leukoencephalopathy.",
"title_normalized": "low frequencies of central memory cd4 t cells in progressive multifocal leukoencephalopathy"
} | [
{
"companynumb": "DE-BIOGENIDEC-2015BI034392",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FINGOLIMOD"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe incidence of gram-negative bacterial haematogenous vertebral osteomyelitis (GNB HVO) is increasing. We performed a retrospective cohort study of patients with this type of infection in an effort to gain an improved understanding of the current clinical presentation, management and outcome.\n\n\nMETHODS\nBetween May 2007 and May 2010, all patients, over the age of 18 years, suffering from GNB HVO were identified and their microbiological diagnoses were evaluated.\n\n\nRESULTS\nThis study identified seventy-nine patients with haematogenous vertebral osteomyelitis (HVO). Of these seventy-nine patients, 10 patients (12.66%) had Gram-negative organisms isolated. These organisms included Escherichia coli (4), Pseudomonas aeruginosa (3), Klebsiella pneumonia (1), Haemophilus influenza (1) and Enterobacter cloacae (1). Eight patients were successfully treated with antibiotics and/or surgery. Of the eight patients whose HVO was cured, five had Ciprofloxacin as part of their definitive antibiotic regime.\n\n\nCONCLUSIONS\nThe treatment of GNB HVO is often challenging because of unpredictable resistance patterns and limited published data on effective treatment regimens. Our study has highlighted the need for prompt microbiological sampling and initiation of early appropriate antibiotic regime. The most effective treatment for GNB HVO was with oral Ciprofloxacin over a period of 6-8 weeks.",
"affiliations": "Academic Department of Trauma and Orthopaedics, Teaching Hospitals NHS Trust, Great George Street, Leeds LS1 3EX, UK. simonmatthewgraham@doctors.org.uk",
"authors": "Graham|Simon Matthew|SM|;Fishlock|Adelle|A|;Millner|Peter|P|;Sandoe|Jonathan|J|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00586-013-2750-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0940-6719",
"issue": "22(8)",
"journal": "European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society",
"keywords": null,
"medline_ta": "Eur Spine J",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin; D015331:Cohort Studies; D015897:Comorbidity; D019299:Decompression, Surgical; D024881:Drug Resistance, Bacterial; D005260:Female; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D008297:Male; D008875:Middle Aged; D010019:Osteomyelitis; D012189:Retrospective Studies; D017211:Treatment Failure; D016896:Treatment Outcome",
"nlm_unique_id": "9301980",
"other_id": null,
"pages": "1845-53",
"pmc": null,
"pmid": "23543389",
"pubdate": "2013-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "3155780;6827150;20463340;13849901;18442854;15015030;14752357;8647777;9431371;9278917;20529294;16217976;3680342;16876033;16523126;908715;8953102;9210692;4584243;9210683;11981730;19271782;17106664;365414;9855235;2652335;8957575;318675;16551691;20567731;9171177;2326732;9199385;370121;1852425;9687408;8549277;15840453;11515764;9056020;17337352;6211138;10870142;2183710",
"title": "The management gram-negative bacterial haematogenous vertebral osteomyelitis: a case series of diagnosis, treatment and therapeutic outcomes.",
"title_normalized": "the management gram negative bacterial haematogenous vertebral osteomyelitis a case series of diagnosis treatment and therapeutic outcomes"
} | [
{
"companynumb": "GB-ACTAVISPR-2014-14094",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating neurological disorder caused by JC virus. Immunocompromised patients such as those with chronic lymphocytic leukemia, AIDS and following organ transplantation are at increased risk. We report a patient with PML complicating longstanding Waldenström's macroglobulinaemia. Although PML is a rare occurrence, the newer highly immunosuppressive treatment approaches for patients with lymphoproliferative disorders necessitate a high index of clinical suspicion. The diagnosis should be considered in patients with compatible clinical features who have received long-term immunosuppressive treatments recognized to impair cellular immunity.",
"affiliations": "Department of Haematology, Peter MacCallum Cancer Institute, Victoria, Australia.",
"authors": "Ng|Christina|C|;Slavin|Monica A|MA|;Seymour|John F|JF|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/1042819031000111071",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "44(10)",
"journal": "Leukemia & lymphoma",
"keywords": null,
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D006801:Humans; D007577:JC Virus; D007968:Leukoencephalopathy, Progressive Multifocal; D008297:Male; D008875:Middle Aged; D008258:Waldenstrom Macroglobulinemia",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "1819-21",
"pmc": null,
"pmid": "14692541",
"pubdate": "2003-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Progressive multifocal leukoencephalopathy complicating Waldenström's macroglobulinaemia.",
"title_normalized": "progressive multifocal leukoencephalopathy complicating waldenstr m s macroglobulinaemia"
} | [
{
"companynumb": "AU-CELGENEUS-AUS-20180201818",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional... |
{
"abstract": "Pisa syndrome (PS), also known as pleurothotonus, is an abnormal posture characterized by lateral flexion of the trunk that typically disappears in supine position. In Parkinson disease (PD), an abnormal forward flexion of the trunk (defined as camptocormia) is a common observation and has been interpreted as a sign of dystonia. Few reports have described PS mainly related to dopaminergic therapy in this kind of patients.Levodopa/carbidopa, levodopa/benserazide, levodopa/carbidopa/entacapone, pergolide, and pramipexole may cause PS, whereas no reports for ropinirole have been described.Here, we describe a case of a patient with PD who developed severe and reversible PS due to ropinirole intake.",
"affiliations": "Department of Neurology, Neurocenter of Southern Switzerland, Lugano, Switzerland.",
"authors": "Galati|Salvatore|S|;Möller|Jens Carsten|JC|;Städler|Claudio|C|",
"chemical_list": "D018491:Dopamine Agonists; D007211:Indoles; C046649:ropinirole",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "37(2)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000368:Aged; D018491:Dopamine Agonists; D004421:Dystonia; D005260:Female; D006801:Humans; D007211:Indoles; D010300:Parkinson Disease; D013577:Syndrome",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "58-9",
"pmc": null,
"pmid": "24614668",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Ropinirole-induced Pisa syndrome in Parkinson disease.",
"title_normalized": "ropinirole induced pisa syndrome in parkinson disease"
} | [
{
"companynumb": "CH-WATSON-2015-05038",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ROPINIROLE HYDROCHLORIDE"
},
"drugadditional": nul... |
{
"abstract": "OBJECTIVE\nCatatonia is an underdiagnosed syndrome that may occur in severely ill patients. The malignant subtype, consisting of motor symptoms, autonomic instability and fever, is associated with high mortality rates, though exact current mortality rates are unknown. This subtype requires a fast detection and treatment with high doses of a benzodiazepine or electroconvulsive therapy (ECT), preferably in an intensive care unit (ICU) setting.\n\n\nMETHODS\nCase series and qualitative literature review.\n\n\nRESULTS\nThis paper presents four patients admitted to the ICU of an academic hospital diagnosed with malignant catatonia. All patients received ECT after an ineffective trial of high-dose intravenous benzodiazepine treatment. The duration of ECT ranged from 6 to 23 treatments after which the catatonic features partially or fully remitted. In addition, we have reviewed the diagnostic challenges, neurobiology, possible causes, differential diagnosis and treatment options of catatonia, focusing on the treatment with ECT and the importance of detection and multidisciplinary collaboration.\n\n\nCONCLUSIONS\nMalignant catatonia is an underdiagnosed, potentially life-threatening syndrome that requires fast recognition and prompt treatment, preferably in an ICU setting.",
"affiliations": "Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: F.M.Dessens@lumc.nl.;Department of Intensive Care Medicine of Leiden University Medical Center, Leiden, The Netherlands. Electronic address: J.van_Paassen@lumc.nl.;Department of Intensive Care Medicine of Leiden University Medical Center, Leiden, The Netherlands. Electronic address: D.J.van_Westerloo@lumc.nl.;Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: N.J.A.van_der_Wee@lumc.nl.;Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: I.M.van_Vliet@lumc.nl.;Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: M.S.van_Noorden@lumc.nl.",
"authors": "Dessens|Femke M|FM|;van Paassen|Judith|J|;van Westerloo|David J|DJ|;van der Wee|Nic J|NJ|;van Vliet|Irene M|IM|;van Noorden|Martijn S|MS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-8343",
"issue": "38()",
"journal": "General hospital psychiatry",
"keywords": "Catatonia; ECT; Electroconvulsive therapy; Intensive care unit; Malignant catatonia",
"medline_ta": "Gen Hosp Psychiatry",
"mesh_terms": "D000328:Adult; D001714:Bipolar Disorder; D002389:Catatonia; D004565:Electroconvulsive Therapy; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D009459:Neuroleptic Malignant Syndrome; D011618:Psychotic Disorders; D012563:Schizophrenia, Paranoid",
"nlm_unique_id": "7905527",
"other_id": null,
"pages": "37-41",
"pmc": null,
"pmid": "26589764",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Electroconvulsive therapy in the intensive care unit for the treatment of catatonia: a case series and review of the literature.",
"title_normalized": "electroconvulsive therapy in the intensive care unit for the treatment of catatonia a case series and review of the literature"
} | [
{
"companynumb": "NL-MYLANLABS-2016M1051379",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Inferior mesentery artery (IMA) aneurysm rupture is easily overlooked in patients with abdominal pain due to its uncommon occurrence. It may result in catastrophic consequence once misdiagnosed as spontaneous bowel hematoma in patients with anticoagulant overdose and intra-abdominal hematoma, as treatment strategy for both diseases varies differently. We present a case of a 70-year-old male who came to our emergency department with the chief complaint of abdominal pain over periumbilical area, eventually diagnosed as anticoagulant overdose associated IMA aneurysm rupture without occlusion of superior mesentery artery (SMA) and celiac artery (CA). This case report alerts us to consider the rare other source of bleeding, for instance ruptured inferior mesentery aneurysm, while encountering such an extraordinary large intra-abdominal hematoma in patients on anticoagulant.",
"affiliations": "Cathay General Hospital Department of Emergency Medicine Taipei Taiwan.;Cathay General Hospital Department of Surgery Taipei Taiwan.;Cathay General Hospital Department of Emergency Medicine Taipei Taiwan.;Cathay General Hospital Department of Emergency Medicine Taipei Taiwan.;Cathay General Hospital Department of Emergency Medicine Taipei Taiwan.",
"authors": "Chen|Yen-An|YA|;Tai|Feng-Chuan|FC|;Chen|Jiann-Hwa|JH|;Chen|Wei-Lung|WL|;Chung|Jui-Yuan|JY|",
"chemical_list": null,
"country": "China (Republic : 1949- )",
"delete": false,
"doi": "10.6705/j.jacme.201812_8(4).0007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-5587",
"issue": "8(4)",
"journal": "Journal of acute medicine",
"keywords": "abdomen pain; inferior mesentery artery aneurysm; spontaneous bowel hematoma",
"medline_ta": "J Acute Med",
"mesh_terms": null,
"nlm_unique_id": "101574304",
"other_id": null,
"pages": "186-189",
"pmc": null,
"pmid": "32995222",
"pubdate": "2018-12-01",
"publication_types": "D002363:Case Reports",
"references": "20534123;23555406;23641294;18209923;8996479;9146723;12925294;21315542;22679130",
"title": "Warfarin Overdose Associated Inferior Mesentery Artery Aneurysm Rupture Mimicking Spontaneous Bowel Hematoma.",
"title_normalized": "warfarin overdose associated inferior mesentery artery aneurysm rupture mimicking spontaneous bowel hematoma"
} | [
{
"companynumb": "TW-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-099878",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN SODIUM"
},
"dr... |
{
"abstract": "Botulinum toxin A (BTA) injections into lacrimal gland are being used for refractory epiphora due to intractable lacrimal disorders with success rates reported from 18% to 86%. Most common side effects are transient ptosis and diplopia. We report a case of a 59-year-old female injected with 2.5 units of BTA injection in each lacrimal gland for functional epiphora. The patient had a history of herpes simplex viral keratitis that was quiescent for more than 2 years. After 3 weeks, she developed reactivation of viral keratitis bilaterally, which was successfully managed with antivirals and topical steroids. Reactivation of quiescent herpes simplex keratitis is a possibility after lacrimal gland BTA and caution should be exercised in such cases.",
"affiliations": "Cornea Services, LJ Eye Institute, Ambala, Haryana, India.;Oculoplasty Services, LJ Eye Institute, Ambala, Haryana, India.;Cornea Services, LJ Eye Institute, Ambala, Haryana, India.",
"authors": "Narang|Purvasha|P|;Singh|Swati|S|;Mittal|Vikas|V|",
"chemical_list": "D000998:Antiviral Agents; D005782:Gels; D009465:Neuromuscular Agents; D019274:Botulinum Toxins, Type A; D015774:Ganciclovir",
"country": "India",
"delete": false,
"doi": "10.4103/ijo.IJO_904_17",
"fulltext": "\n==== Front\nIndian J OphthalmolIndian J OphthalmolIJOIndian Journal of Ophthalmology0301-47381998-3689Medknow Publications & Media Pvt Ltd India 29676321IJO-66-69710.4103/ijo.IJO_904_17Case ReportsBilateral herpes simplex keratitis reactivation after lacrimal gland botulinum toxin injection Narang Purvasha Singh Swati 1Mittal Vikas Cornea Services, LJ Eye Institute, Ambala, Haryana, India1 Oculoplasty Services, LJ Eye Institute, Ambala, Haryana, IndiaCorrespondence to: Dr. Vikas Mittal, LJ Eye Institute, Ambala - 134 003, Haryana, India. E-mail: vikas_mittal@hotmail.com5 2018 66 5 697 699 10 10 2017 21 12 2017 Copyright: © 2018 Indian Journal of Ophthalmology2018This 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.Botulinum toxin A (BTA) injections into lacrimal gland are being used for refractory epiphora due to intractable lacrimal disorders with success rates reported from 18% to 86%. Most common side effects are transient ptosis and diplopia. We report a case of a 59-year-old female injected with 2.5 units of BTA injection in each lacrimal gland for functional epiphora. The patient had a history of herpes simplex viral keratitis that was quiescent for more than 2 years. After 3 weeks, she developed reactivation of viral keratitis bilaterally, which was successfully managed with antivirals and topical steroids. Reactivation of quiescent herpes simplex keratitis is a possibility after lacrimal gland BTA and caution should be exercised in such cases.\n\nBotulinum toxinfunctional epiphoraherpes simplex keratitislacrimal glandreactivation\n==== Body\nLacrimal gland botulinum toxin A (BTA) injections successfully alleviate epiphora with documented improvement in Munk scores.[123] The toxin inhibits release of acetylcholine in all parasympathetic and cholinergic postganglionic sympathetic neurons, resulting in reduced tear secretion.[4] Injections are generally well tolerated and the side effects reported after this procedure are transient ptosis (7–25%) and diplopia (7%) in a few cases.[3] Other systemic side effects include an influenza-like illness and, rarely, weakness of distant muscles or generalized weakness, possibly due to the toxin spreading in the blood.[5] Two cases of primary episodes of cutaneous herpes zoster have been reported after BTA injections into forehead and lateral periorbital areas.[6] No case of ocular herpes reactivation postlacrimal gland BTA injection has been reported in the past. We hereby describe an unusual case of bilateral reactivation of herpes simplex keratitis following lacrimal gland BTA injections.\n\nCase Report\nA 59-year-old female had complaints of watering and discomfort in both the eyes for 6 months. She had a past history of resolved bilateral herpes simplex viral (HSV) stromal keratitis (maintained on prophylactic dose of oral valacyclovir 500 mg once daily) that occurred 2 years ago. Slit-lamp examination showed residual corneal scars. Grade 1 punctal stenosis in both eyes was successfully managed with punctal dilatation and monocanalicular intubation (Aurostent, Aurolab, India). Stents were removed after 4 weeks; with good anatomical and functional outcome evident by a freely patent lacrimal drainage on irrigation and 90% reduction in epiphora. Five months later, she had recurrence of watering in both the eyes (bilateral Grade 3 Munk score). Grade 1 fluorescein dye disappearance test with freely patent lacrimal drainage system supported the diagnosis of functional epiphora. Two and a half units of BTA were injected transconjunctivally into the palpebral lobe of each lacrimal gland under topical anesthesia. Symptomatic improvement (90% reduction in epiphora) was noted at 1 week but she developed ptosis in the right eye following the injection [Fig. 1a]. She was counseled regarding the eventual spontaneous recovery of ptosis. Schirmer test without anesthesia was 20 mm and 14 mm in both eyes pre- and postinjection, respectively.\n\nFigure 1 (a) Ptosis of right upper lid 1 week after botulinum toxin A injection into the lacrimal glands for functional epiphora. (b) Complete resolution of ptosis of right upper lid at 4 weeks\n\nThree weeks later, she developed redness, pain, and foreign body sensation in both the eyes. Clinical examination revealed bilateral circumciliary congestion with large epithelial defects and stromal edema [Fig. 2a–d] suggesting a recurrence of HSV stromal keratitis.\n\nFigure 2 Slit-lamp photograph after reactivation of herpes simplex viral keratitis (large dendritic ulcers), 3 weeks after botulinum toxin A; (a and b) without and (c and d) with fluorescein stain in both eyes, following botulinum toxin A injection. (e and f) Slit-lamp photograph of right and left eyes showing resolution of keratitis within 4 weeks of treatment\n\nSystemic immunosuppression was excluded after physician consultation and appropriate investigations. Patient had stopped oral valacyclovir prophylaxis after stent removal. Topical antiviral (ganciclovir 0.15% gel) and frequent lubricants were started and oral valacyclovir 500 mg was prescribed thrice daily. One week later, after resolution of epithelial defects, topical 1% prednisolone acetate was started at four times daily and tapered over 4 weeks. Complete resolution of viral keratitis and ptosis occurred within a month [Figs. 1b and 2e, f]. Thereafter, she was on a maintenance dose of once daily oral valacyclovir (500 mg) and topical lubricants.\n\nDiscussion\nThis case report describes a reactivation of HSV stromal keratitis after lacrimal gland BTA injection for functional epiphora and highlights the need for oral antiviral prophylaxis before BTA injections.\n\nHSV 1 remains latent in the sensory and autonomic neurons after ocular infection. HSV reactivation is thought to be multi-factorial. According to the Herpetic Eye Disease Study, age, gender, ethnicity, history of epithelial keratitis or of nonocular HSV infection, exogenous catalysts, and psychogenic profile were not significantly associated with recurrences.[7] On the contrary, fever, exposure to wind, sunburn, trauma, and surgical manipulation of the trigeminal ganglion have been implicated in its recurrence by another study.[8] In a report, two patients developed facial herpes zoster along the first branch of trigeminal nerve that erupted soon after cosmetic treatment with BTA without any prior history of the disease.[6] The patients described in that report bring to light the possibility that BTA injections may act as a trigger to reactivate the varicella zoster virus. The exact mechanism is unknown although the role of mechanical trauma and local inflammation was postulated in reactivating varicella infection.\n\nAlthough the same surgeon has injected the same dose in lacrimal glands on both the sides, painlessly, severe ptosis developed in one eye, maybe due to toxin diffusion into levator muscle. As the patient was very apprehensive regarding the ptosis, this might have induced psychogenic stress, which in turn reactivated the virus on both sides. Another possibility is surgical stress and local inflammation in periocular region which could have altered the local immune response leading to bilateral reactivation of this latent virus. The temporal sequence of recurrence of keratitis postocular intervention can be an association only. Careful probing did not reveal any history of factors reported for HSV recurrence in the current case; thus, this association cannot be purely coincidental. The mentioned contra-indications to the use of BTA are in patients afflicted with a preexisting motor neuron disease, myasthenia gravis, Eaton–Lambert syndrome, neuropathies, psychological instability, history of reaction to toxin or albumin, pregnancy and lactating females, certain drugs, and infection at the injection site.[9] Till date, BTA has not been implicated as a potential risk factor for HSV reactivation. However, based on a single case report, we cannot label patients with quiescent herpes viral keratitis as a contraindication for BTA use. In our case, it seemed that BTA had an association with the recurrence of HSV stromal keratitis although the exact mechanism is not known.\n\nConclusion\nWe recommend that caution should definitely be exercised in all cases of resolved herpes viral keratitis undergoing BTA injections, in the form of preinjection patient counseling and appropriate antiviral prophylaxis in such cases.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Kaynak P Karabulut GO Ozturker C Fazil K Arat YO Perente I Comparison of botulinum toxin-A injection in lacrimal gland and conjunctivodacryocystorhinostomy for treatment of epiphora due to proximal lacrimal system obstruction Eye (Lond) 2016 30 1056 62 27197871 \n2 Ziahosseini K Al-Abbadi Z Malhotra R Botulinum toxin injection for the treatment of epiphora in lacrimal outflow obstruction Eye (Lond) 2015 29 656 61 25744443 \n3 Singh S Ali MJ Paulsen F A review on use of botulinum toxin for intractable lacrimal drainage disorders EyInt Ophthalmol 2017 [Epub ahead of print] \n4 Münchau A Bhatia KP Uses of botulinum toxin injection in medicine today BMJ 2000 320 161 5 10634738 \n5 Bhatia KP Münchau A Thompson PD Houser M Chauhan VS Hutchinson M Generalised muscular weakness after botulinum toxin injections for dystonia: A report of three cases J Neurol Neurosurg Psychiatry 1999 67 90 3 10369829 \n6 Graber EM Dover JS Arndt KA Two cases of herpes zoster appearing after botulinum toxin type a injections J Clin Aesthet Dermatol 2011 4 49 51 22010056 \n7 Predictors of recurrent herpes simplex virus keratitis. Herpetic Eye Disease Study Group Cornea 2001 20 123 8 11248812 \n8 Toma HS Murina AT Areaux RG Jr Neumann DM Bhattacharjee PS Foster TP Ocular HSV-1 latency, reactivation and recurrent disease Semin Ophthalmol 2008 23 249 73 18584563 \n9 Naik MN Soparkar CN Murthy R Honavar SG Botulinum toxin in ophthalmic plastic surgery Indian J Ophthalmol 2005 53 279 88 16333182\n\n",
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"issue": "66(5)",
"journal": "Indian journal of ophthalmology",
"keywords": "Botulinum toxin; functional epiphora; herpes simplex keratitis; lacrimal gland; reactivation",
"medline_ta": "Indian J Ophthalmol",
"mesh_terms": "D000287:Administration, Topical; D000998:Antiviral Agents; D019274:Botulinum Toxins, Type A; D003319:Corneal Stroma; D005260:Female; D015774:Ganciclovir; D005782:Gels; D018259:Herpesvirus 1, Human; D006801:Humans; D007267:Injections; D016849:Keratitis, Herpetic; D007765:Lacrimal Apparatus; D007767:Lacrimal Duct Obstruction; D008875:Middle Aged; D009465:Neuromuscular Agents; D014775:Virus Activation",
"nlm_unique_id": "0405376",
"other_id": null,
"pages": "697-699",
"pmc": null,
"pmid": "29676321",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports",
"references": "16333182;10369829;11248812;27197871;18584563;22010056;28766277;10634738;25744443",
"title": "Bilateral herpes simplex keratitis reactivation after lacrimal gland botulinum toxin injection.",
"title_normalized": "bilateral herpes simplex keratitis reactivation after lacrimal gland botulinum toxin injection"
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"companynumb": "IN-IPSEN BIOPHARMACEUTICALS, INC.-2018-06293",
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"abstract": "BACKGROUND\nThe aim of this study was to assess the clinical usefulness of therapeutic drug monitoring (TDM) of voriconazole (VOR) in a university hospital.\n\n\nMETHODS\nA retrospective review was conducted on the clinical records of 52 patients treated with VOR and on whom TDM was performed. Steady-state trough plasma VOR concentration was measured at least 5 days after starting treatment. The therapeutic range of plasma VOR concentration was defined as 1-5.5μg/mL.\n\n\nRESULTS\nThe most frequent underlying conditions in the study population were lung transplant (48.1%) and hematological malignancies (26.9%). At the first TDM in each patient, VOR levels were outside the therapeutic range in 16 (30.7%) cases: <1μg/mL in 10 (19.2%) and >5.5μg/mL in 6 (11.5%). Eleven patients (21.2%) experienced severe muscle weakness and had considerable difficulty walking. All these patients were receiving concomitant treatment with corticosteroids. Age younger than 30 years (p=.005) and cystic fibrosis as the underlying disease (p=.04) were factors associated with low VOR levels. Almost all patients who had VOR concentrations >1μg/mL at the first TDM had a successful outcome (96%).\n\n\nCONCLUSIONS\nPlasma VOR concentrations were outside the therapeutic range at the first TDM in 30% (16/52) of patients. Age younger than 30 years and cystic fibrosis were factors associated with low VOR levels. The potential interactions between corticosteroids and VOR should be highlighted, as they could be responsible for a high rate of muscle weakness observed in our patients. Prospective trials are needed to investigate VOR TDM and corticosteroid pharmacokinetics.",
"affiliations": "Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address: evelyn.cabral.galeano@gmail.com.;Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.;Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.;Therapeutic Drug Monitoring Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.;Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.;Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.;Therapeutic Drug Monitoring Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.;Hematology Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.;Pulmonology Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.;Pulmonology Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.;Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.;Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.",
"authors": "Cabral-Galeano|Evelyn|E|;Ruiz-Camps|Isabel|I|;Len-Abad|Oscar|O|;Pou-Clavé|Leonor|L|;Sordé-Masip|Roger|R|;Meije-Castillo|Yolanda|Y|;Blanco-Grau|Albert|A|;Barba-Suñol|Pere|P|;Monforte-Torres|Victor|V|;Román-Broto|Antonio|A|;Pahissa-Berga|Albert|A|;Gavaldà-Santapau|Joan|J|",
"chemical_list": "D000935:Antifungal Agents; D065819:Voriconazole",
"country": "Spain",
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"issue": "33(5)",
"journal": "Enfermedades infecciosas y microbiologia clinica",
"keywords": "Aspergillosis; Aspergilosis; Drug interaction; Evaluación de la concentración plasmática; Interacciones farmacológicas; Tacrolimus; Therapeutic drug monitoring; Voriconazol; Voriconazole",
"medline_ta": "Enferm Infecc Microbiol Clin",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents; D001228:Aspergillosis; D016903:Drug Monitoring; D005260:Female; D006785:Hospitals, University; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D065819:Voriconazole; D055815:Young Adult",
"nlm_unique_id": "9104081",
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"pages": "298-302",
"pmc": null,
"pmid": "25459191",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical usefulness of therapeutic drug monitoring of voriconazole in a university hospital.",
"title_normalized": "clinical usefulness of therapeutic drug monitoring of voriconazole in a university hospital"
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"activesubstancename": "TACROLIMUS"
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{
"abstract": "Diffuse alveolar hemorrhage (DAH) is a clinical condition characterized by the rapid onset of dyspnea, hemoptysis and acute respiratory failure (ARF). It is commonly caused by autoimmune systemic vasculitis, pulmonary infections, drugs and tumors. Here, we report a case of DAH caused by frequent cannabis smoking. A 16-year old boy presented with hemoptysis, dyspnea and ARF soon after laparoscopic surgery for varicocele in general anesthesia. The suspected diagnosis of DAH emerged from the initial chest radiography, and it was then confirmed by CT scan findings and the bronchoalveolar lavage. His general conditions completely recovered after only 24 h of oxygen supplementation and after intravenous corticosteroid and antibiotic therapy. This is the first pediatric case of DAH related to smoking marijuana, even though the inhalational anesthetic agent sevoflurane might have also been involved in this pathogenesis. Other possible causes of DAH have been considered. Negative-pressure pulmonary edema could be ruled out because no clinical evidence of upper airway obstruction was observed during general anesthesia and throughout the surgery. In addition, a possible causative role of cannabis additives/contaminants could not be excluded. Given the high prevalence of cannabis smoking in young people and that DAH can be a complication in cannabis smokers, a careful history and high index of suspicion are recommended as part of the pre-operative assessment before these patients are proceeded to receive general anesthesia.",
"affiliations": "Pediatric Unit, Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.;Pediatric Unit, Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.;Anesthesiology and Intensive Care Unit, Accident and Emergency Department, University of Eastern Piedmont, Novara, Italy.;Neonatal and Pediatric Intensive Care Unit, Maggiore della Carità University Hospital, Novara, Italy.;Anesthesiology and Intensive Care Unit, Accident and Emergency Department, University of Eastern Piedmont, Novara, Italy.;Pediatric Unit, Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.",
"authors": "Bucchino|Laura|L|;Monzani|Alice|A|;Fracon|Sara|S|;Genoni|Giulia|G|;Cena|Tiziana|T|;Bellone|Simonetta|S|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fped.2019.00468",
"fulltext": "\n==== Front\nFront PediatrFront PediatrFront. Pediatr.Frontiers in Pediatrics2296-2360Frontiers Media S.A. 10.3389/fped.2019.00468PediatricsCase ReportCannabis-Related Diffuse Alveolar Hemorrhage in a 16-Year-Old Patient: A Case Report Bucchino Laura 1Monzani Alice 1*Fracon Sara 2Genoni Giulia 3Cena Tiziana 2Bellone Simonetta 11Pediatric Unit, Department of Health Sciences, University of Eastern Piedmont, Novara, Italy2Anesthesiology and Intensive Care Unit, Accident and Emergency Department, University of Eastern Piedmont, Novara, Italy3Neonatal and Pediatric Intensive Care Unit, Maggiore della Carità University Hospital, Novara, ItalyEdited by: Renato Cutrera, Bambino Gesù Children Hospital (IRCCS), Italy\n\nReviewed by: Matthias Griese, LMU Munich, Germany; Jackson Y. W. Wong, Peak Pulmonary Specialty Clinic, Canada\n\n*Correspondence: Alice Monzani alice.monzani@med.uniupo.itThis article was submitted to Pediatric Pulmonology, a section of the journal Frontiers in Pediatrics\n\n14 11 2019 2019 7 46829 7 2019 28 10 2019 Copyright © 2019 Bucchino, Monzani, Fracon, Genoni, Cena and Bellone.2019Bucchino, Monzani, Fracon, Genoni, Cena and BelloneThis 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.Diffuse alveolar hemorrhage (DAH) is a clinical condition characterized by the rapid onset of dyspnea, hemoptysis and acute respiratory failure (ARF). It is commonly caused by autoimmune systemic vasculitis, pulmonary infections, drugs and tumors. Here, we report a case of DAH caused by frequent cannabis smoking. A 16-year old boy presented with hemoptysis, dyspnea and ARF soon after laparoscopic surgery for varicocele in general anesthesia. The suspected diagnosis of DAH emerged from the initial chest radiography, and it was then confirmed by CT scan findings and the bronchoalveolar lavage. His general conditions completely recovered after only 24 h of oxygen supplementation and after intravenous corticosteroid and antibiotic therapy. This is the first pediatric case of DAH related to smoking marijuana, even though the inhalational anesthetic agent sevoflurane might have also been involved in this pathogenesis. Other possible causes of DAH have been considered. Negative-pressure pulmonary edema could be ruled out because no clinical evidence of upper airway obstruction was observed during general anesthesia and throughout the surgery. In addition, a possible causative role of cannabis additives/contaminants could not be excluded. Given the high prevalence of cannabis smoking in young people and that DAH can be a complication in cannabis smokers, a careful history and high index of suspicion are recommended as part of the pre-operative assessment before these patients are proceeded to receive general anesthesia.\n\ndiffuse alveolar hemorrhageacute respiratory failurepediatricscannabissevofluraneanesthesia\n==== Body\nBackground\nDiffuse alveolar hemorrhage (DAH) is a medical condition characterized by bleeding into the alveolar spaces of the lungs due to the disruption of the alveolar-capillary basement membrane. It manifests as rapid onset of dyspnea, hemoptysis and acute respiratory failure (ARF) (1).\n\nThe etiology can vary from autoimmune systemic vasculitis to pulmonary infections, drugs, and tumors, which can lead to pulmonary capillaritis, bland pulmonary hemorrhage, or diffuse alveolar damage (2–4). In particular, a strong association between DAH and the use of recreational drugs, such as cocaine, amphetamine and crack, has been well-documented (5, 6).\n\nRegarding pot smoking and DAH, literature is very poor since only few cases in adult patients have been described so far (7–11). Nonetheless, the prevalence of this recreational drug is increasing worldwide, including Italy where the lifetime prevalence of cannabis use is 27% among adolescents aged 16 years old (12, 13). In this regard, Italy has experienced a boom in light cannabis smoking since Law No. 242 went into effect December 2016, legalizing hemp cultivation and commercialization but paradoxically not its consumption (14).\n\nIn this scenario, it is more important than ever to raise a greater awareness about cannabis smoking and all the medical problems resulting from this habit. Here, we report an unprecedented case of DAH caused by cannabis abuse in a pediatric patient.\n\nCase Presentation\nA 16-year old boy underwent laparoscopic surgery for varicocele. His past medical history was uneventful, except for febrile seizures during early childhood. He had no allergies, history of recurrent pneumonia or other chronic respiratory diseases. Likewise, his family history was unremarkable. Smoking habits were asked but not disclosed. Complete blood cells count, liver and kidney function tests and first level coagulation studies (platelets count, prothrombin time test, activated partial thromboplastin time, and fibrinogen) were all normal before the general anesthesia. According to the American Society of Anesthesiologists (ASA) risk classification1, he was a healthy patient (ASA 1).\n\nPrior to the operation, the patient was given general anesthesia consisting of propofol (2 mg/kg) and rocuronium (0.6 mg/kg), with remifentanil (0.25 mcg/kg/min) for intubation. General anesthesia was maintained with 2% sevoflurane and remifentanil (0.25–0.125 mcg/kg/min). Sugammadex (2 mg/Kg) was administered before extubation (TOF ratio > 0.9). Both surgery and extubation were conducted without any complications and the patient had no obvious signs of upper airway obstruction, neither cough nor laryngospasm.\n\nThirty minutes after waking up, he manifested hemoptysis, dyspnea, and ARF. He was alert, tachypnoeic, and normothermic. His Glasgow Coma Scale was 15, and his initial vital signs were: pulse 80 bpm, blood pressure 90/60 mmHg and oxygen saturation averaging 73% on room air. Arterial blood gas analysis revealed: pH 7.37; pCO2 39.6 mmHg (5.27 kPa); pO2 39.5 mmHg (5.26 kPa); oxyhemoglobin (oxyHb) 73.7%; and HCO3− 23.1 mEq/L. Otorhinolaryngoiatric evaluation with nasal and laryngeal fibro-endoscopy unveiled no evidence of previous bleeding from the upper respiratory tract. Respiratory auscultation revealed diffuse rhonchi, with no other remarkable signs. His initial chest x-ray (Figure 1) showed infiltrative opacification pattern mainly seen in the mid zones with apical sparing suggestive for impaired pulmonary microcirculation, raising the suspect of DAH (15, 16). To further investigate our hypothesis, a chest CT scan (Figure 2) was performed, which revealed multiple dense opacities with blurred, confluent margins due to diffuse alveolar involvement in the pulmonary lobes.\n\nFigure 1 Chest x-ray at clinical onset of symptoms, consistent with diffuse alveolar hemorrhage (DAH). There can be observed infiltrative opacification pattern mainly seen in the mid zones with apical sparing suggestive for impaired pulmonary microcirculation. There can be noticed areas of subdiaphragmatic air due to laparoscopy.\n\nFigure 2 Chest CT scan without contrast medium confirming the diagnosis of DAH.\n\nGiven the evidence of hypoxemic respiratory failure and the suspect of DAH, the patient was transferred to the Intensive Care Unit, where he was subjected to immediate bronchoalveolar lavage, revealing the presence of abundant blood, but after the bronchoalveolar lavage with 0.9% sodium chloride solution, the bronchial mucosa appeared without signs of pathological lesions. More specifically, three lavage of 50 mLs each were done and afterwards 35, 35, and 50 mLs of BAL fluid were retrieved. Direct microscopic examination showed leucocytes, macrophages and bronchial epithelial cells. Further confirmation arrived from cytologic analysis of his bronchoalveolar lavage secretions which described the presence of blood, 85% of alveolar macrophages and 15% of granulocytes. Hemosiderin was not assessed because hemoptysis started 4 h before and the endoscopic appearance of the bleeding itself appeared to be very recent, undergoing from <48 h. The patient was given fraction inspired oxygen (FiO2) (40%; 12 L/min) by means of a Venturi mask for ARF, intravenous ceftriaxone 2 g per day as antibiotic prophylaxis and intravenous methylprednisolone 1 g per day for anti-inflammatory action for 5 days, while waiting for the results of microbial studies and autoimmune diseases screening (17).\n\nInitial blood tests performed at Day 1 revealed: hemoglobin levels 13.5 g/dl (135 g/L); leukocytosis 14.540 mm−3 (14.54 109/L), of which 83.7% were neutrophils, and normal platelet count (221 × 109 /L). Renal function, liver function, electrolytes, coagulation studies (prothrombin time, activated partial thromboplastin time, and fibrinogen) were all normal. Von Willebrand factor deficiency was also ruled out on the basis of Von Willebrand factor antigen and Ristocetin cofactor activities which resulted within normal range (Von Willebrand factor antigen was 90%, with a normal reference range between 57 and 147%; Ristocetin cofactor was 120% with a normal reference range of 51–147% considering our patient's specific age group). Urinalysis was unremarkable, and direct microscopic exam did not reveal any dysmorphic red blood cells (RBCs). The diagnostic work-up, which included serological exams and blood and sputum cultures for Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila, Aspergillus, Mycobacterium tuberculosis, Nocardia spp., Chlamydia pneumoniae, Mycoplasma pneumoniae, Pneumocystis Jirovecii, Herpesviruses, and the complete respiratory viral panel, ruled out any pulmonary infections. An extensive rheumatological serologic evaluation including CRP, c-ANCA, p-ANCA, ANA, and ENA panel came back negative as well. Lastly, the echocardiography was completely normal, excluding any congenital or acquired cardiomyopathy as well as pulmonary hypertension.\n\nQuestioned on smoking habits, the boy revealed to be a frequent cannabis smoker since few years. He admitted to have smoked about 1–2 joints per day in the last month before surgery and to have used a marijuana smoking device known as “water bong” at least once. Moreover, he denied having used any other type of street drugs. We therefore performed a toxicological urine test that resulted positive for cannabinoids. Cocaine was not tested since the patient's parents declined their consent.\n\nThe patient's general conditions rapidly improved after 24 h: he was no longer dyspneic, and oxygen supplementation was stopped on day 2 of hospitalization after a second chest radiograph (Figure 3) revealed the resolution of DAH. He was discharged after 6 days with tapering prednisone. Although he was recommended an ambulatory follow-up, his parents declined.\n\nFigure 3 Chest x-ray after 48 h showing both lungs clear of significant parenchymal opacities and no signs of pleural effusions.\n\nDiscussion\nDAH is due to disruption of the alveolar-capillary basement membrane. Common initial signs and symptoms include abrupt onset with cough, hemoptysis, fever, and dyspnea. Some patients, however, present with severe hypoxemic respiratory failure requiring immediate ventilatory support with mechanical ventilation.\n\nIllicit drug abuse, especially cocaine, amphetamine, and synthetic cannabinoids, has been associated with DAH (5–8). To date, only five cases of DAH related to marijuana have been published, all in adult subjects. Two of these cases were individuals that had inhaled synthetic cannabinoid (7, 8), one had smoked marijuana using a homemade plastic bong (9) and died of DAH, one had smoked several marijuana joints (10) and the last one was a frequent cannabis smoker receiving general anesthesia (11). In addition, in a 16–year–old boy a case of hemoptysis was reported in association with cannabis smoking mixed with micro-particles of silicon dioxide (18). To our knowledge, our patient is the first pediatric case of DAH associated with non-synthetic cannabis smoking.\n\nCannabis, also known as marijuana, pot or weed, is the most popular recreational drug worldwide as it is easy to find and can be bought at an affordable price (19). According to the 2015 European School Survey Project on Alcohol and Other Drugs (ESPAD), cannabis is rated as the most widespread illicit drug in ESPAD countries, with 16% of European students having used cannabis at least once in their lifetime, ranging from 4% in Moldova to 37% in the Czech Republic. Typically, lifetime cannabis use is higher among boys than girls (19 vs. 14%, respectively) (13).\n\nEurope is not the only geographical area with high cannabis use prevalence. A 2017 survey by the United States (US) Centers for Disease Control and Prevention (CDC) through the Youth Risk Behavior Surveillance System (YRBSS) indicates that 35.6% of US high schools students have used marijuana once or more during their life, with 6.8% of them having tried it for the first time before the age of 13 (8.3% male students; 5.3% female students) (20). Interestingly, 19.8% of US students reported current marijuana use at least once during the 30 days before taking the survey.\n\nEven though cannabis consumption can result in generalized airway inflammation with evidence of respiratory epithelial cell injury and damage to alveolar macrophages (21), its potential role in DAH has not been well-investigated. Here, we show that DAH is associated with frequent cannabis smoking, further supporting a detrimental effect of weed smoking habit on the respiratory system of otherwise healthy individuals.\n\nOther etiologies could explain DAH occurring after general anesthesia, such as negative-pressure pulmonary edema (NPPE). This is a well-recognized post-operative clinical entity which has been described as causative factor of DAH. Generation of a negative pleural pressure on inspiration against an upper airway obstruction is the mechanism of stress failure of the alveolar-capillary membrane in NPPE (22). In our case, we did not observe airway obstruction during general anesthesia and the surgery was conducted without any complications.\n\nAnother limitation of our study is that we cannot rule out that the anesthetic drugs used for induction and maintenance of general anesthesia could have also played a role in DAH. All of them are somehow related to pulmonary complications. For instance, sugammadex is known to cause negative-pressure pulmonary edema, remifentanil is related to respiratory depression, as well as propofol to acute lung injury and pulmonary edema2 Regarding rocuronium, no evidence of lung injury effect exists. In some cases sevoflurane has been associated to DAH. In the literature, 4 cases of sevoflurane-related DAH have been reported, with one of them being a cannabis smoker (11, 23–25). In this regard, it has been proposed that sevoflurane, as well as other inhalational anesthetic agents, could increase alveolar permeability, oxidative stress and inflammatory response, thereby promoting DAH. Moreover, in one case report, a young adult patient developed DAH due to negative-pressure pulmonary edema as a result of muscle rigidity after a bolus of remifentanil. This was reversed by neuromuscular blockade with sugammadex (26). Thus, it is not only difficult to disentangle the possible additive or synergistic effects of anesthetic drugs and cannabis smoke, but it is also tempting to speculate that the chronic cannabis use may have predisposed our patient to airway inflammation and alveolar epithelial damage, which could have been exacerbated by sevoflurane inhalation, resulting in inhalational injury.\n\nOur speculation is limited by a paucity of information about our patient's smoking habits. We did not know how long our patient had been smoking and the declared amount of joints per day may be underestimated. Moreover, we did not know how much cannabis and tobacco were used to prepare joints. For instance, psychoactive inert herbs or synthetical additives may be mixed to Cannabis. Even if a causative role of cannabis additives/ contaminants in airways inflammation could not be excluded, our patient declared to smoke only Cannabis sativa and anatomopathological analysis of his bronchoalveolar lavage secretions did not describe the presence of any additives or contaminants.\n\nIn addition to that, cocaine use should be considered in the differential diagnosis of DAH. However, we did not know if our patient ever used cocaine since he denied this habit and his parents declined their consent to the specific test.\n\nAnother limitation is the incomplete and perhaps unreliable patient history, combined with lack of any information regarding the follow-up due to the refusal of the patient's parents to collaborate. The follow-up would possibly have corroborate our speculation, because it is unlikely that smoking joints had been stopped and, if there actually was a close link to the DAH, it might have relapsed.\n\nConclusions\nAlthough it is still not clear how high the risk of cannabis-related DAH may be, the high prevalence of cannabis smoking among young adolescents calls for a more thorough assessment of this potential risk before any surgery under general anesthesia. In this regard, further studies are urgently needed to confirm the association between marijuana smoking and lung injury.\n\nTherefore, despite the absence of a precise estimation of the risk, we recommend caution in cannabis smokers undergoing general anesthesia, as they may be more susceptible to develop respiratory complications, such as DAH.\n\nAuthor Contributions\nLB and AM contributed conception and design of the study. LB wrote the first draft of the manuscript. SF and TC wrote sections of the manuscript. AM, GG, and SB reviewed and edited the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.\n\nConflict of Interest\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\nThe authors are thankful to the School of Medicine of the University of Eastern Piedmont, Novara, Italy, especially to Dr. Mario Pirisi, Director of the Residency Program at A.O.U. Maggiore della Carità for their educational and financial support. We also thank Dr. Marcello Arsura for proofreading the manuscript.\n\n1https://www.asahq.org/standards-and-guidelines/asa-physical-status-classification-system\n\n2https://www.pneumotox.com/drug/index/\n\nAbbreviations\nARFacute respiratory failure\n\nDAHdiffuse alveolar hemorrhage.\n==== Refs\nReferences\n1. Franks TJ Koss MN . Pulmonary capillaritis . Curr Opin Pulm Med. (2000 ) 6 :430 –5 .10958235 \n2. Martínez-Martínez MU Oostdam DAH Abud-Mendoza C . Diffuse alveolar hemorrhage in autoimmune diseases . Curr Rheumatol Rep. (2017 ) 19 :27 . 10.1007/s11926-017-0651-y 28397125 \n3. Spira D Wirths S Skowronski F Pintoffl J Kaufmann S Brodoefel H . Diffuse alveolar hemorrhage in patients with hematological malignancies: HRCT patterns of pulmonary involvement and disease course . Clin Imaging. (2013 ) 37 :680 –6 . 10.1016/j.clinimag.2012.11.005 23313188 \n4. Kim EA Lee KS Primack SL Yoon HK Byun HS Kim TS . Viral pneumonias in adults: radiologic and pathologic findings . Radiographics. (2002 ) 22 :S137 –49 . 10.1148/radiographics.22.suppl_1.g02oc15s137 12376607 \n5. Underner M Perriot J Wallaert B Peiffer G Meurice JC Jaafari N . [Alveolar hemorrhage and cocaine use] . Rev Mal Respir. (2018 ) 35 :134 –48 . French. 10.1016/j.rmr.2017.06.005 29459175 \n6. Peters NF Gosselin R Verstraete KL . A rare case of diffuse alveolar hemorrhage following oral amphetamine intake . JBR-BTR . (2014 ) 97 :42 –3 .24765773 \n7. Alhadi S Tiwari A Vohra R Gerona R Acharya J Bilello K . High times, low sats: diffuse pulmonary infiltrates associated with chronic synthetic cannabinoid use . J Med Toxicol. (2013 ) 9 :199 –206 . 10.1007/s13181-013-0288-9 23539384 \n8. Loschner A Cihla A Jalali F Ghamande S \nDiffuse alveolar hemorrhage: add “greenhouse effect” to the growing list . Chest. (2011 ) 140 :149A \n10.1378/chest.1119854 \n9. Grassin F André M Rallec B Combes E Vinsonneau U Paleiron N \n[Fatal alveolar haemorrhage following a “bang” of cannabis] Rev Mal Respir . (2011 ) 28 :919 –23 . French. 10.1016/j.rmr.2011.05.005 \n10. Shafi M Liaquat S Auckley D . Up in smoke: an unusual case of diffuse alveolar hemorrhage from marijuana . Respir Med Case Rep. (2018 ) 25 :22 –24 . 10.1016/j.rmcr.2018.05.028 29998053 \n11. Murray AW Smith JD Ibinson JW . Diffuse alveolar hemorrhage, anesthesia, and cannabis [letter] . Ann Am Thorac Soc. (2014 ) 11 :1338 –9 . 10.1513/AnnalsATS.201407-337LE 25343207 \n12. Shi Y Lenzi M An R . Cannabis liberalization and adolescent cannabis use: a cross-national study in 38 countries . PLoS ONE. (2015 ) 10 :e0143562 . 10.1371/journal.pone.0143562 26605550 \n13. Kraus L Guttormsson U Leifman H Arpa S Molinaro S Monshouwer K \nResults from the European School Survey Project on Alcohol and Other Drugs . European Monitoring Centre for Drugs and Drug Addiction (2015 ).\n14. G.U. 30/12/16. Public Law No. 242. 2–5 (December 2, 2016).\n15. Lichtenberger JP Digumarthy SR Abbott GF Shepard JAO Sharma A . Diffuse pulmonary hemorrhage: clues to the diagnosis . Curr Probl Diagn Radiol. (2014 ) 43 :128 –39 . 10.1067/j.cpradiol.2014.01.002 24791616 \n16. Cortese G Nicali R Placido R Gariazzo G Anrò P . Radiological aspects of diffuse alveolar haemorrhage . Radiol Med. (2008 ) 113 :16 –28 . 10.1007/s11547-008-0229-x 18338124 \n17. Nasser M Cottin V . Alveolar hemorrhage in vasculitis (primary and secondary) . Semin Respir Crit Care Med. (2018 ) 39 :482 –93 . 10.1055/s-0038-1668533 30404115 \n18. Monfort M Larakeb A Gouraud F . [Hemoptysis in a young man smoking cannabis] . Arch Pédiatrie. (2013 ) 20 :637 –9 . French. 10.1016/j.arcped.2013.03.008 23619207 \n19. Greydanus DE Hawver EK Greydanus MM Merrick J . Marijuana: current concepts (†) . Front. Public Heal. (2013 ) 1 :42 . 10.3389/fpubh.2013.00042 24350211 \n20. Kann L McManus T Harris WA Shanklin SL Flint KH Queen B . Youth Risk Behavior Surveillance — United States, 2017. Morbidity and Mortality Weekly Report Centers for Disease Control and Prevention (2017 ).\n21. Tashkin DP . Airway effects of marijuana, cocaine, and other inhaled illicit agents . Curr Opin Pulm Med. (2001 ) 7 :43 –61 .11224724 \n22. Hao D Basnet S Melnick S Kim J . Negative pressure pulmonary edema-related diffuse alveolar hemorrhage associated with sevoflurane and cigarette smoking . J Community Hosp Intern Med Perspect. (2019 ) 9 :247 –51 . 10.1080/20009666.2019.1608140 31258867 \n23. Mersh R Ross C \nPostoperative diffuse alveolar haemorrhage: insidious negative pressure or sevoflurane induced? \nBMJ Case Rep. (2018 ) bcr-2017-222010. 10.1136/bcr-2017-222010 \n24. Austin A Modi A Judson MA Chopra A . Sevoflurane induced diffuse alveolar hemorrhage in a young patient . Respir Med Case Rep. (2017 ) 20 :14 –15 . 10.1016/j.rmcr.2016.11.001 27872805 \n25. Kim CA Liu R Hsia DW . Diffuse alveolar hemorrhage induced by sevoflurane . Ann Am Thorac Soc. (2014 ) 11 :853 –5 . 10.1513/AnnalsATS.201402-067LE 24936702 \n26. Choi WK Lee JM Kim JB Im KS Park BH Bin YS . Diffuse alveolar hemorrhage following sugammadex and remifentanil administration: a case report . Med Baltimore. (2019 ) 98 :e14626 . 10.1097/MD.0000000000014626 30813195\n\n",
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"abstract": "BACKGROUND\nPneumopericardium in neonates is often associated with respiratory diseases, of which positive pressure ventilation (PPV) is an exacerbating factor. Here, we present a neonate case of pneumopericardium after cardiac surgery which was resolved after applying PPV.\n\n\nMETHODS\nA 28-day-old neonate with left recurrent nerve palsy after aortic reconstruction for interrupted aortic arch developed pericardial effusion. Pericardiocentesis was performed under general anesthesia, and a drainage tube was left in the pericardium. After extubation, stridor gradually exacerbated, following hemodynamic deterioration. A chest X-ray demonstrated pneumopericardium. Upper airway stenosis due to recurrent nerve palsy developed excessive negative pleural pressure, and air was drawn into pericardium via the insertion site of the drainage tube. After tracheal intubation and applying PPV, the pneumopericardium improved.\n\n\nCONCLUSIONS\nPPV does not always exacerbate pneumopericardium. In a patient with pericardial-atmosphere communication, increased inspiration effort can cause pneumopericardium, and PPV is a therapeutic option to alleviate the pneumopericardium.",
"affiliations": "Department of Anesthesiology and Resuscitology, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan. tani-m1@cc.okayama-u.ac.jp.;Department of Anesthesiology and Resuscitology, Okayama University Hospital, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.;Department of Anesthesiology and Resuscitology, Okayama University Hospital, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.;Department of Anesthesiology and Resuscitology, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.;Department of Anesthesiology and Resuscitology, Okayama University Hospital, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.;Department of Anesthesiology and Resuscitology, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.",
"authors": "Tani|Makiko|M|http://orcid.org/0000-0003-0265-8247;Kanazawa|Tomoyuki|T|;Shioji|Naohiro|N|;Shimizu|Kazuyoshi|K|;Iwasaki|Tatsuo|T|;Morimatsu|Hiroshi|H|",
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"fulltext": "\n==== Front\nJA Clin Rep\nJA Clin Rep\nJA Clinical Reports\n2363-9024 Springer Berlin Heidelberg Berlin/Heidelberg \n\n384\n10.1186/s40981-020-00384-x\nCase Report\nSuccessful treatment with positive airway pressure ventilation for tension pneumopericardium after pericardiocentesis in a neonate: a case report\nhttp://orcid.org/0000-0003-0265-8247Tani Makiko tani-m1@cc.okayama-u.ac.jp 1 Kanazawa Tomoyuki 2 Shioji Naohiro 2 Shimizu Kazuyoshi 1 Iwasaki Tatsuo 2 Morimatsu Hiroshi 1 1 grid.261356.50000 0001 1302 4472Department of Anesthesiology and Resuscitology, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558 Japan \n2 grid.412342.20000 0004 0631 9477Department of Anesthesiology and Resuscitology, Okayama University Hospital, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558 Japan \n7 10 2020 \n7 10 2020 \n12 2020 \n6 7920 9 2020 27 9 2020 29 9 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/.Background\nPneumopericardium in neonates is often associated with respiratory diseases, of which positive pressure ventilation (PPV) is an exacerbating factor. Here, we present a neonate case of pneumopericardium after cardiac surgery which was resolved after applying PPV.\n\nCase presentation\nA 28-day-old neonate with left recurrent nerve palsy after aortic reconstruction for interrupted aortic arch developed pericardial effusion. Pericardiocentesis was performed under general anesthesia, and a drainage tube was left in the pericardium. After extubation, stridor gradually exacerbated, following hemodynamic deterioration. A chest X-ray demonstrated pneumopericardium. Upper airway stenosis due to recurrent nerve palsy developed excessive negative pleural pressure, and air was drawn into pericardium via the insertion site of the drainage tube. After tracheal intubation and applying PPV, the pneumopericardium improved.\n\nConclusion\nPPV does not always exacerbate pneumopericardium. In a patient with pericardial-atmosphere communication, increased inspiration effort can cause pneumopericardium, and PPV is a therapeutic option to alleviate the pneumopericardium.\n\nKeywords\nPneumopericardiumPericardiocentesisRecurrent nerve palsyPleural pressurePositive pressure ventilationissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nPneumopericardium is defined as the collection of air or gas in the pericardium [1]. Pneumopericardium is categorized into two types according to its pathogenesis: spontaneous and traumatic. Spontaneous pneumopericardium in neonates is associated with pulmonary diseases such as hypoplasia and respiratory distress syndrome [2]. Traumatic pneumopericardium occurs by pleural–pericardial communication associated with chest trauma and iatrogenic chest injury. Mechanism of pneumopericardium is presence of direct communication between the pericardium and airways. In addition, pericardium has relatively more negative pressure than intrapleural pressure [3]. Hence, in both spontaneous and traumatic pneumopericardium, PPV could be an exacerbating factor and should be avoided once pneumopericardium is diagnosed [4–6].\n\nWhen clinically categorized, pneumopericardium is divided into nontension and tension. Tension pneumopericardium leads to hemodynamic collapse which should be treated immediately [7]. Pneumopericardium resulting in cardiac tamponade had been reported to receive PPV [1]. This is also the reason that PPV for patient with pneumopericardium is avoided.\n\nHere, we present a 28-day-old neonate undergoing pericardiocentesis in sub-acute phase after aortic arch anastomosis who developed cardiac tamponade secondary to tension pneumopericardium under spontaneous breathing. Unlike usual pneumopericardium in neonates, the pneumopericardium in this patient exacerbated with increasing spontaneous inspiratory effort due to upper airway stenosis. We ceased spontaneous breathing and successfully treated the tension pneumopericardium by tracheal intubation and PPV.\n\nCase presentation\nThis patient was a 28-day-old female neonate born at gestational age of 39 weeks with no prenatal diagnosis. The neonate was diagnosed as having interrupted aortic arch (IAA) type B, patent ductus arteriosus (PDA), ventricular septal defect (VSD), and atrial septal defect. At 13-days old, this neonate underwent aortic arch reconstruction by extended aortic arch anastomosis, PDA ligation, and VSD patch closure under general anesthesia using 3.5 mm of uncuffed endotracheal tube (ETT). Immediately after the extubation on postoperative day (POD) 2, the patient presented hoarseness and severe stridor that were diagnosed as left recurrent nerve palsy by an otolaryngologist with fiberoptic examination of the vocal cords. Although stridor occurred when asleep, the patient was uneventfully discharged from the intensive care unit (ICU) on POD4 without any respiratory support. On POD 15, elective pericardiocentesis in the operating room (OR) was scheduled for increasing pericardial effusion. Pericardiocentesis was performed uneventfully by epigastric approach under general anesthesia with tracheal intubation. Ten milliliters of serosanguineous fluid was drained, and a silicon drainage tube was left in the pericardium. The tube was connected to a drainage system applying negative pressure of 8 cmH2O. After confirming no pneumothorax or pneumopericardium on chest X-ray (Fig. 1a), the patient was extubated in the OR and was transferred to the ICU. The clinical course of this patient after admission to the ICU is shown on Fig. 2.\nFig. 1 Chest X-rays in the operating room and in the intensive care unit. a Right after the pericardiocentesis, b before re-intubation approximately 2.5 h after admission to the ICU, c 10 min after re-intubation, and d after the drainage tube was removed. The red and blue arrows indicate pneumopericardium and pneumomediastinum, respectively\n\nFig. 2 Clinical course in the intensive care unit. O2, oxygen; FIO2, fraction of inspiratory oxygen; ABP, arterial blood pressure; HR, heart rate; bpm, beats per minute; RR, respiratory rate; SpO2, peripheral oxygen saturation; PPV, positive pressure ventilation. The chest X-rays of Fig. 1 b and c were taken at the time shown as Xp1 and Xp2, respectively, in this chart\n\n\n\nIn the ICU, the patient presented with tachypnea, tachycardia, hypertension, and stridor, and was given acetaminophen for analgesia. The acetaminophen was not effective, and the patient was administered 0.7 mcg ⋅ kg−1 ⋅ hour−1 of dexmedetomidine for analgesia and sedation in the hope of decreasing work of breathing. However, the stridor deteriorated, and retraction developed. In addition, systolic arterial blood pressure (sABP) dropped to 40 mmHg in 15 min although the heart rate was kept over 140 beats per minute. Because of new onset of mandibular breathing in addition to progressive hypotension, we stopped dexmedetomidine infusion and started bag-valve-mask ventilation 2 h after admission to the ICU. After starting positive pressure ventilation, blood pressure slightly increased. A chest X-ray revealed pneumopericardium and pneumomediastinum without pneumothorax (Fig. 1b). The cause of the hemodynamic deterioration was thought to be developing cardiac tamponade secondary to tension pneumopericardium. Inspection of the drainage system showed no loose connection which could suck air into the pericardium through the drainage tube or obstruction by blood, clots, and bending. In addition, we confirmed that excessive negative pleural pressure was generated because negative pressure alarm in the drainage system sounded and the drainage fluid was about to draw into the pericardial space. As a result, we concluded that (1) inspiratory effort by upper airway stenosis due to the existing left recurrent nerve palsy was exacerbated by glossoptosis induced by sedation and that (2) negative pleural pressure augmented by the increased inspiratory effort caused air suction into pericardium via insertion route of a drainage tube. The patient was intubated and was placed on mechanical ventilation. Eventually, sABP became stable to 70 mmHg, and pneumopericardium decreased on the chest X-ray (Fig. 1c). Two days later, confirming no remaining pneumopericardium or adverse events, the drainage tube was removed, and the patient was extubated again (Fig. 1d). The patient used high flow nasal cannula for 1 day in the ICU and spent an additional 6 days in the ward with no recurrent pericardial effusion or pneumopericardium before being discharged from the hospital.\n\nDiscussion\nThis is a case in which pneumopericardium after pericardiocentesis developed by excessive negative pleural pressure due to upper airway stenosis. The cause of the pneumopericardium and the reason that PPV was effective are discussed below.\n\nIn this case, pneumopericardium resulting in cardiac tamponade was successfully treated by PPV. Cummings et al. reported that over 60% of causes of pneumopericardium leading to cardiac tamponade were chest trauma and diseases in lung-pleura [1]. And, PPV is one of the reasons for hemodynamic collapse. Thus, it was critical to diagnose the cause of the pneumopericardium in the patient to justify PPV for improving hemodynamic deterioration. This patient did not have any lung disease. In addition, neither pneumothorax nor pneumopericardium were confirmed in the chest X-ray during PPV in the OR. These findings suggested this pneumopericardium occurred by some causes which happened after extubation. Pneumopericardium after pericardiocentesis was reported to occur by pleural-pericardial communication [8–10]. However, no air in the pleural space or loose connection in the drainage was found. Absence of air in the pleural space with existence of pneumopericardium under negative pressure ventilation indicated that there was no pleural-pericardial communication. Eventually, we diagnosed that the cause of pneumopericardium was the negative pressure applied to the pericardium which exceeded drainage suction pressure and that air was sucked through the slit between the skin and the pericardium drainage tube.\n\nAnother distinctive feature in this case is the reason for excessive negative intra-pericardial pressure. First, increasing inspiratory effort by upper airway stenosis produced markedly negative pleural pressure. The patient had left recurrent nerve palsy as a complication after repair of aortic arch anastomosis for IAA (type B). It was reported that vocal cord palsy occurred in 47.2% of infants after aortic arch augmentation for IAA or hypoplastic aortic arch [11]. In addition to the recurrent nerve palsy, glossoptosis induced by sedation aggravated upper airway stenosis. The negative airway pressure elicited airway deformity, and triggered ventilatory overshoot [12], which exacerbated negative pleural pressure. Because the pericardium is contiguous with pleural space, the negative pleural pressure was propagated to the pericardium.\n\nA previous case report presented pneumopericardium by leaky drainage system [10]. However, there was no loose connection in the pericardium drainage system, and - 8 cmH2O was applied to the system in this case. Negative airway pressure accompanied by obstructive upper airway has been reported to exceed - 50 cmH2O [13, 14]. The vacuum pressure of the drainage was much less than negative pleural pressure in this patient and was not effective to evacuate the air that was drawn from the atmosphere.\n\nPPV had two effects in this case: (1) positive pressure was propagated to the pericardium and stopped the sucking of air into the pericardium from the slit between the skin and the drainage tube and (2) air in the pericardium was drained into the drainage bottle because the pericardial pressure was relatively positive compared with the pressure applied to the drainage bottle.\n\nThere is a limitation in our approach to this pneumopericardium. We diagnosed this patient as cardiac tamponade just by clinical symptoms and chest X-ray. We should have performed echocardiogram to confirm the diagnosis and to assess effectiveness of the therapeutic intervention.\n\nIn conclusion, positive airway pressure is not always an exacerbating factor of pneumopericardium. In a patient with pericardial-atmosphere communication, increased inspiration effort can be a cause of pneumopericardium, resulting in cardiac tamponade, and PPV is a therapeutic option to alleviate the pneumopericardium.\n\nAbbreviations\nPPVPositive pressure ventilation\n\nIAAInterrupted aortic arch\n\nPDAPatent ductus arteriosus\n\nVSDVentricular septal defect\n\nETTEndotracheal tube\n\nPODPostoperative day\n\nICUIntensive care unit\n\nOROperating room\n\nsABPSystolic arterial blood pressure\n\nO2Oxygen\n\nFIO2Fraction of inspiratory oxygen\n\nABPArterial blood pressure\n\nHRHeart rate\n\nbpmBeats per minute\n\nRRRespiratory rate\n\nSpO2Peripheral oxygen saturation\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe would like to thank Ms. Rebecca Lahniche for English language editing.\n\nAuthors’ contributions\nMT reviewed the literature and elaborated on the manuscript. TK and NS helped in the conception of the article and provided critical revisions. KS, TI and HM provided critical revision. The authors read and approved the final manuscript.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nNot applicable due to patient privacy concerns.\n\nEthics approval and consent to participate\nNot applicable\n\nConsent for publication\nParents of the patient have provided written consent to publish this case.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Cummings RG Wesly RL Adams DH Lowe JE Pneumopericardium resulting in cardiac tamponade Ann Thorac Surg. 1984 37 511 518 10.1016/S0003-4975(10)61146-0 6375601 \n2. Papoff P. MC. Pulmonary air leakage. Neonatology. Milano: Springer; 2012. p. 460-468.\n3. Lansdorp B Hofhuizen C van Lavieren M van Swieten H Lemson J van Putten MJ Mechanical ventilation-induced intrathoracic pressure distribution and heart-lung interactions* Crit Care Med. 2014 42 1983 1990 10.1097/CCM.0000000000000345 24743042 \n4. Varano LA Maisels MJ Pneumopericardium in the newborn: diagnosis and pathogenesis Pediatrics. 1974 53 941 945 4832436 \n5. Macklin CC Transport of air along sheaths of pulmonic blood vessels from alveoli to mediastinum: clinical implications Arch Intern Med. 1939 64 913 926 10.1001/archinte.1939.00190050019003 \n6. Mansfield PB Graham CB Beckwith JB Hall DG Sauvage LR Pneumopericardium and pneumomediastinum in infants and children J Pediatr Surg. 1973 8 691 699 10.1016/0022-3468(73)90408-9 4584830 \n7. Bonardi CM Spadini S Fazio PC Galiazzo M Voltan E Coscini N Nontraumatic tension pneumopericardium in nonventilated pediatric patients: a review J Card Surg. 2019 34 829 836 10.1111/jocs.14159 31269314 \n8. Mullens W Dupont M De Raedt H Pneumopericardium after pericardiocentesis Int J Cardiol. 2007 118 e57 10.1016/j.ijcard.2006.12.082 17399808 \n9. Choi WH Hwang YM Park MY Lee SJ Lee HY Kim SW Pneumopericardium as a complication of pericardiocentesis Korean Circ J. 2011 41 280 282 10.4070/kcj.2011.41.5.280 21731571 \n10. Cho SH Hwang HJ Park CB Pneumopericardium after pericardiostomy J Formos Med Assoc. 2016 115 816 817 10.1016/j.jfma.2016.03.003 27117885 \n11. Lee MGY Millar J Rose E Jones A Wood D Luitingh TL Laryngeal ultrasound detects a high incidence of vocal cord paresis after aortic arch repair in neonates and young children J Thorac Cardiovasc Surg. 2018 155 2579 2587 10.1016/j.jtcvs.2017.12.133 29510943 \n12. Harms CA Zeng YJ Smith CA Vidruk EH Dempsey JA Negative pressure-induced deformation of the upper airway causes central apnea in awake and sleeping dogs J Appl Physiol. 1996 80 1528 1539 10.1152/jappl.1996.80.5.1528 8727536 \n13. Newton-John H Pulmonary oedema in upper airway obstruction Lancet. 1977 2 510 10.1016/S0140-6736(77)91638-5 \n14. Lang SA Duncan PG Shephard DA Ha HC Pulmonary oedema associated with airway obstruction Can J Anaesth. 1990 37 210 218 10.1007/BF03005472 2178789\n\n",
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"affiliations": "1 University of Connecticut School of Pharmacy, Storrs, CT, USA.;2 Hartford Hospital, Hartford, CT, USA.;3 Department of Hematology/Oncology, University of Connecticut, Farmington, CT, USA.;2 Hartford Hospital, Hartford, CT, USA.;4 Smilow Cancer Hospital at Yale New Haven, New Haven, CT, USA.",
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"keywords": "Hepatotoxicity; asparaginase; levocarnitine; pegasparagase; vitamin B",
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"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D001215:Asparaginase; D002331:Carnitine; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D011092:Polyethylene Glycols; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D014803:Vitamin B Complex",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "393-397",
"pmc": null,
"pmid": "28523950",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Levocarnitine and vitamin B complex for the treatment of pegaspargase-induced hepatotoxicity: A case report and review of the literature.",
"title_normalized": "levocarnitine and vitamin b complex for the treatment of pegaspargase induced hepatotoxicity a case report and review of the literature"
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"abstract": "Tumor necrosis factor alpha (TNFα) antagonist is recognized as an effective treatment to achieve clinical remission and healing mucosal in patients with moderate to severe active Crohn's disease. Considering that it plays a central role in immune-mediated modulation, there are some obvious concerns about its long-term safety. There is evidence that it may increase the risk of opportunistic infections such as tuberculosis, particularly reactivation of previous latent infection. Due to the global high incidence of tuberculosis and its frequent severity in immunocompromised patients, the exclusion of latent infection is currently part of the screening prior to anti-TNFα therapy. Only a few cases of life-threatening disseminated tuberculosis have been reported in immunocompromised patients probably related to widespread use of higher-accuracy screening tests, such as interferon-γ release assays. However, despite negative screening, the risk of active tuberculosis infection remains during treatment. In that instance, tuberculosis infection becomes considerably more difficult to diagnose due to its altered pattern presentation (extrapulmonary and disseminated infection) and is harder to treat because of the high rate of resistance and its associated relevant morbidity and mortality. We report an enigmatic case of a miliary tuberculosis despite negative latent infection screening, using interferon-γ release assays, in a Crohn's disease patient undergoing treatment with infliximab and azathioprine, focusing on the screening and diagnostic and therapeutic challenge. This case enhances the awareness of anti-TNFα therapy management and the need for strategies to diagnose and treat tuberculosis in this context.",
"affiliations": "Gastroenterology Department of Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal.;Gastroenterology Department of Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal.;Gastroenterology Department of Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal.;Gastroenterology Department of Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal.;Gastroenterology Department of Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal.",
"authors": "Carvalho|Liliana Pereira|LP|;Túlio|Maria Ana|MA|;Rodrigues|José Pedro|JP|;Bana E Costa|Tiago|T|;Chagas|Cristina|C|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000487297",
"fulltext": null,
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"issn_linking": "2387-1954",
"issue": "26(1)",
"journal": "GE Portuguese journal of gastroenterology",
"keywords": "Anti-TNFα therapy; Crohn's disease; Interferon-γ release assays; Miliary tuberculosis",
"medline_ta": "GE Port J Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101685861",
"other_id": null,
"pages": "64-69",
"pmc": null,
"pmid": "30675506",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports",
"references": "17990157;20530046;20722065;21030451;21122488;21172250;21175228;21420564;22677117;22749231;23583099;24042192;24788997;25195652;25617816;26100999;26893500;26917222;28274215;28605520",
"title": "Miliary Tuberculosis in a Crohn's Disease Patient: The Risk beyond the Screening.",
"title_normalized": "miliary tuberculosis in a crohn s disease patient the risk beyond the screening"
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"companynumb": "PT-BAUSCH-BL-2019-002056",
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"abstract": "Patients with myelodysplastic syndrome (MDS) who present with isolated thrombocytopenia (TCP) constitute a poorly described subgroup. The aim of the present study was to retrospectively evaluate disease characteristics and prognosis in patients with MDS and isolated TCP at a tertiary care center. Fifty patients (12 %) had isolated thrombocytopenia as the first presentation of MDS. Patients had varying MDS sub-classifications and cytogenetic profiles. The most common IPSS-R risk score was low (n = 24), although half of the patients had either IPSS-R intermediate (n = 18), high or very high risk disease (n = 7). Leukemic transformation occurred in 10 patients and there were 14 deaths (28 %) amongst all IPSS-R risk scores. Therapeutic agents used in this patient subgroup included hypomethylating agents and thrombopoietin receptor agonists. Overall, MDS with isolated TCP did not appear to have an inherently indolent course, as has been suggested previously. Future studies are needed to improve risk stratification, identify relevant contributors to disease pathogenesis, and better define treatment modalities.",
"affiliations": "Department of Internal Medicine, Northwestern University Feinberg School of Medicine, 251 E Huron St, Chicago, IL, 60611, USA. Julie.waisbren@northwestern.edu.;Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, 645 N. Michigan Ave, Suit 1020, Chicago, IL, 60611, USA.;Division of Hematology/Oncology, Robert H. Lurie Medical Research Center, Northwestern University Feinberg School of Medicine, 303 E Superior Room 5-111, Chicago, IL, 60611, USA.;Division of Hematology/Oncology, Northwestern University Feniberg School of Medicine, NMH/Arkes Family Pavilion Suite 850, 676 N.Saint Clair, Chicago, IL, 60611, USA.;Department of Preventative Medicine, Northwestern University Feinberg School of Medicine, 680 N. Lake Shore Drive, Suit 1400, Chicago, IL, 60611, USA.;Department of Pathology, Northwestern University Feinberg School of Medicine, NMH/Feinberg Room 7-209A, 251 E Huron St, Chicago, IL, 60611, USA.;Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, 645 N. Michigan Ave, Suit 1020, Chicago, IL, 60611, USA.;Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, 645 N. Michigan Ave, Suit 1020, Chicago, IL, 60611, USA.",
"authors": "Waisbren|Julie|J|;Dinner|Shira|S|;Altman|Jessica|J|;Frankfurt|Olga|O|;Helenowski|Irena|I|;Gao|Juehua|J|;McMahon|Brandon J|BJ|;Stein|Brady L|BL|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; D011961:Receptors, Fc; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; D000077209:Decitabine; D013926:Thrombopoietin; C488777:romiplostim; D001374:Azacitidine; C520809:eltrombopag",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-016-2081-4",
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"issue": "105(1)",
"journal": "International journal of hematology",
"keywords": "Acute Myeloid Leukemia; Myelodysplastic syndrome; Myeloid leukemia and dysplasia; Thrombocytopenia; Thrombopoietin analogs",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D001565:Benzoates; D000077209:Decitabine; D005260:Female; D006801:Humans; D006834:Hydrazines; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D011379:Prognosis; D011720:Pyrazoles; D011961:Receptors, Fc; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; D012189:Retrospective Studies; D012306:Risk; D013921:Thrombocytopenia; D013926:Thrombopoietin",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "44-51",
"pmc": null,
"pmid": "27558575",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article",
"references": "20445325;16609072;21714648;23796988;24754962;12373085;24372512;19357394;3669333;25155450;1485603;17764468;22735753;15765783;12769343;25237199;22740453;12181032;2819658;9058730;11503953;16438486;21300984;24238640;22735748;19846889;20678218;8704187",
"title": "Disease characteristics and prognosis of myelodysplastic syndrome presenting with isolated thrombocytopenia.",
"title_normalized": "disease characteristics and prognosis of myelodysplastic syndrome presenting with isolated thrombocytopenia"
} | [
{
"companynumb": "PHHY2017US009615",
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"activesubstancename": "ELTROMBOPAG"
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{
"abstract": "BACKGROUND\nDengue fever is one of the commonest mosquito-borne diseases in the tropics, and Sri Lanka is no exception. Despite its commonness, dengue fever has rarely been described among patients who have undergone transplantation. We report the case of a patient with dengue fever after liver transplantation, which, to the best of our knowledge, is the first such reported case outside Brazil.\n\n\nMETHODS\nOur patient was a 46-year-old Sri Lakan man who presented to our institution two years after undergoing an ABO-compatible cadaveric liver transplant. At presentation, he had typical symptoms of dengue fever. He was taking prednisolone 5mg daily and tacrolimus 3mg twice daily as immunosuppression. Initial investigations showed thrombocytopenia and neutropenia that reached a nadir by day 7 of his illness. He had elevated liver enzymes as well. The diagnosis was confirmed on the basis of NS1 antigen detection by enzyme-linked immunosorbent assay. His blood cultures and polymerase chain reaction tests for cytomegalovirus were negative. He made an uneventful recovery and was discharged by day 9 of his illness. However, normalization of liver function took nearly two weeks. In three previously reported Brazilian cases of dengue after liver transplantation, the patients presented with dengue shock syndrome, in contrast to the relatively milder presentation of our patient. Because of the lack of case reports in the literature, it is difficult to ascertain the risk factors for severe dengue infection in transplants, but dengue fever reported in renal transplants sheds some light on them. High-dose steroids increase the risk of thrombocytopenia, whereas tacrolimus has been reported to prolong the duration of symptoms. Otherwise, dengue fever is a relatively mild illness in patients who have undergone renal transplantation, and renal allograft survival has been reported to be 86% following dengue fever.\n\n\nCONCLUSIONS\nDengue is a rarely reported infection in patients who have undergone transplantation. A high degree of suspicion is required for diagnosis. Dengue NS1 antigen detection is a useful addition to the already existing methods of diagnosis. Steroids and tacrolimus have effects on the morbidity of the disease. Graft outcomes following the infection has been excellent in all reported cases.",
"affiliations": "University Medical Unit, National Hospital of Sri Lanka, Regent Street, Colombo 9 CO00900, Sri Lanka. rangamw2003@yahoo.com.",
"authors": "Weerakkody|Ranga Migara|RM|;Palangasinghe|Dhammika Randula|DR|;Dalpatadu|Kaluthanthri Patabandi Chamila|KP|;Rankothkumbura|Jeewan Pradeep|JP|;Cassim|Mohammed Rezni Nizam|MR|;Karunanayake|Panduka|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/1752-1947-8-378",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-8-3782541269910.1186/1752-1947-8-378Case ReportDengue fever in a liver-transplanted patient: a case report Weerakkody Ranga Migara 1rangamw2003@yahoo.comPalangasinghe Dhammika Randula 1dhammika27@yahoo.comDalpatadu Kaluthanthri Patabandi Chamila 1chamila.gunarathne@gmail.comRankothkumbura Jeewan Pradeep 1jeewan.med@gmail.comCassim Mohammed Rezni Nizam 2reznicassim@yahoo.co.ukKarunanayake Panduka 3pandukaru@mail.com1 University Medical Unit, National Hospital of Sri Lanka, Regent Street, Colombo 9 CO00900, Sri Lanka2 Department of Surgery, Faculty of Medicine, University of Colombo, Kynsey Road, Colombo 8 CO00800, Sri Lanka3 Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Kynsey Road, Colombo 8 CO00800, Sri Lanka2014 21 11 2014 8 378 378 28 6 2014 23 9 2014 Copyright © 2014 Weerakkody et al.; licensee BioMed Central Ltd.2014Weerakkody 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/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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.Introduction\nDengue fever is one of the commonest mosquito-borne diseases in the tropics, and Sri Lanka is no exception. Despite its commonness, dengue fever has rarely been described among patients who have undergone transplantation. We report the case of a patient with dengue fever after liver transplantation, which, to the best of our knowledge, is the first such reported case outside Brazil.\n\nCase presentation\nOur patient was a 46-year-old Sri Lakan man who presented to our institution two years after undergoing an ABO-compatible cadaveric liver transplant. At presentation, he had typical symptoms of dengue fever. He was taking prednisolone 5mg daily and tacrolimus 3mg twice daily as immunosuppression. Initial investigations showed thrombocytopenia and neutropenia that reached a nadir by day 7 of his illness. He had elevated liver enzymes as well. The diagnosis was confirmed on the basis of NS1 antigen detection by enzyme-linked immunosorbent assay. His blood cultures and polymerase chain reaction tests for cytomegalovirus were negative. He made an uneventful recovery and was discharged by day 9 of his illness. However, normalization of liver function took nearly two weeks. In three previously reported Brazilian cases of dengue after liver transplantation, the patients presented with dengue shock syndrome, in contrast to the relatively milder presentation of our patient. Because of the lack of case reports in the literature, it is difficult to ascertain the risk factors for severe dengue infection in transplants, but dengue fever reported in renal transplants sheds some light on them. High-dose steroids increase the risk of thrombocytopenia, whereas tacrolimus has been reported to prolong the duration of symptoms. Otherwise, dengue fever is a relatively mild illness in patients who have undergone renal transplantation, and renal allograft survival has been reported to be 86% following dengue fever.\n\nConclusion\nDengue is a rarely reported infection in patients who have undergone transplantation. A high degree of suspicion is required for diagnosis. Dengue NS1 antigen detection is a useful addition to the already existing methods of diagnosis. Steroids and tacrolimus have effects on the morbidity of the disease. Graft outcomes following the infection has been excellent in all reported cases.\n\nDengueLiver transplantNS1 antigenTacrolimus toxicity\n==== Body\nIntroduction\nDengue fever (DF) is one of the commonest mosquito-borne diseases in the tropics and has become hyperendemic in Sri Lanka. Although thousands of cases are reported yearly in Sri Lanka, dengue has been a rarely reported disease in patients who have undergone transplantation [1]. We describe the case of a patient with DF after a liver transplant (LT). To the best of our knowledge, this is the first such reported case outside Brazil.\n\nCase presentation\nA 46-year-old Sri Lankan man presented to our institution with high-grade fever associated with severe retro-ocular pain, photophobia, bone pain and severe body aches of three days’ duration. He was a recipient of an ABO-compatible cadaveric LT 26 months previously for treatment of end-stage cryptogenic cirrhosis. The immediate post-transplant period had been complicated by acute rejection, but he made a full recovery with an allograft. He was maintained on prednisolone 5mg daily and tacrolimus 3mg twice daily. He had developed diabetes after the third month post-LT. His two sons had had a febrile illness, diagnosed as DF, one week before coming to our institution. He did not complain of respiratory, urinary or bowel symptoms or a rash. An examination did not reveal jaundice, rashes or neck stiffness, but demonstrated a fine tremor in outstretched hands. His right frontal sinus was tender on palpation.\n\nHis initial full blood count revealed thrombocytopenia (90,000/μL), and, with a suggestive clinical picture, a provisional diagnosis of DF was made. His skull X-ray demonstrated a fluid level in the right frontal sinus confirming acute sinusitis, which was treated with intravenous ceftriaxone 1g twice daily. Over the next few days, his white cell count and platelet count gradually dropped, reaching a nadir by day 4 of the illness. Dengue NS1 antigen was detected in his day 3 serum sample, confirming the diagnosis of DF. His liver enzymes rose sharply until day 7 before starting to recover. His bilirubin levels and coagulation profile were normal. He entered the leakage (critical) phase on day 6 of his illness, and he recovered by day 8 without any complications with standard supportive DF management. DNA detection of cytomegalovirus was negative, and his blood cultures were sterile. However, liver enzyme normalization took more than two weeks. Throughout his hospital stay, his serum creatinine was around 140μmol/L and, together with fine tremors, was suggestive of tacrolimus toxicity (T0 = 13.4ng/dL). Tacrolimus was reduced to 4mg daily as a result. His creatinine levels dropped to 104μmol/L by the time of discharge. The day 7 and day 14 dengue immunoglobulin M (IgM) titers showed an eightfold increase. Figure 1 shows the changes in parameters over time.\n\nFigure 1 Graphical representation of changing hematological and biochemical parameters. Hb, Hemoglobin; PCV, Packed cell volume; WBC, White blood cell.\n\nDiscussion\nDF is the most widespread mosquito-borne disease in Sri Lanka. Despite the high prevalence, it is a rarely reported disease in patients who have received solid-organ transplants. Patients who have undergone transplantation may have diminished T-cell responses and may be at low risk for contracting DF, which perhaps accounts for the lack of clinical reports describing such patients [2]. In addition, there are relatively few patients living with allografts in Sri Lanka. Our literature search showed only three cases, all of which were in Brazil [3,4] and were diagnosed as dengue shock syndrome (DSS). One of these patients had jaundice, a lowest platelet count of 30,000/μL and extremely high liver enzyme levels in the range of 104U/L. The laboratory examination findings for the other two previously reported patients are not available. Our patient had lower platelet counts than these patients, but his liver enzymes were much lower and he never had jaundice. One of the previously reported patients developed DSS three weeks following the transplant [4], and the other two contracted it in the ninth month post-transplantation [3]. Contrary to the pattern in the previously reported cases, our patient developed the illness two years after transplantation. The clinical picture was that of DF, not DSS as in the previously reported cases. Our patient had a fever pattern that is different from that seen in normal DF, by virtue of a prolonged febrile phase, which ran up to one week. Superadded sinusitis may have had an effect on the length of the febrile phase. Photophobia is an uncommon symptom of DF, but dengue meningoencephalitis can present with that symptom. Sinus tenderness and an abnormal X-ray view of the sinuses makes diagnosis of acute frontal sinusitis more likely. A lumbar puncture and CSF analysis would have been extremely useful in this situation, but the rapid resolution of symptoms with antibiotics and in the face of thrombocytopenia, lumbar puncture was not tried.\n\nAlthough data on LT are limited, data from a large case series on patients who received renal transplants (RTs) have been reported [5]. Nasim and colleagues reported that the mean duration of high-grade fever was 3.4 ± 1.5 days and that of low-grade fever was 6.0 ± 3.5 days. Our patient went through a febrile phase that was similar in length, but his fever was high-grade. In the patients described by Nasim and colleagues, severe primary disease was seen more often in patients receiving high doses of steroids (>7.5mg/d) compared to low-dose regimens (≤7.5mg/d). Thrombocytopenia was most severe in patients receiving steroids, azathioprine (AZA) and cyclosporin A (CyA) concomitantly. Mycophenolate mofetil (MMF) or AZA had no effect on the severity of thrombocytopenia, whereas tacrolimus prolonged the duration of thrombocytopenia compared to MMF or AZA alone or to either one in combination with CyA [5]. The deaths that occurred were not related to DF, and graft survival was excellent (86%) following the infection.\n\nDiagnosing DF is challenging in patients who have undergone transplantation, owing to immunosuppression, which may suppress some of the cardinal features of DF. The diagnosis may be delayed if fever and thrombocytopenia are initially attributed to co-morbidities such as cytomegalovirus sepsis or because of anti-mitotic agents or hepatitis C virus [5]. It is prudent to believe that most of the infections in patients with immunosuppression may be subclinical and indistinguishable from a non-specific viral fever and, as a result, may never be reported. The actual infection rates could be much higher than reported. Additionally, the diagnosis in the previously reported cases, as well as in series where RT was involved, were arrived at using antibody (IgM) detection. In comparison, we used both NS1 antigen detection and IgM titer. Dengue NS1 antigen detection has better sensitivity and specificity than other methods of detection of dengue virus [6] and provide confirmation of the diagnosis as early as day 3 of illness. We believe that use of antigen detection as a screening test will help to diagnose more cases of DF in patients who have received transplants. In almost all patients with DF, the infection is vector-borne. Interestingly, hematogenic spread of dengue has also been reported in patients who have undergone transplantation [7], from the donor via the allograft, which is the only record of mortality.\n\nData on sequelae following DF in LT patients are scarce because of the extremely limited number of cases reported in the literature to date. Data from case series involving RT patients show no increase in graft failures or episodes of acute rejection [8]. Although it included no patients with DF who had received LTs, a Taiwan series showed an increased incidence of biliary atresia following a DF epidemic in 2002 [9].\n\nConclusions\nDF is a rarely reported infection in transplanted patients and requires a high degree of suspicion for proper diagnosis. Dengue NS1 antigen detection is a useful addition to the already existing methods of diagnosis. Steroids and tacrolimus increase the morbidity of the disease. The graft outcome following the infection in our patient has been excellent, as in previously reported cases.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nAZA: Azathioprine; CyA: Cyclosporin A; DF: Dengue fever; DSS: Dengue shock syndrome; LT: Liver transplant; MMF: Mycophenolate mofetil; NS1: Nonspecific antigen 1; RT: Renal transplant.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nThe patient was under the primary care of MRNC for liver transplantation. PK was the primary care physician under whom the patient was admitted to our institution and was the supervisor of DRP, KPCD and JPR. DRP, KPCD and JPR were the team who took care of the patient’s primary illness. RMW designed the manuscript, did the literature survey and helped with immunosuppression modifications. DRP and JPR wrote the manuscript, and RMW and KPCD critically analyzed it. All authors read and approved the final manuscript.\n==== Refs\nSri Lanka Ministry of Health, Medical Statistics Unit Annual Health Bulletin 2012 63 \nFranco-Paredes C Jacob JT Hidron A Rodriguez-Morales AJ Kuhar D Caliendo AM Transplantation and tropical infectious diseases Int J Infect Dis 2010 14 e189 e196 19647464 \nBatista MV Pierrotti LC Abdala E Clemente WT Girão ES Rosa DR Ianhez LE Bonazzi PR Lima AS Fernandes PF Pádua-Neto MV Bacchella T Oliveira AP Viana CF Ferreira MS Shikanai-Yasuda MA Endemic and opportunistic infections in Brazilian solid organ transplant recipients Trop Med Int Health 2011 16 1134 1142 10.1111/j.1365-3156.2011.02816.x 21692958 \nGarcia JH Rocha TD Viana CF Gonçalves BP Girão ES Vasconcelos JB Coelho GR Schreen D Costa PE Brasil IR Dengue shock syndrome in a liver transplant recipient Transplantation 2006 82 850 851 17006337 \nNasim A Anis S Baqi S Akhtar SF Baig-Ansari N Clinical presentation and outcome of dengue viral infection in live-related renal transplant recipients in Karachi, Pakistan Transpl Infect Dis 2013 15 516 525 23890225 \nKumarasamy V Abdul Wahab AH Chua SK Hassan Z Chem YK Mohamad M Chua KB Evaluation of a commercial dengue NS1 antigen-capture ELISA for laboratory diagnosis of acute dengue virus infection J Virol Methods 2007 140 75 79 10.1016/j.jviromet.2006.11.001 17140671 \nSaigal S Choudhary NS Saraf N Kataria S Mohanka R Soin AS Transmission of dengue virus from a donor to a recipient after living donor liver transplantation Liver Transpl 2013 19 1413 1414 10.1002/lt.23755 24115243 \nAzevedo LS Carvalho DB Matuck T Alvarenga MF Morgado L Magalhães I Ianhez LE Boulos M David-Neto E Dengue in renal transplant patients: a retrospective analysis Transplantation 2007 84 792 794 10.1097/01.tp.0000280547.91617.25 17893614 \nTiao MM Tsai SS Kuo HW Chen CL Yang CY Epidemiological features of biliary atresia in Taiwan, a national study 1996-2003 J Gastroenterol Hepatol 2008 23 62 66 17725591\n\n",
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"issn_linking": "1752-1947",
"issue": "8()",
"journal": "Journal of medical case reports",
"keywords": null,
"medline_ta": "J Med Case Rep",
"mesh_terms": "D003715:Dengue; D006801:Humans; D016867:Immunocompromised Host; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D013188:Sri Lanka",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "378",
"pmc": null,
"pmid": "25412699",
"pubdate": "2014-11-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23890225;24115243;17006337;21692958;17893614;17725591;19647464;17140671",
"title": "Dengue fever in a liver-transplanted patient: a case report.",
"title_normalized": "dengue fever in a liver transplanted patient a case report"
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{
"abstract": "Aneurysmal bone cyst (ABC) is a benign tumour whose progression involves the RANK/RANKL signalling pathway. Surgery is the reference standard treatment but carries risks that vary with the site of the tumour. Denosumab is a human monoclonal IgG2 antibody that targets the RANK/RANKL pathway and may therefore hold promise for inhibiting ABC progression. The objective of this study was to evaluate denosumab use in paediatric patients (younger than 18 years) with ABC and to describe the clinical and radiological outcomes, as well as the side effect profile.\n\n\n\nDenosumab is a viable option in children with ABC refractory to standard treatments.\n\n\n\nWe retrospectively reviewed the medical files of paediatric patients given denosumab to treat ABC in any of 32 centres affiliated with the French Paediatric Cancer Society (Société Française du Cancer de l'Enfant, SFCE) and French Sarcoma Group (Groupe Sarcome Français, GSF-GETO). We identified 5 patients treated between March 2015 and June 2018. Median age was 8 years (range, 7-17 years). Pain was a symptom in all 5 patients and neurological deficits were present in 3 patients. Surgery was performed in 4 patients, either before (n=3) or after (n=1) denosumab therapy; the remaining patient had no surgery. Denosumab was given as monthly injections in a dosage of 70mg/m2 for a median of 12 months (range, 4-23 months). The clinical outcomes and changes in computed tomography and/or magnetic resonance imaging findings were evaluated.\n\n\n\nAbnormalities in calcium and phosphate levels secondary to the ABC occurred in 2 patients. At median of 24 months (range, 0-28 months) after denosumab initiation, all 5 patients were free of pain, and the neurological deficits in 3 patients had improved. Central remineralisation and cortical reconstitution were demonstrated consistently by the imaging studies.\n\n\n\nDenosumab is a viable treatment option in selected paediatric patients with inoperable ABC. The immediate adverse effect profile is acceptable. A larger study with a longer follow-up would be welcome to further assess the contribution of denosumab to the treatment of ABC.\n\n\n\nIV.",
"affiliations": "Département de chirurgie infantile, HFME, 59, boulevard Pinel, 69677 Bron, France. Electronic address: sebastien.raux@chu-lyon.fr.;IHOP, 1, place Professeur Joseph-Renaut, 69008 Lyon, France.;IGR, 114, rue Édouard-Vaillant, 94800 Villejuif, France.;IGR, 114, rue Édouard-Vaillant, 94800 Villejuif, France.;Hôpital Mère-Enfant Hautepierre, 1, avenue Molière, 67200 Strasbourg, France.;Hôpital universitaire Robert-Debré, 48, boulevard Sérurier, 75019 Paris, France.;Département de chirurgie infantile, HFME, 59, boulevard Pinel, 69677 Bron, France.;Centre Léon-Bérard, 69008 Lyon, France.;IHOP, 1, place Professeur Joseph-Renaut, 69008 Lyon, France.",
"authors": "Raux|Sébastien|S|;Bouhamama|Amine|A|;Gaspar|Nathalie|N|;Brugières|Laurence|L|;Entz-Werlé|Natacha|N|;Mallet|Cindy|C|;Dijoud|Frédérique|F|;Gouin|François|F|;Marec-Bérard|Perrine|P|",
"chemical_list": "D050071:Bone Density Conservation Agents; D000069448:Denosumab",
"country": "France",
"delete": false,
"doi": "10.1016/j.otsr.2019.04.028",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1877-0568",
"issue": "105(6)",
"journal": "Orthopaedics & traumatology, surgery & research : OTSR",
"keywords": "Aneurysmal bone cyst; Denosumab; RANKL antagonist",
"medline_ta": "Orthop Traumatol Surg Res",
"mesh_terms": "D000293:Adolescent; D017824:Bone Cysts, Aneurysmal; D050071:Bone Density Conservation Agents; D002648:Child; D000069448:Denosumab; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008279:Magnetic Resonance Imaging; D008297:Male; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101494830",
"other_id": null,
"pages": "1181-1185",
"pmc": null,
"pmid": "31358461",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Denosumab for treating aneurysmal bone cysts in children.",
"title_normalized": "denosumab for treating aneurysmal bone cysts in children"
} | [
{
"companynumb": "FR-AMGEN-FRASP2019125995",
"fulfillexpeditecriteria": "2",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CALCIUM"
},
"drugadditional": null,
... |
{
"abstract": "The main objective of this article is to present and discuss a case of localized ulcerative nodular amyloidosis with deep involvement clinically manifesting as ulcerative panniculitis and discuss its impact on the choice of treatment.\nWe present a 73-year-old woman with a history of painful ulcerated nodules on the inferior limbs. Microscopy confirmed amyloid deposits deep in the dermis and subcutaneous fat. No systemic involvement was found. Considering that skin-directed treatments often are not able to reach subcutaneous fat or were contraindicated because of the ulcers, she was successfully treated with cyclophosphamide and prednisone.\nLocalized ulcerative nodular amyloidosis with deep involvement is a rare clinical presentation that can present as ulcerative panniculitis. Such a clinical manifestation might be misleading. Systemic treatment might be necessary to control symptoms when conventional skin-directed therapies are contraindicated.",
"affiliations": "University of Sherbrooke, Sherbrooke, QC, Canada.;University of Sherbrooke, Sherbrooke, QC, Canada.;University of Sherbrooke, Sherbrooke, QC, Canada.;University of Sherbrooke, Sherbrooke, QC, Canada.;University of Sherbrooke, Sherbrooke, QC, Canada.",
"authors": "Fernandes|Carolina|C|;Éthier|Vincent|V|;Marouan|Sofia|S|;Chababi-Atallah|Myrna|M|;Veilleux|Mylène|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2050313X19890755",
"fulltext": "\n==== Front\nSAGE Open Med Case RepSAGE Open Med Case RepSCOspscoSAGE Open Medical Case Reports2050-313XSAGE Publications Sage UK: London, England 10.1177/2050313X1989075510.1177_2050313X19890755JCMS Case ReportLocalized ulcerative nodular amyloidosis presenting as ulcerative panniculitis, an unusual clinical manifestation: A case report Fernandes Carolina Éthier Vincent Marouan Sofia Chababi-Atallah Myrna Veilleux Mylène University of Sherbrooke, Sherbrooke, QC, CanadaCarolina Fernandes, University of Sherbrooke, 580 Rue Bowen S, Sherbrooke, QC J1G 2E8, Canada. Email: carolina.lucena.fernandes@usherbrooke.ca29 11 2019 2019 7 2050313X19890755© The Author(s) 20192019SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Introduction and objectives:\nThe main objective of this article is to present and discuss a case of localized ulcerative nodular amyloidosis with deep involvement clinically manifesting as ulcerative panniculitis and discuss its impact on the choice of treatment.\n\nMethods and results:\nWe present a 73-year-old woman with a history of painful ulcerated nodules on the inferior limbs. Microscopy confirmed amyloid deposits deep in the dermis and subcutaneous fat. No systemic involvement was found. Considering that skin-directed treatments often are not able to reach subcutaneous fat or were contraindicated because of the ulcers, she was successfully treated with cyclophosphamide and prednisone.\n\nConclusion:\nLocalized ulcerative nodular amyloidosis with deep involvement is a rare clinical presentation that can present as ulcerative panniculitis. Such a clinical manifestation might be misleading. Systemic treatment might be necessary to control symptoms when conventional skin-directed therapies are contraindicated.\n\nCancerdermatologywoundcover-dateJanuary-December 2019\n==== Body\nIntroduction\nPrimary cutaneous nodular amyloidosis is a rare form of localized cutaneous amyloidosis presenting as waxy infiltrated plaques and nodules.1 Its clinical appearance sometimes resembles that of systemic amyloidosis.1 Secondary ulcers have rarely been described.\n\nWe aim to discuss a case of localized ulcerative nodular amyloidosis with extensive involvement of dermis and subcutaneous fat clinically manifesting as ulcerative panniculitis and discuss its impact on the choice of treatment.\n\nCase report\nA 73-year-old woman presented with a history of painful ulcerated nodules on lower limbs slowly progressing over a 7-month period (Figure 1). Vascular investigation was normal. She had been taking methotrexate for 2 years for a seronegative arthritis. She had had an aortic valve replacement the preceding year as well as a history of pulmonary embolism.\n\nFigure 1. Painful ulcerated nodules on the inferior limbs slowly progressing over a 7-month period.\n\nSkin biopsy of lesions revealed amyloid deposits deep in the dermis and subcutaneous fat (Figure 2) (Figure 3). Amyloid deposits were of the amyloid light-chain (AL). Monoclonal plasma cells were found around blood vessels, and monotypic kappa light-chain restriction was observed (Figure 4). Immunochemistry failed to reveal underlying cutaneous lymphoma.2\n\nFigure 2. Amyloid deposits deep in the dermis and subcutaneous fat on H&E.\n\nFigure 3. Amyloid deposit on thioflavine immunofluorescence.\n\nFigure 4. Plasma cell perivascular infiltrate on H&E. Monotypic kappa light-chain restriction was observed on immunohistochemistry.\n\nPatient presented with elevated serum light chains kappa and elevated troponins. However, cardiac magnetic resonance imaging was normal as well as microscopic re-evaluation of aortic valve for amyloid deposits. Biopsy of abdominal fat, renal function, bone marrow biopsy and positron emission tomography scan were unremarkable. Ultimately, investigation did not show evidence of systemic amyloidosis or multiple myeloma, and patient was found to have an ulcerated form of primary cutaneous nodular amyloidosis.\n\nLesions were too deep to consider conventional skin-directed treatments such as cryotherapy, electrodesiccation or CO2 laser. The wide extent of lesions contraindicated surgical excision. Steroid injections and radiotherapy were avoided because of infection risk related to the ulcers. Methotrexate was stopped, but lesions kept nonetheless progressing. The patient was then treated with cyclophosphamide and prednisone. Ulcers slowly healed after a 12-month period. The patient remained free of disease after 1 year of follow-up.\n\nDiscussion\nPrimary cutaneous nodular amyloidosis is a rare form of localized cutaneous amyloidosis.1 It usually presents as waxy infiltrated plaques and nodules, most commonly on the trunk or extremities.1 Secondary ulceration has rarely been described.1\n\nIt is a disease that occurs predominantly in women, with a mean age at diagnosis of 60 years.3 It has sometimes been described in association with systemic diseases such as Sjögren syndrome,4 diabetes mellitus and CREST syndrome.5 Two cases of concomitant paraproteinemia have also been reported.1,3–6\n\nHistopathologic analysis classically shows amyloid deposits diffusely infiltrating dermis, subcutis and blood vessel walls.7 In nodular amyloidosis, a monoclonal population of plasma cells produces the amyloid protein,6 the latter being of the light-chain (AL) type (λ, κ or both).7 Gene rearrangement studies confirm clonality of the amyloid-producing plasma cells in the skin but not in the bone marrow.7\n\nIn our case, clinical presentation was misleading. Lesions presented as deep painful nodules instead of asymptomatic waxy plaques and were secondarily ulcerated, which is an unusual presentation for cutaneous nodular amyloidosis. Methotrexate might have been involved to some extent in the ulceration process. However, lesions did not heal when the medication was stopped and histopathologic findings did point towards classic presentation of methotrexate-induced ulcers.\n\nIn the absence of an underlying treatable cause, the management of localized cutaneous nodular amyloidosis is difficult, as there is no consistently effective treatment. Various modes of treatment have been reported for improving the appearance of lesions, such as surgical excision, cryotherapy, electrodesiccation and curettage, intralesional steroid injection and, more recently, treatment with the CO2 laser.7 Radiotherapy has also been reported with mitigated results.8 Unfortunately, the rate of local recurrence in this type of amyloid is high.7\n\nIn our case, lesions were too deep to consider skin-directed treatments. The wide extent of lesions contraindicated surgical excision. Steroid injections and radiotherapy were avoided because of infection risk related to the ulcers.\n\nPatient had a paraproteinemia as well as elevated troponins but did not have enough criteria for a diagnosis of myeloma or systemic amyloidosis. However, normalization of those biological parameters with systemic therapy might indicate subclinical systemic disease.\n\nIn patients with localized cutaneous nodular amyloidosis, reported progression rate to systemic disease is 50%.1 However, more recent case studies seem to indicate that it is more around 6%.5–6 Patients presenting concomitant paraproteinaemia at the time of diagnosis seem to be more at risk.6 It is not known whether the presence of ulceration alters the risk of progression to systemic disease. In our case, no cutaneous recurrence and no systemic progression was observed 1 year after clinical remission. Localized ulcerative nodular amyloidosis with deep extensive involvement is a rare clinical presentation that can present as an ulcerative panniculitis. Its clinical manifestation might be misleading and clinicians should be alert of its existence. In this case, methotrexate might have also been involved in the ulceration process. Deep involvement of amyloid deposits along with the ulceration process may contraindicate conventional treatments. Systemic treatment might be necessary to control symptoms. Long-term follow-up is necessary, since the risk of systemic development of this deep ulcerated form is unknown.\n\nAuthors’ Note: Poster presented at the World Congress of Dermatology (June 2019) and at the Canadian Dermatology Association Conference (June 2019).\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship and/or publication of this article.\n\nInformed consent: Informed patient’s consent has been obtained for publication of the images and case report information.\n==== Refs\nReferences\n1 \nVillar M Burgues M Rodriguez-Peralto JL , et al\nLocalized primary cutaneous nodular amyloidosis in a patient with paraproteinemia . Actas Dermosifiliogr \n2012 ; 103 (2 ): 161 –162 .21885025 \n2 \nWalsh NM Lano IM Green P , et al\nAL amyloidoma of the skin/subcutis: cutaneous amyloidosis, plasma cell dyscrasia or a manifestation of primary cutaneous marginal zone lymphoma? \nAm J Surg Pathol \n2017 ; 41 (8 ): 1069 –1076 .28505007 \n3 \nSchwendiman MN Beachkofsky TM Wisco OJ , et al\nPrimary cutaneous nodular amyloidosis: case report and review of the literature . Cutis \n2009 ; 84 (2 ): 87 –92 .19746766 \n4 \nChavarría E González-Carrascosa M Hernanz JM , et al\nAmiloidosis cutánea nodular primaria asociada a síndrome de Sjögren: presentación de un caso . Actas Dermosifiliogr \n2005 ; 96 : 446 –449 .16476272 \n5 \nShiman M Ricotti C Miteva M , et al\nPrimary localized cutaneous nodular amyloidosis associated with CREST (calcinosis, Raynaud’s phenomenon, esophageal motility disorders, sclerodactyly, and telangiectasia) syndrome . Int J Dermatol \n2010 ; 49 : 229 –230 .20465653 \n6 \nMoon AO Calamia KT Walsh JS. \nNodular amyloidosis: review and long-term follow-up of 16 cases . Arch Dermatol \n2003 ; 139 (9 ): 1157 –1159 .12975157 \n7 \nWoollons A Black MM. \nNodular localized primary cutaneous amyloidosis: a long-term follow-up study . Br J Dermatol \n2001 ; 145 (1 ): 105 –109 .11453916 \n8 \nGerard E Ly S Cogrel O , et al\nPrimary localized cutaneous nodular amyloidosis: a diagnostic and therapeutic challenge . Ann Dermatol Venereol \n2016 ; 143 (2 ): 134 –138 .26724842\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-313X",
"issue": "7()",
"journal": "SAGE open medical case reports",
"keywords": "Cancer; dermatology; wound",
"medline_ta": "SAGE Open Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101638686",
"other_id": null,
"pages": "2050313X19890755",
"pmc": null,
"pmid": "31827797",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "12975157;11453916;20465653;26724842;19746766;21885025;28505007;16476272",
"title": "Localized ulcerative nodular amyloidosis presenting as ulcerative panniculitis, an unusual clinical manifestation: A case report.",
"title_normalized": "localized ulcerative nodular amyloidosis presenting as ulcerative panniculitis an unusual clinical manifestation a case report"
} | [
{
"companynumb": "CA-PFIZER INC-2019554300",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": "1",... |
{
"abstract": "Lineage switch occurs in rare leukemias, and the mechanism is unclear. We report two cases of B-lymphoblastic leukemia (B-ALL) relapsed as acute myeloid leukemia (AML).\nRetrospective review of clinical and laboratory data.\nComplex cytogenetic abnormalities were detected in B-ALL for both cases with subclone heterogeneity. Postchemotherapy marrow biopsies showed trilineage hematopoiesis without detectable B-ALL. Cytogenetics in both showed stemline abnormalities. The cases were considered \"occult\" myelodysplastic syndrome (MDS) preceding B-ALL. The patients relapsed 6.5 and 9 months following induction, respectively. Case 1 relapsed as AML-M5 initially, was treated as such, and then relapsed again as B-ALL. Case 2 relapsed as AML-M6. Cytogenetics demonstrated persistent abnormalities. Both patients died soon after relapse.\nLineage switch between B-ALL and AML could be intermediated by occult MDS. A pluripotent progenitor likely undergoes neoplastic transformation, resulting in a genomically unstable clone. This leads to a repertoire of heterogeneous subclones that may be selected by chemotherapy. Lineage switch heralds a dismal clinical outcome.",
"affiliations": "Division of Hematology, Department of Medicine, Shengjing Hospital affiliated with China Medical University, Shenyang, People's Republic of China.;Department of Pathology, Duke University Medical Center, Durham, NC.;Department of Pathology, Duke University Medical Center, Durham, NC.;Department of Pathology, Duke University Medical Center, Durham, NC.;Department of Pathology, Duke University Medical Center, Durham, NC.;Department of Pathology, Duke University Medical Center, Durham, NC.;Department of Pathology, Duke University Medical Center, Durham, NC.;Department of Pathology, Duke University Medical Center, Durham, NC.",
"authors": "Wu|Bin|B|;Jug|Rachel|R|;Luedke|Catherine|C|;Su|Pu|P|;Rehder|Catherine|C|;McCall|Chad|C|;Lagoo|Anand S|AS|;Wang|Endi|E|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ajcp/aqx055",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9173",
"issue": "148(2)",
"journal": "American journal of clinical pathology",
"keywords": "Acute myeloid leukemia; B-lymphoblastic leukemia; Lineage switch; Myelodysplastic syndrome; Phenotypic switch",
"medline_ta": "Am J Clin Pathol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002471:Cell Transformation, Neoplastic; D002869:Chromosome Aberrations; D042822:Genomic Instability; D006801:Humans; D015448:Leukemia, B-Cell; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009190:Myelodysplastic Syndromes; D016609:Neoplasms, Second Primary; D055815:Young Adult",
"nlm_unique_id": "0370470",
"other_id": null,
"pages": "136-147",
"pmc": null,
"pmid": "28898985",
"pubdate": "2017-08-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lineage Switch Between B-Lymphoblastic Leukemia and Acute Myeloid Leukemia Intermediated by \"Occult\" Myelodysplastic Neoplasm: Two Cases of Adult Patients With Evidence of Genomic Instability and Clonal Selection by Chemotherapy.",
"title_normalized": "lineage switch between b lymphoblastic leukemia and acute myeloid leukemia intermediated by occult myelodysplastic neoplasm two cases of adult patients with evidence of genomic instability and clonal selection by chemotherapy"
} | [
{
"companynumb": "CN-BRISTOL-MYERS SQUIBB COMPANY-BMS-2017-088349",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYUREA"
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{
"abstract": "OBJECTIVE\nActivation and dimerization of the ERBB family play a role in the pathogenesis and progression of ovarian cancer. We conducted a phase II trial to evaluate the activity and tolerability of lapatinib in patients with recurrent or persistent epithelial ovarian cancer (EOC) and to explore the clinical value of expression levels of epidermal growth factor receptors (EGFR), phosphorylated EGFR, HER-2/neu, and Ki-67, and the presence of EGFR mutations.\n\n\nMETHODS\nEligible patients had recurrent or persistent EOC or primary peritoneal carcinoma, measurable disease, and up to 2 prior chemotherapy regimens for recurrent disease. Patients were treated with lapatinib 1500 mg/day. The primary endpoint of efficacy was 6-month progression free survival (PFS).\n\n\nRESULTS\nTwenty-five of 28 patients were eligible and evaluable for analysis of efficacy and toxicity. Two (8.0%) were alive and progression-free at 6 months. No objective responses were observed. There were 1 grade 4 toxicity (fatigue) and few grade 3 toxicities. Associations between Ki-67 with prior platinum-free interval, PFS, and a polymorphism in EGFR were suggested.\n\n\nCONCLUSIONS\nLapatinib has minimal activity in recurrent ovarian cancer. Ki-67 expression may be associated with prior PFS and a polymorphism in EGFR exon 20 (2361G>A, Q787Q).",
"affiliations": "University of Southern California, Los Angeles, CA, USA. aagarcia@usc.edu",
"authors": "Garcia|Agustin A|AA|;Sill|Michael W|MW|;Lankes|Heather A|HA|;Godwin|Andrew K|AK|;Mannel|Robert S|RS|;Armstrong|Deborah K|DK|;Carolla|Robert L|RL|;Liepman|Marcia K|MK|;Spirtos|Nick M|NM|;Fischer|Edgar G|EG|;Leslie|Kimberly K|KK|",
"chemical_list": "D000970:Antineoplastic Agents; D019394:Ki-67 Antigen; D011799:Quinazolines; D000077341:Lapatinib; D066246:ErbB Receptors",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ygyno.2011.10.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-8258",
"issue": "124(3)",
"journal": "Gynecologic oncology",
"keywords": null,
"medline_ta": "Gynecol Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000077216:Carcinoma, Ovarian Epithelial; D018572:Disease-Free Survival; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen; D000077341:Lapatinib; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009375:Neoplasms, Glandular and Epithelial; D010051:Ovarian Neoplasms; D010534:Peritoneal Neoplasms; D011110:Polymorphism, Genetic; D011799:Quinazolines",
"nlm_unique_id": "0365304",
"other_id": null,
"pages": "569-74",
"pmc": null,
"pmid": "22037316",
"pubdate": "2012-03",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": "9790065;21006841;19179558;12217791;11058872;15374980;8562334;19162309;2470152;1972347;9989823;12525520;11562388;17532033;16061871;16896006;16174225;11585755;17330838;10733345;9819829;12214266;20610543;10655437;20346177;19901115;14871800;16265675",
"title": "A phase II evaluation of lapatinib in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: a gynecologic oncology group study.",
"title_normalized": "a phase ii evaluation of lapatinib in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma a gynecologic oncology group study"
} | [
{
"companynumb": "NVSC2019US055579",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAPATINIB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Research suggests that the prevalence of obesity in children with autism spectrum disorder (ASD) is higher than in typically developing children. The US Preventive Services Task Force and the American Academy of Pediatrics (AAP) have endorsed screening children for overweight and obesity as part of the standard of care for physicians. However, the pediatric provider community has been inadequately prepared to address this issue in children with ASD. The Healthy Weight Research Network, a national research network of pediatric obesity and autism experts funded by the US Health Resources and Service Administration Maternal and Child Health Bureau, developed recommendations for managing overweight and obesity in children with ASD, which include adaptations to the AAP's 2007 guidance. These recommendations were developed from extant scientific evidence in children with ASD, and when evidence was unavailable, consensus was established on the basis of clinical experience. It should be noted that these recommendations do not reflect official AAP policy. Many of the AAP recommendations remain appropriate for primary care practitioners to implement with their patients with ASD; however, the significant challenges experienced by this population in both dietary and physical activity domains, as well as the stress experienced by their families, require adaptations and modifications for both preventive and intervention efforts. These recommendations can assist pediatric providers in providing tailored guidance on weight management to children with ASD and their families.",
"affiliations": "Healthy Weight Research Network, University of Massachusetts Medical School, Worcester, Massachusetts; carol.curtin@umassmed.edu.;Healthy Weight Research Network, University of Massachusetts Medical School, Worcester, Massachusetts.;Healthy Weight Research Network, University of Massachusetts Medical School, Worcester, Massachusetts.;Healthy Weight Research Network, University of Massachusetts Medical School, Worcester, Massachusetts.;Healthy Weight Research Network, University of Massachusetts Medical School, Worcester, Massachusetts.;Healthy Weight Research Network, University of Massachusetts Medical School, Worcester, Massachusetts.;Healthy Weight Research Network, University of Massachusetts Medical School, Worcester, Massachusetts.;Healthy Weight Research Network, University of Massachusetts Medical School, Worcester, Massachusetts.;Healthy Weight Research Network, University of Massachusetts Medical School, Worcester, Massachusetts.;Healthy Weight Research Network, University of Massachusetts Medical School, Worcester, Massachusetts.",
"authors": "Curtin|Carol|C|;Hyman|Susan L|SL|;Boas|Diane D|DD|;Hassink|Sandra|S|;Broder-Fingert|Sarabeth|S|;Ptomey|Lauren T|LT|;Gillette|Meredith Dreyer|MD|;Fleming|Richard K|RK|;Must|Aviva|A|;Bandini|Linda G|LG|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2019-1895P",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "145(Suppl 1)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D000067877:Autism Spectrum Disorder; D002648:Child; D006801:Humans; D063766:Pediatric Obesity; D017410:Practice Guidelines as Topic; D011320:Primary Health Care",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": "S126-S139",
"pmc": null,
"pmid": "32238539",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Weight Management in Primary Care for Children With Autism: Expert Recommendations.",
"title_normalized": "weight management in primary care for children with autism expert recommendations"
} | [
{
"companynumb": "US-OTSUKA-2020_016333",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "PTLD is a rare but potentially life-threatening condition, which shows a higher prevalence in children than in adults. From 129 children who underwent LT, we reported 5 cases with biopsy-proven PTLD at a single teaching hospital. Four patients had shared clinical presentations including fever, lymphadenopathy, and splenomegaly. They were noted to be given a prolonged course of IS due to the management of comorbid complications such as acute cellular rejection or severe food allergy or eosinophilic gastrointestinal disease. The other one patient presented with upper gastrointestinal bleeding from gastric mass during an early post-transplantation period. Notably, hypoalbuminemia was noted in all reported patients. Similar to previous studies, both EBV serology mismatch between the donor and recipient with high EBV viral load were noted in all except one case, whose EBV serology was unknown before LT. At least one episode of CMV reactivation was also observed in 3 of 5 patients prior to the PTLD diagnosis. The histopathology revealed 1 of 5 early PTLD, 1 of 5 polymorphic PTLD, and 3 of 5 monomorphic PTLD. The treatment included IS withdrawal, chemotherapy, and/or rituximab. One patient died of multiorgan dysfunction, one remains in complete remission, and three patients are either still on treatment or await response evaluation. Even though most of our reported PTLD cases had shared manifestations with fever, lymphadenopathy, splenomegaly, EBV serology mismatch, and high EBV viral load, various initial presentations such as respiratory symptoms, hypoalbuminemia, and prolonged use of IS from other causes such as significant food allergy were noted.",
"affiliations": "Faculty of Medicine Ramathibodi Hospital, Department of Pediatrics, Division of Gastroenterology, Mahidol University, Bangkok, Thailand.;Faculty of Medicine Ramathibodi Hospital, Department of Pediatrics, Division of Gastroenterology, Mahidol University, Bangkok, Thailand.;Faculty of Medicine Ramathibodi Hospital, Department of Pediatrics, Division of Gastroenterology, Mahidol University, Bangkok, Thailand.;Faculty of Medicine Ramathibodi Hospital, Department of Pediatrics, Division of Hematology and Oncology, Mahidol University, Bangkok, Thailand.;Faculty of Medicine Ramathibodi Hospital, Department of Pediatrics, Division of Hematology and Oncology, Mahidol University, Bangkok, Thailand.;Faculty of Medicine Ramathibodi Hospital, Department of Pediatrics, Division of Hematology and Oncology, Mahidol University, Bangkok, Thailand.;Faculty of Medicine Ramathibodi Hospital, Department of Pediatrics, Division of Gastroenterology, Mahidol University, Bangkok, Thailand.;Faculty of Medicine Ramathibodi Hospital, Department of Pediatrics, Division of Gastroenterology, Mahidol University, Bangkok, Thailand.",
"authors": "Simakachorn|Lila|L|;Tanpowpong|Pornthep|P|0000-0002-9374-8805;Lertudomphonwanit|Chatmanee|C|;Anurathapan|Usanarat|U|;Pakakasama|Samart|S|;Hongeng|Suradej|S|;Treepongkaruna|Suporn|S|0000-0002-6651-2282;Phuapradit|Pornpimon|P|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13357",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "23(2)",
"journal": "Pediatric transplantation",
"keywords": "anemia; food allergy; hypoalbuminemia; immunosuppression; lymphoma",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000293:Adolescent; D002675:Child, Preschool; D020031:Epstein-Barr Virus Infections; D005260:Female; D006801:Humans; D016031:Liver Transplantation; D008232:Lymphoproliferative Disorders; D008297:Male; D009894:Opportunistic Infections; D011183:Postoperative Complications",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13357",
"pmc": null,
"pmid": "30661283",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Various initial presentations of Epstein-Barr virus infection-associated post-transplant lymphoproliferative disorder in pediatric liver transplantation recipients: Case series and literature review.",
"title_normalized": "various initial presentations of epstein barr virus infection associated post transplant lymphoproliferative disorder in pediatric liver transplantation recipients case series and literature review"
} | [
{
"companynumb": "TH-ACCORD-114223",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drug... |
{
"abstract": "Bortezomib, an antineoplastic agent used in Multiple Myeloma, is a modified dipeptidyl boronic acid that is selectively and reversibly attached to the 26S proteasome. Bortezomib may be combined with corticosteroids in treatment-resistant multiple myeloma patients. Corticosteroids can cause many psychiatric disorders ncluding mania, depression, psychosis, delirium, suicide and aggression. To date only one case of mania associated with the use of bortezomib was reported in which the patient responded to the treatment with olanzapine and valproic acid. In this article, we present a 57-year-old female with multiple myeloma in whom mania developed after the use of bortezomib combined with dexamethasone.Psychiatric symptoms such as sleep deprivation, increased self-esteem and excessive speech appeared within the first week of bortezomib and dexamethasone treatment. Quetiapine was administered for the treatment of psychiatric symptoms. A gradual improvement was noted in manic symptoms after treatment. Bortezomib is a relatively new drug and there are only a few reports with respect to its psychiatric side effects. While using antineoplastic drugs such as bortezomib, caution should be exercised with regards to the psychiatric symptoms.",
"affiliations": null,
"authors": "Geniş|Bahadır|B|;Coşar|Behcet|B|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D000069286:Bortezomib; D003907:Dexamethasone",
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1300-2163",
"issue": "29(3)",
"journal": "Turk psikiyatri dergisi = Turkish journal of psychiatry",
"keywords": null,
"medline_ta": "Turk Psikiyatri Derg",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D001714:Bipolar Disorder; D000069286:Bortezomib; D003907:Dexamethasone; D003937:Diagnosis, Differential; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008875:Middle Aged; D009101:Multiple Myeloma",
"nlm_unique_id": "9425936",
"other_id": null,
"pages": "209-215",
"pmc": null,
"pmid": "30260467",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mania Associated with the Use of Bortezomib and Dexamethasone.",
"title_normalized": "mania associated with the use of bortezomib and dexamethasone"
} | [
{
"companynumb": "TR-BAUSCH-BL-2019-001261",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": "3",
... |
{
"abstract": "A 75-year-old woman was diagnosed with symptomatic IgG-l multiple myeloma (good-prognosis group) in December 2010. A stringent complete response (sCR) was achieved by using induction therapy with bortezomib (BOR, Velcade®)+ dexamethasone (DEX)(VD) and consolidation therapy with BOR+lenalidomide (LEN, Revlimid®)+DEX(VRD). Although maintenance therapy with Revlimid®+DEX(Rd) was initiated, a pancreatic neuroendocrine tumor was detected in April 2013. Therefore, LEN was discontinued and distal pancreatectomy was performed in September 2013. Because discontinuation of LEN was followed by exacerbation of myeloma, LEN was resumed with the consent of the patient; however, she became resistant to the treatment. The course of this case suggests that some patients must continue to receive LEN even if a sCR is achieved.",
"affiliations": "Dept. of Gastroenterology and Hematology/Clinical Oncology, Internal Medicine, Steel Memorial Muroran Hospital.",
"authors": "Kuroda|Hiroyuki|H|;Yoshida|Masahiro|M|;Usami|Makoto|M|;Shimoyama|Saori|S|;Sakamoto|Hiroki|H|;Yamada|Michiko|M|;Fujii|Shigeyuki|S|;Maeda|Masahiro|M|;Fujita|Miri|M|;Kanari|Yusuke|Y|;Sato|Tsutomu|T|;Kato|Junji|J|",
"chemical_list": "D013792:Thalidomide; D000077269:Lenalidomide",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "42(8)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D009101:Multiple Myeloma; D016609:Neoplasms, Second Primary; D010190:Pancreatic Neoplasms; D013792:Thalidomide; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1009-12",
"pmc": null,
"pmid": "26321720",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Newly Diagnosed Case of Multiple Myeloma in Which Lenalidomide Was Continued after Surgery for a Pancreatic Neuroendocrine Tumor That Developed during Lenalidomide Maintenance Therapy.",
"title_normalized": "a newly diagnosed case of multiple myeloma in which lenalidomide was continued after surgery for a pancreatic neuroendocrine tumor that developed during lenalidomide maintenance therapy"
} | [
{
"companynumb": "JP-TAKEDA-2015MPI006006",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Anterior spinal artery syndrome has rarely been reported as a cause of permanent neurologic complications after neuraxial anesthesia in obstetric patients. A parturient developed anterior spinal artery syndrome after spinal anesthesia for cesarean delivery. A healthy 32-year-old parturient presented at 41(2/7) weeks for primary elective caesarean delivery for breech presentation. Spinal anesthesia was easily performed with clear cerebrospinal fluid, and block height was T4 at 5 minutes. Intraoperative course was uneventful except for symptomatic bradycardia (37-40 beats per minute) and hypotension (88/44 mm Hg) 4 minutes postspinal anesthesia, treated with ephedrine and atropine. Dense motor block persisted 9 hours after spinal anesthesia, and magnetic resonance imaging of the lumbosacral region was normal, finding no spinal cord compression or lesion. Physical examination revealed deficits consistent with a spinal cord lesion at T6, impacting the anterior spinal cord while sparing the posterior tracts.",
"affiliations": "IWK Health Centre, Dalhousie University, Halifax, NS, Canada.;IWK Health Centre, Dalhousie University, Halifax, NS, Canada. Electronic address: dolores.mckeen@iwk.nshealth.ca.;IWK Health Centre, Dalhousie University, Halifax, NS, Canada.;IWK Health Centre, Dalhousie University, Halifax, NS, Canada.",
"authors": "Zaphiratos|Valerie|V|;McKeen|Dolores M|DM|;Macaulay|Bruce|B|;George|Ronald B|RB|",
"chemical_list": "D004809:Ephedrine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0952-8180",
"issue": "27(1)",
"journal": "Journal of clinical anesthesia",
"keywords": "Adverse outcome; Anterior spinal artery syndrome; Cesarean delivery; Neuraxial anesthesia; Neurologic complication; Paralysis/paraplegia; Spinal anesthesia",
"medline_ta": "J Clin Anesth",
"mesh_terms": "D000328:Adult; D000773:Anesthesia, Obstetrical; D000775:Anesthesia, Spinal; D020759:Anterior Spinal Artery Syndrome; D002585:Cesarean Section; D004809:Ephedrine; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D010243:Paralysis; D011247:Pregnancy; D013997:Time Factors",
"nlm_unique_id": "8812166",
"other_id": null,
"pages": "68-72",
"pmc": null,
"pmid": "25433726",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Persistent paralysis after spinal anesthesia for cesarean delivery.",
"title_normalized": "persistent paralysis after spinal anesthesia for cesarean delivery"
} | [
{
"companynumb": "CA-FRESENIUS KABI-FK201305138",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MORPHINE"
},
"drugadditional": null,
... |
{
"abstract": "Crohn disease (CD) may be complicated by contiguous, metastatic, or associated inflammatory cutaneous lesions. Vulvar CD is a rare phenomenon characterized by granulomatous genital inflammation that occurs independently from fistulizing CD. Left untreated, vulvar CD can result in debilitating lymphedema, disfiguring anatomic changes, secondary abscesses, cellulitis, and squamous cell carcinoma. We present a series of cases to highlight the clinical presentation of vulvar CD, the diagnostic testing required to distinguish complicating conditions, the asynchronous courses of skin and intestinal disease, and the complexities in the management of this disease and associated conditions. We review our multidisciplinary approach to care, aimed at reducing morbidity and improving patient quality of life.",
"affiliations": "Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States.;University of Wisconsin, School of Medicine and Public Health, Madison, WI, United States.;Department of Dermatology, University of Wisconsin, School of Medicine and Public Health, Madison, WI, United States.;Department of Dermatology, University of Wisconsin, School of Medicine and Public Health, Madison, WI, United States.",
"authors": "Shields|Bridget E|BE|;Richardson|Catherine|C|;Arkin|Lisa|L|;Kornik|Rachel|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ijwd.2020.09.007",
"fulltext": "\n==== Front\nInt J Womens Dermatol\nInt J Womens Dermatol\nInternational Journal of Women's Dermatology\n2352-6475\nElsevier\n\nS2352-6475(20)30142-8\n10.1016/j.ijwd.2020.09.007\nOriginal Research\nVulvar Crohn disease: Diagnostic challenges and approach to therapy\nShields Bridget E. MD bshields@dermatology.wisc.edu\na⁎\nRichardson Catherine BS b\nArkin Lisa MD c\nKornik Rachel MD c\na Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States\nb University of Wisconsin, School of Medicine and Public Health, Madison, WI, United States\nc Department of Dermatology, University of Wisconsin, School of Medicine and Public Health, Madison, WI, United States\n⁎ Corresponding author. bshields@dermatology.wisc.edu\n17 9 2020\n12 2020\n17 9 2020\n6 5 390394\n14 5 2020\n6 9 2020\n9 9 2020\n© 2020 Published by Elsevier Inc. on behalf of Women's Dermatologic Society.\n2020\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nCrohn disease (CD) may be complicated by contiguous, metastatic, or associated inflammatory cutaneous lesions. Vulvar CD is a rare phenomenon characterized by granulomatous genital inflammation that occurs independently from fistulizing CD. Left untreated, vulvar CD can result in debilitating lymphedema, disfiguring anatomic changes, secondary abscesses, cellulitis, and squamous cell carcinoma. We present a series of cases to highlight the clinical presentation of vulvar CD, the diagnostic testing required to distinguish complicating conditions, the asynchronous courses of skin and intestinal disease, and the complexities in the management of this disease and associated conditions. We review our multidisciplinary approach to care, aimed at reducing morbidity and improving patient quality of life.\n\nKeywords\n\nVulvar Crohn disease\nMetastatic Crohn disease\nAnogenital granulomatosis\nInflammatory bowel disease\n==== Body\nIntroduction\n\nThe prevalence of inflammatory bowel disease is increasing worldwide with Crohn disease (CD), affecting >780,000 Americans each year (Kurtzman et al., 2014, Molodecky et al., 2012). Recurrent inflammation frequently results in abscesses, bowel strictures, and fistulae (van Loo et al., 2012). Cutaneous involvement may complicate up to 44% of CD cases as contiguous, metastatic, or associated inflammatory lesions (Albuquerque et al., 2011, Burgdorf, 1981, Kurtzman et al., 2014, Marotta and Reynolds, 1996) Metastatic CD (MCD) is a rare and likely underrecognized phenomenon characterized by granulomatous inflammation of the skin, discontinuous from the gastrointestinal tract (Albuquerque et al., 2011, Farhi et al., 2007, Marotta and Reynolds, 1996). Vulvar CD (anogenital granulomatosis) is a variant of MCD and defined by granulomatous genital inflammation independently from fistulizing CD.\n\nVulvar CD may present clinically with erythema, edema, knife-cut ulceration, and fissuring that may involve the labia, clitoris, mons pubis, or entire anogenital region, including the genitocrural folds, vagina, and buttocks (Alexakis et al., 2017, Duhra and Paul, 1988, Kurtzman et al., 2014). Vulvar CD may precede a diagnosis of intestinal disease in 20% to 36% of patients, either due to quiescent intestinal symptoms that go unnoticed or delayed onset of enteropathy (Andreani et al., 2010, Laftah et al., 2015, Zhang et al., 2015). A subset of patients may manifest vulvar CD in the absence of gastrointestinal CD (Leu et al., 2009). If left untreated, vulvar CD can result in recurrent abscesses and cellulitis, with or without hidradenitis suppurativa, and result in debilitating lymphatic destruction and secondary lymphedema, lymphangiectasia, and lymphangiomas (Núñez et al., 2014, Papalas et al., 2010). Perianal tags frequently develop secondary to chronic lymphatic obstruction and are recognized as a classic harbinger of CD (Kurtzman et al., 2014, Moreno et al., 2019). Disfiguring anatomic distortion and squamous cell carcinoma may also occur and impart significant morbidity and impact on quality of life (Alexakis et al., 2017, Kesterson et al., 2008). The treatment of vulvar CD requires multidisciplinary efforts involving gynecologists, gastroenterologists, infectious disease specialists, and dermatologists to achieve disease control and improve patient quality of life.\n\nThe following three cases highlight the clinical presentation of vulvar CD, the diagnostic testing required to distinguish complicating conditions (e.g., infections), the asynchronous courses of skin and intestinal disease, and the complexities of the management of the disease and associated conditions.\n\nCase 1\n\nA 31-year-old female patient with a longstanding history of CD presented for evaluation of worsening biopsy-proven vulvar CD. Her intestinal disease was well controlled after a colectomy and end ileostomy. However, treatment with certolizumab pegol, adalimumab, infliximab, and mercaptopurine prior to surgery had failed. The patient complained of vaginal discharge, vulvar erythema, erosions, and pruritus with associated fissuring, cracking, and weeping of the labia majora, which had been previously managed with courses of oral prednisone, intralesional triamcinolone, topical pimecrolimus 1% cream, clobetasol 0.05% ointment, and metronidazole 0.75% gel without improvement. Her cutaneous disease resolved with the initiation of oral metronidazole but discontinuation was necessitated due to the development of peripheral neuropathy.\n\nA physical examination revealed an erythematous, scaly plaque studded with pustules on the mons pubis. Edematous, verruciform plaques of the labia majora (Fig. 1A), deep knife-cut ulcerations in the inguinal folds and intergluteal cleft, and erythema with woody induration of the medial buttocks were noted (Fig. 1B). A vaginal examination revealed diffuse erythema and copious yellow discharge. A vaginal saline wet mount showed sheets of white blood cells. A skin culture grew methicillin-resistant Staphylococcus aureus (MRSA) and group A Streptococcus. The patient was started on doxycycline and rifampin for MRSA treatment, as well as a short course of amoxicillin (500 mg twice daily for 5 days for coverage of streptococcus) while awaiting the culture susceptibilities. She was subsequently tailored to doxycycline (100 mg twice daily) in combination with a topical regimen (tacrolimus 0.1% ointment, topical metronidazole 0.75% gel, mupirocin 2% ointment, and bleach baths) leading to sustained improvement.Fig. 1 (A) Hypertrophied and edematous plaques of the labia majora, and (B) erythematous, verrucous plaques of the medial buttocks with perianal tags.\n\nAt the follow-up visit, the vulvar fissuring, pustules, and erythema had resolved. The induration of the medial buttocks had softened and the swelling of the labia majora had improved. The patient continued a month-long course of oral doxycycline with continued resolution. Unfortunately, the patient only returned for two follow-up visits due to insurance changes (6-week intervals) with sustained clearance on mupirocin ointment 5 days per month, tacrolimus ointment weekly, and bleach baths twice weekly.\n\nCase 2\n\nA 31-year-old female patient with CD and systemic lupus erythematous, treated with adalimumab and hydroxychloroquine, presented with a 1-year history of worsening vulvar pain, edema, fissuring, and pruritus. She reported prior vulvar abscesses and cellulitis of the vulva and buttocks, which resolved with antibiotic therapy. A physical examination revealed pink, scaly plaques involving the genitocrural folds and mons pubis. The labia majora were grossly enlarged and indurated, and an exophytic nodule was present on the right periclitoral skin (Fig. 2). An internal examination was deferred due to pain. Rapid plasma reagin and herpes simplex virus reverse-transcription polymerase chain-reaction testing were negative. Cultures grew methicillin-susceptible Staphylococcus aureus (MSSA) and group B Streptococcus. Tests of biopsy tissues of the periclitoral skin demonstrated psoriasiform and lichenoid dermatitis, perivascular and interstitial lymphoplasmacytic infiltrate, and mixed dermal inflammation with histiocytes and giant cells, which is consistent with vulvar CD. Tissue cultures confirmed the presence of MSSA.Fig. 2 (A) Labia majora with gross edema and erythema, and (B) scaly plaques of the genitocrural folds and linear ulceration of the anterior labial commissure.\n\nThe patient was started on cephalexin (500 mg every 6 hours for 14 days), topical metronidazole 0.75% cream, and bleach baths. A compression garment was recommended for the edema. The patient exhibited an initial resolution with antibiotic treatment and subsequently stopped taking adalimumab because she thought the drug exacerbated her vulvar symptoms. At the follow-up dermatology visit, repeat skin cultures grew MSSA and group B Streptococcus. Mupirocin and chlorhexidine wash were added and intralesional kenalog (1 ml of 20 mg/ml) injections were performed into the indurated areas. Persistently low vitamin D levels were noted despite daily supplementation, and a high-dose vitamin D supplement was initiated. The patient did not return for follow-up visits, but a subsequent primary care physician note (5 months after the last dermatology appointment) documents that the vulvar symptoms improved and the patient reported doing well.\n\nCase 3\n\nA 15-year-old female patient with well-controlled CD treated with infliximab presented with a 1-year history of persistent erythema, edema, and desquamative inflammatory vaginitis (DIV) with discharge from the perianal and vulvar skin. A physical examination showed edematous, lichenified plaques involving the labia majora and mons pubis (Fig. 3A). She was started on methotrexate (25 mg subcutaneous injection per week), with significant disease progression despite compliance and continued treatment with infliximab. The methotrexate was discontinued and the patient was treated with serial intralesional triamcinolone, weekly bleach baths, and topical treatments (clobetasol 0.05% ointment mixed with tacrolimus 0.1% ointment and metronidazole 1% cream), with short-term improvement.Fig. 3 (A) Edematous, lichenified plaques involving the labia majora and mons pubis with associated discharge, and (B) abscess of the left labium majus.\n\nShe subsequently developed an abscess of the left labium majus that grew MSSA on tissue culture (Fig. 3B). Fistulizing CD was excluded via magnetic resonance enterography. Her disease course was complicated by multiple MSSA and group A streptococcal infections. The patient had been treated with incision and drainage, intermittent courses of oral metronidazole, topical metronidazole cream mixed with clobetasol and tacrolimus, weekly bleach baths, and serial intralesional triamcinolone (1 ml of 20 mg/ml). Flaring was consistently noted with the discontinuation of oral metronidazole. Rising inflammatory markers, persistently elevated fecal calprotectin, and worsening gastrointestinal symptoms prompted a switch in therapy to ustekinumab. A nutritional assessment revealed a vitamin D deficiency, which was corrected with supplementation, resulting in significant improvement in DIV with decreased discharge, but no change in vulvar CD.\n\nDiscussion\n\nAs illustrated in our case series, the clinical presentation of vulvar CD can be highly variable, representing a diagnostic challenge. The diagnosis of vulvar CD should be considered when patients present with aphthous ulcerations, vulvar edema, lymphedema or lymphangiectasia, knife-cut ulcers, recurrent aphthous ulcerations, perianal tags or fistulae, and suppurative nodules (Table 2). Included in the differential of vulvar CD are other inflammatory and infectious processes as outlined in Table 1. Awareness of these imitating conditions should guide a thorough history, review of systems, and targeted physical and laboratory evaluation. The diagnosis of vulvar CD rests on a clinical–pathologic correlation; however, wide-ranging histological presentations of CD have been reported (Aberumand and Howard, 2017). Although noncaseating granulomas and chronic lymphocytic inflammation represent classic histopathologic features, they are identified in <50% of cases (Bhoyrul and Lyon, 2018). Intralymphatic granulomas with dilated lymphatic channels, edema, and epidermal change are suggestive of vulvar CD (Alexakis et al., 2017). Hidradenitis suppurativa can mimic vulvar CD both clinically and with histopathology. When present, suppurative granulomatous inflammation that predominantly affects the follicles, as well as keratin plugging, may point to hidradenitis suppurativa and help distinguish from MCD (Siroy and Wasman, 2012).Table 1 Differential diagnosis of vulvar Crohn disease and common imitatorsa.\n\nDifferential diagnosis of metastatic Crohn disease\t\nCategory\tSubtype\t\nInflammatory\tHidradenitis suppurativa\t\nPyoderma gangrenosum\t\nAtopic dermatitis\t\nPsoriasis\t\nSarcoidosis\t\nIrritant contact dermatitis\t\nAllergic contact dermatitis\t\nMedication reaction\t\nInfectious\tBacterial:Staphylococcus aureus\n\nStreptococcus\n\nChlamydia trachomatis\n\nNeisseria gonorrhoeae\n\nMycobacterium Tuberculosis\n\nSpirochete:Treponema pallidum\n\nViral:Herpes simplex virus\n\nHuman papilloma virus\n\nFungal:Candida\n\n\t\nNutritional\tZinc deficiency\t\nMalignant\tSquamous cell carcinoma\nPaget disease\nHigh-grade squamous intraepithelial lesions\nDifferentiated vulvar intraepithelial neoplasia\t\na Barret et al., 2014, Granese et al., 2018, Loftus, 2004.\n\nTable 2 Genital manifestations of Crohn disease.\n\nAphthous ulcerations\t\nEdema\t\nErosions\t\nErythema\t\nFissures\t\nLymphangiectasia\t\nLymphangioma\t\nLymphedema\t\nPerianal tags\t\nVerrucous, condyloma-like papules and plaques\t\nKnife-cut ulcerations\t\n\nVulvovaginal symptoms, including vulvar and vaginal discomfort, vaginal discharge, and vulvovaginal pain, are commonly reported in women with inflammatory bowel disease (IBD) and may correlate with intestinal disease severity in a subset of patients (Ona et al., 2020). Vaginitis requires vaginal microscopy and testing for sexually transmitted infections, such as Chlamydia trachomatis and Neisseria gonorrhoeae (Granese et al., 2018). Bacterial cultures, often with tissue culture, should be considered when fluctuant lesions do not improve. Patients frequently develop recurrent streptococcal cellulitis that goes unrecognized, resulting in worsening edema, lymphatic destruction, and lymphangiectasia. Imaging, specifically ultrasonography and magnetic resonance enterography, can also be helpful in identifying abscesses or fistulae (Moreno et al., 2019). Given the increased risk of squamous cell carcinoma in this population, biopsy tissue testing to exclude malignancy should not be delayed. However, repetitive biopsy testing of the genital skin can result in wounds that are challenging to heal in the setting of underlying lymphedema.\n\nEach of our patients developed recurrent Staphylococcus aureus infections that eventuated in cyclical worsening of their vulvar CD. Well-described in atopic dermatitis, cutaneous dysbiosis and the emergence of S. aureus as a dominant skin colonizer both predisposes to infection and modifies disease severity (Di Domenico et al., 2019, Paller et al., 2019). The host-vulvar microbiome may play a similar role in driving vulvar CD.\n\nStaphylococcal colonization may be the result of increased contact with the health care system because patients with CD are more than twice as likely to require emergency room and outpatient clinical visits, hospital admissions, and home health care assistance than the general population (Longobardi et al., 2004). Hospitalized patients with IBD have an increased risk of MRSA colonization compared with patients with non-IBD gastrointestinal disease and general medicine inpatients (Nguyen et al., 2010).\n\nS. aureus proliferation on the skin has been postulated to result from the prolonged use of immunosuppressive medications (Leung et al., 2012). More than two-thirds of patients with CD require corticosteroid treatment, and almost 15% of patients are treated with other immunomodulatory agents (Brown et al., 2014, Hutfless et al., 2007). An alteration of the vulvar microbiome by medication, inflammation, or immunosuppression may predispose to more severe vulvar CD.\n\nNutritional deficiencies are often overlooked but routinely described in patients with IBD (Weisshof and Chermesh, 2015). These deficiencies may result from malabsorption or immunosuppressive therapies (Molodecky et al., 2012). Vitamin D and zinc have emerged as particularly important in both intestinal and cutaneous function. Vitamin D has been shown to regulate the gastrointestinal microbiota, enhance barrier protection, and aid in antiinflammatory responses (Fletcher et al., 2019). Vitamin D is also known to upregulate antimicrobial peptides at the cutaneous surface and promote epithelial immunity (Wang et al., 2015). As such, children with a vitamin D deficiency or insufficiency are at an increased risk of recurrent S. aureus skin and soft tissue infections (Wang et al., 2015). Furthermore, vitamin D supplementation has been shown to reduce S. aureus skin colonization (Udompataikul et al., 2015).\n\nDesquamative inflammatory vaginitis is a poorly reported but well-known clinical entity associated with CD. DIV is a chronic condition characterized by vaginal discharge, burning, pruritus, and dyspareunia. DIV has been reported in association with CD and vitamin D deficiency and, in a case series of these patients, optimization of 25-hydroxyvitamin D to levels >50 ng/ml for a minimum of 12 weeks led to the complete resolution of DIV (Peacocke et al., 2010). Unfortunately, limited additional evidence exists in support of the use of vitamin D in the treatment of DIV. The vulvar and vaginal surfaces may require adequate vitamin D stores for normal function, which suggests that vitamin D replacement may be a beneficial adjunct to CD-associated vulvovaginal disease.\n\nAs exemplified in our series, the treatment of vulvar CD is often individualized. Clinical trials are lacking and therapeutic guidelines have not been established for children or adults (Aberumand and Howard, 2017, Guest and Fink, 2000, Hackzell-Bradley et al., 1996, Molodecky et al., 2012). Topical, intralesional, and oral corticosteroid treatments have exhibited a favorable response and are often used as first-line modalities (Aberumand and Howard, 2017, Chen et al., 1996, Hackzell-Bradley et al., 1996). Corticosteroid treatments are very helpful for limited periods of time, but prolonged use should be avoided to minimize side effects. Balancing the treatment of inflammation with the risk of immunosuppression and cutaneous infection in patients with IBD remains one of the challenges in therapy. Topical calcineurin inhibitors can serve as a nonsteroid alternative option for maintenance treatment (Sánchez et al., 2014). Superpotent topical corticosteroid agents may be used to gain disease control, followed by a transition to a topical calcineurin inhibitor as maintenance therapy. Intralesional triamcinolone can be very helpful for persistent inflammatory lesions and areas of edema.\n\nMultiple antibiotic drugs have been reported as adjunct therapies in the treatment of MCD. Oral metronidazole (10–20 mg/kg/day) has the best evidence and has been successful in treating MCD even after patients have failed on corticosteroid treatments (Duhra and Paul, 1988). Metronidazole has previously resulted in response rates of >87% when used alone or in combination with systemic corticosteroid treatments, but typically does not result in disease remission. Topical metronidazole may represent a safe alternative to oral therapy in patients who develop side effects. Tetracyclines, cephalexin, and ciprofloxacin have been used with mixed results (Guest and Fink, 2000, Kurtzman et al., 2014, Miller et al., 2001).\n\nUnfortunately, refractory disease is common and necessitates the addition of other antiinflammatory and immunosuppressive medications. Cyclosporine, azathioprine, methotrexate, mycophenolate mofetil, dapsone, and sulfasalazine have shown efficacy but lack consistency or long-term follow-up data (Aberumand and Howard, 2017). Infliximab, certolizumab, golimumab, and adalimumab have shown promising results in select patients and are often used as second- or third-line treatments in refractory disease (Aberumand and Howard, 2017, Boxhoorn et al., 2017, Kiuru et al., 2015, Miller et al., 2001). These treatments are ideally used in patients with active CD who may require tumor necrosis factor (TNF) inhibition for intestinal disease control simultaneously. Prior studies report a complete clearance of vulval CD in 53% of patients requiring TNF-alpha inhibition and partial clearance in 33% of patients (Bhoyrul and Lyon, 2018). As in our first and second cases, intestinal disease may be well controlled with a TNF-inhibitor, but vulvar CD may continue to flare, representing a further challenge to therapy. Ustekinumab binds the p40 subunit of interleukin-12/23 and mediates Th1 and Th17 signaling, and has recently emerged as beneficial in the treatment of both intestinal and metastatic CD (Phillips et al., 2020).\n\nOther rarely employed treatment modalities include hyperbaric oxygen, curettage with simultaneous oral zinc sulfate, mesalamine, and surgical debridement or excision (Aberumand and Howard, 2017). Importantly, the surgical removal of areas of the intestine affected by CD does not improve MCD elsewhere nor does the removal of metastatic lesions prevent future development (Cockburn et al., 1980, Ploysangam et al., 1997). Kurtzman et al. (2014) proposed the first therapeutic approach to MCD dependent on localization and the number of lesions present. Randomized controlled trials are ultimately needed to shed light on effective treatment modalities given the often asynchronous courses of skin and intestinal disease.\n\nConclusion\n\nAwareness of vulvar CD and common clinical mimickers and an approach to diagnosis and therapy are critical to the care of patients with CD. A multidisciplinary management model should be employed in refractory cases. Infections can complicate vulvar CD; thus, cultures should be considered routinely with a low threshold for imaging to exclude abscesses or fistulae. The evaluation and treatment of nutritional deficiencies may serve as an adjunct to therapy. Treatment should be individualized to ensure optimization of both intestinal and cutaneous disease and improve patient quality of life.\n\nConflicts of Interest\n\nNone.\n\nFunding\n\nNone.\n\nStudy Approval\n\nThe author(s) confirm that any aspect of the work covered in this manuscript that has involved human patients has been conducted with the ethical approval of all relevant bodies.\n==== Refs\nReferences\n\nAberumand B. Howard J. Metastatic Crohn's disease: an approach to an uncommon but important cutaneous disorder Biomed Res Int 2017 2017 8192150 28127561\nAlbuquerque A. Magro F. Rodrigues S. Lopes J. Lopes S. Dias J.M. Metastatic cutaneous Crohn's disease of the face: A case report and review of the literature Eur J Gastroenterol Hepatol 23 10 2011 954 956 21900789\nAlexakis C. Gordon K. Mellor R. Chong H. Mortimer P. Pollok R. Ano-genital granulomatosis and Crohn's disease: A case series of males presenting with genital lymphoedema J Crohns Colitis 11 4 2017 454 459 27683802\nAndreani S.M. Ratnasingham K. Dang H.H. Gravante G. Giordano P. Crohn's disease of the vulva Int J Surg 8 1 2010 2 5 19800432\nBarret M. de Parades V. Battistella M. Sokol H. Lemarchand N. Marteau P. Crohn's disease of the vulva J Crohn's Colitis 8 7 2014 563 570 24252167\nBhoyrul B. Lyon C. Crohn’s disease of the vulva: a prospective study J Gastroenterol Hepatol 33 12 2018 1969 1974 29845642\nBoxhoorn L. Stoof T.J. de Meij T. Hoentjen F. Oldenburg B. Bouma G. Clinical experience and diagnostic algorithm of vulval Crohn’s disease Eur J Gastroenterol Hepatol 29 7 2017 838 843 28430699\nBrown A.F. Leech J.M. Rogers T.R. McLoughlin R.M. Staphylococcus aureus colonization: Modulation of host immune response and impact on human vaccine design Front Immunol 4 2014 507 24409186\nBurgdorf W. Cutaneous manifestations of Crohn's disease J Am Acad Dermatol 5 6 1981 689 695 6459345\nChen W. Blume-Peytavi U. Goerdt S. Orfanos C.E. Metastatic Crohn's disease of the face J Am Acad Dermatol 35 6 1996 986 988 8959961\nCockburn A.G. Krolikowski J. Balogh K. Roth R.A. Crohn disease of penile and scrotal skin Urology 15 6 1980 596 598 7394990\nDi Domenico E.G. Cavallo I. Capitanio B. Ascenzioni F. Pimpinelli F. Morrone A. Staphylococcus aureus and the cutaneous microbiota biofilms in the pathogenesis of atopic dermatitis Microorganisms 7 9 2019 301\nDuhra P. Paul C.J. Metastatic Crohn's disease responding to metronidazole Br J Dermatol 119 1 1988 87 91 3408668\nFarhi D. Duriez P. Aractingi S. Cosnes J. Khosrotehrani K. Misleading pustular plaques of the lower limbs during Crohn's disease: two case reports J Med Case Rep 1 2007 109 17910771\nFletcher J. Cooper S.C. Ghosh S. Hewison M. The role of vitamin D in inflammatory bowel disease: Mechanism to management Nutrients 11 5 2019\nGranese R. Calagna G. Morabito G. Carriero C. Perino A. Tonni G. Romano C. Vulvar involvement in pediatric Crohn’s disease: a systematic review Arch Gynecol Obstet 297 1 2018 3 11 28948431\nGuest G.D. Fink R.L. Metastatic Crohn's disease: case report of an unusual variant and review of the literature Dis Colon Rectum 43 12 2000 1764 1766 11156465\nHackzell-Bradley M. Hedblad M.A. Stephansson E.A. Metastatic Crohn's disease. Report of 3 cases with special reference to histopathologic findings Arch Dermatol 132 8 1996 928 932 8712843\nHutfless S.M. Weng X. Liu L. Allison J. Herrinton L.J. Mortality by medication use among patients with inflammatory bowel disease, 1996–2003 Gastroenterology 133 6 2007 1779 1786 18054550\nKesterson J.P. South S. Lele S. Squamous cell carcinoma of the vulva in a young woman with Crohn's disease Eur J Gynaecol Oncol 29 6 2008 651 652 19115698\nKiuru M. Camp B. Adhami K. Jacob V. Magro C. Wildman H. Treatment of metastatic cutaneous Crohn disease with certolizumab Dermatol Online J 21 11 2015\nKurtzman D.J.B. Jones T. Lian F. Peng L.S. Metastatic Crohn's disease: a review and approach to therapy J Am Acad Dermatol 71 4 2014 804 813 24888520\nLaftah Z. Bailey C. Zaheri S. Setterfield J. Fuller L.C. Lewis F. Vulval Crohn's Disease: a clinical study of 22 patients J Crohns Colitis 9 4 2015 318 325 25687208\nLeu S. Sun P.K. Collyer J. Smidt A. Stika C.S. Schlosser B. Clinical spectrum of vulva metastatic Crohn's disease Dig Dis Sci 54 7 2009 1565 1571 19421856\nLeung W. Malhi G. Willey B.M. McGeer A.J. Borgundvaag B. Thanabalan R. Prevalence and predictors of MRSA, ESBL, and VRE colonization in the ambulatory IBD population J Crohns Colitis 6 7 2012 743 749 22398097\nLoftus E.V. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences Gastroenterology 126 6 2004 1504 1517 15168363\nLongobardi T. Jacobs P. Bernstein C.N. Utilization of health care resources by individuals with inflammatory bowel disease in the United States: a profile of time since diagnosis Am J Gastroenterol 99 4 2004 650 655 15089897\nMarotta P.J. Reynolds R.P. Metastatic Crohn's disease Am J Gastroenterol 91 2 1996 373 375 8607510\nMiller A.M. Elliott P.R. Fink R. Connell W. Rapid response of severe refractory metastatic Crohn's disease to infliximab J Gastroenterol Hepatol 16 8 2001 940 942 11555113\nMolodecky N.A. Soon I.S. Rabi D.M. Ghali W.A. Ferris M. Chernoff G. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review Gastroenterology 142 1 2012 46–54.e42; quiz e30\nMoreno A.C. Goje O. Piliang M.P. Batur P. Vulvar and gluteal manifestations of Crohn disease Cleve Clin J Med 86 10 2019 645 646 31597081\nNguyen G.C. Patel H. Chong R.Y. Increased prevalence of and associated mortality with methicillin-resistant Staphylococcus aureus among hospitalized IBD patients Am J Gastroenterol 105 2 2010 371 377 19809406\nNúñez E.C. Peñaranda J.M. Alonso M.S. Ortiz-Rey J.A. Acquired vulvar lymphangioma: a case series with emphasis on expanding clinical contexts Int J Gynecol Pathol 33 3 2014 235 240 24681732\nOna S. James K. Ananthakrishnan A.N. Long M.D. Martin C. Chen W. Association between vulvovaginal discomfort and activity of inflammatory bowel diseases Clin Gastroenterol Hepatol 18 3 2020 604–11.e1\nPaller A.S. Kong H.H. Seed P. Naik S. Scharschmidt T.C. Gallo R.L. The microbiome in patients with atopic dermatitis J Allergy Clin Immunol 143 1 2019 26 35 30476499\nPapalas JA, Robboy SJ, Burchette JL, Foo WC, Selim MA. Acquired vulvar lymphangioma circumscriptum: A comparison of 12 cases with Crohn's associated lesions or radiation therapy induced tumors. J Cutan Pathol 2010;37(9):958–65.\nPeacocke M. Djurkinak E. Tsou H.C. Thys-Jacobs S. Desquamative inflammatory vaginitis as a manifestation of vitamin D deficiency associated with Crohn disease: case reports and review of the literature Cutis 86 1 2010 39 46 21049766\nPhillips F.M. Verstockt B. Sebastian S. Ribaldone D.G. Vavricka S. Katsanos K. Inflammatory cutaneous lesions in inflammatory bowel disease treated with vedolizumab or ustekinumab: an ECCO CONFER multicentre case series J Crohns Colitis 2020 [Epub ahead of publication]\nPloysangam T. Heubi J.E. Eisen D. Balistreri W.F. Lucky A.W. Cutaneous Crohn's disease in children J Am Acad Dermatol 36 5 Pt 1 1997 697 704 9146530\nSiroy A. Wasman J. Metastatic Crohn disease: a rare cutaneous entity Arch Pathol Lab Med 136 3 2012 329 332 22372910\nSánchez L. Cabanillas M. Alvarez J.C. Echarri A. Topical tacrolimus for recurrent penile Crohn's disease J Crohns Colitis 8 10 2014 1145 1146 24815787\nUdompataikul M. Huajai S. Chalermchai T. Taweechotipatr M. Kamanamool N. The effects of oral vitamin D supplement on atopic dermatitis: a clinical trial with Staphylococcus aureus colonization determination J Med Assoc Thai 98 Suppl 9 2015 S23 S30\nvan Loo E.S. Dijkstra G. Ploeg R.J. Nieuwenhuijs V.B. Prevention of postoperative recurrence of Crohn's disease J Crohns Colitis 6 6 2012 637 646 22398096\nWang J.W. Hogan P.G. Hunstad D.A. Fritz S.A. Vitamin D sufficiency and Staphylococcus aureus infection in children Pediatr Infect Dis J 34 5 2015 544 545 25860535\nWeisshof R. Chermesh I. Micronutrient deficiencies in inflammatory bowel disease Curr Opin Clin Nutr Metab Care 18 6 2015 576 581 26418823\nZhang A.-J. Zhan S.-H. Chang H. Gao Y.-Q. Li Y.-Q. Crohn Disease of the Vulva without Gastrointestinal Manifestations in a 16-Year-Old Girl J Cutan Med Surg 19 1 2015 81 83 25775670\n\n",
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"journal": "International journal of women's dermatology",
"keywords": "Anogenital granulomatosis; Inflammatory bowel disease; Metastatic Crohn disease; Vulvar Crohn disease",
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"title": "Vulvar Crohn disease: Diagnostic challenges and approach to therapy.",
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"abstract": "While thrombotic microangiopathy (TMA) can commonly affect the kidney, peripheral nerve involvement has not been reported to date. A 56-year-old man, recipient of a kidney allograft, reported severe headaches, tremors, and diarrhea followed by sudden-onset right foot drop after increasing his dose of tacrolimus. He then developed acute right hand pain, numbness, and weakness. At presentation, neurological examination and electroneuromyography confirmed the presence of right worse than left, sciatic and ulnar mononeuropathies. Kidney biopsy showed evidence of a thrombotic microangiopathy. Similarly, nerve biopsy showed thrombosis of epineurial blood vessels with minimal inflammation. Herein, we demonstrated that thrombotic microangiopathy can involve the peripheral nerves, resulting in major morbidity. Distinguishing TMA from vasculitis is important because it has major treatment implications.",
"affiliations": "Department of Neurology, Mayo Clinic, Rochester, Minnesota.;Department of Neurology, Mayo Clinic, Rochester, Minnesota.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.;Division of Nephrology and Hypertension, and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota.",
"authors": "Naddaf|Elie|E|0000-0001-6212-1236;James B Dyck|P|P|;Said|Samar|S|;Amer|Hatem|H|",
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"issue": "20(5)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research/practice; kidney transplantation/nephrology; kidney transplantation: living donor; neurology; rejection: vascular; thrombosis and thromboembolism",
"medline_ta": "Am J Transplant",
"mesh_terms": "D064591:Allografts; D006801:Humans; D007668:Kidney; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010525:Peripheral Nerves; D057049:Thrombotic Microangiopathies",
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"publication_types": "D002363:Case Reports",
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"title": "Thrombotic microangiopathy involving kidney allograft and peripheral nerves.",
"title_normalized": "thrombotic microangiopathy involving kidney allograft and peripheral nerves"
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"abstract": "BACKGROUND Hemorrhagic cholecystitis is a rare disease which can be fatal in some cases. Hemorrhagic cholecystitis can sometimes be confused with common biliary diagnoses, as its symptoms imitate other hepatobiliary diseases. We report a case of hemorrhagic cholecystitis with hemobilia caused by the administration of anticoagulant agents. CASE REPORT A 70-year-old man was admitted with abdominal distention and pain. Ultrasound (US) and computed tomography (CT) showed a distended and wall-thickened gallbladder with hyperdense materials. Based on these findings and the laboratory data, the patient was diagnosed with acute cholecystitis with cholangitis. Because the patient's hemodynamics were stable, endoscopic retrograde cholangiopancreatography (ERCP) was performed first to improve the bile flow. The results of ERCP showed blood from the common bile duct by cannulation, which was suspected to reflect hemorrhagic cholecystitis. As the abdominal symptom and CT findings worsened on the day after ERCP, emergency laparoscopic cholecystectomy was performed. An examination of the specimen revealed ulcer formation on the mucosal side of the gallbladder. The patient was discharged 6 days after the operation without any surgical complications. CONCLUSIONS ERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia. Early diagnosis and treatment can lead to good outcomes in patients with hemorrhagic cholecystitis. Since the number of patients who are taking antithrombotic agents is increasing, hemorrhagic cholecystitis should be considered when any unusual imaging findings associated with cholecystitis are observed.",
"affiliations": "Department of Surgery, Baba Memorial Hospital, Sakai City, Osaka, Japan.;Department of Surgery, Baba Memorial Hospital, Sakai City, Osaka, Japan.;Department of Surgery, Baba Memorial Hospital, Sakai City, Osaka, Japan.;Department of Surgery, Baba Memorial Hospital, Sakai City, Osaka, Japan.;Department of Gastroenterology, Baba Memorial Hospital, Sakai City, Osaka, Japan.;Department of Gastroenterology, Baba Memorial Hospital, Sakai City, Osaka, Japan.;Department of Surgery, Baba Memorial Hospital, Sakai City, Osaka, Japan.",
"authors": "Hasegawa|Tsuyoshi|T|;Sakuma|Takashi|T|;Kinoshita|Haruhito|H|;Nakagawa|Yasuo|Y|;Kawachiya|Tomohiro|T|;Hara|Junichi|J|;Teraoka|Hitoshi|H|",
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"doi": "10.12659/AJCR.927849",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n33419958\n10.12659/AJCR.927849\n927849\nArticles\nA Case of Hemorrhagic Cholecystitis and Hemobilia Under Anticoagulation Therapy\nHasegawa Tsuyoshi ABCDEFG1 Sakuma Takashi F1 Kinoshita Haruhito A1 Nakagawa Yasuo F1 Kawachiya Tomohiro F2 Hara Junichi F2 Teraoka Hitoshi ADFG1 \n1 Department of Surgery, Baba Memorial Hospital, Sakai City, Osaka, Japan\n\n2 Department of Gastroenterology, Baba Memorial Hospital, Sakai City, Osaka, Japan\nCorresponding Author: Tsuyoshi Hasegawa, e-mail: gdhfm399@yahoo.co.jpAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2021 \n09 1 2021 \n22 e927849-1 e927849-6\n05 8 2020 04 11 2020 18 11 2020 © Am J Case Rep, 20212021This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 70-year-old\n\nFinal Diagnosis: Hemobilia • hemorrhagic cholecystitis\n\nSymptoms: Abdominal distension • abdominal pain\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Gastroenterology and Hepatology\n\nObjective:\nRare disease\n\nBackground:\nHemorrhagic cholecystitis is a rare disease which can be fatal in some cases. Hemorrhagic cholecystitis can sometimes be confused with common biliary diagnoses, as its symptoms imitate other hepatobiliary diseases. We report a case of hemorrhagic cholecystitis with hemobilia caused by the administration of anticoagulant agents.\n\nCase Report:\nA 70-year-old man was admitted with abdominal distention and pain. Ultrasound (US) and computed tomography (CT) showed a distended and wall-thickened gallbladder with hyperdense materials. Based on these findings and the laboratory data, the patient was diagnosed with acute cholecystitis with cholangitis. Because the patient’s hemodynamics were stable, endoscopic retrograde cholangiopancreatography (ERCP) was performed first to improve the bile flow. The results of ERCP showed blood from the common bile duct by cannulation, which was suspected to reflect hemorrhagic cholecystitis. As the abdominal symptom and CT findings worsened on the day after ERCP, emergency laparoscopic cholecystectomy was performed. An examination of the specimen revealed ulcer formation on the mucosal side of the gallbladder. The patient was discharged 6 days after the operation without any surgical complications.\n\nConclusions:\nERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia. Early diagnosis and treatment can lead to good outcomes in patients with hemorrhagic cholecystitis. Since the number of patients who are taking antithrombotic agents is increasing, hemorrhagic cholecystitis should be considered when any unusual imaging findings associated with cholecystitis are observed.\n\nMeSH Keywords:\nCholecystectomy, LaparoscopicCholecystitisHemobilia\n==== Body\nBackground\nHemorrhagic cholecystitis is a specific condition of acute cholecystitis and is potentially fatal [1]. Hemorrhage in the gallbladder may be caused by various reasons, including trauma, iatrogenic causes, cancer, and bleeding disorders. In many cases, symptoms of hemorrhagic cholecystitis, which include right upper-quadrant pain, fever, and increasing leukocytes, resemble those of calculous cholecystitis. Hemorrhagic cholecystitis may be hard to detect because it frequently shows symptoms that similar to other common diagnoses. Imaging can reveal the characteristic findings to help diagnose this rare disease. An early diagnosis can lead to good treatment outcomes. We herein describe a case of hemorrhagic cholecystitis with hemobilia due to bleeding from the gallbladder, performed with early laparoscopic cholecystectomy.\n\nCase Report\nA 70-year-old man with a 7-h history of abdominal distension, pain, and nausea was admitted to our hospital. His past medical history included lumbar disc herniation, congestive heart failure, old myocardial infarction, and thrombosis in the left ventricle. He had been taking warfarin (3.0 mg) and aspirin (100 mg). Clopidogrel (75 mg) was started under the suspicion of angina pectoris, 3 weeks prior to his admission, and treatment at the Cardiology Department of our hospital had been planned. At presentation, he was afebrile, with blood pressure 131/84 mmHg and pulse 117 beats/min. An abdominal examination revealed a soft and flat abdomen; tenderness was present over the right upper quadrant, without any involuntary guarding or rebound tenderness. He had no change in bowel movements and no melena. The laboratory findings at the time of presentation were: white blood cell count, 13 000/uL; hemoglobin, 15.1 g/dL; platelet count, 19 5000/uL; total bilirubin, 2.3 mg/dL; aspartate aminotransferase, 1481 IU/L; alanine aminotransferase, 988 IU/L; alkaline phosphatase, 1058 IU/L; gamma-glutamyltranspeptidase, 315 IU/L; C-reactive protein, 0.96 mg/dL; and activated partial thromboplastin time, 34.8 s. Two days before he came to our hospital, his international normalized ratio (INR) was 2.41. Cholangitis was suspected based on these laboratory data, and acute cholecystitis was confirmed with computed tomography (CT) of the abdomen. It showed a distended, edematous gallbladder containing hyperdense material, suggestive of blood. There was no dilatation at the common or intrahepatic bile ducts. Ascites was not detected in the abdominal cavity (Figure 1A, 1B). Ultrasound (US) showed a slightly distended gallbladder with wall-thickening, gallstones, and mass-like debris without shadowing, which suggested the possibility of pus or hemorrhage (Figure 1C). Due to jaundice, suspected cholangitis, and stable hemodynamics, endoscopic retrograde cholangiopancreatography (ERCP) was performed. Fresh blood was observed on the duodenal papilla. After cannulation of the bile duct, the flow of old blood from the mammary papilla was recognized (Figure 2A, 2B). On cholangiography, numerous defects in the common bile duct were noticed and the common bile duct seemed to be filled with clots (Figure 2C). The hemobilia was initially improved, and an endoscopic retrograde biliary drainage (ERBD) tube was placed.\n\nOn the next day of admission, contrast CT was performed, as an abdominal physical examination showed the appearance of peritoneal irritation at the right upper quadrant. The contrast-enhanced phase revealed extravasation of contrast medium into the gallbladder lumen (Figure 3A). CT demonstrated the appearance of fluid accumulation in the Morrison fossa (Figure 3B). Since the abdominal symptoms and CT findings were exacerbated, emergency laparoscopic cholecystectomy was performed, showing a distended edematous gallbladder with a small amount of hemorrhagic ascites. Subtotal cholecystectomy was conducted under laparoscopy, and a “C-tube” was placed into the common bile duct through the cystic duct. The sample showed that the gallbladder was filled with dark blood, clots, and gallstones (Figure 4). A pathological examination of the specimen confirmed hemorrhaging, acute inflammation, and the formation of an ulcer on the mucosal side of the gallbladder. There was a muscular artery on the bottom of the ulcer, which might have been broken due to inflammation. No malignancy was detected. The postoperative course was uneventful. Anticoagulation therapy was successfully restarted on postoperative day 2. The C-tube was removed on postoperative day 3. He was discharged without any complications 6 days after the procedure.\n\nDiscussion\nHemorrhagic cholecystitis with hemobilia is a rare disease associated with high rates of morbidity and mortality if perforation or necrosis occurs [1]. Sandblom published the first report of bleeding from the hepatobiliary system as hemobilia in 1948 [2]. Shah and Clegg first reported hemobilia caused by cholecystitis as hemorrhagic cholecystitis in 1979 [3]. Iatrogenic and non-iatrogenic factors can cause bleeding from the gall-bladder. The non-iatrogenic causes of hemobilia include trauma, malignancy, administration anticoagulants, and bleeding associated with renal failure or cirrhosis [1].\n\nCholelithiasis might be associated with microbleeding from the gallbladder, which results in injuries to the mucosa and vessel walls. Furthermore, it is thought that high pressure in the gallbladder due to acute cholecystitis can lead to bleeding because of damage to the mucosa and vessel walls [4–6]. Gremmels et al. [7] described pathological findings of acute cholecystitis, showing that intramural inflammation led to erosion of the mucosa, infarction, and ischemia. The mucosal breakdown may cause bleeding into the gallbladder, and the intraluminal effusions and debris may mix with blood [7]. In our case, the specimen showed the formation of an ulcer on the mucosal side of the gallbladder, which might have caused the bleeding. No specific bleeding disorder was observed; however, he was taking 3 antithrombotic agents. Although he had been taking 2 antithrombotic drugs for a long time, acute hemorrhagic cholecystitis occurred 3 weeks after an additional anti-thrombotic drug was started. PT-INR were prolonged at admission. Gallbladder stone and antithrombotic drugs might play an important role in development of this disease. Without anticoagulant therapy, mucosal ulcers caused by gallbladder stones may heal quickly, but they will not heal while an anticoagulant drug is being taken. That causes continuous bleeding, which results in acute hemorrhagic cholecystitis. Cholecystolithiasis and the oral administration of antithrombotic agents seemed to both be associated with the bleeding in the present case.\n\nThe characteristic symptoms of hemobilia are abdominal pain, jaundice, and gastrointestinal bleeding through the common bile duct [8]. As these symptoms resemble those of common hepatobiliary diseases (right upper-quadrant pain, a Murphy sign, and leukocytosis), hemorrhagic cholecystitis can be easily missed by both physical and laboratory examinations [9]. History taking, a physical examination, laboratory findings, and imaging are important for the initiation of appropriate treatment of hemorrhagic cholecystitis. Although the physical and laboratory findings are similar to those for calculous acute cholecystitis, it is crucial to assess the patients’ history and investigate the administration of anticoagulants. Imaging findings can help in the diagnosis and demonstrate the characteristic findings of wall thickening of the distended gall-bladder and heterogeneous materials inside. US findings can show gallbladder distension with wall thickening, and heterogeneous echogenic materials. Blood is visualized as hyper-echoic, non-shadowing, non-mobile intraluminal materials in the gallbladder lumen [10]. CT can show the same findings as US. Furthermore, Pandya and O’Malley emphasized the value of the arterial phase of contrast-enhanced CT, which can indicate active extravasation of contrast into the gallbladder [11].\n\nMany cases of hemorrhagic cholecystitis require endoscopic treatment, radiologic intervention, or surgery [12]. ERCP plays an important role in the treatment of hemobilia. As clots from a bleeding gallbladder may also cause common bile duct obstruction and jaundice, removing them in the common bile duct could lead to an improvement in bile flow [13]. Bleeding from the papilla of Vater is recognized in 30% of patients with hemorrhage cholecystitis when ERCP is performed [14]. Regardless of cause, the treatment for cholecystitis should follow the Tokyo Guideline 2018 (TG2018) [15]. TG2018 states that cholecystectomy is a definitive treatment for cholecystitis, while a percutaneous cholecystostomy can be performed for acute management bridging to surgery in patients with significant comorbidities [16]. However, strategies for treatment should be carefully selected. There was a case report of 1 case that underwent urgent cholecystostomy under anticoagulant therapy; unfortunately, the hyperdense contents increased within the gallbladder and CBD on follow-up CT [11]. Thus, cholecystostomy should be considered an option for preventing the need for surgery or as a bridge to surgery. TG2018 recommends early laparoscopic cholecystectomy for cholecystitis in patients without significant comorbidities, because laparoscopic surgery is becoming safer due to the development of techniques and devices. Laparoscopic cholecystectomy for patients receiving antithrombotic therapy has been controversial. However, there are a few reports of the safe performance of laparoscopic surgery for patients under antithrombotic therapy [17]. Thus, urgent surgical management, which is now recommended early in laparoscopic cholecystectomy, should be considered, according to surgeon experience, in order to prevent more serious complications [9,15]. In our case, as laboratory data showed suspected cholangitis and the patient’s hemodynamics were stable after he was admitted to our hospital, so ERCP was performed first in order to improve the flow of bile. The detection of blood in the biliary tract can reveal hemorrhagic cholecystitis. An emergency operation was performed because perforation was suspected based on the appearance of ascites and the worsening of abdominal symptoms on the following day.\n\nConclusions\nERCP and early laparoscopic cholecystectomy were performed for a patient with hemorrhagic cholecystitis and hemobilia who was receiving antithrombotic agents. Early diagnosis and treatment are the most important aspects in the management of hemorrhagic cholecystitis, and can lead to good outcomes. Since large numbers of patients are treated with various antithrombotic agents, hemorrhagic cholecystitis should be considered when unusual presentations of cholecystitis are encountered.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Imaging findings of abdomen at admission. (A, B) Non-contrast CT showed hyperdense materials in the wall-thickening gallbladder (arrow) and no ascites. (C) The abdominal ultrasound demonstrated distended gallbladder with stones, echogenic materials, and a thickened wall.\n\nFigure 2. Results of ERCP. (A) Duodenoscopy showed blood around the duodenal papilla. (B) Cannulation led to the flow of old blood and clots from the common bile duct. (C) On cholangiography, many defects were observed in the common bile duct (arrowheads).\n\nFigure 3. Contrast CT scan: An arterial-phase contrast CT scan revealed extravasation (arrow) into the gallbladder lumen (A) and fluid accumulation on the Morison fossa (circle) (B).\n\nFigure 4. Photo of the gallbladder specimen showing dark blood, clots, and gallstones in the gallbladder. The ulcer (arrow) is formed on the mucosal side.\n==== Refs\nReferences:\n1. Parekh J Corvera CU Hemorrhagic cholecystitis Arch Surg 2010 145 2 202 4 20157090 \n2. Sandblom P Hemorrhage into the biliary tract following trauma; traumatic hemobilia Surgery 1948 24 3 571 86 18884132 \n3. Shah VR Clegg JF Haemorrhagic cholecystitis Br J Surg 1979 66 6 404 5 466021 \n4. Bloechle C Izbicki JR Rashed MY Hemobilia: Presentation, diagnosis, and management Am J Gastroenterol 1994 89 9 1537 40 8079933 \n5. Willemsen PJ Vanderveken ML De Caluwe DO Tielliu IF Hemobilia: A rare complication of cholecystitis and cholecystolithiasis. Case report Acta Chir Belg 1996 96 2 93 94 8686409 \n6. Brady E Welch JP Acute hemorrhagic cholecystitis causing hemobilia and colonic necrosis Dis Colon Rectum 1985 28 3 185 87 3971827 \n7. Gremmels JM Kruskal JB Parangi S Kane RA Hemorrhagic cholecystitis simulating gallbladder carcinoma J Ultrasound Med 2004 23 7 993 95 15292572 \n8. Grove WJ Biliary tract hemorrhage as a cause of hematemesis Arch Surg 1961 83 67 72 13709151 \n9. Kwon JN Hemorrhagic cholecystitis: Report of a case Korean J Hepatobiliary Pancreat Surg 2012 16 3 120 22 26388920 \n10. Chinn DH Miller EI Piper N Hemorrhagic cholecystitis. Sonographic appearance and clinical presentation J Ultrasound Med 1987 6 6 313 17 3302297 \n11. Pandya R O’Malley C Hemorrhagic cholecystitis as a complication of anticoagulant therapy: role of CT in its diagnosis Abdom Imaging 2008 33 6 652 53 18629579 \n12. Kim KH Kim TN Etiology, clinical features, and endoscopic management of hemobilia: A retrospective analysis of 37 cases Korean J Gastroenterol 2012 59 4 296 302 22544027 \n13. Shishida M Ikeda M Karakuchi N Hemorrhagic cholecystitis in a patient on maintenance dialysis Case Rep Gastroenterol 2017 11 2 488 93 29033767 \n14. Shin KY Heo J Kim JY A case of hemocholecyst associated with hemobilia following radiofrequency ablation therapy for hepatocellular carcinoma Korean J Hepatol 2011 17 2 148 51 21757986 \n15. Miura F Okamoto K Takada T Tokyo Guidelines 2018: initial management of acute biliary infection and flowchart for acute cholangitis J Hepatobiliary Pancreat Sci 2018 25 1 31 40 28941329 \n16. Reens D Podgorski B Hemorrhagic cholecystitis: A case of expedited diagnosis by point-of-care ultrasound in the Emergency Department J Emerg Med 2019 57 1 74 76 31000429 \n17. Imamura H Minami S Isagawa Y The impact of antithrombotic therapy in patients undergoing emergency laparoscopic cholecystectomy for acute cholecystitis – a single center experience Asian J Endosc Surg 2020 13 3 359 65 31430063\n\n",
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"abstract": "The authors present the first case of a Cushing ulcer in an infant with medulloblastoma who, despite being administered stress ulcer prophylaxis, worsened after corticosteroids were initiated. An 8-month-old boy presented with progressive vomiting, lethargy, and decreased oral intake. Imaging revealed a heterogeneous fourth ventricular mass. Preoperatively, the patient was started on dexamethasone. The patient underwent an uncomplicated external ventricular drain placement and suboccipital craniotomy for resection of the lesion. The results of the pathological analysis were consistent with medulloblastoma. Postoperatively, the patient had melanotic stools, which were reported to be occurring for months prior to presentation. Two proximal duodenal bulb ulcers were found and required definitive surgical repair. The patient recovered from the acute postsurgical course after continued stress ulcer prophylaxis and is currently undergoing chemotherapy.",
"affiliations": "1 Department of Neurosurgery, Division of Pediatric Neurosurgery, 2 Department of Surgery, Division of Pediatric Surgery, Primary Children's Hospital, University of Utah, Salt Lake City, Utah, USA.;1 Department of Neurosurgery, Division of Pediatric Neurosurgery, 2 Department of Surgery, Division of Pediatric Surgery, Primary Children's Hospital, University of Utah, Salt Lake City, Utah, USA.;1 Department of Neurosurgery, Division of Pediatric Neurosurgery, 2 Department of Surgery, Division of Pediatric Surgery, Primary Children's Hospital, University of Utah, Salt Lake City, Utah, USA.;1 Department of Neurosurgery, Division of Pediatric Neurosurgery, 2 Department of Surgery, Division of Pediatric Surgery, Primary Children's Hospital, University of Utah, Salt Lake City, Utah, USA.",
"authors": "Sivakumar|Walavan|W|;Spader|Heather S|HS|;Scaife|Eric|E|;Bollo|Robert J|RJ|",
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"title": "A case of Cushing ulcer in an 8-month-old patient with medulloblastoma.",
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"abstract": "Adrenal insufficiency (AI) is a potential immune-related adverse event (irAE) of immunotherapy (e.g., checkpoint inhibitor). If not identified and treated promptly, AI can be life-threatening. Unlike other irAEs, AI may be irreversible, requiring long-term glucocorticoid and mineralocorticoid replacement. Provider and patient education are essential in the management of immune checkpoint inhibitor-induced AI.",
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"abstract": "Giant cell interstitial pneumonia (GIP) is a rare form of chronic interstitial pneumonia typically associated with hard metal exposure. Only two cases of GIP induced by nitrofurantoin have been reported in the medical literature. We are reporting a case of recurrent nitrofurantoin-induced GIP. Although extremely rare, GIP needs to be included in the differential diagnosis in patients with chronic nitrofurantoin use who present with respiratory illness.",
"affiliations": "Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA, USA.;Department of Internal Medicine, Saint Joseph Hospital, Presence Health, Chicago, IL, USA.;Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.;Department of Internal Medicine, Saint Joseph Hospital, Presence Health, Chicago, IL, USA.",
"authors": "Lee|Boeun|B|;Balavenkataraman|Arvind|A|;Sanghavi|Devang|D|;Walter|Kristin|K|",
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"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(15)00003-910.1016/j.rmcr.2015.01.002Case ReportRecurrent nitrofurantoin-induced giant cell interstitial pneumonia: Case report and literature review Lee Boeun Blee4@tuftsmedicalcenter.orga∗Balavenkataraman Arvind bSanghavi Devang cWalter Kristin ba Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA, USAb Department of Internal Medicine, Saint Joseph Hospital, Presence Health, Chicago, IL, USAc Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA∗ Corresponding author. 800 Washington Street, Tufts Medical Center, Boston, MA 02111, USA. Tel.: +1 6176365000; fax: +1 6176361580. Blee4@tuftsmedicalcenter.org29 1 2015 2015 29 1 2015 14 49 52 © 2015 The Authors2015This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Giant cell interstitial pneumonia (GIP) is a rare form of chronic interstitial pneumonia typically associated with hard metal exposure. Only two cases of GIP induced by nitrofurantoin have been reported in the medical literature. We are reporting a case of recurrent nitrofurantoin-induced GIP. Although extremely rare, GIP needs to be included in the differential diagnosis in patients with chronic nitrofurantoin use who present with respiratory illness.\n\nKeywords\nGiant cellsNitrofurantoinLung toxicityInterstitial pneumoniaMetals\n==== Body\nCase report\nA 76-year old Caucasian priest with hypothyroidism and recurrent urinary tract infections (UTIs) presented to our hospital in 2010 with shortness of breath, a non-productive cough and right-sided pleuritic chest pain of a few weeks duration. He had a 78 pack-year history of tobacco use, but quit in 1986. He had no prior history of asthma, COPD, pneumonia or interstitial lung disease. At baseline, he was very active and had no limitation to exercise. Upon presentation to the hospital, he was experiencing shortness of breath with minimal exertion and reported a 40-pound weight loss and dysphagia. He reported no fevers, chills, wheezing, palpitations, or joint pain. His medications included levothyroxine, calcium, and nitrofurantoin which he had taken daily for approximately 15 years for suppression of UTIs. He had no history of exposure to heavy metals or asbestos. He had a negative PPD test in the 1960's and had no known exposure to tuberculosis.\n\nOn physical examination, the patient appeared uncomfortable with moderate respiratory distress. Blood pressure was 110/65 mm Hg, heart rate was 85 beats per minute, temperature 97.3 F. He was tachypneic with respiratory rate at 30 breaths per minute and oxygen saturation of 93% at rest on room air. He had diminished breath sounds bilaterally with dry crackles, more prominent on the right side. Laboratory studies revealed a normal white blood cell count of 8.4 × 109/L (reference range: 4.4–5.7 × 109/L) with a normal differential. The chemistry panel was also within normal range. Erythrocyte sedimentation rate was over 140 mm/h (normal range: 1–15 mm/h for men). ANA screen was positive, but all other serologies for rheumatologic disorders were negative, including anti-double stranded DNA, Rheumatoid Factor, Scl-70, anti-centromere B, anti-Jo, anti-ribosomal P, anti-RNP, anti-Sm, anti-SS/A and SS/b and ACE level. Testing for HIV 1&2 and Quantiferon TB Gold was negative. CXR showed extensive basilar fibrosis, pleural thickening and possible basilar infiltrates (Fig. 1). Chest computed tomography (CT) scan with intravenous contrast showed severe fibrotic changes in both lungs, with honeycombing especially at the lung bases and diffuse pleural wall thickening (Fig. 2).\n\nNitrofurantoin was stopped on the day of hospital admission. The patient underwent video-assisted thoracoscopy (VATS) with lung and pleural biopsy to establish a diagnosis. The routine aerobic and anaerobic, fungal and mycobacterial cultures from the lung tissue and pleural fluid were all negative. A biopsy specimen from left lower lung demonstrated marked interstitial chronic inflammation, subpleural interstitial fibrosis and numerous prominent multi-nucleated giant cells, consistent with Giant Cell Interstitial Pneumonia (Fig. 3A and B). Since he had no exposure to hard metals, GIP was determined to be due to chronic nitrofurantoin use. He was treated with prednisone 60 mg daily and weaned off steroids over the course of 6 months. His dyspnea on exertion gradually resolved and he was weaned off oxygen as an outpatient. During a visit to pulmonary clinic five months after his initial hospitalization he was noted to have no shortness of breath at rest or with exertion. He was walking 4–5 miles per day and SpO2 was 99% on room air. On a 6-min walk testing, the lowest oxygen saturation on room air was 93%. His physical exam was normal other than mild crackles noted at the right lung base. CXR at that time showed a significant decrease in the pulmonary infiltrates and pleural thickening (Fig. 4). Pulmonary Function Testing (PFT) performed soon after hospital discharge showed a severe obstructive and moderate restrictive ventilatory defect which improved significantly on follow-up PFT performed five months later (Fig. 6A and B).\n\nTwo and a half years later, after having no further respiratory complaints, he presented to pulmonary clinic with recurrent fatigue and progressive dyspnea on exertion, which had developed over a 6-week period. He was found to be tachypneic and hypoxemic with SpO2 85% upon walking into the office. Physical exam revealed extensive crackles in both lung bases. A hall walk showed desaturation to 84% at 85 feet of walking. CXR performed that day showed extensive bilateral interstitial infiltrates and opacities (Fig. 5). On further inquiry, he reported that approximately 6 weeks prior to the onset of his recurrent dyspnea. a urologist had placed him back on nitrofurantoin for UTI prophylaxis. Due to the concern of recurrent GIP caused by nitrofurantion, he was instructed to stop nitrofurantoin immediately. He was initially treated as an outpatient with Prednisone 60 mg daily and oxygen. However, on follow-up visit one week later, he was found to be severely dyspneic and tachypneic. SpO2 while on oxygen 4 L/minute decreased from 97% at rest to 81% in less than one minute of walking. He had not been fully complaint with the outpatient steroid regimen prescribed one week earlier. He was directly admitted to the hospital where he was treated with high-dose intravenous methylprednisolone 60 mg intravenously every 6 h initially and oxygen. No additional Chest CT or lung biopsy was performed as the patient improved with steroid treatment. He was discharged to a nursing home on oxygen 2 L/min continuously and 6 L/min overnight. He completed another 6-month taper of Prednisone, starting at 60 mg, as an outpatient. Although he has been weaned off steroids and does not have shortness of breath at rest currently, he experiences dyspnea on exertion and requires 3 L oxygen with exercise if walking more than three minutes. He now wears a medical allergy band documenting his allergy to nitrofurantoin.\n\nDiscussion\nNitrofurantoin is a synthetic nitrofurane which is active against many gram-negative bacilli including Eschericia coli\n[1]. It has been widely used to treat urinary tract infections for more than 50 years. It recently became a first-line treatment option for acute uncomplicated cystitis based on its efficacy, low cost and minimal resistance [2]. Nitrofurantoin is also commonly used for chronic suppression of recurrent urinary tract infections [3].\n\nPulmonary adverse reactions to nitrofurantoin have been well described in the literature. Both acute and chronic manifestations have been reported [4,5]. Acute pulmonary reactions, which occur hours to days into a course of nitrofurantoin, are more common and typically manifest as an eosinophilic pneumonia or hypersensitivity reaction [6,7]. Chronic pulmonary reactions to nitrofurantoin, which occur months to years after daily nitrofurantoin use, present as interstitial pneumonitis and fibrosis. Chronic reactions have been associated with advanced age and prolonged use of nitrofurantoin but a dose-dependent relationship has not been established [6].\n\nGiant cell interstitial pneumonia (GIP) is a rare form of chronic interstitial pneumonia typically associated with hard metal exposure. GIP was first designated as a distinct entity by Liebow and Carrington in 1969 in the histologic classification system of idiopathic interstitial pneumonias [8]. However, GIP was subsequently excluded from the American Thoracic Society and the European Respiratory Society 2002 consensus statements on idiopathic interstitial pneumonias [9]. Currently GIP is classified as a pneumoconiosis associated with exposure to hard metals, typically cobalt and tungsten carbide [10]. GIP has also been described in literature as Hard Metal Disease, Giant Cell Pneumonitis and Cobalt Lung. The pathogenesis of GIP remains unclear but an autoimmune mechanism has been suggested [10].\n\nThe hallmarks of GIP on lung biopsy are bizarre appearing multi-nucleated giant cells, which have been described as cannibalistic, and centrilobular fibrosis [11]. Interstitial inflammation and organizing pneumonia can also be seen. Advanced GIP lesions present with fibrosis and honeycombing [12]. On high resolution Chest CT scans, GIP can present with ground-glass opacities, irregular linear opacities, small centrilobular nodules and/or honeycombing [13].\n\nWhile the vast majority of patients with GIP have had a past exposure to hard metals, there have been case reports of GIP associated with viral, mycobacterial, fungal infections and malignancy in patients without hard metal exposure [14]. Only two cases of nitrofurantoin-associated GIP have been reported in the literature [15,16]. All three cases, including ours, share the following characteristics: 1) insidious onset and gradually worsening dyspnea following long-term nitrofurantoin treatment 2) combined mild obstructive and restrictive patterns on pulmonary function tests 3) bilateral infiltration on imaging and 4) good response to nitrofurantoin withdrawal and systemic administration of steroids. Our case report is unique since this lung biopsy proven case of nitrofurantoin-induced GIP, appears to have recurred approximately 3 years later, just six weeks after the reintroduction of nitrofurantoin.\n\nConclusion\nOur case highlights that GIP can occur in the absence of hard metal exposure, can be associated with chronic nitrofurantoin use and can recur if the patient is re-exposed to nitrofurantoin. Early recognition and prompt discontinuation of nitrofurantoin is the mainstay of treatment, along with a course of oral steroids. GIP should be recognized as a potential adverse reaction to nitrofurantoin, and taken into consideration, especially before committing to long-term treatment with nitrofurantoin.\n\nAcknowledgment\nThe authors acknowledge Dr. Teresita Zdunek in pathology department for providing and interpreting a pathology slide for this report.\n\nFig. 1 Chest X-ray, (during first hospitalization) shows extensive basilar-predominant fibrosis, pleural thickening and possible pneumonic infiltrates in bilateral lower lobes of the lungs. No previous CXR was available for comparison.\n\nFig. 2 CT scan of the chest (during first hospitalization) shows pleural thickening and severe fibrotic changes with honeycombing in both lungs.\n\nFig. 3 Histology from VATS lung biopsy reveals A) marked fibrosis and chronic inflammation with B) giant cell reactions (hematoxylin-eosin, A.25× B.100×). An arrow shows a multi-nucleated giant cell.\n\nFig. 4 Chest X-ray, (4 months after initial hospitalization) shows minimal left sided pleural effusion and a significant decrease in the pulmonary infiltrates and pleural thickening.\n\nFig. 5 Chest X-ray (during second hospitalization) shows a dramatic increase in bilateral opacities compared with previous CXR.\n\nFig. 6 A: PFT performed approximately 2 months after the initial hospitalization shows a severe obstructive and a moderate restrictive ventilation defect and moderately decreased DLCO. B: PFT performed approximately 4 months later shows a significant improvement with a mild restrictive ventilatory defect, resolution of the obstructive ventilatory defect and only a mildly reduced DLCO.\n==== Refs\nReferences\n1 Garau J. Other antimicrobials of interest in the era of extended-spectrum beta-lactamases: fosfomycin, nitrofurantoin and tigecycline Clin Microbiol Infect 1 2008 198 202 18154548 \n2 Gupta K. Hooton T.M. Naber K.G. Wullt B. Colgan R. Miller L.G. Infectious Diseases Society of America European Society for Microbiology and Infectious Diseases International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases Clin Infect Dis 52 2011 e103 e120 21292654 \n3 Lichtenberger P. Hooton T.M. Antimicrobial prophylaxis in women with recurrent urinary tract infections Int J Antimicrob Agents 38 2011 36 41 22055655 \n4 Holmberg L. Boman G. Pulmonary reactions to nitrofurantoin. 447 cases reported to the Swedish adverse drug reaction committee Eur J Respir Dis 62 1981 80 89 \n5 Jick S. Jick H. Walker A. Hunter J.R. Hospitalizations for pulmonary reactions following nitrofurantoin use Chest 96 1989 512 515 2766810 \n6 Holmberg L. Boman G. Böttiger L.E. Eriksson B. Spross R. Wessling A. Adverse reactions to nitrofurantoin. Analysis of 921 reports Am J Med 69 1980 733 738 7435512 \n7 Madani Y. Mann B. Nitrofurantoin-induced lung disease and prophylaxis of urinary tract infections Prim Care Respir J 21 2012 337 341 22836745 \n8 Liebow A. Carrington C. The interstitial pneumonias Simon M. Potchen E.J. LeMay M. Frontiers of pulmonary radiology 1st ed. 1969 Grune & Stratton New York, NY 102 141 \n9 American Thoracic Society American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias Am J Respir Crit Care Med 165 2002 277 304 11790668 \n10 Katzenstein A. Myers J. Nonspecific interstitial pneumonia and the other idiopathic interstitial pneumonias: classification and diagnostic criteria Am J Surg Path 24 2000 1 3 10632482 \n11 Tanaka J. Moriyama H. Terada M. Takada T. Suzuki E. Narita I. An observational study of giant cell interstitial pneumonia and lung fibrosis in hard metal lung disease BMJ Open 4 2014 e004407 \n12 Naqvi A. Hunt A. Burnett B. Abraham J. Pathologic spectrum and lung dust Burden in giant cell interstitial pneumonia (Hard metal Disease/Cobalt pneumonitis): review of 100 cases Arch Environ Occup Health 63 2 2008 51 70 18628077 \n13 Choi J. Lee K. Chung M. Han J. Chung M.J. Park J.S. Giant cell interstitial pneumonia: high-resolution CT and pathologic findings in four adult patients AJR Am J Roentgenol 184 1 2005 268 272 15615987 \n14 Ohori N.P. Sciurba F.C. Owens G.R. Hodgson M.J. Yousem S.A. Giant-cell interstitial pneumonia and hard-metal pneumoconiosis. a clinicopathologic study of four cases and review of the literature J Surg Pathol 13 1989 581 587 \n15 Hargett C.W. Sporn T.A. Roggli V.L. Hollingsworth J.W. Giant cell interstitial pneumonia associated with nitrofurantoin Lung 184 2006 147 149 16902839 \n16 Magee F. Wright J.L. Chan N. Two unusual pathological reactions to nitrofurantoin: case reports Histopathology 10 1986 701 706 3744305\n\n",
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"title": "Recurrent nitrofurantoin-induced giant cell interstitial pneumonia: Case report and literature review.",
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"abstract": "Aplasia cutis congenita is a rare disease characterized by absence of skin layers. Usually the scalp is affected, but the whole body can be involved. We report extensive aplasia of a baby born of a HIV-positive mother taking antiretroviral drugs. Conservative treatment was not enough to ensure her survival.",
"affiliations": "Pediatric and Neonatal Department Central Hospital of Beira Sofala Mozambique.;Department of Medicine (DIMED) Surgical Pathology and Cytopathology Unit University of Padua Padua Italy.;Pediatric and Neonatal Department Central Hospital of Beira Sofala Mozambique.;Operational Research Unit Doctors with Africa CUAMM Padua Italy.;Pediatric and Neonatal Department Central Hospital of Beira Sofala Mozambique.;Operational Research Unit Doctors with Africa CUAMM Padua Italy.;Department of Woman's and Child's Health University of Padua Padua Italy.;Operational Research Unit Doctors with Africa CUAMM Beira Mozambique.",
"authors": "Wingi|Olivier|O|;Cappellesso|Rocco|R|;Arego|Raul|R|;Cuppini|Elena|E|;Muhelo|Arlindo|A|;Putoto|Giovanni|G|;Da Dalt|Liviana|L|;Pizzol|Damiano|D|",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.611CCR3611Case ReportCase ReportsFailed conservative management of a case of aplasia cutis congenita in a low‐income country O. Wingi et al.Wingi Olivier \n1\nCappellesso Rocco \n2\nArego Raul \n1\nCuppini Elena \n3\nMuhelo Arlindo \n1\nPutoto Giovanni \n3\nDa Dalt Liviana \n4\nPizzol Damiano \n5\n1 Pediatric and Neonatal DepartmentCentral Hospital of BeiraSofalaMozambique2 Department of Medicine (DIMED)Surgical Pathology and Cytopathology UnitUniversity of PaduaPaduaItaly3 Operational Research UnitDoctors with Africa CUAMMPaduaItaly4 Department of Woman's and Child's HealthUniversity of PaduaPaduaItaly5 Operational Research UnitDoctors with Africa CUAMMBeiraMozambique* Correspondence\n\nDamiano Pizzol, Operational Research Unit, Doctors with Africa CUAMM; Beira, Mozambique. Tel: +258824358263; Fax: +25823328543; E‐mail: d.pizzol@cuamm.org\n30 6 2016 8 2016 4 8 10.1111/ccr3.2016.4.issue-8756 758 18 12 2015 16 4 2016 30 5 2016 © 2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Key Clinical Message\nAplasia cutis congenita is a rare disease characterized by absence of skin layers. Usually the scalp is affected, but the whole body can be involved. We report extensive aplasia of a baby born of a HIV‐positive mother taking antiretroviral drugs. Conservative treatment was not enough to ensure her survival.\n\nAplasia cutis congenitadermatologypediatrics source-schema-version-number2.0component-idccr3611cover-dateAugust 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:05.08.2016All authors have given their consent for publication. The mother, sole holder of parental rights of the child, released written informed consent. Privacy was respected and there are no data that can bring the child any harm.\n==== Body\nIntroduction\nAplasia cutis congenita (ACC) is a rare condition characterized by the congenital absence of all skin layers 1. The first description of ACC dates back to 1767 by Cordon 2; since then, more than 500 cases have been reported in the literature. Most commonly, ACC presents as a localized solitary lesion involving the vertex of the scalp. However, it may affect larger areas of the face, trunk, buttocks, and extremities. The reported incidence ranges from 0.5 to 2.8/10,000 newborns, with a male:female ratio of 1:7 3, 4. Aplasia cutis congenita is usually an isolated clinical finding, but it can also occur in several syndromes, and different classifications based on etiology and/or presentation have been so far proposed 5, 6. The management of ACC in a newborn with a widespread skin defect presents a dilemma, since best treatment has not yet been determined. Surgical reconstruction of the skin with and without grafts, as well as conservative cures has been attempted, with different outcomes 7, 8, 9, 10. We report a challenging case of severe ACC conservatively treated in a low‐income country.\n\nCase Report\nA newborn female was presented to us, in Beira Central Hospital (Mozambique), after a few hours of birth at home (Apgar score unknown). Fifth‐born child, born at term, from a 28‐year‐old HIV‐positive mother, in therapy for 2 years and treated with the following antiretroviral drugs: Tenofovir 300 mg, Lamivudina 300 mg, and Efavirenz 600 mg. The child's birth weight was 1480 g, her body length 47 cm, and her head circumference 33 cm. Despite a rosy complexion, the crying sound, a good tone, and responsiveness, her general conditions were compromised. She showed extensive discontinuity of the skin on the scalp, trunk, abdomen, limbs, and bilaterally on the extremities for more than 60% of the body surface. In these areas, a thin, shiny, and diaphanous membrane was present, and a network of small vessels was visible. Other abnormalities and dysmorphic features were not recognized. In the absence of diagnostic tests, ACC was clinically diagnosed (Fig. 1).\n\nFigure 1 (A) At birth – Characteristic scalp lesion. (B) At birth – Extensive skin discontinuity on the trunk, abdomen, limbs, and extremities. (C and D) At 18 days. Extensive areas of tissue necrosis and desquamation of healed areas.\n\nSystemic intravenous treatment was as follows: cefotaxime 70 mg for 12 h, gentamicin 6 mg for 1 day, and azidothymidine 0.5 mL every 12 h. The only pain therapy available was paracetamol, 15 mg every 8 h. Skin lesions were treated with silver sulfadiazine dressing. For the first 5 days, she was able to breastfeed, she had no fever or other complications, and we registered a weight loss of 180 g. Despite recording attempt to cicatrization, areas of necrosis with scattered leak fluid remained. From the 6th to the 10th day, her general conditions worsened: her body temperature reached 38°C, necrotic areas increased and began to tear. On the 15th day, she weighed 1010 g, showed extensive areas of tissue necrosis, desquamation of healed areas, distended abdomen, inability to feed, and irritability. Intravenous vancomycin was administered (with a first administration of 15 mg, and then of 10 mg every 12 h), as well as cefepime (30 mg every 12 h), and fluconazole (6 mg every 72 h), still in association with silver sulfadiazine dressing. General conditions continued worsening, her weight decreased to 950 g, and fistulas appeared in abdominal necrotic areas. On the 24th day, she died.\n\nDiscussion\nAplasia cutis congenita is a multifactorial skin alteration usually presenting as an isolated small lesion at the scalp. In the case reported here, however, we faced an extensive congenital malformation. The diagnosis is mainly based on the clinical presentation and on histological demonstration of complete lack of skin. Some authors suggested the following tests as complement: maternal and fetal alpha‐fetoprotein and acetylcholinesterase dosage as prenatal screening, as well as ultrasound, X‐ray, and magnetic resonance imaging (MRI) as postnatal tests 11. In the absence of other inherited abnormalities, prenatal tests, information about the placenta, or about a possible fetus papyraceus, we hypothesize a teratogenic role of maternal HIV infection and/or long‐standing antiretroviral treatment in the pathogenesis of the disease. Indeed, drug consumption (e.g., methimazole, valproic acid, misoprostol, marijuana, and cocaine) during pregnancy is a well‐known factor associated with ACC. Virus transmission (e.g., herpes simplex virus or varicella zoster virus) from the mother to the fetus is another recognized teratogen. These may cause placental alterations affecting the normal skin development in the fetus. Unfortunately, it is not possible neither to confirm nor to refute our hypothesis and, in the future, only a proper follow‐up of the mother during pregnancy – of particular importance in low‐income countries with high HIV prevalence – will allow us to clarify the issues hypothesized above, as well as all other related issues.\n\nThe correct management and treatment of ACC is still debated. Both surgical and conservative approaches have been attempted in order to achieve a complete closure of the skin defect, while avoiding complications such as meningitis, hemorrhages, trauma, and thrombosis 12, 13. The management of ACC presenting extensive lesions is even more difficult in low‐income countries due to the absence of specialized clinicians, diagnostic tools, and, frequently, medicaments.\n\nIn our case, appropriate diagnostic tests were not available. However, we can state with of ACC certainty that, due to its characteristic presentation and because only few other conditions, we can rule out the following, presenting with ulcerations or scars in the newborn period: epidermolysis bullosa, focal dermal hypoplasia syndrome, and nevus sebaceous. Lacking even a plastic surgeon, conservative medical therapy was the only empirical treatment provided. Although contraindicated in newborns, we used silver sulfadiazine dressing as reported in several papers 12, 14, 15. Moreover, we administered systemic antibiotic therapy – another medication that is not appropriate in the management of large skin defects, mainly because it may cause the emergence of resistant bacteria – to prevent infection and sepsis. The only available analgesic treatment, albeit possibly inappropriate and certainly inadequate, was paracetamol.\n\nConsidering the bad prognostic factors, this case would be difficult to treat even in high‐income countries, particularly more so when taking into account the possible complications that may occur during treatment, such as infection and sepsis, fluid leakage, weight loss, electrolyte imbalance, bleeding, and pain. Therefore, and very sadly, failure of successfully treating this case of ACC, which presented extensive lesions in a setting with limited therapeutic options, was almost a foregone conclusion. This case, once again, points out that it is mandatory to improve maternal and child health in countries with limited resources in order to guarantee the possibility of a more appropriate therapeutic approach while at the same time allowing research progress.\n\nConflict of Interest\nNo author has any conflict of interest.\n\nAcknowledgments\nThe authors thank Dr. Pelizzon Alessandro, of the School of Law and Justice, Southern Cross University‐East Lismore NSW 2480‐Australia, for his kind and careful editing.\n==== Refs\nReferences\n1 \n\nIrons , G. B. \n, and \nR. M. \nOlson \n. 1980 \nAplasia cutis congenita . Plast. Reconstr. Surg. \n66 :199 –203 .6996008 \n2 \n\nCordon , M. \n\nExtrait d'une lettre au sujet de trois enfants de la meme mere nes avec partie des extremities denee de peau . J. Med. Chir. Pharm. \n1767 ; 26 : 556 –557 \n\n3 \n\nBaselga , E. \n, \nA. \nTorrelo \n, \nB. A. \nDrolet \n, \nA. \nZambrano \n, \nA. \nAlomar \n, and \nN. B. \nEsterly \n. 2005 \nFamilial nonmembranous aplasia cutis of the scalp . Pediatr. Dermatol. \n22 :213 –217 .15916567 \n4 \n\nCasanova , D. \n, \nE. \nAmar \n, \nJ. \nBardot \n, and \nG. \nMagalon \n. 2001 \nAplasia cutis congenita. Report on 5 family cases involving the scalp . Eur. J. Pediatr. Surg. \n11 :280 –284 .11558023 \n5 \n\nFrieden , I. J. \n\n1986 \nAplasia cutis congenital: a clinical review and proposal for classification . J. Am. Acad. Dermatol. \n14 :646 –660 .3514708 \n6 \n\nEvers , M. E. J. \n, \nP. M. \nSteijlen \n, and \nB. C. \nHamel \n. 1995 \nAplasia cutis congenital and associated disorders: an update . Clin. Genet. \n47 :295 –301 .7554362 \n7 \n\nAhcan , U. \n, and \nT. \nJanezic \n. 2002 \nManagement of aplasia cutis congenita in a non‐scalp location . Br. J. Plast. Surg. \n55 :530 –532 .12479434 \n8 \n\nWexler , A. \n, \nM. \nHarris \n, and \nM. \nLesavoy \n. 1990 \nConservative treatment of cutis aplasia . Plast. Reconstr. Surg. \n86 :1066 –1071 .2243847 \n9 \n\nRoss , D. A. \n, \nS. W. S. \nLaurie \n, \nC. J. \nCoombs \n, and \nK. L. \nMutimer \n. 1995 \nAplasia cutis congenita: failed conservative treatment . Plast. Reconstr. Surg. \n95 :124 –129 .7809224 \n10 \n\nSimman , R. \n, \nC. J. \nJr\nPriebe \n, and \nM. \nSimon \n. 2000 \nReconstruction of aplasia cutis congenita of the trunk in a newborn infant using acellular allogenic dermal graft and cultured epithelial autografts . Ann. Plast. Surg. \n44 :451 –454 .10783107 \n11 \n\nIljin , A. \n, and \nJ. \nKruk‐Jeromin \n. 2010 \nAplasia Cutis Congenita . Adv. Clin. Exp. Med. \n19 :121 –125 .\n12 \n\nSilberstein , E. \n, \nV. A. \nPagkalos \n, \nD. \nLandau \n, \nA. B. \nBerezovsky \n, \nY. \nKrieger \n, \nY. \nShoham \n, et al. 2014 \nAplasia cutis congenita: clinical management and a new classification system . Plast. Reconstr. Surg. \n134 :766e –774e .\n13 \n\nKantor , J. \n, \nA. C. \nYan \n, \nC. M. \nHivnor \n, \nP. J. \nHonig \n, and \nR. \nKirschner \n. 2005 \nExtensive aplasia cutis congenita and the risk of sagittal sinus thrombosis . Arch. Dermatol. \n141 :554 –556 .15897375 \n14 \n\nFröjd , V. \n, \nG. \nMaltese \n, \nL. \nKölby \n, and \nP. \nTarnow \n. 2014 \nConservative healing of an 11 × 9‐cm Aplasia Cutis Congenita of the scalp with bone defect . J. Neurol. Surg. Rep. \n75 :e220 –e223 .25485218 \n15 \n\nYin , H. Y. \n, \nX. J. \nTang \n, \nW. \nLiu \n, \nL. \nShi \n, \nL. \nYin \n, \nB. \nYang \n, et al. 2013 \nAplasia cutis congenital: a case of large scalp and skull defects treated with conservative approach . Chin. Med. J. (Engl). \n126 :2795 –2796 .23876918\n\n",
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"abstract": "Noma is an opportunistic infection characterized by devastating gangrenous stomatitis leading to severe tissue destruction that predominantly affects malnourished children in sub-Saharan Africa. Only a few cases have been reported in immunocompromised patients from developed countries. We present an unusual case of nomalike necrotizing stomatitis in a previously healthy child with Crohn's disease in Korea.",
"affiliations": "Department of Dermatology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.;Department of Dermatology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.;Department of Dermatology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.;Department of Dermatology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.;Department of Dermatology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.;Department of Dermatology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.",
"authors": "Lee|Ye Jin|YJ|http://orcid.org/0000-0002-3032-2428;Kim|Young Jae|YJ|http://orcid.org/0000-0001-9841-5797;Won|Chong Hyun|CH|;Chang|Sung Eun|SE|;Lee|Mi Woo|MW|;Choi|Jee Ho|JH|",
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"title": "Nomalike Necrotizing Stomatitis in a Child with Crohn's Disease.",
"title_normalized": "nomalike necrotizing stomatitis in a child with crohn s disease"
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"abstract": "Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation. It occurs because of severe inflammation due to uncontrolled proliferation of activated lymphocytes and histiocytes, characterized by the production of excessive levels of cytokines. Virus-associated HLH is a well-known entity, and parvovirus B19 is one of the common causes. Parvovirus B19 can also affect blood cell lineages. Therefore, HLH may be accompanied by several diseases such as cytopenia, aplastic anemia, and myelodysplastic syndrome. Herein, we report the case of a patient with hereditary spherocytosis who was diagnosed with parvovirus B19-induced HLH and aplastic crisis. A 7-year-old girl presented to our hospital with fever, pleural effusion, pancytopenia, hepatosplenomegaly, and hypotension. A bone marrow biopsy was performed under the suspicion of HLH, which revealed hemophagocytes. The diagnostic criteria for HLH were met, and prompt chemoimmunotherapy was initiated considering the clinically unstable situation. Her health improved rapidly after initiating treatment. Further study revealed that she had hereditary spherocytosis, and parvovirus B19 had caused aplastic crisis and HLH. The patient's clinical progress was excellent, and chemoimmunotherapy was reduced and discontinued at an early stage. This case shows that aplastic crisis and HLH can coexist with parvovirus B19 infection in patients with hereditary spherocytosis. Although the prognosis was good in this case of HLH caused by parvovirus B19, early detection and active treatment are essential.",
"affiliations": "Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.;Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.;Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.;Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.;Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.;Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.;Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.",
"authors": "Kim|Ki Tae|KT|;Hong|Kyung Taek|KT|https://orcid.org/0000-0002-8822-1988;Kim|Bo Kyung|BK|;An|Hong Yul|HY|https://orcid.org/0000-0003-1083-4589;Choi|Jung Yoon|JY|https://orcid.org/0000-0001-8758-3074;Chang|Yoon Hwan|YH|https://orcid.org/0000-0002-9010-5281;Kang|Hyoung Jin|HJ|https://orcid.org/0000-0003-1009-6002",
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"abstract": "BACKGROUND\nPreformed donor-specific human leukocyte antigen antibodies (DSAs) in patients undergoing simultaneous liver and kidney transplantation (SLKT) are an independent risk factor for poorer patient and renal allograft survival. The outcomes of patients highly sensitized (HS) against HLA antigens undergoing SLKT and select HS SLKT recipients undergoing desensitization at a high-volume desensitization center were investigated.\n\n\nMETHODS\nSeventy-five patients undergoing SLKT at a high-volume desensitization center between January 1, 2001, and December 31, 2015, were retrospectively reviewed. HS patients were defined by panel-reactive antibody (PRA) >30% (n = 17 patients), 11 of whom received pre- or perioperative desensitization with high-dose intravenous immunoglobulin (IVIG) ± rituximab.\n\n\nRESULTS\nHS patients had significantly higher class I and class II PRA (class I = 41.3% ± 40.0% vs 2.5% ± 6.3%; class II = 45.7% ± 36.4% vs 1.0% ± 2.9%; P < .001), were more likely to be female (P = .05), and more likely to have had a prior transplant (P = .03). HS patients demonstrated greater susceptibility to renal cell-mediated rejection (CMR) (23.5% vs 5.2%, P = .02) compared to nonsensitized patients. Higher renal antibody-mediated rejection (ABMR) was also observed in HS patients, 11.8% vs 3.4%, but did not reach significance (P = .18). Desensitization in select HS SLKT patients was well tolerated but did not improve patient and allograft survival or significantly curtail rejection.\n\n\nCONCLUSIONS\nHS SLKT recipients demonstrated increased allograft rejection, particularly CMR, but patient and graft survival were not impacted in the first year post-transplant. Select HS SLKT patients tolerated desensitization with high-dose IVIG ± rituximab and may have received additional immunoprotection against ABMR but survival was not affected.",
"affiliations": "Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.;Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.;Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.;Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.;Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.;Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.;Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.;Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.;Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.;Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.;Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA. Electronic address: Irene.kim@cshs.org.",
"authors": "Steggerda|J A|JA|;Kang|A|A|;Pan|S-H|SH|;Sundaram|V|V|;Nissen|N N|NN|;Klein|A S|AS|;Todo|T|T|;Annamalai|A|A|;Vo|A|A|;Jordan|S C|SC|;Kim|I K|IK|",
"chemical_list": "D000906:Antibodies; D006680:HLA Antigens; D016756:Immunoglobulins, Intravenous; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2017.01.079",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "49(6)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000906:Antibodies; D003888:Desensitization, Immunologic; D005260:Female; D006085:Graft Survival; D006680:HLA Antigens; D006801:Humans; D016756:Immunoglobulins, Intravenous; D016030:Kidney Transplantation; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000069283:Rituximab; D014019:Tissue Donors; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1394-1401",
"pmc": null,
"pmid": "28736013",
"pubdate": "2017",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Outcomes of Highly Sensitized Patients Undergoing Simultaneous Liver and Kidney Transplantation: A Single-Center Experience With Desensitization.",
"title_normalized": "outcomes of highly sensitized patients undergoing simultaneous liver and kidney transplantation a single center experience with desensitization"
} | [
{
"companynumb": "PHHY2017US112667",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
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"drugadditional": "3",
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{
"abstract": "We report the case of a young woman diagnosed with metastatic urachal carcinoma. A multimodal approach was used for the management of this patient. Due to disease progression despite surgery and two different chemotherapy regimens (neoadjuvant capecitabine + irinotecan + oxaliplatin and docetaxel + cisplatin after surgery), treatment with sunitinib was eventually started. Treatment with sunitinib resulted in stable disease and improvement of symptoms. Sunitinib was discontinued due to the occurrence of metrorrhagia, and restarted one week later. Disease eventually progressed and the patient died 18 months after the onset of symptoms. This is the first report on the use of sunitinib for the management of urachal carcinoma and provides initial evidence supporting the use of targeted therapy in this setting.",
"affiliations": "Istituto Nazionale Tumori , Milan, Italy.;Istituto Nazionale Tumori , Milan, Italy.;Istituto Nazionale Tumori , Milan, Italy.;Istituto Nazionale Tumori , Milan, Italy.;Istituto Nazionale Tumori , Milan, Italy.;Istituto Nazionale Tumori , Milan, Italy.",
"authors": "Testa|Isabella|I|;Verzoni|Elena|E|;Grassi|Paolo|P|;Colecchia|Maurizio|M|;Panzone|Filomena|F|;Procopio|Giuseppe|G|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.4081/rt.2014.5529",
"fulltext": "\n==== Front\nRare TumorsRare TumorsRTRare Tumors2036-36052036-3613PAGEPress Publications, Pavia, Italy 10.4081/rt.2014.5529Case ReportResponse to Targeted Therapy in Urachal Adenocarcinoma Testa Isabella Verzoni Elena Grassi Paolo Colecchia Maurizio Panzone Filomena Procopio Giuseppe Istituto Nazionale Tumori, Milan, ItalyDepartment of Medical Oncology, Unit 1, Fondazione IRCCS, Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133, Milan, Italy. +39.02.239.04450 - +39.02.2390.2149. giuseppe.procopio@istitutotumori.mi.itContributions: the authors contributed equally.\n\nConflict of interests: the authors declare no potential conflict of interests.\n\n09 12 2014 27 10 2014 6 4 552925 6 2014 20 8 2014 ©Copyright I. Testa, et al.2014Licensee 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.We report the case of a young woman diagnosed with metastatic urachal carcinoma. A multimodal approach was used for the management of this patient. Due to disease progression despite surgery and two different chemotherapy regimens (neoadjuvant capecitabine + irinotecan + oxaliplatin and docetaxel + cisplatin after surgery), treatment with sunitinib was eventually started. Treatment with sunitinib resulted in stable disease and improvement of symptoms. Sunitinib was discontinued due to the occurrence of metrorrhagia, and restarted one week later. Disease eventually progressed and the patient died 18 months after the onset of symptoms. This is the first report on the use of sunitinib for the management of urachal carcinoma and provides initial evidence supporting the use of targeted therapy in this setting.\n\nKey words\nsunitinibtargeted therapiesurachal adenocarcinoma\n==== Body\nIntroduction\nThe urachal ligament, an embryologic remnant, connects the dome of the bladder to the umbilicus via the ligamentum commune; it is the main excretory organ of the fetus and it is still present in all newborns, then gradually degenerates into a single fibrous band.1 In approximately 30% of the general population, the urachal remnant may persist with tubular or cystic structures consisting of mucosa, connective tissue and smooth muscle. Tumors of the urachal ligament are extremely rare, accounting for 0.2% of all bladder cancers.2 These tumors are usually diagnosed at an advanced stage due to the extravescical growth and the lack of symptoms during early disease. Symptoms often occur only after the disease has progressed, the most common clinical presentation being gross hematuria and,3 at more advanced stages, abdominal pain and/or development of abdominal mass. Adenocarcinoma is the most common histological type and accounts for over 90% of all cases, the enteric type being the most frequent subtype.4 Two different staging systems have been described for urachal cancers, i.e. the Sheldon system and the Mayo system (Table 1): these systems predict cancer-specific mortality equally well.5 The diagnostic approach should include computed tomography (CT) or magnetic resonance imaging (MRI) evaluation of the abdomen and pelvis; a cystoscopy is crucial for precisely localizing and performing biopsies of the tumor, since most lesions are located in the dome and anterior wall of the bladder. Since the embryological origin of the urachus is the same as the colon, and most urachal carcinomas are adenocarcinomas, an elevation in tumor markers associated with gastrointestinal tumors, including carcinoembryonic antigen (CEA), CA 125 and CA 19.9, is common.6,7 The primary therapeutic approach is surgical resection with partial or radical cystectomy and en bloc resection of the urachal ligament with the umbilicus and bladder.8 At present, no guidelines or standard of care for the management of this tumor in local and/or advanced disease exist, mainly due to the infrequency of this cancer. Available information on the treatment of this cancer is mainly derived from case reports, and therefore we believe that it is of great importance to make the experiences on the management of patients with urachal ligament carcinoma available to clinicians facing this rare malignancy. We report a case of metastatic urachal carcinoma treated with multimodal approach (surgery, chemotherapy and targeted therapy). Considering the lack of guidelines and clinical experience in this disease a discussion in a multidisciplinary team was made in order to select a treatment oriented on the patient and disease.\n\nCase Report\nPresentation of case and initial assessment\nOn November 2009 a 33-year old woman with no significant previous medical history was referred to her gynecologist due to complaints of pelvic pain. A right ovarian cyst was diagnosed upon examination. However, due to persistent pain, a CT scan was performed that revealed a right pelvic mass. On 12 November 2009 the patient’s gynecologist performed laparoscopic surgery during which a sub peritoneal lesion likely to start from the bladder was found. The mass was removed but ruptured during surgery, with intraoperative spillage of mucinous material. A cystoscopy was performed postoperatively, which showed a reddish lesion of the dome of the bladder. The intraoperative histological diagnosis was mucinous adenocarcinoma. This was then confirmed by the final histological examination.\n\nFurther assessment at a referral center\nThe patient was referred to our hospital, Istituto Nazionale Tumori (National Tumors Institute), Milan, Italy, a referral center for the treatment of oncological disease in Italy, and a histological review was performed by our genitourinary pathology expert. The immunohistochemical analysis was positive for CDX-2 and CK20 and negative for CK 7, suggesting a diagnosis of mucinous adenocarcinoma originating from the urachal ligament.3,9 We then performed a whole body CT scan that showed two metastases in the right lung, one at the lower lobe and one in the middle lobe, with a diameter of 15.6 and 8.5 mm, respectively, and one lesion anterior to the bladder wall and the dome that extended through the bladder wall, protruding into the lumen. Serum CEA was 15.39 ng/mL (normal <5), CA 19.9 was 70.1 U/mL (normal <37), CA 125 negative, CA 15.3 negative.\n\nManagement\nWe discussed the case of the patient with the urological surgeon and, given the extension of the disease, we decided to treat the patient with systemic chemotherapy rather than performing surgery.\n\nThe histological type, the strong mucinous component and the phenotypic similarities with a cancer of gastroenteric origin, rather than urothelial, prompted us to use the association of three drugs: irinotecan 180 mg/m2 (300 mg tot.) on day 1, oxaliplatin 85 mg/m2 (145 mg tot.) on day 2 and capecitabine 2000 mg/m2/day (days 2-6); cycles were repeated every 2 weeks. This association was undertaken based on the clinical experience of our group in gastrointestinal tumors.10\n\nWe started this chemotherapy regimen on 16 Dec 2009 and continued for 6 cycles, until 03 March 2010, with evidence of radiologically stable disease on CT scans after 3 and 6 cycles, and biochemical response (CA 19.9: 15.2 U/mL, CEA 1.59 ng/mL).\n\nTreatment was well tolerated, except for nausea (G2) and neutropenia (G2). Since the second cycle, granulocyte colony-stimulating factor (G-CSF) for secondary prophylaxis was administered on days 8-13 of each cycle.\n\nIn light of the young age of the patient and the stabilization of the disease we decided to reconsider the surgical approach, after a pre-operative abdomen MRI was performed (Figure 1). On 06 April 2010 umbilical resection with the bladder dome and the urachal remnant was performed (Figure 2). No postoperative complications arose.\n\nThe final histology report confirmed the diagnosis of urachal adenocarcinoma with mucinous components (CDX-2 positive, CK 20 positive, CK 7 negative, CK 34 beta E12 negative, beta-catenin positive); surgery was radical, with negative surgical margins. Follow up was then activated (Figure 3).\n\nThe CT scan performed after two months showed the presence of two right lung nodules.\n\nOn 17 June 2010 the patient underwent precision resection of the 3 right lung nodules (for 2 of them, the CT scan was positive for metastasis from urachal carcinoma; the third, supposed by the surgeon to be malignant, resulted benign fibrotic parenchymal tissue). Surgery was radical and then follow up was started. A subsequent CT scan (24 August 2010) was negative for metastatic disease, although some small lesions, equivocal but suggestive of peritoneal involvement, were detected. Given both the absence of symptoms and the negativity of serum markers we decided, in agreement with the patient, to proceed only with clinical and radiological follow up. A CT scan performed after three months showed peritoneal disease in close contact with the uterus and bladder wall. Serum markers were elevated (CEA: 174 ng/mL, CA 19.9: 321 U/mL).\n\nThe patient was symptomatic for abdominal pain, therefore transdermal therapy with fentanyl (50 mcg/h) was started. Since the disease was progressing, we considered starting a second-line chemotherapy. Among the few chemotherapeutic regimens tested in this rare tumor,8 we chose a platinum/taxane combination. On 01 December 2010, we started chemotherapy with cisplatin (75 mg/m2: 130 mg tot.) and docetaxel 75 mg/m2 (130 mg tot.) day 1, q 21 for three cycles (until 18 January 2011). Primary prophylaxis with a single subcutaneous injection of pegfilgrastim was also performed. Treatment was well tolerated, with only nausea (G2) as adverse event; however, a CT scan performed after the end of the third cycle showed evidence of abdominal disease progression. Within few weeks since the end of chemotherapy, the patient reported moderate asthenia. Physical examination revealed paleness and a palpable, hard central pelvic mass (maximum diameter 5 cm). Hematological tests showed acute anemia (Hb 7.3 g/dL); the patient received transfusion of 2 units of red blood cells (05 February 2011) with return to satisfactory Hb values (Hb 10.5 g/dL on 08 February 2011).\n\nThe disease was progressing despite chemotherapy and surgery on both primary and metastatic sites. Nevertheless, the patient was in relatively good clinical conditions: vital signs were within the normal range and organ functions, as assessed by blood laboratory tests, were good. Given the young age of the patient, who was also a mother of two kids, we decided to try another treatment and to initiate off label therapy with the multikinase inhibitor sunitinib. On 23 February 2011 we started therapy with sunitinib at the dose of 25 mg continuously, with close clinical and hematological monitoring; after two weeks since the start of treatment the patient reported feeling better, with improvement of pain, no adverse events and good hematological profile. After about 50 days, analgesic treatment was discontinued because of pain disappearance; we performed a CT scan that showed stable disease, with evidence of necrotic evolution of the abdominal mass, which was also smaller and softer upon physical examination. The patient received sunitinib until May 2011, when she developed metrorrhagia. For this reason, sunitinib therapy was discontinued for seven days, with resolution of bleeding but also a prompt recurrence of abdominal pain. Treatment with sunitinib was started again, but metrorrhagia persisted. A radiation oncology consult was obtained, and hemostatic radiotherapy (total dose: 15 Gy in 3 fraction) was administered, with control of bleeding.\n\nThe patient continued sunitinib until 10 July 2011, when symptoms of intestinal obstruction appeared; treatment was finally stopped and the patient started only supportive care at home. She died on 29 July 2011.\n\nDiscussion\nUrachal carcinomas are rare, and there is paucity of data on the best chemotherapy regimen for the treatment of this disease. Since the commonest histologic subtype of urachal carcinoma is adenocarcinoma with enteric features,3 chemotherapy regimens used to treat gastrointestinal tumors, i.e. 5-fluorouracil and taxanes, are commonly used in the management of this malignancy.8 Other drugs that have been used in this setting include cisplatin, methotrexate, vinblastine and gemcitabine.8 Although surgery is generally recommended for urachal carcinoma, due to the extension of disease we did not perform curative surgery initially, and we decided to administer systemic chemotherapy with capecitabine, irinotecan and oxaliplatin, a regimen used for the treatment of metastatic colon cancer.11 The patient exhibited a marker response to this regimen, which also resulted in radiological stabilization of disease. Umbilical resection with removal of the bladder dome and urachal remnant was then performed, followed by resection of lung metastases. However, few months after surgery we observed recurrence of disease, with elevation of serum markers and peritoneal spread that did not respond to chemotherapy with cisplatin and docetaxel. Peritoneal dissemination of urachal adenocarcinoma is a rarely encountered aggressive facet of this disease, observed typically with the mucinous subtype.12 Furthermore, the possibility that peritoneal spread was due to tumor rupture during the first surgery cannot be excluded. Given the young age of the patient and the relatively good clinical conditions despite disease progression, we initiated off-label treatment with sunitinib. We chose sunitinib because of its great efficacy in other advanced malignancies and good safety profile.13,14 We started with a reduced dose, to test tolerability. To the best of our knowledge, this is the first report on the use of sunitinib for the treatment of urachal carcinoma. Few, scattered reports are available on the use of targeted therapies for this malignancy.8 Sunitinib is a multikinase inhibitor indicated for the treatment of advanced malignant gastrointestinal stromal tumors, renal cell metastatic carcinoma and progressive, well-differentiated pancreatic neuroendocrine tumors. Sunitinib inhibits the vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor (PDGF) receptor, and c-Kit in addition to other kinases.15 In the present case, treatment with sunitinib resulted in partial necrosis of the tumor that was paralleled by an improvement of symptoms. Unfortunately, treatment had to be stopped due to the occurrence of metrorrhagia. Bleeding is an established adverse effect of sunitinib,16 but whether metrorrhagia was due to treatment or to the disease itself cannot be conclusively determined, since eventually the tumor infiltrated the uterus. Although sunitinib was started again after seven days, the temporary suspension of treatment may have limited the efficacy of the drug. However, published data suggest that the median survival of patients with urachal carcinoma ranges from 12 to 24 months.5,17 In the present case, treatment with sunitinib noticeably delayed the progression of disease, leading to an overall survival of 18 months since the onset of symptoms and to rapid symptomatic benefit.\n\nConclusions\nThe case discussed here indicates that targeted therapy with sunitinib might have a role in the management of patients with advanced urachal carcinoma. However, this is the first report on the use of sunitinib in this setting, and the indications and clinical benefits of this strategy remain to be determined. Multi-institutional collaborations will be important to explore the impact of targeted treatments in the management of urachal carcinoma.\n\nAcknowledgments\nEditorial assistance for the preparation of this manuscript was provided by Luca Giacomelli, PhD, and was supported by internal funds.\n\nFigure 1. Abdominal magnetic resonance imaging (pre-surgery).\n\nFigure 2. Macroscopic tumor sample.\n\nFigure 3. Histopathological preparation (Haematoxylin and Eosin). Urachal mucinous adenocarcinoma.\n\nTable 1. Urachal cancer staging systems.\n\n\tStage I\tStage II\tStage III\tStage IV\t\nSheldon staging system\tUrachal cancer confined to urachal mucosa\tUrachal cancer with invasion confined to urachus itself\tLocal urachal cancer extension to: A) bladder; B) abdominal wall; C) peritoneum\tMetastatic urachal cancer to: A) lymph nodes; B) distant sites\t\nMayo staging system\tTumor confined to the urachus and/or bladder\tTumor extending beyond the muscular layer of the urachus and/or the bladder\tTumors infiltrating the regional lymph nodes\tTumor infiltrating nonregional lymph nodes or other distant sites\n==== Refs\n1. Begg RC \nThe urachus: its anatomy, histology and development . J Anatom 1930 ;64 : 170 -8 .\n2. Bruins HM Visser O Ploeg M \nThe clinical epidemiology of urachal carcinoma: results of a large, population based study . J Urol 2012 ;188 :1102 -7 .22901574 \n3. Gopalan A Sharp DS Fine SW \nUrachal carcinoma: a clinicopathologic analysis of 24 cases with outcome correlation . Am J Surg Pathol 2009 ;33 :659 -68 .19252435 \n4. Sheldon CA Clayman RV Gonzalez R \nMalignant urachal lesions . J Urol 1984 ;131 :1 -8 .6361280 \n5. Ashley RA Inman BA Sebo TJ \nUrachal carcinoma: clinicopathologic features and long-term outcomes of an aggressive malignancy . Cancer 2006 ;107 :712 -20 .16826585 \n6. Guarnaccia S Pais V Grous J Spirito N \nAdenocarcinoma of the urachus associated with elevated levels of CA 125 . J Urol 1991 ;145 :140 -1 .1984074 \n7. Kikuno N Urakami S Shigeno K \nUrachal carcinoma associated with increased carbohydrate antigen 19-9 and carcinoembryonic antigen . J Urol 2001 ;166 :604 .11458079 \n8. Siefker-Radtke A \nUrachal adenocarcinoma: a clinician’s guide for treatment . Semin Oncol 2012 ;39 :619 -24 .23040259 \n9. Lee W \nUrachal adenocarcinoma metastatic to the ovaries resembling primary ovarian mucinous carcinoma: a case report with the immunohistochemical study . Int J Clin Exp Pathol 2010 ;4 :118 -23 .21228934 \n10. Bajetta E Verzoni E Ferrario E \nFeasibility study of biweekly capecitabine, oxaliplatin, and irinotecan in patients with untreated advanced gastric cancer . Tumori 2009 ;95 :43 -7 .19366055 \n11. Zarate R Rodriguez J Bandres E \nOxaliplatin, irinotecan and capecitabine as first-line therapy in metastatic colorectal cancer (mCRC): a dose-finding study and pharmacogenomic analysis . Br J Cancer 2010 ;102 :987 -94 .20216541 \n12. Sugarbaker PH Verghese M Yan TD Brun E \nManagement of mucinous urachal neoplasm presenting as pseudomyxoma peritonei . Tumori 2008 ;94 :732 -6 .19112949 \n13. Motzer RJ Hutson TE Tomczak P \nSunitinib versus interferon alfa in metastatic renal-cell carcinoma . New Engl J Med 2007 ;356 :115 -24 .17215529 \n14. Raymond E Dahan L Raoul JL \nSunitinib malate for the treatment of pancreatic neuroendocrine tumors . New Engl J Med 2011 ;364 :501 -13 .21306237 \n15. Mena AC Pulido EG Guillen-Ponce C \nUnderstanding the molecular-based mechanism of action of the tyrosine kinase inhibitor: sunitinib . Anticancer Drugs 2010 ;21 :S3 -11 .20110785 \n16. Je Y Schutz FA Choueiri TK \nRisk of bleeding with vascular endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials . Lancet Oncol 2009 ;10 :967 -74 .19767240 \n17. Siefker-Radtke AO Gee J Shen Y \nMultimodality management of urachal carcinoma: the M. D. Anderson Cancer Center experience . J Urol 2003 ;169 :1295 -8 .12629346\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2036-3605",
"issue": "6(4)",
"journal": "Rare tumors",
"keywords": "sunitinib; targeted therapies; urachal adenocarcinoma",
"medline_ta": "Rare Tumors",
"mesh_terms": null,
"nlm_unique_id": "101526926",
"other_id": null,
"pages": "5529",
"pmc": null,
"pmid": "25568747",
"pubdate": "2014-10-27",
"publication_types": "D002363:Case Reports",
"references": "21306237;20110785;23040259;22901574;17215529;19366055;17104266;11458079;6361280;19112949;16826585;21228934;19252435;1984074;19767240;20216541;12629346",
"title": "Response to targeted therapy in urachal adenocarcinoma.",
"title_normalized": "response to targeted therapy in urachal adenocarcinoma"
} | [
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"companynumb": "IT-MYLANLABS-2015M1003077",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
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"actiondrug": "5",
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"activesubstancename": "IRINOTECAN"
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{
"abstract": "OBJECTIVE\nTo assess the current frequency of ART-associated grade 3-4 transaminase elevations (TE) and grade 4 total bilirubin elevations (TBE) in HIV-infected patients with chronic hepatitis B and/or C, who start a new regimen of ART.\n\n\nMETHODS\nA total of 192 pre-treated or treatment-naive HIV infected patients with HBV and/or HCV-coinfection who started ART in eight Southern Spanish centers from July/2011-December/2013, were followed for 12 months in this prospective study.\n\n\nRESULTS\nForty-one (21.4%) subjects had been naïve to ART, median (IQR) follow-up was 11.6 (5.6-12.9) months. The most frequently initiated NRTI were tenofovir/emtricitabine [49 patients (25.5%)]. Eighty-nine (46.4%) patients started a ritonavir-boosted protease inhibitor and 77 (40.1%) individuals a NNRTI. Raltegravir and maraviroc were initiated in 24 (12.5%) and 9 (4.7%) individuals. Ten [5.21%; 95% confidence interval (CI): 2.53%-9.37%] patients presented grade 3 TE, while 8 (4.17%; 95%CI: 1.82%-8.04%) subjects showed grade 4 TBE. No episodes of grade 4 TE or ART discontinuation due to hepatotoxic events were observed. The use of ritonavir-boosted atazanavir was the only independent predictor for grade 4 TBE [adjusted odds ratio: 7.327 (95%CI: 1.417-37.89); p = 0.018] in an analysis adjusted for age, sex and baseline HIV-RNA levels, while no factor could be independently associated with grade 3-4 TE.\n\n\nCONCLUSIONS\nCurrently, the frequency of severe ART-associated TE and TBE under real-life conditions in patients with chronic viral hepatitis is similar to what has been reported previously. However, episodes of grade 4 TE are less frequent and severe TE appears to be of lesser concern.",
"affiliations": "Unit of Infectious Diseases and Microbiology, Hospital Universitario de Valme, Seville, Spain.;Internal Medicine Service, Hospital Universitario de Valme, Seville, Spain.;Internal Medicine Department, Hospital Torrecárdenas, Almeria, Spain.;Internal Medicine Department, Hospital Torrecárdenas, Almeria, Spain.;Unit of Infectious Diseases and Microbiology, Hospital Universitario de Valme, Seville, Spain.;Unit of Infectious Diseases, Hospital Universitario Virgen de la Victoria, Malaga, Spain.;Unit of Infectious Diseases, Hospital Universitario Virgen de la Macarena, Seville, Spain.;Internal Medicine Service, Hospital Juan Ramón Jiménez. Huelva, Spain.;Unit of Infectious Diseases, Hospital de La Línea de la Concepción, Cadiz, Spain.;Unit of Tropical Medicine, Hospital Poniente, El Ejido, Spain.;Internal Medicine Department, Hospital Torrecárdenas, Almeria, Spain.;Unit of Infectious Diseases, Hospital Universitario Reina Sofia, Maimonides Institute for Biomedical Research (IMIBIC), University of Cordoba, Cordoba, Spain.;Unit of Infectious Diseases and Microbiology, Hospital Universitario de Valme, Seville, Spain.",
"authors": "Neukam|Karin|K|;Mira|José A|JA|;Collado|Antonio|A|;Rivero-Juárez|Antonio|A|;Monje-Agudo|Patricia|P|;Ruiz-Morales|Josefa|J|;Ríos|María José|MJ|;Merino|Dolores|D|;Téllez|Francisco|F|;Pérez-Camacho|Inés|I|;Gálvez-Contreras|María Carmen|MC|;Rivero|Antonio|A|;Pineda|Juan A|JA|;|||",
"chemical_list": "D019380:Anti-HIV Agents; D000637:Transaminases; D001663:Bilirubin",
"country": "United States",
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"doi": "10.1371/journal.pone.0148104",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2684897510.1371/journal.pone.0148104PONE-D-15-53243Research ArticleBiology and Life SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesPharmacologyDrugsAntimicrobialsAntiviralsAntiretroviralsBiology and Life SciencesMicrobiologyMicrobial ControlAntimicrobialsAntiviralsAntiretroviralsBiology and Life SciencesMicrobiologyVirologyAntiviralsAntiretroviralsBiology and life sciencesOrganismsVirusesRNA virusesFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensFlavivirusesHepacivirusHepatitis C virusMedicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesOrganismsVirusesViral pathogensFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensHepatitis virusesHepatitis C virusMedicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensHepatitis virusesHepatitis C virusBiology and life sciencesOrganismsVirusesViral pathogensHepatitis virusesHepatitis C virusMedicine and Health SciencesPharmacologyDrug InteractionsMedicine and Health SciencesPharmacologyDrug InteractionsDrug-Drug InteractionsMedicine and Health SciencesGastroenterology and HepatologyLiver DiseasesChronic Liver DiseaseChronic HepatitisBiology and Life SciencesAnatomyBody FluidsBileBilirubinMedicine and Health SciencesAnatomyBody FluidsBileBilirubinBiology and Life SciencesPhysiologyBody FluidsBileBilirubinMedicine and Health SciencesPhysiologyBody FluidsBileBilirubinMedicine and Health SciencesPharmaceuticsDrug TherapyDrug AdministrationLiver Toxicity of Current Antiretroviral Regimens in HIV-Infected Patients with Chronic Viral Hepatitis in a Real-Life Setting: The HEPAVIR SEG-HEP Cohort Liver Safety of Current ART in Viral Hepatitis CoinfectionNeukam Karin 12*Mira José A. 3Collado Antonio 4Rivero-Juárez Antonio 4Monje-Agudo Patricia 12Ruiz-Morales Josefa 6Ríos María José 7Merino Dolores 8Téllez Francisco 9Pérez-Camacho Inés 10Gálvez-Contreras María Carmen 4Rivero Antonio 5Pineda Juan A. 1HEPAVIR SEG-HEP-2007 Study Group of the Sociedad Andaluza de Enfermedades Infecciosas (SAEI) ¶1 \nUnit of Infectious Diseases and Microbiology, Hospital Universitario de Valme, Seville, Spain2 \nInstituto de Biomedicina de Sevilla (IBiS), Seville, Spain3 \nInternal Medicine Service, Hospital Universitario de Valme, Seville, Spain4 \nInternal Medicine Department, Hospital Torrecárdenas, Almeria, Spain5 \nUnit of Infectious Diseases, Hospital Universitario Reina Sofia, Maimonides Institute for Biomedical Research (IMIBIC), University of Cordoba, Cordoba, Spain6 \nUnit of Infectious Diseases, Hospital Universitario Virgen de la Victoria, Malaga, Spain7 \nUnit of Infectious Diseases, Hospital Universitario Virgen de la Macarena, Seville, Spain8 \nInternal Medicine Service, Hospital Juan Ramón Jiménez. Huelva, Spain9 \nUnit of Infectious Diseases, Hospital de La Línea de la Concepción, Cadiz, Spain10 \nUnit of Tropical Medicine, Hospital Poniente, El Ejido, SpainApetrei Cristian EditorUniversity of Pittsburgh Center for Vaccine Research, UNITED STATESCompeting Interests: K.N. has received lecture fees from Janssen-Cilag, Roche, Bristol-Meyers Squibb and Merck Sharp & Dohme and has received research support from Janssen-Cilag, Bristol-Meyers Squibb, Merck Sharp & Dohme, Gilead Sciences and Abbott Pharmaceuticals. A.R.J has received lecture fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, ViiV Healthcare and Roche. D.M. reports having received consultancy fees from Janssen Cilag, Merck Sharp & Dohme, Bristol-Myers Squibb, Gilead Sciences, AbbVie and ViiH Healthcare. A.C. reports having received consultancy fees from Janssen-Cilag, Merck Sharp & Dohme, Bristol-Myers Squibb, Gilead Sciences, Pfizer and AbbVie. A.R. reports having received consulting fees from GlaxoSmithKline, Bristol-Myers Squibb, Abbott Pharmaceuticals, Gilead Sciences, Merck Sharp & Dohme, Schering-Plough, Janssen-Cilag and Boehringer Ingelheim. He has received research support from GlaxoSmithKline, Roche, Bristol-Myers Squibb, Schering-Plough, Abbott Pharmaceuticals and Boehringer Ingelheim, and has received lecture fees from GlaxoSmithKline, Roche, Abbott Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme, Janssen-Cilag, Boehringer Ingelheim and Schering-Plough. J.A.P. reports having received consulting fees from GlaxoSmithKline, Bristol-Myers Squibb, Abbott Pharmaceuticals, Gilead Sciences, Merck Sharp & Dohme, Schering-Plough, Janssen-Cilag and Boehringer Ingelheim. He has received research support from GlaxoSmithKline, Roche, Bristol-Myers Squibb, Schering-Plough, Abbott Pharmaceuticals and Boehringer Ingelheim, and has received lecture fees from GlaxoSmithKline, Roche, Abbott Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme, Janssen-Cilag, Boehringer Ingelheim and Schering-Plough. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.\n\nConceived and designed the experiments: KN JAM JAP. Performed the experiments: KN JAM AC ARJ PMA JRM MJR DM FT IPC MCGC AR JAP. Analyzed the data: KN JAM JAP. Contributed reagents/materials/analysis tools: KN JAM AC ARJ PMA JRM MJR DM FT IPC MCGC AR JAP. Wrote the paper: KN JAM AC ARJ PMA JRM MJR DM FT IPC MCGC AR JAP.\n\n¶ Complete membership of the author group can be found in the Acknowledgments.\n\n* E-mail: karin.neukam@gmail.com5 2 2016 2016 11 2 e01481048 12 2015 13 1 2016 © 2016 Neukam et al2016Neukam et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Objective\nTo assess the current frequency of ART-associated grade 3–4 transaminase elevations (TE) and grade 4 total bilirubin elevations (TBE) in HIV-infected patients with chronic hepatitis B and/or C, who start a new regimen of ART.\n\nPatients and Methods\nA total of 192 pre-treated or treatment-naive HIV infected patients with HBV and/or HCV-coinfection who started ART in eight Southern Spanish centers from July/2011-December/2013, were followed for 12 months in this prospective study.\n\nResults\nForty-one (21.4%) subjects had been naïve to ART, median (IQR) follow-up was 11.6 (5.6–12.9) months. The most frequently initiated NRTI were tenofovir/emtricitabine [49 patients (25.5%)]. Eighty-nine (46.4%) patients started a ritonavir-boosted protease inhibitor and 77 (40.1%) individuals a NNRTI. Raltegravir and maraviroc were initiated in 24 (12.5%) and 9 (4.7%) individuals. Ten [5.21%; 95% confidence interval (CI): 2.53%-9.37%] patients presented grade 3 TE, while 8 (4.17%; 95%CI: 1.82%-8.04%) subjects showed grade 4 TBE. No episodes of grade 4 TE or ART discontinuation due to hepatotoxic events were observed. The use of ritonavir-boosted atazanavir was the only independent predictor for grade 4 TBE [adjusted odds ratio: 7.327 (95%CI: 1.417–37.89); p = 0.018] in an analysis adjusted for age, sex and baseline HIV-RNA levels, while no factor could be independently associated with grade 3–4 TE.\n\nConclusions\nCurrently, the frequency of severe ART-associated TE and TBE under real-life conditions in patients with chronic viral hepatitis is similar to what has been reported previously. However, episodes of grade 4 TE are less frequent and severe TE appears to be of lesser concern.\n\nThis work was supported by the Red de Investigación en SIDA (ISCIII-RETIC RD06/006 and ISCIII-RETIC RD12/0017), the Ministerio de Sanidad y Servicios Sociales (grant number EC11-303) and the Consejería de Salud of the Junta de Andalucía (grant number AC-0095-2013). KN is the recipient of a Miguel Servet research grant from the Instituto de Salud Carlos III (grant number CP13/00187). A.R.-J. is the recipient of a post-doctoral extension grant of the Fundación Progreso y Salud of the Junta de Andalucía (grant number RH-0024-2013). JAP is the recipient of an intensification grant from the Instituto de Salud Carlos III (grant number Programa-I3SNS). Data AvailabilityAll relevant data are within the paper.Data Availability\nAll relevant data are within the paper.\n==== Body\nIntroduction\nHepatotoxic events associated with antiretroviral drugs, including liver transaminase elevations (TE), acute liver failure and death, are of high concern in HIV-infected patients. Coinfection with hepatitis viruses can promote the development of ART-induced TE [1–6]. Nevertheless, the number of patients with HCV and/or HBV coinfection included in clinical trials on various HIV drugs that assess TE is usually low [7–12].\n\nData on the current rates of TE observed among HIV-infected patients with hepatitis virus coinfection obtained in the clinical practice have been described within different cohorts [1, 3–5, 13–20]. However, most of these studies have a retrospective design. Additionally, often only specific ART regimens are considered, mainly ritonavir-boosted PI (PI/r) or the NNRTI efavirenz and nevirapine [1,4,5,13,14,16,20]. Also, real-life data on some drugs, such as rilpivirine, darunavir and dolutegravir in patients with HCV-coinfection are scarce, while other studies include concomitant antiretroviral drugs that are no longer recommended. Furthermore, in some of these studies, selection criteria lead to the exclusion of subjects according to their previous regimen or liver damage, or require an optimized background ART combination. Finally, the initiation of a NRTI within an existing regimen may play a role in the development of hepatotoxic events in this setting. Therefore, due to the regimens and study populations analyzed, the studies available to date may not represent the overall situation of rapidly changing ART strategies in the clinical practice. To date, there is little information on ART-induced hepatotoxicity based on regimens and changes reflecting real-life conditions. In this context, we reported an overall frequency of grade 3–4 TE of 7.6% for a HIV/HCV-coinfected population in a multicenter cohort study conducted from 2007 to 2009 [20]. Still, no changes in NRTI strategies were evaluated and liver toxicity assessment was limited to efavirenz and PI/r in combination with two fixed NRTIs. Taken together, this information is necessary to evaluate potential liver safety differences among currently used ART. These data might be used to optimize the management of HIV-infected patients with viral hepatitis.\n\nThe aim of this study was to evaluate the frequency of hepatotoxicity, determined by grade 3 or 4 TE and grade 4 total bilirubin elevations (TBE), in patients with chronic hepatitis B or C, during the first year after starting one or more currently used antiretroviral drug within one single cohort under real-life conditions.\n\nPatients and Methods\nStudy Design and Population\nPre-treated or treatment-naïve HIV-infected patients who attended the Infectious Diseases Units of eight Southern Spanish centers from July 2011 to December 2013 were consecutively included in this prospective multicentric study (ClinicalTrials.gov ID: NCT01908660) if they fulfilled the following criteria: i) older than 18 years; ii) initiation of one or more antiretroviral drugs; iii) chronic HCV infection as confirmed by HCV antibodies in plasma, as well as a positive HCV viral load determined by PCR and/or chronic HBV infection as detected by positive serum HBV surface antigen (HBsAg) and iv) absence of hepatotoxicity events two months prior to the baseline visit. Clinical visits and blood tests were scheduled at the moment of initiation of the new ART, as well as at weeks 4, 12, 24, 36 and 48. The follow-up was stopped if the patient initiated treatment against HCV or at the moment of discontinuation of one or more antiretroviral drug due to any cause.\n\nAntiretroviral Drug Regimens\nART was indicated following the guidelines of the Spanish Group for the Study of AIDS (Grupo Español para el Estudio del SIDA, GESIDA), the Department of Health and Human Services of the USA (DHHS) or the European AIDS Clinical Society (EACS) at the time of prescription [21–23]. The final decision on the specific drug used was made according to the caring physician.\n\nDefinition of Liver Toxicity\nGrade 3 and 4 TE were defined according to the baseline alanine aminotransferase (ALT) and apartate aminotransferase (AST) values [24]. In patients with normal baseline transaminase levels, grade 3 TE were considered when elevations between 5 and 10 times above the upper level of normality (ULN) were observed at least one of the follow-up visits, while grade 4 TE were defined as ALT or AST values higher than 10 times of the ULN. In patients with elevated baseline transaminase levels, 3.5- to 5-fold elevations were considered grade 3 TE, and elevations higher than 5-fold were defined as grade 4 TE, respectively. Grade 4 TBE were defined as bilirubin levels exceeding 5 mg/dL.\n\nStatistical Analysis\nThe outcome variable of this study was the development of grade 3 or 4 TE during follow-up. Additionally, grade 4 TBE were analyzed as secondary outcome variable. Comparative analyses of TE and TBE were carried out for the different antiretroviral drugs that were initiated in this study, as well as for age, sex and other potential factors that could influence the development of grade 3 or 4 TE or grade 4 TBE. Continuous variables were expressed as median (IQR) and were compared using the Student’s t-test for normal distribution and the Mann-Whitney U-test otherwise. Categorical variables were expressed as number [percentage; 95% confidence interval (CI)] and were analyzed by means of the χ2-test or the Fisher’s test, when applicable. In order to compare the CD4 cell counts and the HIV viral loads at baseline and the end of follow-up, the Wilcoxon Signed Rank test and the McNemar test were applied, respectively. Finally, a logistic regression model was created with those factors that showed an association with the outcome variables in the univariate analysis with a p<0.2, as well as age and sex, in order to identify independent risk factors for the outcome variables. The adjusted odds ratios and the respective 95% CI were calculated. Statistical analysis was performed using the SPSS statistical software package release 22.0 (IBM, Chicago, IL, USA) and STATA 9.0 (StataCorp LP, College Station, TX, USA).\n\nEthical Aspects\nThe study was designed and performed according to the Helsinki declaration and was approved by the Ethics Committee of the Valme University Hospital (Seville, Spain; approval reference number: 4/2011) and the Spanish Agency for Drugs and Sanitary Products (Agencia Española de Medicamentos y Productos Sanitarios, AEMPS). All patients gave their written informed consent before being included in the study.\n\nResults\nStudy Population\nA total of 192 patients were included in the analysis. The median (IQR) follow-up of the study population was 11.6 (5.6–12.9) months and the median (IQR) nadir CD4 cell count was 183 (67.8–274) cells/mL. Sixty-five (33.9%) individuals had received treatment against HCV infection without reaching sustained virologic response. Of these, 38 (58.5%) were non-responders, 8 (12.3%) had discontinued due to adverse events, 7 (10.8%) individuals had relapsed and 4 (6.2%) patients had developed a virologic breakthrough. The remaining 8 (12.3%) patients had dropped out voluntarily. Patient characteristics at the moment of starting a new ART combination are displayed in Table 1. Forty-one (21.4%) individuals started the new ART due to virologic failure, 55 (28.6%) patients due to adverse events to prior ART and 41 (21.4%) individuals had been ART-naïve. Simplification was the reason for switching in 29 (15.1%) individuals and in 20 (10.4%) patients changes were applied in order to avoid pharmacologic interactions with future therapy against HCV infection or other drugs. The remaining 6 (3.6%) changes were due to various reasons.\n\n10.1371/journal.pone.0148104.t001Table 1 Baseline characteristics of the study population (n = 192).\nCharacteristic\tValue\t\nMale sex, n (%)\t169 (88)\t\nAge, years*\t46.4 (42.9–50.6)\t\nPrior injection drug users, n (%)\t150 (78.1)\t\nAlcohol consumption ≥ 50 g/day, n (%)\t30 (15.6)\t\nCDC category C, n (%)\t63 (32.8)\t\nCD4 cell count, cells/mL*\t393 (239–566)\t\nUndetectable HIV viral load, n (%)\t77 (40.1)\t\nHCV-RNA (+)/HBsAg (-), n(%)\t182 (94.8)\t\nHCV-RNA (-)/HBsAg (+), n (%)\t9 (4.7)\t\nHCV-RNA (+)/HBsAg (+), n(%)\t1 (0.5)\t\nALT*, IU/mL\t50 (33–76.8)\t\nAST*, IU/mL\t46 (32.3–71.8)\t\nTotal bilirubin*, mg/dL\t0.63 (0.44–0.9)\t\nLiver stiffness*, kPa\t8.5 (6.7–14.8)\t\nAdvanced fibrosis, n (%)§\t84 (43.8)\t\nCirrhosis, n (%)§\t55 (28.6)\t\nPatients with hepatic decompensations prior to study, n (%)#\t9 (4.7)\t\n*Median (interquartile range)\n\n§determined by transient elastometry: cut-off values were 9.5 kPa for advanced fibrosis and 14.6 kPa for cirrhosis\n\n#number of events: ascites: 5, hepatic encephalopathy: 4, variceal hemorrhage: 2, jaundice: 1, hepatocarcinoma: 2.\n\nNewly Introduced Drugs and Resulting ART\nA total of 342 drug initiations were registered. Among the newly introduced regimens, 77 (40.1%) involved a NRTI, 89 (46.4%) a PI/r and 77 (40.1%) a NNRTI, respectively. The detailed proportions of the drugs within these groups that were subject to change are displayed in Table 2. The majority [157 patients (81.8%)] received triple therapy. Eighteen subjects (9.4%) received dual therapy, 11 (5.7%) individuals received monotherapy, and a regimen consisting of four drugs was administered in 6 (3.1%) subjects.\n\n10.1371/journal.pone.0148104.t002Table 2 Newly introduced antiretroviral therapy (ART).\nAntiretroviral drug\tn (%)\t\nNucleoside analogue reverse transcriptase inhibitors (NRTI)\t\t\n Tenofovir/emtricitabine\t49 (25.5)\t\n Abacavir/lamivudine\t14 (7.3)\t\n Other NRTI combinations\t14 (7.3)\t\n NRTI-sparing\t115 (59.9)\t\nRitonavir-boosted protease inhibitors\t\t\n Lopinavir/ritonavir\t11 (5.7)\t\n Atazanavir/ritonavir\t25 (13)\t\n Darunavir/ritonavir\t53 (27.6)\t\nNon-nucleoside analogue reverse transcriptase inhibitors\t\t\n Efavirenz\t18 (9.4)\t\n Nevirapine\t7 (3.6)\t\n Etravirine\t16 (8.3)\t\n Rilpivirine\t36 (18.8)\t\nIntegrase inhibitors\t\t\n Raltegravir\t24 (12.5)\t\nEntry inhibitors\t\t\n Maraviroc\t9 (4.7)\t\nFollow-Up\nOne-hundred and fourteen (59.4%) patients remained with the new ART until the end of the study follow-up of 48 weeks. The detailed reasons for ART discontinuation or premature stop of follow-up are depicted in Fig 1. The proportion of patients with undetectable HIV RNA was 40% (77/192 patients) at baseline and 81.6% (93/114 individuals) among those who reached the end of follow-up (p<0.001). CD4 levels (IQR) changed from 393 (239–566) cells/mL at baseline to 472 (298–712) cells/mL at the end of follow-up (p = 0.006).\n\n10.1371/journal.pone.0148104.g001Fig 1 Flow chart for patient disposition and treatment outcome.\nLiver safety\nA total of 10 (5.21%; 95%CI: 2.53%-9.37%) individuals developed grade 3 TE: 9 (4.9%) of the HIV/HCV-coinfected patients versus 1 (11.1%) of the HIV/HBV-coinfected individuals. No case of grade 4 TE was observed. Regimens and coinfection status of these patients are listed in Table 3. TBE was observed in 8 (4.17%; 95%CI: 1.82%-8.04%) patients, all of whom were HCV-coinfected and none showed HBV infection. Five (62.5%) individuals who presented TBE received ART based on ritonavir-boosted atazanavir and one respective patient received ritonavir-boosted darunavir, raltegravir or rilpivirine. No patient discontinued therapy due to hepatotoxic events. Liver decompensations during follow-up were developed by 8 (4.2%) patients, none of whom presented grade 3 or 4 TE or grade 4 TBE. In the multivariate analysis (Table 4), no factor was independently associated with grade 3 or 4 TE. The use of ritonavir-boosted atazanavir was the only independent predictor for grade 4 TBE.\n\n10.1371/journal.pone.0148104.t003Table 3 Patient characteristics of those who suffered grade 3 or 4 transaminase elevations (TE).\nNo.\tPrevious regimen\tNew\tMonths\tGrade\tAnti-\tHBsAg\t\n\t\tregimen\tto TE\tof TE\tHCV\t\t\n1\tTDF/FTC/ETV\tLPV/r\t3\t3\tpos\tneg\t\n2\tTDF/3TC/ATV/r\tDRV/r/RAL\t12\t3\tpos\tneg\t\n3\tnaïve\tTDF/FTC/ATV/r\t1\t3\tpos\tneg\t\n4\tTDF/FTC/LPV/r\tDRV/r\t12\t3\tpos\tneg\t\n5\tnaïve\tTDF/FTC/ATV/r\t3\t3\tpos\tneg\t\n6\tTDF/FTC/EFV\tABV/FTC/EFV\t9\t3\tpos\tneg\t\n7\tTDF/FTC/FPV/r\tTDF/FTC/DRV/r\t1\t3\tpos\tneg\t\n8\tDRV/r/ETV/RAL\tDRV/r/ETV/MVC\t3\t3\tpos\tneg\t\n9\tTDF/FTC/EFV\tTDF/FTC/NVP\t3\t3\tpos\tneg\t\n10\tnaïve\tTDF/FTC/DRV/r\t1\t3\tneg\tpos\t\nTDF: tenofovir; FTC: emtricitabine; ETV: etravirine; LPV/r: ritonavir-boosted lopinavir; 3TC: lamivudine; ATV/r: ritonavir-boosted atazanavir; DRV/r: ritonavir-boosted darunavir; RAL: raltegravir; EFV: efavirenz; ABV: abacavir; FPV/r: ritonavir-boosted fosamprenavir; MVC: maraviroc; NVP: nevirapine.\n\n10.1371/journal.pone.0148104.t004Table 4 Univariate and multivariate analysis of factors associated with grade 3 or 4 transaminase elevations (TE) and grade 4 total bilirubin elevations (TBE).\n\tn\tGrade 3 or 4\tp\tAOR\tp\tGrade 4\tp\tAOR\tp\t\n\t\tTE,\tuni-\t(95% CI)\tmulti-\tTBE,\tuni-\t(95% CI)\tmulti-\t\n\t\tn (%)\tvariate\t\tvariate\tn (%)\tvariate\t\tvariate\t\nAge\t\t\t\t\t\t\t\t\t\t\n <46 years\t96\t7 (7.3)\t0.194\t1.027\t0.57\t5 (5.2)\t0.360\t1.052\t0.438\t\n ≥46 years\t96\t3 (3.1)\t\t(0.936–1.127)\t\t3 (3.1)\t\t(0.926–1.193)\t\t\nSex\t\t\t\t\t\t\t\t\t\t\n Male\t169\t9 (5.3)\t0.658\t1.073\t0.949\t7 (4.1)\t0.647\t1.297\t0.826\t\n Female\t23\t1 (4.3)\t\t(0.124–9.303)\t\t1 (4.3)\t\t(0.127–13.225)\t\t\nAlcohol intake\t\t\t\t\t\t\t\t\t\t\n <50 g/day\t162\t7 (4.3)\t0.192\t0.387\t0.202\t8 (4.9)\t0.250\t\t\t\n ≥50 g/day\t30\t3 (10)\t\t(0.09–1.66)\t\t0\t\t\t\t\nALT levels\t\t\t\t\t\t\t\t\t\t\n ≥40 IU/mL\t121\t7 (5.8)\t0.458\t\t\t6 (5)\t0.378\t\t\t\n <40 IU/mL\t71\t3 (4.2)\t\t\t\t2 (2.8)\t\t\t\t\nCDC category C\t\t\t\t\t\t\t\t\t\t\n Yes\t63\t3 (4.8)\t0.574\t\t\t2 (3.2)\t0.479\t\t\t\n No\t129\t7 (5.4)\t\t\t\t6 (4.7)\t\t\t\t\nUndetectable HIV RNA\t\t\t\t\t\t\t\t\t\t\n Yes\t77\t3 (3.9)\t0.376\t\t\t6 (7.8)\t0.047\t0.229\t0.103\t\n No\t115\t7 (6.1)\t\t\t\t2 (1.7)\t\t(0.039–1.344)\t\t\nCD4 cell count\t\t\t\t\t\t\t\t\t\t\n <350 cells/mL\t81\t5 (6.2)\t0.421\t\t\t3 (3.7)\t0.753\t\t\t\n ≥350 cells/mL\t111\t5 (4.5)\t\t\t\t5 (4.5)\t\t\t\t\nBaseline cirrhosis\t\t\t\t\t\t\t\t\t\t\n Yes\t55\t2 (3.6)\t0.415\t\t\t3 (5.5)\t0.414\t\t\t\n No\t137\t8 (5.8)\t\t\t\t5 (3.6)\t\t\t\t\nStart of a NRTI\t\t\t\t\t\t\t\t\t\t\n Yes\t77\t3 (3.9)\t0.503\t\t\t5 (4.3)\t0.593\t\t\t\n No\t115\t3 (4.5)\t\t\t\t3 (3.9)\t\t\t\t\nStart of a PI/r\t\t\t\t\t\t\t\t\t\t\n Yes\t89\t7 (7.9)\t0.124\t1.319\t0.733\t4 (4.5)\t1\t\t\t\n No\t103\t3 (2.9)\t\t(0.269–6.475)\t\t4 (3.9)\t\t\t\t\nUse of ATV/r\t\t\t\t\t\t\t\t\t\t\n Yes\t29\t2 (6.9)\t0.649\t\t\t5 (17.2)\t0.002\t7.327\t0.018\t\n No\t163\t8 (4.9)\t\t\t\t3 (1.8)\t\t(1.417–37.89)\t\t\nStart of a NNRTI\t\t\t\t\t\t\t\t\t\t\n Yes\t77\t1 (1.3)\t0.052\t0.183\t0.748\t1 (1.3)\t0.147\t0.397\t0.43\t\n No\t115\t9 (7.8)\t\t(0.017–1.925)\t\t7 (6.1)\t\t(0.04–3.932)\t\t\nStart of RAL\t\t\t\t\t\t\t\t\t\t\n Yes\t24\t1 (4.2)\t0.683\t\t\t1 (4.2)\t1\t\t\t\n No\t168\t9 (5.4)\t\t\t\t7 (4.2)\t\t\t\t\nStart of a MVC\t\t\t\t\t\t\t\t\t\t\n Yes\t9\t1 (11.1)\t0.389\t\t\t0\t0.676\t\t\t\n No\t183\t9 (4.9)\t\t\t\t8 (4.4)\t\t\t\t\nAOR: adjusted odds ratio; CI: confidence interval; NRTI: nucleot(s)ide reverse transcriptase inhibitor; PI/r: ritonavir-boosted protease inhibitor; ATV/r: ritonavir-boosted atazanavir; NNRTI: non-nucleot(s)ide reverse transcriptase inhibitor; RAL: raltegravir; MVC: maravir\n\nDiscussion\nTo our knowledge, this is the first study to evaluate the hepatic safety of current ART administered in clinical practice within a single prospective cohort consisting of a large sample of patients with chronic viral hepatitis. The frequency of grade 3 or 4 TE, as well as grade 4 TBE, associated with frequently used antiretroviral drug combinations in clinical practice is low in this setting.\n\nTo date, little information on hepatic safety of multiple ART regimens under current real-life conditions is available [4,5,20]. Our group reported in 2011 a frequency of 7.6% of grade 3 to 4 TE among HIV/HCV-coinfected patients, with no impact of the ART applied [20]. However, only efavirenz and PI/r were considered in this study, and the number of patients who received ritonavir-boosted atazanavir and ritonavir-boosted darunavir was low. Thus, that cohort does not reflect the current situation and indeed, in the present study, ritonavir-boosted atazanavir and ritonavir-boosted darunavir represent the most frequently prescribed PI/r, which is in accordance with international guidelines applied during the inclusion period, while potentially hepatotoxic drugs like saquinavir [25] and fosamprenavir [26] were not among the applied regimens. Furthermore, a considerable proportion of the patients received newer NNRTI, as well as maraviroc and raltegravir. It is to note that the frequencies of grade 3 or 4 TE and grade 4 TBE are low in this setting and was to be contributed to a specific drug. Furthermore, the frequencies of these hepatotoxicity events have decreased as compared to what was observed in a similar population from 2007 to 2009, analysed in the same centers and with a comparable study design [20], although they are somewhat higher as described in a different cohort [6]. Currently used ART can generally be considered to be well tolerated. In fact, no grade 4 TE was observed, and no discontinuation due to TE or TBE was reported. These are important findings, since they imply that the frequency of hepatotoxic events in HIV/HBV- and/or HCV-coinfected has decreased with the newer regimens as compared to what was reported at the beginning of the era of highly active ART [27–30]. Finally, the outcome of TE is good and discontinuations are of lesser concern, which results in a lower exploitation of treatment options and an augmentation of life quality for the patient.\n\nIn the history of safety studies involving antiretroviral drugs, the question of whether the presence of advanced fibrosis has an impact on the prevalence of ART-induced hepatotoxic events has risen especially regarding the hepatitis virus coinfected population [31,32]. However, various cohort studies published afterwards failed to confirm a relationship between the fibrosis stage and liver enzyme elevations in patients treated with various regimens [14–16,19,20] and an impact of advanced liver damage on grade 3 or 4 TE is therefore unlikely. Nevertheless, especially cirrhotic patients may have plasma levels of antiretrovirals that are above the safety concentration and HCV infection itself may have an impact on plasma levels of ART components such as ritonavir-boosted atazanavir, efavirenz and etravirine [33–35]. In the present study, a considerably high number of patients were administered the antiretroviral drugs susceptible to suffer plasma level elevations due to advanced liver disease. It is to point out that no association between cirrhosis at baseline and grade 3 or 4 TE or grade 4 TBE was observed.\n\nA considerable number of patients started a new ART regimen with the prospect of possible initiation of treatment against HCV infection. This is not surprising since the study was conducted at the beginning of the era of direct-acting antivirals (DAA) against hepatitis C. In this context, in 2012, the protease inhibitors telaprevir and boceprevir were the first DAA approved for treatment against chronic hepatitis C in HIV/HCV-coinfected patients in Europe [23]. Unfortunately, drug-drug interactions resulted in contraindications for the concomitant use of these drugs with ritonavir-boosted lopinavir or ritonavir-boosted darunavir and required dose adjustments of telaprevir if ART included efavirenz [36,37]. Although with the next-generation DAA drug-drug interactions may be of lesser concern, this issue remains an important consideration, especially regarding HCV PI and will likely be reflected in the composition of future ART regimens [23]. In the present study, the considerably high proportion of patients who initiated ritonavir-boosted atazanavir account for this finding. We point out that the use of ritonavir-boosted atazanavir was independently associated with grade 4 TBE, which stands in accordance with former studies [13,38,39]. However, atazanavir-induced hyperbilirubinemia did not lead to treatment interruptions and was not associated with the clinical outcome of ART in the short and the long term [38,39]. Although bilirubin levels should be monitored in this setting, a clinical impact of this phenomenon is unlikely.\n\nSustained virological response to therapy against HCV infection leads to a marked decrease in the risk of drug-related liver toxicity in HIV/HCV-coinfected patients [40]. This fact prompted the recommendation of treating hepatitis C before HIV-infection in subjects with high CD4 cell count [21–23]. However, as shown here, the risk of severe liver toxicity with the currently used drugs is very low. In addition, the results of the START Study [41] support immediate ART after HIV infection diagnosis. Because of these reasons, and given that the interactions of antiretroviral drugs and direct-acting antivirals are manageable, in our opinion, deferring ART until having treated chronic hepatitis C infection is no longer justified in HIV/HCV-coinfected subjects.\n\nThis study has limitations. Due to the high variety of possible ART regimens, some drugs were applied to a lesser extent. Still, the antiretroviral drugs approved at the time of the recruitment of patients were administered in an adequate number and the composition of the regimens studied herein well reflect the situation of ART during the inclusion period. Finally, most recently approved drugs like dolutegravir and elvitegravir/cobicistat were not available during patient recruitment and should be considered in future study designs.\n\nIn conclusion, currently applied ART regimens can be considered safe in HIV-infected patients with viral hepatitis and advanced liver damage did not impact on the development of severe laboratory abnormalities analyzed herein. Although the frequencies are similar to what has been reported previously, the severity of hepatotoxic side effects have decreased throughout the last years and are unlikely to lead to treatment discontinuations.\n\nOther members of the HEPAVIR SEG-HEP-2007 Study Group are: Ángela Camacho, Emilio Campos Dávila, Francisco Javier Casas Círia, Mario Casas-Frías, Francisca Cuenca, Elisa Fernández Fuertes, Africa García Navarrete, María José Garrido Vega, Ana Gordon, Diego Rodríguez-Cano, Juan Macías, María Mancebo, Manuel Márquez, Sandra Lorenzo Moncada, Montserrat Pérez Pérez, Miguel Raffo Márquez, José Carlos Roldán Morales, Enrique Nuño, Guillermo Ojeda, Rosario Palacios and Jesús Santos.\n==== Refs\nReferences\n1 Di Biagio A , Nicolini LA , Lorenzini P , Puoti M , Antinori A , Cozzi-Lepri A , et al (2014 ) Liver enzyme elevation during darunavir-based antiretroviral treatment in HIV-1-infected patients with or without hepatitis C coinfection: data from the ICONA foundation cohort . 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"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "11(2)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D001663:Bilirubin; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections; D019694:Hepatitis B, Chronic; D019698:Hepatitis C, Chronic; D006801:Humans; D008099:Liver; D008297:Male; D008875:Middle Aged; D000637:Transaminases",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0148104",
"pmc": null,
"pmid": "26848975",
"pubdate": "2016",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "25285539;18276600;21398295;26192873;17674307;21544015;21903660;21599819;22592097;22510353;22404426;12671779;17330787;25143024;25723139;15712082;25661363;11786975;22510355;25875396;24522178;17651028;23088336;25394081;21490905;17197379;24074642;24458137;16720565;22015077;22413955;11073757;23739226;23829329",
"title": "Liver Toxicity of Current Antiretroviral Regimens in HIV-Infected Patients with Chronic Viral Hepatitis in a Real-Life Setting: The HEPAVIR SEG-HEP Cohort.",
"title_normalized": "liver toxicity of current antiretroviral regimens in hiv infected patients with chronic viral hepatitis in a real life setting the hepavir seg hep cohort"
} | [
{
"companynumb": "ES-CIPLA LTD.-2016ES01160",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE"
},
"drugadditi... |
{
"abstract": "The phase III PROSELICA trial showed that cabazitaxel 20 mg/m (C20) was not inferior and better tolerated compared to cabazitaxel 25 mg/m (C25) in patients with metastatic castration-resistant prostate cancer (mCRPC) who had progressed during or after docetaxel. Here, we report on a real-world retrospective analysis concerning the safety and the activity of C20 schedule in patients with mCRPC treated at our Institution. We identified 35 patients with mCRPC who received C20 as baseline dose treatment because they were frail or experienced serious toxicities to previous treatments. Adverse events assessment was performed at each visit during the treatment. Progression-free survival (PFS) and overall survival (OS) curves were obtained using the Kaplan-Meyer product-limit estimator. Median age was 71 years. All patients received a previous treatment with docetaxel; 19 patients (54%) received one additional line of therapy and 9 (26%) two or more. Patients received a median of 4 cycles (range: 2-10). Only one patient experienced grade 3 neutropenia (3%), two patients grade 3 anemia (6%), and one patient grade 3 fatigue (3%); three patients were treated with prophylactic Granulocyte colony-stimulating factor (9%). The most frequent adverse events of all grades were: anemia (39%), fatigue (33%), and diarrhea (15%). Median PFS was 3.7 months [95% confidence interval (CI): 3.31-4.09]; median OS was 10.3 months (95% CI: 4.63-15.97). Our real-world analysis confirms that C20 is a feasible option for elderly and heavily pretreated patients with mCRPC, showing activity and good tolerability.",
"affiliations": "Academic Unit of Medical Oncology, IRCCS San Martino Polyclinic Hospital.;Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genoa, Genoa.;Medical Oncology Unit, Santa Chiara Hospital, Trento, Italy.;Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genoa, Genoa.;Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genoa, Genoa.;Academic Unit of Medical Oncology, IRCCS San Martino Polyclinic Hospital.",
"authors": "Vallome|Giacomo|G|;Cattrini|Carlo|C|;Messina|Carlo|C|;Cerbone|Luigi|L|;Boccardo|Francesco|F|;Zanardi|Elisa|E|",
"chemical_list": "D014408:Biomarkers, Tumor; D043823:Taxoids; C552428:cabazitaxel",
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000000805",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-4973",
"issue": "30(8)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D064129:Prostatic Neoplasms, Castration-Resistant; D012189:Retrospective Studies; D015996:Survival Rate; D043823:Taxoids",
"nlm_unique_id": "9100823",
"other_id": null,
"pages": "854-858",
"pmc": null,
"pmid": "31356228",
"pubdate": "2019-09",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Reduced dose of cabazitaxel in metastatic castration-resistant prostate cancer: from PROSELICA trial to the real life: A single institution experience.",
"title_normalized": "reduced dose of cabazitaxel in metastatic castration resistant prostate cancer from proselica trial to the real life a single institution experience"
} | [
{
"companynumb": "IT-TEVA-2019-IT-1121999",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "Acute promyelocytic leukemia (APL) constitutes about 15% of all acute myeloid leukemia patients and can now be treated even without any chemotherapy, with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Acute pancreatitis (AP) is a rare adverse event in APL, which is primarily reported to be secondary to hypertriglyceridemia. Here, we have reported AP developed in a patient of APL, during induction with ATRA and ATO, but it was not associated with hypertriglyceridemia. Rather, it was associated with respiratory distress and weight gain, coincidental leukocytosis, bilateral pleural effusion, and edematous pancreatitis without any necrosis. Hence, AP in this case is diagnosed to be a manifestation of differentiation syndrome, and it responded to steroid.",
"affiliations": "Department of Hematology and Hemato-Oncology, The Mission Hospital, Durgapur, West Bengal, India.;Department of Hematology, Institute of Hematology and Transfusion Medicine, Medical College, Kolkata, West Bengal, India.;Department of Hematology, NRS Medical College, Kolkata, West Bengal, India.",
"authors": "De|Dibyendu|D|;Nath|Uttam Kumar|UK|;Chakrabarti|Prantar|P|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.4103/ijmpo.ijmpo_36_16",
"fulltext": "\n==== Front\nIndian J Med Paediatr OncolIndian J Med Paediatr OncolIJMPOIndian Journal of Medical and Paediatric Oncology : Official Journal of Indian Society of Medical & Paediatric Oncology0971-58510975-2129Medknow Publications & Media Pvt Ltd India IJMPO-38-37110.4103/ijmpo.ijmpo_36_16Case ReportPancreatitis in Acute Promyelocytic Leukemia: Drug-induced or Differentiation Syndrome? De Dibyendu Nath Uttam Kumar 1Chakrabarti Prantar 2Department of Hematology and Hemato-Oncology, The Mission Hospital, Durgapur, West Bengal, India1 Department of Hematology, Institute of Hematology and Transfusion Medicine, Medical College, Kolkata, West Bengal, India2 Department of Hematology, NRS Medical College, Kolkata, West Bengal, IndiaAddress for correspondence: Dr. Dibyendu De, The Mission Hospital, Plot No. 219 (P), Immon Kalyan Sarani, Sector 2c, Bidhan Nagar, Burdwan, Durgapur - 713 212, West Bengal, India. E-mail: de.dibyendu@gmail.comJul-Sep 2017 38 3 371 373 Copyright: © 2017 Indian Journal of Medical and Paediatric Oncology2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Acute promyelocytic leukemia (APL) constitutes about 15% of all acute myeloid leukemia patients and can now be treated even without any chemotherapy, with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Acute pancreatitis (AP) is a rare adverse event in APL, which is primarily reported to be secondary to hypertriglyceridemia. Here, we have reported AP developed in a patient of APL, during induction with ATRA and ATO, but it was not associated with hypertriglyceridemia. Rather, it was associated with respiratory distress and weight gain, coincidental leukocytosis, bilateral pleural effusion, and edematous pancreatitis without any necrosis. Hence, AP in this case is diagnosed to be a manifestation of differentiation syndrome, and it responded to steroid.\n\nKeywords\nAcute promyelocytic leukemiaall-trans-retinoic acidarsenicdifferentiation syndromepancreatitis\n==== Body\nIntroduction\nAcute promyelocytic leukemia (APL) constitutes about 15% of all acute myeloid leukemia (AML) patients[1] and its treatments differ from other AML. With the introduction of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO), APL can now be treated even without any chemotherapy. Careful monitoring and successful treatment of these complications may result in complete remission in about 85% of patients.[2] Reported adverse effects of ATRA vary from dry skin to retinoic acid syndrome.[3] Acute pancreatitis (AP) is a rare adverse event which is primarily reported to be secondary to hypertriglyceridemia. Here, we are presenting an interesting case of APL-developed AP as a manifestation of differentiation syndrome.\n\nCase Report\nAn 18-year-old female patient presented to us with bleeding from gum and multiple purpuric spot all over the body for 7 days, along with mild low-grade fever. At presentation, she was pale, with multiple purpura over the body, presence of wet purpura in buccal mucosa, no icterus, and mild hepatosplenomegaly, without any lymphadenopathy. Her initial blood report revealed total lymphocyte count of 7.2 × 109/L with the presence of abnormal promyelocytes. Bone marrow immunophenotyping and cytogenetics study was suggestive of APL, and polymerase chain reaction for PML-RARA was positive. Hence, diagnosis of APL, Sanz intermediate risk, was made. The patient was started on ATRA (45 mg/m2) and ATO (0.15 mg/Kg) according to the institutional protocol and was monitored for disseminated intravascular coagulation (DIC) as well as for differentiation syndrome. The initial DIC parameters improved within 5 days of starting ATRA; the patient started improving with cessation of bleeding manifestation and subsidence of fever. On day 12 of ATRA therapy, the patient complained of respiratory distress with vague abdominal pain. On examination, there was no icterus, mild abdominal tenderness in epigastrium not radiating to anywhere, bowel sound was sluggish, and there was no rigidity or rebound tenderness. Chest was clear on auscultation. Within next 2 days, the pain increased, along with radiation to back, with abdominal guarding and absent bowel sound. There was diminished breath sound in bilateral lower zone of the chest with crepitation in basal region. She did not have any fever, bleeding, or jaundice, but regular weight monitoring revealed weight gain of about 6 kg in the past 3 days.\n\nThe complete hemogram revealed an increase in total lymphocyte count of 26.5 × 109/L to 62.5 × 109/L from day 12 to day 15 of ATRA therapy. Furthermore, the biochemical parameters revealed an increase in serum lipase, amylase level (peak value 1229 IU/dl and 940 IU/dl, respectively), and mild increase in liver enzymes (serum glutamyl pyruvate transaminase and serum glutamic oxaloacetic transaminase are 346 and 380 IU/dl, respectively). The lipid profile, electrolytes, and calcium level were within normal range (calcium: 9.2 mg/dl, triglyceride: 194 mg/dl) [Figure 1]. The prothrombin time, activated partial thromboplastin time, fibrinogen, and D-dimer were normal. The biochemical parameters were suggestive of AP, and contrast-enhanced computed tomography (CECT) abdomen revealed bulky edematous pancreatitis without any area of necrosis and bilateral pleural effusion [Figures 2 and 3].\n\nFigure 1 Change in total leukocyte count, lipase and triglyceride level during the development of acute pancreatitis\n\nFigure 2 Straight X-ray abdomen in erect posture showing colon cutoff sign\n\nFigure 3 Contrast-enhanced computed tomography abdomen showing bulky edematous pancreatitis\n\nShe was started on empirical broad-spectrum antibiotics after sending blood culture and on dexamethasone 10 mg twice daily. The ATRA and arsenic were kept withheld until symptom subsides, and she improved in next 8 days. The ATRA was started on a lower dose (25 mg/m2) and she achieved complete remission on day 70 of ATRA therapy.\n\nDiscussion\nAP in APL is a rare complication. Very few case reports are available which depicts the development of AP in APL. The exact etiopathogenesis of AP sometimes remains unknown. The two most common causes of AP in general population, namely, alcohol and common bile duct obstruction by gallstone are not applicable here.\n\nDrug-induced AP accounts 1.5%–2% of all AP.[4] Both ATRA and ATO can rarely cause AP. The common mechanism of AP with ATRA is due to the development of hypertriglyceridemia. ATRA-related AP has been previously reported by different authors.[56] In all these cases, patients had hypertriglyceridemia. However, few case reports also described development of AP without hypertriglyceridemia.[7] In our patient, the development of AP was not associated with hypertriglyceridemia.\n\nThe development of AP as a presentation of acute arsenic toxicity is far less common and reported only in four case reports previously.[891011] In all of them, higher dose of ATO or oral administration of ATO is used, and they were associated with manifestation of acute arsenic toxicity such as diarrhea, abdominal pain, and jaundice. Monitoring of urinary arsenic excretion can help. Values >50–100 μg/24 h suggests arsenic intoxication.[8] A fatal dose range lies between 100 and 300 mg although smaller doses may also be life-threatening.[12] Our patient received arsenic at a dose 0.15 mg/kg daily for about 14 days before AP.\n\nThe possible causes of AP in APL are delineated in Table 1. Hypercalcemia was ruled out in our patient by biochemical tests. Probability of the development of microvascular thrombosis in pancreatic bed due to DIC was also unlikely because the patient already had resolution of all bleeding manifestation and DIC markers were normal. Furthermore, DIC after 2 weeks of ATRA therapy is very unlikely in APL patients.\n\nTable 1 Causes of pancreatitis in acute promyelocytic leukemia\n\nThe patient had initial symptoms of respiratory distress before overt AP. Furthermore, the patient had significant weight gain during the development of AP. The total lymphocyte count was also raised during the period. The patient also developed bilateral pleural effusion concomitantly. The CECT showed edematous bulky pancreatitis without any necrosis. The patient's symptoms subsided with stoppage of therapy and dexamethasone. All these lead to a diagnosis of differentiation syndrome which manifested in the form of AP. The differentiation syndrome occurs due to release of cytokines from granules of abnormal promyelocytes while they differentiate which lead to endothelial leakage. This leads to widespread edema, including pulmonary edema and weight gain. The pancreatic edema may cause occlusion of pancreatic duct leading to the development of AP. The manifestation of differentiation syndrome in the form of AP is not mentioned in literature before. To the best of our knowledge, this is first case report, where APL patient developed AP as a manifestation of differentiation syndrome due to ATRA and ATO therapy.\n\nConclusion\nAP is a rare complication of APL during chemotherapy. Multiple etiological factors can cause AP in these patients, of which drug-induced AP is the most common cause. AP as a form of differentiation syndrome is rare and can occur due to edematous pancreatic duct leading to obstruction. Careful monitoring and exclusion of all other causes needed for the management of such lethal complication.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 Warrell RP Jr de The H Wang ZY Degos L Acute promyelocytic leukemia N Engl J Med 1993 329 17 89 \n2 Soignet SL Maslak P Wang ZG Jhanwar S Calleja E Dardashti LJ Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide N Engl J Med 1998 339 1341 8 9801394 \n3 Hatake K Uwai M Ohtsuki T Tomizuka H Izumi T Yoshida M Rare but important adverse effects of all-trans retinoic acid in acute promyelocytic leukemia and their management Int J Hematol 1997 66 13 9 9220656 \n4 Koshy GK Kumar S Hertan HI All-trans-retinoic acid (tretinoin) induced fatal acute pancreatitis Am J Gastroenterol 2003 98 Suppl S9 S164 \n5 Abou Chacra L Ghosn M Ghayad E Honein K A case of pancreatitis associated with all-trans-retinoic acid therapy in acute promyelocytic leukemia Hematol J 2001 2 406 7 11920282 \n6 Izumi T Hatake K Miura Y Acute promyelocytic leukemia N Engl J Med 1994 330 141 \n7 Teng HW Bai LY Chao TC Wang WS Chen PM Acute pancreatitis during all-trans-retinoic acid treatment for acute promyelocytic leukemia in a patient without overt hypertriglyceridemia Jpn J Clin Oncol 2005 35 94 6 15709095 \n8 Zaloga GP Deal J Spurling T Richter J Chernow B Unusual manifestations of arsenic intoxication Am J Med Sci 1985 289 210 4 4003428 \n9 Yamano T Yokote T Akioka T Hara S Oka T Tsuji M Acute pancreatitis during the treatment of relapsed acute promyelocytic leukemia with As2O3 Rinsho Ketsueki 2006 47 23 5 16479979 \n10 Hantson P Haufroid V Buchet JP Mahieu P Acute arsenic poisoning treated by intravenous dimercaptosuccinic acid (DMSA) and combined extrarenal epuration techniques J Toxicol Clin Toxicol 2003 41 1 6 12645960 \n11 Connelly S Zancosky K Farah K Arsenic-induced pancreatitis Case Rep Gastrointest Med 2011 2011 758947 22606427 \n12 Ratnaike RN Acute and chronic arsenic toxicity Postgrad Med J 2003 79 391 6 12897217\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-5851",
"issue": "38(3)",
"journal": "Indian journal of medical and paediatric oncology : official journal of Indian Society of Medical & Paediatric Oncology",
"keywords": "Acute promyelocytic leukemia; all-trans-retinoic acid; arsenic; differentiation syndrome; pancreatitis",
"medline_ta": "Indian J Med Paediatr Oncol",
"mesh_terms": null,
"nlm_unique_id": "9604571",
"other_id": null,
"pages": "371-373",
"pmc": null,
"pmid": "29200694",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "8515790;12897217;11920282;8259178;22606427;16479979;15709095;12645960;4003428;9801394;9220656",
"title": "Pancreatitis in Acute Promyelocytic Leukemia: Drug-induced or Differentiation Syndrome?",
"title_normalized": "pancreatitis in acute promyelocytic leukemia drug induced or differentiation syndrome"
} | [
{
"companynumb": "IN-ZO SKIN HEALTH-2018ZOS00009",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ARSENIC TRIOXIDE"
},
"drugadditional": "... |
{
"abstract": "We present a case-based review of the first five percutaneous fetoscopic in-utero spina bifida repair procedures undertaken in the UK. Our focus is on implications of anaesthesia and analgesia for the mother and fetus, provision of uterine relaxation and fetal immobilisation while providing conditions conducive to surgical access. Minimising risks for fetal acidosis, placental and fetal hypoperfusion, maternal and fetal sepsis and maternal fluid overload were the foremost priorities. We discuss optimisation strategies undertaken to ensure fetal and maternal well-being under anaesthesia, shortcomings in the current approach, and possible directions for improvement.",
"affiliations": "Department of Anaesthesia, King's College Hospital, London, UK. Electronic address: chula.goonasekera@nhs.net.;Department of Anaesthesia, King's College Hospital, London, UK.;Department of Neurosurgery, King's College Hospital, London, UK.;Fetal Medicine Research Institute, King's College Hospital, London, UK.;Department of Obstetrics and Fetal Medicine, Hospital Israelita Albert Einstein, Sao Paulo, Brazil.;Department of Obstetrics and Fetal Medicine, Fetal Medicine Research Institute, King's College Hospital, London, UK.;Department of Neurosurgery, King's College Hospital, London, UK.;Department of Neonatology, King's College Hospital, London, UK.;Department of Neonatology, King's College Hospital, London, UK.;Department of Anaesthesia, Hospital Israelita Albert Einstein, Sao Paulo, Brazil.",
"authors": "Goonasekera|C D|CD|;Skelton|V A|VA|;Zebian|B|B|;Nicolaides|K|K|;Araujo Lapa|D|D|;Santorum-Perez|M|M|;Bleil|C|C|;Hickey|A|A|;Bhat|R|R|;Oliva Gatto|B E|BE|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijoa.2020.04.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-289X",
"issue": "43()",
"journal": "International journal of obstetric anesthesia",
"keywords": "Depth of anaesthesia; Fetal monitoring; Percutaneous fetoscopic spina-bifida repair; Transplacental anaesthesia; Uterine tocolysis",
"medline_ta": "Int J Obstet Anesth",
"mesh_terms": "D000328:Adult; D000768:Anesthesia, General; D017809:Fatal Outcome; D005260:Female; D005332:Fetoscopy; D006801:Humans; D008279:Magnetic Resonance Imaging; D019990:Perioperative Care; D011247:Pregnancy; D011296:Prenatal Diagnosis; D016135:Spinal Dysraphism; D016896:Treatment Outcome; D016216:Ultrasonography, Prenatal; D006113:United Kingdom",
"nlm_unique_id": "9200430",
"other_id": null,
"pages": "97-105",
"pmc": null,
"pmid": "32386991",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Peri-operative management of percutaneous fetoscopic spina-bifida repair: a descriptive review of five cases from the United Kingdom, with focus on anaesthetic implications.",
"title_normalized": "peri operative management of percutaneous fetoscopic spina bifida repair a descriptive review of five cases from the united kingdom with focus on anaesthetic implications"
} | [
{
"companynumb": "GB-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-259123",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugad... |
{
"abstract": "OBJECTIVE\nWarfarin is standard anticoagulation therapy for patients with a continuous-flow left ventricular assist device (CF-LVAD). However, warfarin requires regular monitoring and dosage adjustments and fails for many patients, causing thromboembolic and bleeding events. Factor Xa inhibitors have been shown to be noninferior to warfarin in preventing strokes and are associated with less intracranial hemorrhage in patients with atrial fibrillation. We evaluated treatment safety and effectiveness in CF-LVAD patients who switched from warfarin to a factor Xa inhibitor (apixaban or rivaroxaban) after warfarin failure.\n\n\nMETHODS\nThis was a retrospective, single-center study of patients treated between 2008 and 2018. We assessed the occurrence of stroke, non-central nervous system (CNS) embolism, pump thrombosis, and major gastrointestinal bleeding and intracranial hemorrhage during therapy.\n\n\nRESULTS\nWe identified seven patients: five were male, the average body mass index was 30 kg/m2, and average age was 56 years. Preimplantation comorbidities included hypertension (all patients) and diabetes mellitus, ischemic cardiomyopathy, atrial fibrillation, and previous myocardial infarction (four patients each). Overall, patients received warfarin for 3968 days and apixaban/rivaroxaban for 1459 days. The warfarin group was within the therapeutic INR range (2.0-3.0) 30% of the time. Complication rates did not differ between warfarin and apixaban/rivaroxaban: strokes, 0.20 vs none, non-CNS embolism, 0.54 vs none; pump thrombosis, 0.27 vs none; major gastrointestinal bleeding, 0.20 vs 0.50; intracranial hemorrhage, 0.13 vs none.\n\n\nCONCLUSIONS\nFactor Xa inhibitors may be viable treatment options for CF-LVAD patients for whom warfarin therapy has failed. Large prospective studies are necessary to confirm these results.",
"affiliations": "Division of Cardiothoracic Transplantation and Circulatory Support, Baylor College of Medicine, 6720 Bertner Ave, Houston, TX, 77030, USA. vparikh2321@gmail.com.;Division of Cardiothoracic Transplantation and Circulatory Support, Baylor College of Medicine, 6720 Bertner Ave, Houston, TX, 77030, USA.;Division of Cardiothoracic Transplantation and Circulatory Support, Baylor College of Medicine, 6720 Bertner Ave, Houston, TX, 77030, USA.;Division of Cardiothoracic Transplantation and Circulatory Support, Baylor College of Medicine, 6720 Bertner Ave, Houston, TX, 77030, USA.;Division of Cardiothoracic Transplantation and Circulatory Support, Baylor College of Medicine, 6720 Bertner Ave, Houston, TX, 77030, USA.;Division of Cardiothoracic Transplantation and Circulatory Support, Baylor College of Medicine, 6720 Bertner Ave, Houston, TX, 77030, USA.;Division of Cardiothoracic Transplantation and Circulatory Support, Baylor College of Medicine, 6720 Bertner Ave, Houston, TX, 77030, USA.;Division of Cardiothoracic Transplantation and Circulatory Support, Baylor College of Medicine, 6720 Bertner Ave, Houston, TX, 77030, USA.;Department of Cardiology, Texas Heart Institute, 6770 Bertner Ave, Houston, TX, 77030, USA.",
"authors": "Parikh|Vishal Y|VY|;Parikh|Umang M|UM|;Moctezuma-Ramirez|Angel|A|;Lamba|Harveen K|HK|;George|Joggy K|JK|;Fedson|Savitri|S|;Nair|Ajith P|AP|;Frazier|O H|OH|;Delgado|Reynolds M|RM|",
"chemical_list": "D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D014859:Warfarin; D000069552:Rivaroxaban",
"country": "Japan",
"delete": false,
"doi": "10.1007/s11748-020-01371-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1863-6705",
"issue": "68(11)",
"journal": "General thoracic and cardiovascular surgery",
"keywords": "Atrial fibrillation; Bleeding; Circulatory support devices; Coagulation/anticoagulation; Thrombosis",
"medline_ta": "Gen Thorac Cardiovasc Surg",
"mesh_terms": "D065427:Factor Xa Inhibitors; D005260:Female; D006333:Heart Failure; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles; D011728:Pyridones; D012189:Retrospective Studies; D000069552:Rivaroxaban; D020521:Stroke; D013923:Thromboembolism; D016896:Treatment Outcome; D014859:Warfarin",
"nlm_unique_id": "101303952",
"other_id": null,
"pages": "1278-1284",
"pmc": null,
"pmid": "32338333",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Factor Xa inhibitors in patients with continuous-flow left ventricular assist devices.",
"title_normalized": "factor xa inhibitors in patients with continuous flow left ventricular assist devices"
} | [
{
"companynumb": "US-CIPLA LTD.-2020US03556",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
... |
{
"abstract": "Radiation therapy (RT)-induced effects in children treated for low grade glioma (LGG) can result in worsening of neurologic symptoms and clinical and radiographic deterioration. Treatment for radiation-induced tumor enlargement is based on symptom control and usually involves steroids.\n\n\n\nWe conducted a retrospective review of children with LGG treated with RT who developed symptomatic radiation-induced tumor enlargement and were managed with bevacizumab. Charts were abstracted for onset and duration of RT changes, toxicity and doses of dexamethasone and bevacizumab. Tumor volumes prior to RT, at maximal size following RT, after bevacizumab administration, and at follow-up were evaluated.\n\n\n\nFive children were treated with bevacizumab for symptomatic radiation-induced tumor enlargement following RT for LGG at a median of 4.2 months (range, 1-11 months) after completion of RT. The median increase in volume of tumor was 195.4% (range, 115.5-309%) compared to the pre-RT volume. Bevacizumab 5-10 mg/kg was administered IV q 2-4 weeks as primary treatment (n = 1) or to assist in weaning patients off steroids (n = 4). All children on high dose steroids (n = 4) were weaned off or to physiologic doses of hydrocortisone. Two children developed avascular necrosis after prolonged steroid use and while on bevacizumab. Radiographically, all children showed significant improvement and are now a median of 31 months (range, 18-50 months) from the completion of radiation without requiring additional tumor-related therapy.\n\n\n\nBevacizumab can play an important role in children with symptomatic radiation changes following LGG treatment, allowing patients to avoid or minimize the toxicity of long-term steroid use. Pediatr Blood Cancer 2015;62:240-245. © 2014 Wiley Periodicals, Inc.",
"affiliations": "Department of Neurosurgery, Children's Hospital of Pittsburgh, Neurosurgery/Faculty Pavilion, Pittsburgh, Pennsylvania.;Department of Neurosurgery, Children's Hospital of Pittsburgh, Neurosurgery/Faculty Pavilion, Pittsburgh, Pennsylvania.;Department of Neurosurgery, Children's Hospital of Pittsburgh, Neurosurgery/Faculty Pavilion, Pittsburgh, Pennsylvania.;Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.",
"authors": "Foster|Kimberly A|KA|;Ares|William J|WJ|;Pollack|Ian F|IF|;Jakacki|Regina I|RI|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D018931:Antineoplastic Agents, Hormonal; D000068258:Bevacizumab; D003907:Dexamethasone",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.25277",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "62(2)",
"journal": "Pediatric blood & cancer",
"keywords": "bevacizumab; low grade glioma; pediatrics; pilocytic astrocytoma; radiation-induced tumor enlargement; radiotherapy",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D020533:Angiogenesis Inhibitors; D018931:Antineoplastic Agents, Hormonal; D000068258:Bevacizumab; D001932:Brain Neoplasms; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone; D005260:Female; D005910:Glioma; D006801:Humans; D008297:Male; D009381:Neoplasms, Radiation-Induced; D011832:Radiation Injuries; D012189:Retrospective Studies",
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"title": "Bevacizumab for symptomatic radiation-induced tumor enlargement in pediatric low grade gliomas.",
"title_normalized": "bevacizumab for symptomatic radiation induced tumor enlargement in pediatric low grade gliomas"
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"abstract": "Arterial dissection is an important cause of stroke in young patients. Various factors influencing arterial dissection included amphetamine abuse and anterior circulation is the majority of stroke locations. We reported the Case of a 40-year-old male patient with chronic amphetamine used since childhood. He had increased the consumption from once a month to every other day in the last year. The patient suffered from acute left-side hemiparesis and neglect. Computed tomography angiography of the brain and neck vessels demonstrated non-atheromatous vasculopathy with a suspected dissection process of the right internal carotid artery and bilateral vertebral arteries. A review of recent data is also provided to clarify the possible mechanism.",
"affiliations": "Division of Neurology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.;Division of Neurology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.",
"authors": "Sirimaharaj|Nopdanai|N|;Thiankhaw|Kitti|K|",
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"doi": "10.1016/j.amsu.2021.102676",
"fulltext": "\n==== Front\nAnn Med Surg (Lond)\nAnn Med Surg (Lond)\nAnnals of Medicine and Surgery\n2049-0801\nElsevier\n\nS2049-0801(21)00626-9\n10.1016/j.amsu.2021.102676\n102676\nCase Report\nInternal carotid artery and bilateral vertebral arteries dissections associated with amphetamine abuse: Case report\nSirimaharaj Nopdanai\nThiankhaw Kitti kitti.th@cmu.ac.th\nnummm.kt@gmail.com\n∗\nDivision of Neurology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand\n∗ Corresponding author. Division of Neurology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, 110, Inthawaroros Road, Sriphum, Chiang Mai, 50200, Thailand. kitti.th@cmu.ac.thnummm.kt@gmail.com\n05 8 2021\n8 2021\n05 8 2021\n68 10267627 6 2021\n1 8 2021\n3 8 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nArterial dissection is an important cause of stroke in young patients. Various factors influencing arterial dissection included amphetamine abuse and anterior circulation is the majority of stroke locations. We reported the Case of a 40-year-old male patient with chronic amphetamine used since childhood. He had increased the consumption from once a month to every other day in the last year. The patient suffered from acute left-side hemiparesis and neglect. Computed tomography angiography of the brain and neck vessels demonstrated non-atheromatous vasculopathy with a suspected dissection process of the right internal carotid artery and bilateral vertebral arteries. A review of recent data is also provided to clarify the possible mechanism.\n\nHighlights\n\n• Arterial dissection is one of the most common causes of stroke in young-adults.\n\n• Dissection of both anterior and posterior cerebral circulations is extremely rare.\n\n• Amphetamine abuse has been described as a potential cause of arterial dissection.\n\n• Drug abuse screening should be performed in stroke in the young presuming dissection.\n\nKeywords\n\nAmphetamine\nArtery dissection\nDrug abuse\nIschemic stroke\n==== Body\n1 Introduction\n\nThis work consists of a single Case report and has been reported in accordance with SCARE 2020 criteria [1]. Cervical artery dissection (CAD) accounts for about 20 % of stroke in younger patients under 45 years old [2]. The clinical features include headache and neck pain, Horner's syndrome, and cranial nerve palsy. Etiopathogenesis of CAD is incompletely understood, though neck trauma, recent systemic or intracranial infections, and underlying arteriopathy are considered important [2,3]. Amphetamine is an increased risk of stroke due to its vasculopathic properties [4]. Some reported cases show internal carotid artery (ICA) or vertebral artery (VA) dissection related to amphetamine abuse; however, there is still limited data on ICA and VA dissections in young-onset stroke patients with amphetamine abuse. The present case reports in this setting and recent data review are also provided to clarify the possible mechanism.\n\n1.1 Case presentation\n\nA previously healthy 40-year-old right-handed male and non-marfanoid habitus presented with acute onset of left side weakness 12-h before admission. The patient had no complaints of headache, neck pain, or abnormal vision. His wife noticed mildly slurred speech and left side disinterestedness. The patient had no preceding trauma or neck manipulation. He confessed to amphetamine used since childhood and increased the consumption from once a month to every other day in the last year. The patient did not abuse any other substance, including cocaine, heroin, or decongestant. He has no family history of cerebrovascular disease or premature atherosclerosis.\n\nGeneral physical examination was unremarkable except for hypertension of 182/76 mm Hg. Apart from left side hemiparesis grade I, neurological examination showed right gaze preference in primary position, left facial weakness, left-side neglect, and mild right arm dysmetria. The initial non-contrasted computed tomography (CT) of the brain revealed hyperacute infarction of the right middle cerebral artery (MCA) territory. A computed tomography angiography (CTA) showed alternating stenosis and dilatation along the wall of the ICA cervical and petrous segment, bilateral VA V2–V3 segments (Fig. 1). These findings are preferred to be the spectrum of non-atheromatous vasculopathy with the suspected dissection process. Extensive workup, including complete blood count, blood chemistry, hypercoagulability and vasculitic profiles, anti-HIV, electrocardiography, Holter monitoring, and transthoracic echocardiography with saline agitation test were all unremarkable. Toxicology screening revealed a significant positive test for amphetamine in the urine.Fig. 1 CTA cerebral vessels demonstrated alternating stenosis and dilation along the right ICA cervical and petrous segment wall (bold white arrow), bilateral VA V2–V3 segment (white dash arrow). Abrupt severe luminal narrowing to occlusion at right ICA supraclinoid segment is noted (white arrowhead). These findings are preferred non-atheromatous vasculopathy with suspected dissection process at the right ICA and bilateral VAs.\n\nFig. 1\n\nThe patient was treated with antiplatelet therapy (aspirin 300 mg), anti-hypertensive agents, and rehabilitation. He was admitted to the acute stroke unit for twelve days and discharged with moderately residual neurological deficit, modified Rankin Scale (mRS) of 4. At one month follow-up, the patient was explicitly improved in motor function. Mild residual dysarthria and still had left-side neglect were observed. We plan to re-evaluate CTA cerebral vessels three to six months after the stroke onset. A multidisciplinary team including a primary physician, psychiatrist, and therapy activist involves helping the patient with amphetamine abstinence. The patient recognizes the adverse effects of amphetamine abuse and is willing to lifelong discontinuation. He continues a home rehabilitation program to enhance stroke recovery.\n\n2 Discussion\n\nThe major causes of stroke in young adults and children differ from those in older people. Arterial dissection is one of many causes that we must not miss due to a life-threatening and treatable condition. They may present as transient attacks (often stereotyped) or complete stroke, which develop in as many as 20 % of cases [5]. ICA dissection is much more common than VA dissection, but both can present simultaneously. Several risk factors have been proposed for CAD, including neck or cervical trauma, inherited connective tissue disorders (Ehlers-Danlos syndrome and Marfan's syndrome), hypertension and migraine without aura [6]. In our Case, there are no clinical clues or laboratory results that explained the cause of ICA and VA dissections unless a history of chronic and incremental amphetamine abuse with a strongly positive result of urine amphetamine.\n\nAmphetamine is a sympathomimetic amine, and it acts as a central nervous system behavioral stimulant. Hemorrhagic stroke, including intracerebral and subarachnoid hemorrhage, is the most common cerebrovascular complication of amphetamine abuse, accounting for 67 % of cases [7]. The remaining one-third is diagnosed as ischemic stroke, and anterior circulation is the majority of stroke locations. Recently, two Case reports described VA dissection in a patient with amphetamine abuse [8,9]. Interestingly, both cases had a history of increasing amphetamine consumption before developing the stroke syndrome, which occurred with our patient. Moreover, the dissection of ICA and VA related to amphetamine abuse is not frequently reporting. A Ewida et al. reported spontaneous dissection of bilateral ICA and VA in a middle-aged woman taking a pill for weight loss containing an amphetamine derivative [10]. Although this may be a coincidental finding, the association between amphetamine abuse and arterial dissection cannot be excluded. Our patient had multiple vascular dissections and raised the possibility for the association with amphetamine abuse.\n\nThe proposed for amphetamine-related vascular injury have been described by several mechanisms, include vasculitis, vasospasm, hypertension, or direct endovascular toxicity [11]. A pathology study in a middle-aged patient with left MCA stroke and multiple anterior circulation vasculopathy due to amphetamine abuse revealed severe atherosclerosis with a ruptured plaque and thrombus formation. Furthermore, there was no evidence of inflammatory cell infiltration in the vessel walls. These findings suggest the process of premature atherosclerosis to be the underlying mechanism [7].\n\nThe current treatment guidelines recommend that intravenous thrombolysis is not contraindicated for patients with hyperacute to acute extracranial cervical and intracranial arterial dissection, except for aortic arch dissection. Based on the CADISS (Cervical Artery Dissection in Stroke Study) in 2015, there were no significant differences in recurrent stroke and all-cause mortality between anticoagulant and antiplatelet therapy in patients with extracranial carotid and VA dissection. It is reasonable to treat patients with either antiplatelet or anticoagulant for three to six months [12]. The prognosis of CAD is favorable, and blood vessel resolution is noted in up to 80 % of patients [13].\n\n3 Conclusion\n\nArterial dissection is a potentially disabling and probably underdiagnosed stroke cause, mainly affecting young adults. Screening tests for amphetamine abuse should be warranted in younger stroke patients who presented with multisite arterial dissections and do not have significant vascular risk factors. More cases and studies are needed to demonstrate a more precise relationship and underlying mechanisms.\n\nSources of funding\n\nNo funding was received for the carrying out of this study and in the preparation of the manuscript.\n\nEthical approval\n\nThe Medical Ethics Committees of the Faculty of Medicine, Chiang Mai University approved this Case report.\n\nConsent\n\nWritten informed consent was obtained from the patient for publication of this Case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor contribution\n\nNopdanai Sirimaharaj, M. D: contributed to data collection, literature review, and first draft manuscript preparation. Kitti Thiankhaw, M. D: contributed to neurological management, data collection, literature review, writing, and manuscript editing.\n\nResearch registration\n\nThis Case report was registered at http://www.researchregistry.com. The unique identifying number is researchregistry7008, and the hyperlink to specific registration is https://www.researchregistry.com/browse-the-registry#home/.\n\nGuarantor\n\nKitti Thiankhaw, M.D.ORCID.\n\nProvenance and peer review\n\nNot commissioned, externally peer-reviewed.\n\nDeclaration of Competing interest\n\nThe authors have no conflicts of interest to declare.\n\nPlease state any sources of funding for your research\n\nNo funding was received for the carrying out of this study and in the preparation of the manuscript.\n\nNopdanai Sirimaharaj, M. D: contributed to data collection, literature review, and first draft manuscript preparation.\n\nKitti Thiankhaw, M. D: contributed to neurological management, data collection, literature review, writing, and manuscript editing.\n\nPlease state any conflicts of interest\n\nThe authors have no conflicts of interest to declare.\n\nRegistration of research studies\n\nIn accordance with the Declaration of Helsinki 2013, all research involving human participants has to be registered in a publicly accessible database. Please enter the name of the registry and the unique identifying number (UIN) of your study.\n\nYou can register any type of research at http://www.researchregistry.com to obtain your UIN if you have not already registered. This is mandatory for human studies only. Trials and certain observational research can also be registered elsewhere such as: ClinicalTrials.gov or ISRCTN or numerous other registries.1. Name of the registry: Internal carotid artery and bilateral vertebral arteries dissections associated with amphetamine abuse: Case report\n\n2. Unique Identifying number or registration ID: researchregistry7008\n\n3. Hyperlink to your specific registration (must be publicly accessible and will be checked): https://www.researchregistry.com/browse-the-registry#home/\n\nGuarantor\n\nKitti Thiankhaw, M.D.\n\nAnnals of medicine and surgery\n\nThe following information is required for submission. Please note that failure to respond to these questions/statements will mean your submission will be returned. If you have nothing to declare in any of these categories then this should be stated.\n\nConsent\n\nWritten informed consent was obtained from the patient for publication of this Case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAppendix A Supplementary data\n\nThe following is the Supplementary data to this article:Multimedia component 1\n\nMultimedia component 1\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2021.102676.\n\nThe Research Ethics Committees of the Faculty of Medicine, Chiang Mai University approved this Case report.\n==== Refs\nReferences\n\n1 Agha R.A. Franchi T. Sohrabi C. Mathew G. Kerwan A. Thoma A. Beamish A.J. Noureldin A. Rao A. Vasudevan B. The SCARE 2020 guideline: updating consensus surgical REport (SCARE) guidelines International Journal of Surgery 84 2020 226 230 Case 33181358\n2 Ekker M.S. Boot E.M. Singhal A.B. Tan K.S. Debette S. Tuladhar A.M. de Leeuw F.-E. Epidemiology, aetiology, and management of ischaemic stroke in young adults Lancet Neurol. 17 9 2018 790 801 30129475\n3 Thanvi B. Munshi S. Dawson S. Robinson T. Carotid and vertebral artery dissection syndromes Postgrad. Med. 81 956 2005 383 388\n4 Indave B.I. Sordo L. Bravo M.J. Sarasa‐Renedo A. Fernández‐Balbuena S. De la Fuente L. Sonego M. Barrio G. Risk of stroke in prescription and other amphetamine‐type stimulants use: a systematic review Drug Alcohol Rev. 37 1 2018 56 69 28485090\n5 Putaala J. Metso A.J. Metso T.M. Konkola N. Kraemer Y. Haapaniemi E. Kaste M. Tatlisumak T. Analysis of 1008 consecutive patients aged 15 to 49 with first-ever ischemic stroke: the Helsinki young stroke registry Stroke 40 4 2009 1195 1203 19246709\n6 Debette S. Pathophysiology and risk factors of cervical artery dissection: what have we learnt from large hospital-based cohorts? Curr. Opin. Neurol. 27 1 2014 20 28 24300790\n7 Ho E.L. Josephson S.A. Lee H.S. Smith W.S. Cerebrovascular complications of methamphetamine abuse Neurocritical Care 10 3 2009 295 305 19132558\n8 Winsløw F. Hansen N.S. Jensen M.B. Vertebral artery dissection related to amphetamine abuse–A report J. Cent. Nerv. Syst. Dis. 12 2020 1179573520939340,Case\n9 Zaidat O.O. Frank J. Vertebral artery dissection with amphetamine abuse J. Stroke Cerebrovasc. Dis. 10 1 2001 27 29 17903796\n10 Ewida A. Ahmed R. Luo A. Masoud H. Spontaneous dissection of bilateral internal carotid and vertebral arteries BMJ Reports CP 14 3 2021 e241173 Case\n11 Westover A.N. Nakonezny P.A. Aortic dissection in young adults who abuse amphetamines Am. Heart J. 160 2 2010 315 321 20691838\n12 Powers W.J. Rabinstein A.A. Ackerson T. Adeoye O.M. Bambakidis N.C. Becker K. Biller J. Brown M. Demaerschalk B.M. Hoh B. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association Stroke 50 12 2019 e344 e418 31662037\n13 von Babo M. De Marchis G.M. Sarikaya H. Stapf C. Buffon F. Fischer U. Heldner M.R. Gralla J. Jung S. Simonetti B.G. Differences and similarities between spontaneous dissections of the internal carotid artery and the vertebral artery Stroke 44 6 2013 1537 1542 23632978\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2049-0801",
"issue": "68()",
"journal": "Annals of medicine and surgery (2012)",
"keywords": "Amphetamine; Artery dissection; Drug abuse; Ischemic stroke",
"medline_ta": "Ann Med Surg (Lond)",
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"nlm_unique_id": "101616869",
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"pages": "102676",
"pmc": null,
"pmid": "34401140",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports",
"references": "33782071;24300790;28485090;20691838;19246709;17903796;19132558;31662037;30129475;23632978;33181358;15937204;32655281",
"title": "Internal carotid artery and bilateral vertebral arteries dissections associated with amphetamine abuse: Case report.",
"title_normalized": "internal carotid artery and bilateral vertebral arteries dissections associated with amphetamine abuse case report"
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"abstract": "An 85-year-old man with a background of transfusion-dependent chronic myelomonocytic leukaemia and chronic kidney disease stage III presented with symptomatic anaemia, acute kidney injury, sepsis and high anion gap metabolic acidosis (HAGMA). Initial treatment with intravenous antibiotics and blood transfusion was complicated by transfusion-associated circulatory overload, necessitating diuresis and non-invasive ventilation. Despite gradual clinical improvement, the patient's HAGMA persisted, and no cause was identified on urine testing or renal ultrasound. As the patient was on long-term dicloxacillin for infective endocarditis prophylaxis and regular paracetamol, pyroglutamic acidosis (PGA) (5-oxoproline acidosis) was considered. This was later confirmed with elevated serum levels, and the HAGMA resolved following cessation of these medications. Although considered an uncommon cause of HAGMA, PGA is likely also under-recognised, and to our knowledge, this may be the second reported case in the context of dicloxacillin.",
"affiliations": "Medicine, Gympie Hospital, Gympie, Queensland, Australia.;Medicine, Greenslopes Private Hospital, Greenslopes, Queensland, Australia dr.almuwais@gmail.com.;Medicine, Sunshine Coast University Hospital, Sunshine Coast, Queensland, Australia.",
"authors": "Zand Irani|Anis|A|;Almuwais|Ahmed|A|http://orcid.org/0000-0002-3840-9608;Gibbons|Holly|H|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000900:Anti-Bacterial Agents; D000082:Acetaminophen; D004009:Dicloxacillin",
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"doi": "10.1136/bcr-2019-233306",
"fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\nbcr-2019-233306\n10.1136/bcr-2019-233306\nFindings That Shed New Light on the Possible Pathogenesis of a Disease or an Adverse Effect\n1506\n1517\n1325\n80\n1561\n382\nCase reportAcquired pyroglutamic acidosis due to long-term dicloxacillin and paracetamol use\nZand Irani Anis 1 http://orcid.org/0000-0002-3840-9608Almuwais Ahmed 2 Gibbons Holly 3 1 Medicine, Gympie Hospital, Gympie, Queensland, Australia\n2 Medicine, Greenslopes Private Hospital, Greenslopes, Queensland, Australia\n3 Medicine, Sunshine Coast University Hospital, Sunshine Coast, Queensland, Australia\nCorrespondence to Dr Ahmed Almuwais; dr.almuwais@gmail.com\n2020 \n8 4 2020 \n8 4 2020 \n13 4 e23330613 3 2020 © BMJ Publishing Group Limited 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.An 85-year-old man with a background of transfusion-dependent chronic myelomonocytic leukaemia and chronic kidney disease stage III presented with symptomatic anaemia, acute kidney injury, sepsis and high anion gap metabolic acidosis (HAGMA). Initial treatment with intravenous antibiotics and blood transfusion was complicated by transfusion-associated circulatory overload, necessitating diuresis and non-invasive ventilation. Despite gradual clinical improvement, the patient’s HAGMA persisted, and no cause was identified on urine testing or renal ultrasound. As the patient was on long-term dicloxacillin for infective endocarditis prophylaxis and regular paracetamol, pyroglutamic acidosis (PGA) (5-oxoproline acidosis) was considered. This was later confirmed with elevated serum levels, and the HAGMA resolved following cessation of these medications. Although considered an uncommon cause of HAGMA, PGA is likely also under-recognised, and to our knowledge, this may be the second reported case in the context of dicloxacillin.\n\nmetabolic disordersunwanted effects / adverse reactionsspecial-featureunlocked\n==== Body\nBackground\nHigh anion gap metabolic acidosis (HAGMA) is a commonly encountered acid-base disturbance in patients in the hospital setting and is generally attributable to ketoacidosis, lactic acidosis, renal failure or ingestion of toxic substances (eg, salicylates, glycols and methanol).\n\nAccumulation of pyroglutamic acidosis (PGA) (5-oxoproline) is a less commonly identified aetiology. This can occur in children with inborn errors of metabolism affecting enzymes in the γ-glutamyl cycle (eg, glutathione synthase deficiency), which produces the antioxidant glutathione, or it can be acquired.1 Acquired PGA occurs in association with glutathione and cysteine depletion, or as an adverse effect of certain medications (eg, flucloxacillin and paracetamol).\n\nComplications due to drug interactions in patients with hepatic and renal dysfunction can be difficult to identify, and unmanaged metabolic acidosis can contribute significantly to mortality.2 Given the common utilisation of paracetamol and penicillins, PGA may be an under-reported issue.\n\nWe report a case of an 85-year-old man with a complex medical history, who developed a multi-factorial HAGMA.\n\nCase presentation\nAn 85-year-old man was brought to emergency department following a fall at home while attempting to change his incontinence pad. He sustained no injuries from the fall; however, he reported a background of several days of worsening lethargy, a productive cough and decreased oral intake. His medical history was complex and included transfusion-dependent chronic myelomonocytic leukaemia type 1 (CMML-1) (see baseline results in table 1), type II diabetes mellitus, atrial fibrillation with a permanent pacemaker, chronic kidney disease stage III (baseline creatinine 100–120 μmol/L), hypertension and a permanent suprapubic catheter due to neurogenic bladder and benign prostatic hypertrophy.\n\nTable 1 Blood biochemistry results during admission\n\n\tBaseline results\tDay 1\tDay 2\tDay 3\tDay 20\tUnit\tReference\t\nHb\t94\t80\t78\t116\t86\tg/L\t125–175\t\nPlatelet\t85\t103\t92\t129\t92\t109/L\t150–400\t\nWCC\t28.0\t40.3\t38.7\t80.4\t20.1\t109/L\t3.5–10.0\t\nNeutrophils\t17.4\t22.91\t22.42\t53.22\t11.28\t109/L\t1.5–6.0\t\nMonocytes\t6.7\t13.43\t12.37\t17.61\t5.84\t109/L\t0–0.9\t\nEosinophils\t0.28\t0.40\t0.00\t1.15\t0.20\t109/L\t0–0.6\t\nBasophils\t0.00\t0.00\t0.00\t0.38\t0.20\t109/L\t0–0.15\t\neGFR\t47\t14\t14\t15\t16\tmL/min/1.73 m2\t>59\t\nCreatinine\t120\t325\t319\t310\t292\tμmol/L\t60–110\t\nCRP\t5.8\t\t165\t\tmg/L\t<5\t\nBNP\t452\t\t1544\t\tng/L\t<100\t\ncTroponin I\t\t<2.42\t\tng/L\t<20\t\nBNP, brain natriuretic peptide; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; Hb, haemoglobin; WCC, white cell count.\n\nHis medical history also included restless leg syndrome, duodenal ulcers, hypercholesterolaemia, renal calculi, pyelonephritis, infective endocarditis of the aortic valve, non-ST elevation myocardial infarction, polymyalgic rheumatoid arthritis and chronic obstructive pulmonary disease.\n\nHis chronic treatment consisted of irbesartan, digoxin, pantoprazole, bisoprolol, apixaban, sulfasalazine, pramipexole, domperidone, atorvastatin, cholecalciferol, mixed insulin, paracetamol and lifelong dicloxacillin (1 g two times per day for the last 10 months) for suppression of infective endocarditis.\n\nHe had a low-grade fever (37.9°C), blood pressure of 131/47 mm Hg, heart rate of 70 bpm, respiratory rate of 21 and oxygen saturation of 93%. Clinical examination was notable only for some crackles at the lung bases bilaterally and massive splenomegaly (first noted 2 months earlier).\n\nInvestigations\nThe initial point of care blood testing indicated a significant acute kidney injury (AKI) (creatinine 325 μmol/L, urea 28 mmol/L, estimated glomerular filtration rate (eGFR) 14 mL/min/1.73 m2). One month prior to this presentation, his eGFR had been 47 mL/min/1.73 m2 and creatinine 120 μmol/L. His serum glucose was 14.2 mmol/L.\n\nThe full blood count showed a haemoglobin of 80 g/L, platelets 103×109/L, white cell count (WCC) 40.3×109/L, neutrophils 22.91×109/L and monocytes 13.43×109/L (table 1). Occasional blasts were seen on the blood film.\n\nVenous blood gas indicated a metabolic acidosis (pH 7.31, bicarbonate 14 mmol/L and lactate 1.3 mmol/L). Following correction for hypoalbuminaemia and hyperglycaemia, his anion gap was calculated to be 21 mmol/L (table 2). Chest X-ray showed patchy perihilar opacification and increased interstitial markings.\n\nTable 2 Venous blood gas in day 2 and day 4 of admission\n\nVenous blood gas\tDay 2\tDay 4\tUnit\tReference\t\npH\t7.31\t7.30\t\t7.32–7.43\t\nBicarbonate\t14\t14\tmmol/L\t22–33\t\npCO2\t27\t29\tmm Hg\t38–54\t\nLactate\t1.3\t1.2\tmmol/L\t0.5–2.2\t\nCalculated anion gap\t21\t21.3\tmmol/L\t8–16\t\npCO2, partial pressure of CO2.\n\nTreatment\nThe initial working diagnosis was a chest and/or urinary infection, complicated by AKI. Medications with potential nephrotoxicity were withheld, his suprapubic catheter was flushed, and he was commenced on ceftriaxone 1 g one time a day intravenously and doxycycline 100 mg two times per day orally.\n\nDue to his low haemoglobin, he received two units of packed red cells. Eight hours following the transfusion, he developed tachypnoea (rate >40/min) and desaturated to 80% on 3 L nasal prongs. His blood pressure was 159/53 mm Hg, heart rate 70 bpm and temperature 39.0°C. He was clinically fluid overloaded with respiratory crackles to mid-zones bilaterally, and his urine output was poor.\n\nArterial blood gas showed significant metabolic acidosis (pH 7.26, bicarbonate 10 mmol/L, lactate 1.1 mmol/L and corrected anion gap 19 mmol/L) (table 3). His eGFR was 14 mL/min/1.73 m2, troponin 42 ng/L and brain natriuretic peptide 1544 ng/L (table 1).\n\nTable 3 Arterial blood gas in day 3 of admission\n\nArterial blood gas\tDay 3\tReference\t\npH\t7.26\t7.35–7.45\t\nBicarbonate\t10\t22–32\t\npCO2\t23\t32–48\t\nLactate\t1.1\t0.5–2.2\t\nCalculated anion gap\t19.0\t8–16\t\npCO2, partial pressure of CO2.\n\nInflammatory markers were significantly raised with C-reactive protein 165 mg/L. WCC was 80.4×109/L (neutrophils 53.22×109/L, lymphocytes 6.13×109/L, monocytes 17.61×109/L, eosinophils 1.15×109/L and basophils 0.38×109/L) (table 1).\n\nThe patient declined dialysis and transfer to an intensive care unit, so non-invasive management was commenced for a provisional diagnosis of sepsis, transfusion-associated circulatory overload with pulmonary oedema and possible haematologic transformation. Intravenous antibiotics were changed to piperacillin–tazobactam intravenously (4.5 g two times per day, dose-adjusted for renal impairment), with the addition of furosemide for diuresis and high-flow nasal prong oxygen up to 50 L/min.\n\nOver the next 24 hours, the patient demonstrated a gradual positive response to diuresis; however, the acidosis persisted with an anion gap of 21.3 mmol/L. Various causes for HAGMA were excluded. Renal ultrasound showed multiple small calculi in the right kidney but no evidence of obstruction or hydronephrosis. Urine was highly positive for leukocytes, and culture grew Candida sp, but negative for eosinophils, casts, monoclonal immunoglobulin and Bence-Jones proteins.\n\nIn the context of sepsis, AKI and long-term treatment with dicloxacillin and paracetamol, PGA was considered. These medications were withheld on day 4 of admission and a request for blood pyroglutamic acid levels was sent. Cephalexin was recommended by infectious diseases as the replacement for the dicloxacillin for long-term infective endocarditis suppression.\n\nGiven the patient’s history of CMML-1, acceleration phase of leukaemia or transformation to CMML-2, and spontaneous tumour lysis syndrome (sTLS) had to be considered as potential contributors to his clinical picture. He met two of the laboratory criteria for TLS (urate 1.28 mmol/L (reference 0.15–0.50) and phosphate 1.83 mmol/L (reference 0.75–1.50)), and at least one of the clinical criteria (increase in creatinine greater than or equal to 1.5 times the upper limit of normal).3\n\nMultiple sets of blood cultures eventually grew pan-sensitive Candida orthopsilosis, so he was commenced on a 2 week course of oral fluconazole (200 mg daily).\n\nOutcome and follow-up\nOver the following weeks of his admission, the patient’s acidosis resolved with overall improvement in his clinical condition. His bicarbonate improved to 26 mmol/L with a calculated anion gap of 14.8 and his renal function stabilised (GFR 16 mL/min/1.73 m2 and creatinine 292 μmol/L). His blood count differential also stabilised (WCC 20.1×109/L, neutrophils 11.28×109/L, monocytes 5.84×109/L and basophils 0.20×109/L) (table 1).\n\nPGA was retrospectively confirmed with blood levels of 62 μmol/L (reference 20–50 μmol/L). As the acidosis resolved following cessation of the paracetamol and dicloxacillin, PGA was likely the main contributor; however, sTLS could not be excluded. After further discussion with the patient and his family, he decided to discontinue the ongoing active treatment and was discharged to a residential aged care facility for symptomatic management and palliative care.\n\nDiscussion\nThe cases of acquired PGA have been increasingly reported since 1989, generally in the context of glutathione deficient states.4 5 Risk factors for this condition have been well-defined in case reports and our case demonstrates some of these, namely advanced age, sepsis, malnutrition, chronic kidney disease, uncontrolled diabetes, isoxazolyl penicillin use and chronic paracetamol use.6–9 Other risk factors include chronic liver disease, female gender and the use of netilmicin or vigabatrin.5–10\n\nPGA occurs in the presence of multiple risk factors and this is related to the underlying pathogenesis and the γ-glutamyl cycle. Depleted glutathione levels remove the negative feedback inhibition on γ-glutamylcysteine synthetase, resulting in the accumulation of γ-glutamylcysteine which can be metabolised to 5-oxoproline.10 Despite the increased activity of γ-glutamylcysteine synthetase, insufficient cysteine levels impair conversion of γ-glutamyl phosphate to γ-glutamyl cysteine, and it is converted instead to 5-oxoproline via a futile ATP-depleting cycle (figure 1).11\n\nFigure 1 The γ-glutamyl cycle. The effect of long-term dicloxacillin and paracetamol use in promoting 5-oxoproline accumulation.\n\nDrug-induced PGA is most commonly seen with chronic paracetamol use as it contributes to cysteine deficiency via direct conjugation and glutathione deficiency through its metabolite, N-acetyl benzoquinone imine, which irreversibly binds glutathione.12\n\n5-oxoprolinase usually degrades 5-oxoproline to glutamate, but this enzyme can be inhibited by flucloxacillin, promoting 5-oxoproline accumulation and the associated acidaemia.13 14 The vast majority of PGA cases associated with antibiotics involve flucloxacillin, and to our knowledge, our case may be the second reported in the context of dicloxacillin.6 Given the limited available evidence, it remains unclear if the association to PGA could represent a class effect of the isoxazolyl penicillins. However, there have been cases where flucloxacillin has been successfully substituted for other β-lactam penicillins, which would support this.15–17\n\nA decline in renal function can further exacerbate PGA as 5-oxoproline, like other organic acids, is excreted in the urine (pyroglutamic aciduria).18 In our patient, deconditioning secondary to infection and declining oral intake likely precipitated his fall, and subsequently, sepsis, AKI and PGA were all contributing factors to the HAGMA.\n\nThe incidence of PGA is unknown, but it is likely underdiagnosed given the common utilisation of the associated medications and the prevalence of the risk factors. Definitive diagnosis can be made by blood pyroglutamic acid levels or urine organic acid profile; however, these tests are only performed in certain laboratories, which limit their practical application.19\n\nIn our case, the return of the blood levels was significantly delayed. PGA was an empirical diagnosis, based on the presence of risk factors and HAGMA, which prompted alterations to management (ie, cessation of dicloxacillin and paracetamol).\n\nThe differential diagnosis for the HAGMA is broad and, once the more common causes have been excluded, should be further expanded to include PGA in patients with the relevant risk factors.19\n\nAccumulation of 5-oxoproline was incorporated into the ‘GOLDMARK’ mnemonic, which was proposed to replace older mnemonics, for example ‘MUDPILES’, that incorporate causes of acidosis that have become exceedingly rare (table 4).20\n\nTable 4 Main causes of high anion gap metabolic acidosis\n\n\tHigh anion gap metabolic acidosis (GOLD MARK)\t\nG\tGlycols (ethylene and propylene)\t\nO\t5-Oxoproline (pyroglutamic acid) chronic paracetamol use, EtOH, poor nutrition, vegetarian diet, renal failure, infection, flucloxacillin/dicloxacillin/netilmicin, Vigabatrin\t\nL\tLactate\t\nD\tD-lactic acid\nAssociated with short bowel syndrome\t\nM\tMethanol and other toxins (ethanol, Aldehyde)\t\nA\tAspirin, salicylates\t\nR\tRenal failure\t\nK\tKetoacidosis\t\nEtOH, ethyl alcohol,.\n\nThe mainstay of management of PGA is cessation of causative medications and supportive care. There have also been reports of bicarbonate supplementation and N-acetyl cysteine (NAC) being used successfully to promote recovery.21 22 However, the effectiveness of NAC in treating PGA is not well established, and the potential risks associated with NAC administration in patients with septic shock are unclear.23 24 There have also been cases of effective haemodialysis clearance of 5-oxoproline, which would have been appropriate in our patient’s situation given the concurrent haematologic crisis and renal impairment if he had opted for active management.25\n\nLearning points\nGiven that a large proportion of patients admitted to hospital are likely to be glutathione deficient, and paracetamol and isoxazolyl penicillins are commonly prescribed medications, pyroglutamic acidosis (PGA) should be considered as a differential diagnosis in patients with risk factors and an unexplained high anion gap metabolic acidosis.\n\nThe mainstay of treatment involves cessation of medications that can influence the γ-glutamyl cycle or glutathione levels, and the implementation of supportive measures.\n\nThe roles of bicarbonate and N-acetyl cysteine are still unclear, but have been used successfully to promote recovery in some cases.\n\nFurther enquiry is required to determine whether the association of flucloxacillin and dicloxacillin with PGA represents an isoxazolyl penicillin class effect.\n\nContributors: Supervised by AZI. Patient was under the care of AI. Report was written by AZI, AA, HG.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Next of kin consent obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Mayatepek E \n5-Oxoprolinuria in patients with and without defects in the -glutamyl cycle\n. Eur J Pediatr \n1999 ;158 :221 –5\n.10.1007/s004310051054 10094443 \n2 Berbee JK , Lammers LA , Krediet CTP , et al \nMetabolic acidosis caused by concomitant use of paracetamol (acetaminophen) and flucloxacillin? A case report and a retrospective study\n. Eur J Clin Pharmacol \n2017 ;73 :1459 –65\n.10.1007/s00228-017-2311-6 28782093 \n3 Cairo MS , Bishop M \nTumour lysis syndrome: new therapeutic strategies and classification\n. Br J Haematol \n2004 ;127 :3 –11\n.10.1111/j.1365-2141.2004.05094.x 15384972 \n4 Creer MH , Lau BW , Jones JD , et al \nPyroglutamic acidemia in an adult patient\n. Clin Chem \n1989 ;35 :684 –6\n.10.1093/clinchem/35.4.684 2702756 \n5 Bonham JK , Rattenbury JM , Meeks A , et al \nPyroglutamicaciduria from vigabatrin\n. The Lancet \n1989 ;333 :1452 –3\n.10.1016/S0140-6736(89)90158-X \n6 Pitt JJ , Hauser S \nTransient 5-oxoprolinuria and high anion gap metabolic acidosis: clinical and biochemical findings in eleven subjects\n. Clin Chem \n1998 ;44 :1497 –503\n.10.1093/clinchem/44.7.1497 9665429 \n7 Sekhar RV , McKay SV , Patel SG , et al \nGlutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine\n. Diabetes Care \n2011 ;34 :162 –7\n.10.2337/dc10-1006 20929994 \n8 Pitt JJ , Brown GK , Clift V , et al \nAtypical pyroglutamic aciduria: possible role of paracetamol\n. J Inherit Metab Dis \n1990 ;13 :755 –6\n.10.1007/BF01799581 2246862 \n9 Croal BL , Glen ACA , Kelly CJG , et al \nTransient 5-oxoprolinuria (pyroglutamic aciduria) with systemic acidosis in an adult receiving antibiotic therapy\n. Clin Chem \n1998 ;44 :336 –40\n.10.1093/clinchem/44.2.336 9474033 \n10 Dempsey GA , Lyall HJ , Corke CF , et al \nPyroglutamic acidemia: a cause of high anion gap metabolic acidosis\n. Crit Care Med \n2000 ;28 :1803 –7\n.10.1097/00003246-200006000-00018 10890623 \n11 Emmett M \nAcetaminophen toxicity and 5-oxoproline (pyroglutamic acid): a tale of two cycles, one an ATP-depleting futile cycle and the other a useful cycle\n. Clin J Am Soc Nephrol \n2014 ;9 :191 –200\n.10.2215/CJN.07730713 24235282 \n12 Liss DB , Paden MS , Schwarz ES , et al \nWhat is the clinical significance of 5-oxoproline (pyroglutamic acid) in high anion gap metabolic acidosis following paracetamol (acetaminophen) exposure?\n\nClin Toxicol \n2013 ;51 :817 –27\n.10.3109/15563650.2013.844822 \n13 Lanoy C , Bouckaert Y \nMetabolic acidosis and 5-oxoprolinuria induced by flucloxacillin and acetaminophen: a case report\n. J Med Case Rep \n2016 ;10 :18410.1186/s13256-016-0964-x 27339215 \n14 Zand L , Muriithi A , Greene EL , et al \nSevere anion gap metabolic acidosis from acetaminophen use secondary to 5-oxoproline (pyroglutamic acid) accumulation\n. Am J Med Sci \n2012 ;344 :501 –4\n.10.1097/MAJ.0b013e318259bd45 22986610 \n15 EH A , Lam K , Umakanthan M , et al \nHigh anion gap metabolic acidosis: a case of pyroglutamic acidosis\n. Nephrology \n2017 ;22 :926 .\n16 Mo L , Liang DL , Madden A , et al \nA case of delayed onset pyroglutamic acidosis in the sub-acute setting\n. Intern Med J \n2016 ;46 :747 –9\n.10.1111/imj.13104 27257155 \n17 Thomas SD \nHigh anion gap metabolic acidosis due to pyroglutamic aciduria (5-oxoprolinuria) in an elderly patient\n. Aust J Sci Med \n2015 ;36 :72 .\n18 Heireman L , Mahieu B , Helbert M , et al \nHigh anion gap metabolic acidosis induced by cumulation of ketones, L- and D-lactate, 5-oxoproline and acute renal failure\n. Acta Clin Belg \n2018 ;73 :313 –6\n.10.1080/17843286.2017.1358504 28749752 \n19 Myall K , Sidney J , Marsh A \nMind the gap! An unusual metabolic acidosis\n. The Lancet \n2011 ;377 :526 10.1016/S0140-6736(10)61383-9 \n20 Mehta AN , Emmett JB , Emmett M \nGold mark: an anion gap mnemonic for the 21st century\n. The Lancet \n2008 ;372 :892 10.1016/S0140-6736(08)61398-7 \n21 Spector SR , Mayan H , Loebstein R , et al \nPyroglutamic acidosis as a cause for high anion gap metabolic acidosis: a prospective study\n. Sci Rep \n2019 ;9 :355410.1038/s41598-019-39257-4 30837497 \n22 Hundemer GL , Fenves AZ \nAcquired 5-oxoproline acidemia successfully treated with N-acetylcysteine\n. Proc \n2017 ;30 :169 –70\n.10.1080/08998280.2017.11929570 \n23 Chertoff J \nN -Acetylcysteine’s Role in Sepsis and Potential Benefit in Patients With Microcirculatory Derangements\n. J Intensive Care Med \n2018 ;33 :87 –96\n.10.1177/0885066617696850 28299952 \n24 Bavakunji RV , Turner JD , Jujjavarapu S , et al \nAn unusual case of severe high anion gap metabolic acidosis\n. Clin Kidney J \n2011 ;4 :90 –2\n.10.1093/ndtplus/sfr009 \n25 Luyasu S , Wamelink MMC , Galanti L , et al \nPyroglutamic acid-induced metabolic acidosis: a case report\n. Acta Clin Belg \n2014 ;69 :221 –3\n.10.1179/2295333714Y.0000000022 24694265\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1757-790X",
"issue": "13(4)",
"journal": "BMJ case reports",
"keywords": "metabolic disorders; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000082:Acetaminophen; D000136:Acid-Base Equilibrium; D000138:Acidosis; D000369:Aged, 80 and over; D018712:Analgesics, Non-Narcotic; D000900:Anti-Bacterial Agents; D003937:Diagnosis, Differential; D004009:Dicloxacillin; D004696:Endocarditis; D006801:Humans; D008297:Male",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32273269",
"pubdate": "2020-04-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27257155;24694265;28749752;2702756;18790311;28299952;27339215;15384972;28405069;2246862;9474033;9665429;10890623;24235282;30837497;21296238;2567460;22986610;24111553;10094443;29044962;20929994;28782093;25984120",
"title": "Acquired pyroglutamic acidosis due to long-term dicloxacillin and paracetamol use.",
"title_normalized": "acquired pyroglutamic acidosis due to long term dicloxacillin and paracetamol use"
} | [
{
"companynumb": "AU-FRESENIUS KABI-FK202004647",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"drugadditional": null,... |
{
"abstract": "Nintedanib, a triple tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has been used in idiopathic pulmonary fibrosis and adenocarcinoma in advanced non-small cell lung cancer. Although vascular endothelial growth factor inhibitors have been reported to cause endothelial injury and glomerular microangiopathy, nintedanib-induced glomerular microangiopathy has not been reported. A 68-year-old man with a history of primary aldosteronism, idiopathic pulmonary fibrosis, and pleomorphic carcinoma of the lung developed proteinuria and leg edema after nintedanib initiation. Kidney biopsy revealed prominent endothelial and mesangial injury. Proteinuria improved after nintedanib withdrawal. To the best of our knowledge, this is the second case report of nintedanib-induced glomerular microangiopathy. Although the incidence of nephropathy among patients receiving nintedanib is unknown at this moment, we recommend monitoring urinary protein excretion and blood pressure in patients receiving nintedanib and performing kidney biopsy to determine any histopathological change.",
"affiliations": "Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan. atsuko_mori@hotmail.com.;Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan.;Department of Ophthalmology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan.;Department of Pathology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan.",
"authors": "Hasegawa|Masataka|M|;Uehara|Atsuko|A|;Suzuki|Tomo|T|;Sekine|Reio|R|;Yazawa|Masahiko|M|;Ichikawa|Daisuke|D|;Koike|Junki|J|;Shibagaki|Yugo|Y|",
"chemical_list": "D007211:Indoles; D047428:Protein Kinase Inhibitors; D017468:Receptors, Fibroblast Growth Factor; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; C530716:nintedanib",
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-020-00474-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "9(4)",
"journal": "CEN case reports",
"keywords": "Glomerular microangiopathy; Nintedanib; Onconephrology; Proteinuria; Pulmonary fibrosis",
"medline_ta": "CEN Case Rep",
"mesh_terms": "D000368:Aged; D002277:Carcinoma; D004730:Endothelium, Vascular; D005920:Glomerular Mesangium; D006801:Humans; D006929:Hyperaldosteronism; D054990:Idiopathic Pulmonary Fibrosis; D007211:Indoles; D007668:Kidney; D007674:Kidney Diseases; D008175:Lung Neoplasms; D008297:Male; D047428:Protein Kinase Inhibitors; D011507:Proteinuria; D017468:Receptors, Fibroblast Growth Factor; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D057049:Thrombotic Microangiopathies; D028761:Withholding Treatment",
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "295-300",
"pmc": null,
"pmid": "32279192",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20538785;21992121;30014486;18559524;24836310;24207130;20056761;18337603;24411639;30642877;25659349;20693161;28779751;31699213;18077793",
"title": "Nintedanib-induced glomerular microangiopathy: a case report.",
"title_normalized": "nintedanib induced glomerular microangiopathy a case report"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-NB-019803",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NINTEDANIB"
},
"... |
{
"abstract": "Nivolumab, a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody, has demonstrated improved survival in previously treated patients with advanced non-small-cell lung cancer (NSCLC). CheckMate 012, a phase I, multicohort study, was conducted to explore the safety and efficacy of nivolumab as monotherapy or combined with current standard therapies in first-line advanced NSCLC. Here, we report results for nivolumab plus platinum-based doublet chemotherapy (PT-DC).\n\n\n\nPatients (N = 56) received nivolumab (intravenously) plus PT-DC concurrently every 3 weeks for four cycles followed by nivolumab alone until progression or unacceptable toxicity. Regimens were nivolumab 10 mg/kg plus gemcitabine-cisplatin (squamous) or pemetrexed-cisplatin (nonsquamous) or nivolumab 5 or 10 mg/kg plus paclitaxel-carboplatin (all histologies). The primary objective was to assess safety and tolerability. Secondary objectives included objective response rate and 24-week progression-free survival rate (per Response Evaluation Criteria in Solid Tumors version 1.1); exploratory objectives included overall survival (OS) and response by tumor programmed death ligand-1 expression.\n\n\n\nNo dose-limiting toxicities occurred during the first 6 weeks of treatment. Forty-five percent of patients (25 of 56 patients) reported grade 3 or 4 treatment-related adverse events (AEs); 7% of patients (n = 4) had pneumonitis. Twenty-one percent of patients (n = 12) discontinued all study therapy as a result of treatment-related AEs. Objective response rates for nivolumab 10 mg/kg plus gemcitabine-cisplatin, nivolumab 10 mg/kg plus pemetrexed-cisplatin, nivolumab 10 mg/kg plus paclitaxel-carboplatin, and nivolumab 5 mg/kg plus paclitaxel-carboplatin were 33%, 47%, 47%, and 43%, respectively; 24-week progression-free survival rates were 51%, 71%, 38%, and 51%, respectively; 2-year OS rates were 25%, 33%, 27%, and 62%, respectively. Responses were achieved regardless of tumor programmed death ligand-1 expression.\n\n\n\nThe safety profile of nivolumab plus PT-DC was consistent with that expected for individual agents; however, treatment discontinuation related to AEs was greater with the combination. Encouraging activity was observed, especially for the nivolumab 5 mg/kg plus paclitaxel-carboplatin group, with a 2-year OS rate of 62%.",
"affiliations": "Naiyer A. Rizvi and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center, New York, NY; Julie R. Brahmer, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Rosalyn A. Juergens, Juravinski Cancer Centre at McMaster University, Hamilton; Scott A. Laurie, Ottawa Hospital Cancer Centre, Ottawa; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Hossein Borghaei, Fox Chase Cancer Center, Philadelphia, PA; Scott Gettinger, Yale Cancer Center, New Haven, CT; Laura Q. Chow, University of Washington, Seattle, WA; David E. Gerber, University of Texas Southwestern Medical Center, Dallas, TX; Jonathan W. Goldman, University of California, Los Angeles, Los Angeles, CA; Allen C. Chen, Yun Shen, Faith E. Nathan, and Christopher T. Harbison, Bristol-Myers Squibb, Princeton, NJ; and Scott Antonia, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. nar2144@cumc.columbia.edu.;Naiyer A. Rizvi and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center, New York, NY; Julie R. Brahmer, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Rosalyn A. Juergens, Juravinski Cancer Centre at McMaster University, Hamilton; Scott A. Laurie, Ottawa Hospital Cancer Centre, Ottawa; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Hossein Borghaei, Fox Chase Cancer Center, Philadelphia, PA; Scott Gettinger, Yale Cancer Center, New Haven, CT; Laura Q. Chow, University of Washington, Seattle, WA; David E. Gerber, University of Texas Southwestern Medical Center, Dallas, TX; Jonathan W. Goldman, University of California, Los Angeles, Los Angeles, CA; Allen C. Chen, Yun Shen, Faith E. Nathan, and Christopher T. Harbison, Bristol-Myers Squibb, Princeton, NJ; and Scott Antonia, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.;Naiyer A. Rizvi and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center, New York, NY; Julie R. Brahmer, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Rosalyn A. Juergens, Juravinski Cancer Centre at McMaster University, Hamilton; Scott A. Laurie, Ottawa Hospital Cancer Centre, Ottawa; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Hossein Borghaei, Fox Chase Cancer Center, Philadelphia, PA; Scott Gettinger, Yale Cancer Center, New Haven, CT; Laura Q. Chow, University of Washington, Seattle, WA; David E. Gerber, University of Texas Southwestern Medical Center, Dallas, TX; Jonathan W. Goldman, University of California, Los Angeles, Los Angeles, CA; Allen C. Chen, Yun Shen, Faith E. Nathan, and Christopher T. Harbison, Bristol-Myers Squibb, Princeton, NJ; and Scott Antonia, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.;Naiyer A. Rizvi and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center, New York, NY; Julie R. Brahmer, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Rosalyn A. Juergens, Juravinski Cancer Centre at McMaster University, Hamilton; Scott A. Laurie, Ottawa Hospital Cancer Centre, Ottawa; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Hossein Borghaei, Fox Chase Cancer Center, Philadelphia, PA; Scott Gettinger, Yale Cancer Center, New Haven, CT; Laura Q. Chow, University of Washington, Seattle, WA; David E. Gerber, University of Texas Southwestern Medical Center, Dallas, TX; Jonathan W. Goldman, University of California, Los Angeles, Los Angeles, CA; Allen C. Chen, Yun Shen, Faith E. Nathan, and Christopher T. Harbison, Bristol-Myers Squibb, Princeton, NJ; and Scott Antonia, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.;Naiyer A. Rizvi and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center, New York, NY; Julie R. Brahmer, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Rosalyn A. Juergens, Juravinski Cancer Centre at McMaster University, Hamilton; Scott A. Laurie, Ottawa Hospital Cancer Centre, Ottawa; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Hossein Borghaei, Fox Chase Cancer Center, Philadelphia, PA; Scott Gettinger, Yale Cancer Center, New Haven, CT; Laura Q. Chow, University of Washington, Seattle, WA; David E. Gerber, University of Texas Southwestern Medical Center, Dallas, TX; Jonathan W. Goldman, University of California, Los Angeles, Los Angeles, CA; Allen C. Chen, Yun Shen, Faith E. Nathan, and Christopher T. Harbison, Bristol-Myers Squibb, Princeton, NJ; and Scott Antonia, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.;Naiyer A. Rizvi and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center, New York, NY; Julie R. Brahmer, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Rosalyn A. Juergens, Juravinski Cancer Centre at McMaster University, Hamilton; Scott A. Laurie, Ottawa Hospital Cancer Centre, Ottawa; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Hossein Borghaei, Fox Chase Cancer Center, Philadelphia, PA; Scott Gettinger, Yale Cancer Center, New Haven, CT; Laura Q. Chow, University of Washington, Seattle, WA; David E. Gerber, University of Texas Southwestern Medical Center, Dallas, TX; Jonathan W. Goldman, University of California, Los Angeles, Los Angeles, CA; Allen C. Chen, Yun Shen, Faith E. Nathan, and Christopher T. Harbison, Bristol-Myers Squibb, Princeton, NJ; and Scott Antonia, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.;Naiyer A. Rizvi and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center, New York, NY; Julie R. Brahmer, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Rosalyn A. Juergens, Juravinski Cancer Centre at McMaster University, Hamilton; Scott A. Laurie, Ottawa Hospital Cancer Centre, Ottawa; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Hossein Borghaei, Fox Chase Cancer Center, Philadelphia, PA; Scott Gettinger, Yale Cancer Center, New Haven, CT; Laura Q. Chow, University of Washington, Seattle, WA; David E. Gerber, University of Texas Southwestern Medical Center, Dallas, TX; Jonathan W. Goldman, University of California, Los Angeles, Los Angeles, CA; Allen C. Chen, Yun Shen, Faith E. Nathan, and Christopher T. Harbison, Bristol-Myers Squibb, Princeton, NJ; and Scott Antonia, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.;Naiyer A. Rizvi and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center, New York, NY; Julie R. Brahmer, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Rosalyn A. Juergens, Juravinski Cancer Centre at McMaster University, Hamilton; Scott A. Laurie, Ottawa Hospital Cancer Centre, Ottawa; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Hossein Borghaei, Fox Chase Cancer Center, Philadelphia, PA; Scott Gettinger, Yale Cancer Center, New Haven, CT; Laura Q. Chow, University of Washington, Seattle, WA; David E. Gerber, University of Texas Southwestern Medical Center, Dallas, TX; Jonathan W. Goldman, University of California, Los Angeles, Los Angeles, CA; Allen C. Chen, Yun Shen, Faith E. Nathan, and Christopher T. Harbison, Bristol-Myers Squibb, Princeton, NJ; and Scott Antonia, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.;Naiyer A. Rizvi and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center, New York, NY; Julie R. Brahmer, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Rosalyn A. Juergens, Juravinski Cancer Centre at McMaster University, Hamilton; Scott A. Laurie, Ottawa Hospital Cancer Centre, Ottawa; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Hossein Borghaei, Fox Chase Cancer Center, Philadelphia, PA; Scott Gettinger, Yale Cancer Center, New Haven, CT; Laura Q. Chow, University of Washington, Seattle, WA; David E. Gerber, University of Texas Southwestern Medical Center, Dallas, TX; Jonathan W. Goldman, University of California, Los Angeles, Los Angeles, CA; Allen C. Chen, Yun Shen, Faith E. Nathan, and Christopher T. Harbison, Bristol-Myers Squibb, Princeton, NJ; and Scott Antonia, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.;Naiyer A. Rizvi and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center, New York, NY; Julie R. Brahmer, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Rosalyn A. Juergens, Juravinski Cancer Centre at McMaster University, Hamilton; Scott A. Laurie, Ottawa Hospital Cancer Centre, Ottawa; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Hossein Borghaei, Fox Chase Cancer Center, Philadelphia, PA; Scott Gettinger, Yale Cancer Center, New Haven, CT; Laura Q. Chow, University of Washington, Seattle, WA; David E. Gerber, University of Texas Southwestern Medical Center, Dallas, TX; Jonathan W. Goldman, University of California, Los Angeles, Los Angeles, CA; Allen C. Chen, Yun Shen, Faith E. Nathan, and Christopher T. Harbison, Bristol-Myers Squibb, Princeton, NJ; and Scott Antonia, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.;Naiyer A. Rizvi and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center, New York, NY; Julie R. Brahmer, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Rosalyn A. Juergens, Juravinski Cancer Centre at McMaster University, Hamilton; Scott A. Laurie, Ottawa Hospital Cancer Centre, Ottawa; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Hossein Borghaei, Fox Chase Cancer Center, Philadelphia, PA; Scott Gettinger, Yale Cancer Center, New Haven, CT; Laura Q. Chow, University of Washington, Seattle, WA; David E. Gerber, University of Texas Southwestern Medical Center, Dallas, TX; Jonathan W. Goldman, University of California, Los Angeles, Los Angeles, CA; Allen C. Chen, Yun Shen, Faith E. Nathan, and Christopher T. Harbison, Bristol-Myers Squibb, Princeton, NJ; and Scott Antonia, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.;Naiyer A. Rizvi and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center, New York, NY; Julie R. Brahmer, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Rosalyn A. Juergens, Juravinski Cancer Centre at McMaster University, Hamilton; Scott A. Laurie, Ottawa Hospital Cancer Centre, Ottawa; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Hossein Borghaei, Fox Chase Cancer Center, Philadelphia, PA; Scott Gettinger, Yale Cancer Center, New Haven, CT; Laura Q. Chow, University of Washington, Seattle, WA; David E. Gerber, University of Texas Southwestern Medical Center, Dallas, TX; Jonathan W. Goldman, University of California, Los Angeles, Los Angeles, CA; Allen C. Chen, Yun Shen, Faith E. Nathan, and Christopher T. Harbison, Bristol-Myers Squibb, Princeton, NJ; and Scott Antonia, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.;Naiyer A. Rizvi and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center, New York, NY; Julie R. Brahmer, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Rosalyn A. Juergens, Juravinski Cancer Centre at McMaster University, Hamilton; Scott A. Laurie, Ottawa Hospital Cancer Centre, Ottawa; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Hossein Borghaei, Fox Chase Cancer Center, Philadelphia, PA; Scott Gettinger, Yale Cancer Center, New Haven, CT; Laura Q. Chow, University of Washington, Seattle, WA; David E. Gerber, University of Texas Southwestern Medical Center, Dallas, TX; Jonathan W. Goldman, University of California, Los Angeles, Los Angeles, CA; Allen C. Chen, Yun Shen, Faith E. Nathan, and Christopher T. Harbison, Bristol-Myers Squibb, Princeton, NJ; and Scott Antonia, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.;Naiyer A. Rizvi and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center, New York, NY; Julie R. Brahmer, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Rosalyn A. Juergens, Juravinski Cancer Centre at McMaster University, Hamilton; Scott A. Laurie, Ottawa Hospital Cancer Centre, Ottawa; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Hossein Borghaei, Fox Chase Cancer Center, Philadelphia, PA; Scott Gettinger, Yale Cancer Center, New Haven, CT; Laura Q. Chow, University of Washington, Seattle, WA; David E. Gerber, University of Texas Southwestern Medical Center, Dallas, TX; Jonathan W. Goldman, University of California, Los Angeles, Los Angeles, CA; Allen C. Chen, Yun Shen, Faith E. Nathan, and Christopher T. Harbison, Bristol-Myers Squibb, Princeton, NJ; and Scott Antonia, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.;Naiyer A. Rizvi and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center, New York, NY; Julie R. Brahmer, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Rosalyn A. Juergens, Juravinski Cancer Centre at McMaster University, Hamilton; Scott A. Laurie, Ottawa Hospital Cancer Centre, Ottawa; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Hossein Borghaei, Fox Chase Cancer Center, Philadelphia, PA; Scott Gettinger, Yale Cancer Center, New Haven, CT; Laura Q. Chow, University of Washington, Seattle, WA; David E. Gerber, University of Texas Southwestern Medical Center, Dallas, TX; Jonathan W. Goldman, University of California, Los Angeles, Los Angeles, CA; Allen C. Chen, Yun Shen, Faith E. Nathan, and Christopher T. Harbison, Bristol-Myers Squibb, Princeton, NJ; and Scott Antonia, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.;Naiyer A. Rizvi and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center, New York, NY; Julie R. Brahmer, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Rosalyn A. Juergens, Juravinski Cancer Centre at McMaster University, Hamilton; Scott A. Laurie, Ottawa Hospital Cancer Centre, Ottawa; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Hossein Borghaei, Fox Chase Cancer Center, Philadelphia, PA; Scott Gettinger, Yale Cancer Center, New Haven, CT; Laura Q. Chow, University of Washington, Seattle, WA; David E. Gerber, University of Texas Southwestern Medical Center, Dallas, TX; Jonathan W. Goldman, University of California, Los Angeles, Los Angeles, CA; Allen C. Chen, Yun Shen, Faith E. Nathan, and Christopher T. Harbison, Bristol-Myers Squibb, Princeton, NJ; and Scott Antonia, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.",
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"title": "Nivolumab in Combination With Platinum-Based Doublet Chemotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer.",
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"abstract": "This is a case of a 71-year-old smoker man who presented with four days of gross hematuria, which turned to be caused by eosinophilic cystitis (EC) proven by bladder biopsy. EC is a rare clinical and pathological inflammatory condition of the bladder with an unknown exact cause. It can present with hematuria, urinary frequency, dysuria, and suprapubic pain. Sometimes, the presentation can mimic urinary tract infection (UTI) or malignancy, especially in older patients.",
"affiliations": "Internal Medicine, Detroit Medical Center Sinai Grace Hospital, Detroit, USA.;Internal Medicine, Detroit Medical Center Sinai Grace Hospital, Detroit, USA.;General Practice, Luzima Hospital, Irbid, JOR.;Urology, Detroit Medical Center Sinai Grace Hospital, Detroit, USA.;Pathology, Detroit Medical Center Sinai Grace Hospital, Detroit, USA.",
"authors": "Al Sbihi|Ali F|AF|;Manasrah|Nouraldeen|N|;Al Qasem|Sarah|S|;Abdelhady|Mazen|M|;Shi|Dongping|D|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.12400\nInternal Medicine\nPathology\nUrology\nGross Hematuria in an Elderly Smoker Male Due to Eosinophilic Cystitis\nMuacevic Alexander Adler John R Al Sbihi Ali F 1 Manasrah Nouraldeen 1 Al Qasem Sarah 2 Abdelhady Mazen 3 Shi Dongping 4 \n1 \nInternal Medicine, Detroit Medical Center Sinai Grace Hospital, Detroit, USA \n\n2 \nGeneral Practice, Luzima Hospital, Irbid, JOR \n\n3 \nUrology, Detroit Medical Center Sinai Grace Hospital, Detroit, USA \n\n4 \nPathology, Detroit Medical Center Sinai Grace Hospital, Detroit, USA \n\nAli F. Al Sbihi ali_faisal_ahmad@yahoo.com\n31 12 2020 \n12 2020 \n12 12 e1240031 12 2020 Copyright © 2020, Al Sbihi et al.2020Al Sbihi et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/47855-gross-hematuria-in-an-elderly-smoker-male-due-to-eosinophilic-cystitisThis is a case of a 71-year-old smoker man who presented with four days of gross hematuria, which turned to be caused by eosinophilic cystitis (EC) proven by bladder biopsy. EC is a rare clinical and pathological inflammatory condition of the bladder with an unknown exact cause. It can present with hematuria, urinary frequency, dysuria, and suprapubic pain. Sometimes, the presentation can mimic urinary tract infection (UTI) or malignancy, especially in older patients.\n\nhematuriaeosinophilic cystitisbladderThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nEC was first described by Brown and Palubinskas in 1960 [1, 2]. This inflammation is characterized by transmural involvement of the bladder predominantly with eosinophils. It is associated with fibrosis with or without muscle necrosis. It fairly affects adult men and women, although a very minimal male predominance is seen among the pediatric age group [3]. EC has associations with numerous factors, such as allergy, bladder tumor, bladder trauma, parasitic infections, and chemotherapeutic agents with no clear cause for it [4]. This case report discusses the presentation, diagnosis, and management of EC.\n\nCase presentation\nA 71-year-old male with a history of stroke, peripheral vascular disease, and polysubstance abuse was admitted to the hospital with gross hematuria for four days. The patient was also complaining of mild pain with urination. He denied any difficulty urinating, flank pain, suprapubic pain, abdominal pain, other urinary symptoms, or weight loss. He also denied other sources of bleeding, recent trauma, recent drug, or alcohol use. He is not sexually active. He is a 25-pack year cigarette smoker, but he had recently quit. Medications include baby aspirin and rosuvastatin. There was no family history of similar presentations.\n\nOn presentation, his blood pressure was 159/66 mmHg, heart rate was 78 beats/minute, respiratory rate was 17 breaths/minute, oxygen saturation was 96% on room air, and he had a temperature of 36.6 Celsius. Physical examination revealed circumcised phallus, urethral meatus in orthotopic position, and bilateral descended testicles. There was no ecchymosis or signs of external trauma to the scrotum, perineum, or penis. The bladder was palpable. There was no crepitus, erythema, or warmth over the scrotum. The abdomen was soft, non-tender, and non-distended.\n\nLaboratory findings showed hemoglobin of 8.4 g/dl (baseline: 10-11 g/dl; normal:14-17). White blood cell (WBC) count was 7300 cells/mm3 (4000-11,000 cells/mm3) and absolute eosinophil count was 0.2 cell/mm3, it was up to 700-800 cell/mm3 in the last three months (normal: 0-500 cell/mm3). Mean corpuscular volume (MCV) was 89.6 femtoliter (80-100 femtoliter), red cell distribution width (RDW) was 13.7% (11.8- 14.5%), prothrombin time (PT) was 10.3 seconds (11-13.5 seconds), international normalized ratio (INR) was 0.96 (0.9-1.1), and platelet count was 281,000/mm3 (150,000-400,000/mm3). Electrolytes were within normal limits.\n\nUrinalysis showed cloudy red urine, red blood cell (RBC) count was more than 100 cell/high power field (HPF) (0-4 cell/HPF), WBC count was less than 5 cell/HPF (2-5 cell/HPF), squamous cells were less than 5 cell/HFP (0-5 cell/HPF), urine blood was 3+, urine protein was 3+, urine pH was 7.5 (4.6-8.0), and there were 2+ bacteria. Bilirubin, urobilinogen, leukocyte esterase, casts, crystals, and nitrite were negative. Urine drug screening was negative.\n\nPelvis X-ray showed no acute fractures or dislocation, kidneys-ureters-bladder (KUB) X-ray showed no evidence of stones or injuries. Computed tomography (CT) scan of the abdomen and pelvis with contrast showed diffuse nodular thickening of the bladder wall with multiple polypoid projections into the lumen, which were concerning for malignancy with interval development of mild hydroureter within the distal right ureter without hydronephrosis (Figure 1). The patient was given one-liter intravenous fluids (IVF) bolus, and a 1g IV ceftriaxone course was started.\n\nFigure 1 CT of abdomen-pelvis showed thickened bladder wall and polypoid projections into the bladder’s lumen\nUrology was consulted who performed cystoscopy, clot evacuation, bladder biopsy fulguration, and bilateral retrograde pyelogram. The latter study was unremarkable. Foley’s catheter was inserted, and IVF continued. Urine culture came negative for growth, urine started to gradually clear up, and the antibiotics course was stopped after five days.\n\nBladder cancer was highly suspected, and then interestingly, the bladder biopsy showed acute phase eosinophilic cystitis in the posterior and right lateral walls with prominent submucosal hemorrhage in the right and left lateral walls (Figure 2). The biopsy was negative for carcinoma. Foley’s catheter was maintained as an inpatient; the hospital course continued to be uncomplicated. The patient continued close outpatient follow-up with no recurrence of symptoms or microscopic hematuria, as proven by urine analysis. The patient did not require any further management except for close follow-up.\n\nFigure 2 Bladder biopsy\nImage A shows acute cystitis with eosinophilic infiltrates; image B shows increased eosinophils; image C is a high power field view showing eosinophilic infiltrates; image D shows Charcot-Leyden crystals. \n\nYamada and Taguchi criteria are 20 or more eosinophils per five 20x fields with edema and occasional muscle necrosis with possible Charcot-Leyden crystals [5].\n\nDiscussion\nEC is a bladder inflammation that is primarily caused by eosinophils. It can mimic UTI or malignancy by its presentation. The most common symptoms of EC are frequency, hematuria, dysuria, and suprapubic pain. Less common ones include nocturia and urinary retention, with the latter being more frequently reported in women and children. Proteinuria, microscopic/macroscopic hematuria, and peripheral eosinophilia are found only in a small percentage of patients [3, 6]. Cystoscopy with biopsy is the gold standard test for diagnosis.\n\nHellstrom et al. described that EC occurs either in patients with allergy, asthma, atopy, and peripheral eosinophilia, it is commonly seen in women and children or in patients with a history of bladder trauma; this tends to occur in elderly men with a history of surgery for benign prostatic hyperplasia, open bladder surgery or resection of bladder tumor [4]. EC is likely caused by the antigen-antibody reaction, leading to the production of numerous immunoglobulins that cause eosinophils’ activation and initiate the inflammatory process. Due to reported cases of eosinophilic cystitis in patients with celiac disease, an underlying malfunctioning of the immune system has also been proposed [7].\n\nUrinalysis may show proteinuria and microscopic hematuria; however, urine cultures are usually negative [3]. Eosinophiluria is rare due to many factors, including prompt degradation of eosinophils, minimal mucosal shedding from the urothelium, and that eosinophilia is present in other renal and urological conditions, so the presence of eosinophiluria is not diagnostic [8]. In blood tests, eosinophilia may be useful; however, it is found in approximately 50% of patients with a history of allergy or atopy [9].\n\nOn imaging, varying degrees of bladder wall thickening may be found, from diffuse thickening to mass formation, and that depends on the stage of EC [10]. Hydronephrosis with bladder and ureteral filling defects were noted in some studies [6, 8].\n\nA biopsy is the gold standard test for the diagnosis of EC; it usually shows a transmural inflammation of eosinophils, mainly in the lamina propria. EC can be classified as acute or chronic, based on histology. Tissue eosinophilia, mucosal edema, hyperemia, and muscle necrosis are more commonly found in acute phases. Chronically, scarring can be clearly noticed, but tissue eosinophilia is not common [10, 11].\n\nUTI or medications like tranilast and mitomycin C must be identified as precipitating factors [8]. Afterward, nonsteroidal anti-inflammatory drugs (NSAIDs) or antihistamines are the first-line medications for the management of EC, corticosteroids are the second line, with azathioprine and cyclosporine-A come as the third line. After medical management failure, operative intervention should be considered like diathermy, lesion resection, or cystectomy. Algorithms for EC management have been suggested as there are no standards for treatment. One example of these algorithms is shown (Figure 3) [11]. Our patient did not require any medical management because the cystoscopy procedure was diagnostic and therapeutic at the same time.\n\nFigure 3 Algorithm for EC treatment\nThe permission to republish the image is obtained from the original publisher. Source: [11]\n\nEC - eosinophilic cystitis; IVU - intravenous urogram; FBC - full blood count; USS - ultrasound scan; NSAID - nonsteroidal anti-inflammatory drug; Rx - treatment\n\nPrognosis is usually benign with complete resolution in most affected patients. Long term monitoring by blood tests, urine analysis, and imaging is crucial. Sometimes, cystoscopy may be indicated to avoid renal and bladder damage and to rule out bladder cancer. Because lesions tend to recur despite the above therapy, long‐term follow‐up is mandatory [11, 12].\n\nConclusions\nEC is a rare inflammatory condition of unknown cause that mimics other urological conditions. A biopsy is the gold standard test for the diagnosis. EC is best managed by a combination of oral medical therapy and surgical intervention. Although most patients are cured, recurrence is common, so follow up after diagnosis and treatment is mandatory.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Eosinophilic granuloma of the bladder J Urol Brown EW 665 668 83 1960 13804922 \n2 Eosinophilic cystitis and haematuria: case report of a rare disease and common presentation Int J Surg Case Rep Chia D 43 45 24 2016 27179336 \n3 Diagnosis and management of eosinophilic cystitis: a pooled analysis of 135 cases Eur Urol van den Ouden D 386 394 37 2000 10765067 \n4 Eosinophilic cystitis. A study of 16 cases Am J Clin Pathol Hellstrom HR Davis BK Shonnard JW 777 784 72 1979 506991 \n5 Clinical study of eosinophilic cystitis. I. On the definition of eosinophilic cystitis. I-1. Histological observation of eosinophilic infiltration Hinyokika Kiyo Yamada T Taguchi H 1781 1784 30 1984 https://pubmed.ncbi.nlm.nih.gov/6532205/ 6532205 \n6 Eosinophilic cystitis presenting as urinary retention Urol Int van den Ouden D van Kaam N Eland D 22 26 66 2001 11150946 \n7 The spectrum of eosinophilic cystitis in males: case series and literature review Arch Pathol Lab Med Popescu OE Landas SK Haas GP 289 294 133 2009 https://pubmed.ncbi.nlm.nih.gov/19195972/ 19195972 \n8 Eosinophilic cystitis in adults J Urol Itano NM Malek RS 805 807 165 2001 11176473 \n9 Eosinophilic cystitis with eosinophilic cholecystitis: a rare association Case Rep Urol Mallat F Hmida W Mestiri S 1 5 2013 2013 \n10 Ultrasonographic detection and control of eosinophilic cystitis Abdom Imaging Leibovitch I Heyman Z Ben Chaim J Goldwasser B 270 271 19 1994 8019361 \n11 Eosinophilic cystitis and its management Int J Clin Pract Teegavarapu PS Sahai A Chandra A Dasgupta P Khan MS 356 360 59 2005 15857336 \n12 Eosinophilic cystitis presenting as invasive bladder cancer: comments on pathogenesis and management J Urol Thijssen A Gerridzen RG 977 979 144 1990 2204734\n\n",
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"title": "Gross Hematuria in an Elderly Smoker Male Due to Eosinophilic Cystitis.",
"title_normalized": "gross hematuria in an elderly smoker male due to eosinophilic cystitis"
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"activesubstancename": "ASPIRIN"
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{
"abstract": "Warfarin is a high-alert medication, which may result in bleeding if used improperly. In our case, one elderly female with atrial fibrillation had taken warfarin for more than half a year, and her international normalized ratio (INR) was maintained within the therapeutic range. The patient began to take tramadol to alleviate her shoulder pain. Three days later she presented hematuresis and had ecchymosis in her right upper arm, and in the meantime her INR rose to 10.04. Clinical pharmacists analyzed the cause for bleeding by searching relevant literature, and finally discovered the interaction between warfarin and tramadol. On the basis of that, the clinical pharmacists provided pharmaceutical care, offered specific medication education, as well as assisted the physicians to establish the medication plan for warfarin reuse. Eventually, her INR declined to reference ranges, and her hematuresis and ecchymosis were alleviated significantly. This successful case reveals that clinical pharmacy services contribute to better treatment outcomes. Clinical pharmacists can play an active role in anticoagulation management in healthcare team.",
"affiliations": "Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China; Department of Pharmaceutical Administration and Clinical Pharmacy, Peking University, Beijing 100191, China.;Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China.;Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China; Department of Pharmaceutical Administration and Clinical Pharmacy, Peking University, Beijing 100191, China.;Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China.",
"authors": "Dong|Shu-jie|SJ|;Zhang|Ting|T|;Li|Yan|Y|;Zhai|Suo-di|SD|",
"chemical_list": "D000925:Anticoagulants; D014147:Tramadol; D014859:Warfarin",
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1671-167X",
"issue": "46(5)",
"journal": "Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences",
"keywords": null,
"medline_ta": "Beijing Da Xue Xue Bao Yi Xue Ban",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D004347:Drug Interactions; D005260:Female; D006470:Hemorrhage; D006801:Humans; D019934:International Normalized Ratio; D014147:Tramadol; D016896:Treatment Outcome; D014859:Warfarin",
"nlm_unique_id": "101125284",
"other_id": null,
"pages": "809-13",
"pmc": null,
"pmid": "25331411",
"pubdate": "2014-10-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pharmaceutical care of serious bleeding induced by tramadol-warfarin interaction: a case report.",
"title_normalized": "pharmaceutical care of serious bleeding induced by tramadol warfarin interaction a case report"
} | [
{
"companynumb": "PHHY2015CN115156",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "WARFARIN"
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"abstract": "Filgrastim (FIL) is the most common growth factor combined with plerixafor for autologous hematopoietic progenitor cell mobilization, but requires daily, multi-injection administration. We adopted a standardized mobilization regimen with pegfilgrastim (PEG) and upfront plerixafor, allowing for a single injection given the long half-life and slow elimination of PEG. Between 2015 and 2017, a total of 235 patients with lymphoma or plasma cell dyscrasias underwent mobilization with PEG 6 mg on day 1 and upfront plerixafor 24 mg on day 3, followed by apheresis on day 4 regardless of peripheral blood CD34+ cells. The median CD34+ cells/mm3 in peripheral blood on first day of collection was 48 and median collection yield was 7.27 × 106 CD34+ cells/kg (range, 0.32 to 39.6 × 106 CD34+ cells/kg) after a mean of 1.6 apheresis collections. Overall, 83% of patients achieved the mobilization target, and 95% reached the minimum necessary CD34+ cell yield to proceed with transplantation (2 × 106 CD34+ cells/kg). Because FIL is weight-based and dosed daily, the cost comparison with PEG is influenced by patient weight and number of apheresis sessions required. A cost simulation using actual patient data indicates that PEG is associated with lower cost than FIL for the majority of patients. Autologous hematopoietic progenitor cell mobilization with PEG and plerixafor is practical, effective, and not associated with increased cost compared with FIL mobilization.",
"affiliations": "Department of Pharmacy, University of Alabama at Birmingham Hospital, Birmingham, Alabama.;Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.;Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.;Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.;Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.;Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.;Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.;Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.;Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama. Electronic address: Ljmegale@gmail.com.",
"authors": "Watts|Nicole L|NL|;Marques|Marisa B|MB|;Peavey|Daniel B|DB|;Innis-Shelton|Racquel|R|;Saad|Ayman|A|;Ad|Stasi|S|;Salzman|Donna|D|;Lamb|Lawrence S|LS|;Costa|Luciano J|LJ|",
"chemical_list": "C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2018.09.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "25(2)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Cost analysis; Pegfilgrastim; Plerixafor; Stem cell mobilization",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D003365:Costs and Cost Analysis; D005260:Female; D000069585:Filgrastim; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation; D011092:Polyethylene Glycols; D014182:Transplantation, Autologous",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "233-238",
"pmc": null,
"pmid": "30219699",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Mobilization of Hematopoietic Progenitor Cells for Autologous Transplantation Using Pegfilgrastim and Plerixafor: Efficacy and Cost Implications.",
"title_normalized": "mobilization of hematopoietic progenitor cells for autologous transplantation using pegfilgrastim and plerixafor efficacy and cost implications"
} | [
{
"companynumb": "US-AMGEN-USASP2018134825",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
},
"drugadditional": "3",
... |
{
"abstract": "With the improvement of long-term cancer survival rates, growing numbers of female survivors are suffering from treatment-related premature ovarian insufficiency (POI). Although pre-treatment embryo and oocyte storage are effective fertility preservation strategies, they are not possible for pre-pubertal girls or women who cannot delay treatment. In these cases, the only available treatment option is ovarian cortex cryopreservation and subsequent re-implantation. A 32-year-old woman had ovarian cortex cryopreserved 10 years previously before commencing high-dose chemotherapy and undergoing a haematopoietic stem cell transplant for recurrent adult Wilms tumour, which resulted in POI. She underwent laparoscopic orthotopic transplantation of cryopreserved ovarian cortex to the original site of biopsy on the left ovary. She ovulated at 15 and 29 weeks post-re-implantation with AMH detectable, then rising, from 21 weeks, and conceived naturally following the second ovulation. The pregnancy was uncomplicated and a healthy male infant was born by elective Caesarean section at 36+4 weeks gestation. This is the first report of ovarian cortex re-implantation in the UK. Despite the patient receiving low-risk chemotherapy prior to cryopreservation and the prolonged tissue storage duration, the re-implantation resulted in rapid restoration of ovarian function and natural conception with successful pregnancy.",
"affiliations": "Simpson's Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, EH16 4SA, UK. Cheryl.Dunlop@ed.ac.uk.;Simpson's Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, EH16 4SA, UK.;Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK.;Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK.;Beatson West of Scotland Cancer Centre, Glasgow, G12 0YN, UK.;Beatson West of Scotland Cancer Centre, Glasgow, G12 0YN, UK.;Tissue and Cells Services, Scottish National Blood Transfusion Service, Edinburgh, EH17 7QT, UK.;Royal Hospital for Sick Children, Edinburgh, EH9 1LF, UK.;Simpson's Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, EH16 4SA, UK.",
"authors": "Dunlop|C E|CE|;Brady|B M|BM|;McLaughlin|M|M|;Telfer|E E|EE|;White|J|J|;Cowie|F|F|;Zahra|S|S|;Wallace|W H B|WH|;Anderson|R A|RA|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10815-016-0805-2",
"fulltext": "\n==== Front\nJ Assist Reprod GenetJ. Assist. Reprod. GenetJournal of Assisted Reproduction and Genetics1058-04681573-7330Springer US New York 2763999680510.1007/s10815-016-0805-2Fertility PreservationRe-implantation of cryopreserved ovarian cortex resulting in restoration of ovarian function, natural conception and successful pregnancy after haematopoietic stem cell transplantation for Wilms tumour Dunlop C. E. 0131 242 9300Cheryl.Dunlop@ed.ac.uk 12Brady B. M. 1McLaughlin M. 3Telfer E. E. 3White J. 4Cowie F. 4Zahra S. 5Wallace W. H. B. 6Anderson R. A. 121 Simpson’s Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, EH16 4SA UK 2 MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, EH16 4TJ UK 3 Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD UK 4 Beatson West of Scotland Cancer Centre, Glasgow, G12 0YN UK 5 Tissue and Cells Services, Scottish National Blood Transfusion Service, Edinburgh, EH17 7QT UK 6 Royal Hospital for Sick Children, Edinburgh, EH9 1LF UK 17 9 2016 17 9 2016 12 2016 33 12 1615 1620 28 7 2016 29 8 2016 © The Author(s) 2016\nOpen Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.With the improvement of long-term cancer survival rates, growing numbers of female survivors are suffering from treatment-related premature ovarian insufficiency (POI). Although pre-treatment embryo and oocyte storage are effective fertility preservation strategies, they are not possible for pre-pubertal girls or women who cannot delay treatment. In these cases, the only available treatment option is ovarian cortex cryopreservation and subsequent re-implantation. A 32-year-old woman had ovarian cortex cryopreserved 10 years previously before commencing high-dose chemotherapy and undergoing a haematopoietic stem cell transplant for recurrent adult Wilms tumour, which resulted in POI. She underwent laparoscopic orthotopic transplantation of cryopreserved ovarian cortex to the original site of biopsy on the left ovary. She ovulated at 15 and 29 weeks post-re-implantation with AMH detectable, then rising, from 21 weeks, and conceived naturally following the second ovulation. The pregnancy was uncomplicated and a healthy male infant was born by elective Caesarean section at 36+4 weeks gestation. This is the first report of ovarian cortex re-implantation in the UK. Despite the patient receiving low-risk chemotherapy prior to cryopreservation and the prolonged tissue storage duration, the re-implantation resulted in rapid restoration of ovarian function and natural conception with successful pregnancy.\n\nKeywords\nOvarian cortex re-implantationFertility preservationPremature ovarian insufficiencyAMHhttp://dx.doi.org/10.13039/501100000265Medical Research CouncilG1100357issue-copyright-statement© Springer Science+Business Media New York 2016\n==== Body\nIntroduction\nThe developments in cancer treatments over the last few decades have resulted in greatly increasing numbers of survivors. However, this has come at a cost, with many patients suffering long-term adverse effects of their life-saving treatment. The ovaries are particularly susceptible to damage by chemotherapy and radiotherapy with the type and dose of therapy and age of the patient influencing the extent of the injury [1, 2]. Loss of fertility is a major concern for young women facing potentially sterilising treatment [3]; one study found that almost three quarters of female cancer survivors of reproductive age have concerns regarding infertility and that survivors with irregular menses reported a lower quality of life than those with regular menstrual cycles [4]. Recent years have consequently seen significant developments in approaches to preserve fertility in those women and girls who are at risk of undergoing treatment-related premature ovarian insufficiency (POI) [5].\n\nEmbryo and oocyte cryopreservation are now established fertility preservation strategies [2, 5]; however, these are not appropriate in pre-pubertal girls, and in adult women the necessary ovarian stimulation may delay the start of cancer treatment. Ovarian tissue cryopreservation remains the only option in these situations. This approach was first validated in a large animal model [6] and has been offered to selected patients since 1993 [7]. The first human live birth as a result of ovarian cortex re-implantation was reported over a decade ago [8], and since then, there have been at least 60 live births described globally [9]. Yet, it is still regarded as an experimental technique with an uncertain success rate. We here describe the first human ovarian cortex re-implantation in the UK and report resumption of ovarian function resulting in a natural conception and pregnancy.\n\nMethods\nThe patient was first referred to the Fertility Preservation service in Edinburgh, UK, at 22 years of age for discussion of ovarian cortex cryopreservation. She was a nulliparous, non-smoker with a normal body mass index and a past medical history of juvenile rheumatoid arthritis. She had presented with a right-sided abdominal mass at 21 years old and diagnosed with a stage 1 adult Wilms tumour of the right kidney. Following a right nephrectomy and adrenalectomy, she received adjuvant chemotherapy in the form of 5 cycles of vincristine and actinomycin D, following which her menstrual cycles continued. However, 3 months later, she had a recurrence of the tumour in the right renal bed, and a CT scan detected multiple pulmonary metastases. As the proposed treatment was deemed to be gonadotoxic, she was counselled regarding fertility preservation options. She elected for ovarian cortex cryopreservation, and 5 months following initial chemotherapy, she underwent laparoscopic removal of 18 biopsies of ovarian cortex from the left ovary with subsequent slow freezing [6] and long-term storage in the vapour phase of liquid nitrogen, with informed consent and ethical committee approval of the protocol. A piece of ovarian cortex sent for histopathological analysis showed the presence of a single primordial follicle, a corpus albicans, normal ovarian stroma and no evidence of malignant contamination (Fig. 1).Fig. 1 Biopsy of ovarian cortex removed at the time of ovarian cortex cryopreservation demonstrating a single primordial follicle with two nucleoli surrounded by normal ovarian stroma. The patient had already received non-sterilising chemotherapy prior to this biopsy\n\n\n\n\nSubsequently, she received curative treatment consisting of chemotherapy comprising carboplatin (area under the curve (AUC) 10; 3 doses), etoposide (200 mg/m2; 9 doses), cyclophosphamide (500 mg/m2; 12 doses) and doxorubicin (30 mg/m2; 6 doses), resection of the recurrent tumour including partial hepatectomy, an autologous peripheral blood stem cell transplant (PBSCT) with pre-conditioning using high-dose melphalan (200 mg/m2; 1 dose) and radiotherapy. She received radiotherapy to the whole of both lungs (with a boost to the residual tumour sites) and to the right flank. The lower (inferior) border of the flank radiotherapy was the inferior edge of L2, and it extended from midline to the right lateral abdominal wall. The total dose to this region was 3000 cGy with the estimated dose to the right ovary being 100 cGy. The uterus was not in the field of radiation. This was followed by bilateral lower lobe resection of both lungs, with pathology showing no residual disease. These treatments induced POI, which was diagnosed by the presence of amenorrhoea, elevated gonadotrophins (follicle stimulating hormone (FSH) >100 IU/L and LH 53.1 IU/L) and low estradiol (E2; <70 pmol/L). Similar hormone measurements were obtained on repeat sampling, and hormone replacement therapy was commenced in the form of a combined oral contraceptive pill (COCP).\n\nAt 32 years of age, the patient was disease-free and in a stable relationship, and requested re-implantation of her stored ovarian cortex with the aim of achieving a pregnancy. She had continued on COCP for hormone replacement in the interim. Given her medical history, she was reviewed in the pre-conceptual obstetric clinic and underwent cardio-respiratory assessment with an exercise tolerance test to assess her ability to carry a pregnancy. Pelvic ultrasound showed a normal uterus. Laparoscopic orthotopic transplantation of thawed ovarian cortex was performed in May 2015 (Fig. 2). The site of previous resection of ovarian cortex was clearly visible on the left ovary (Fig. 2a), with both ovaries atrophic but the pelvis otherwise normal with no adhesions. The tissue was thawed using a previously reported and validated protocol [6, 10]. A longitudinal incision along the left ovary was carried out and eight pieces of cortex (each approximately 1 cm × 1 cm × 0.5 cm) were then introduced onto the resultant cut ovarian surface, which was vascular but did not bleed actively. The tissue pieces were adhered to the ovary using fibrin sealant without suturing. The patient stopped her COCP at the time of the operation.Fig. 2 Laparoscopic orthotopic ovarian cortex re-implantation. a The atrophic native left ovary with scarring from previous ovarian cortical biopsy clearly visible. b A longitudinal incision was made along the left ovary resulting in a vascular surface. c Eight pieces of ovarian cortex were placed inside the native left ovary and adhered with fibrin sealant\n\n\n\n\nResults\nThe patient was followed up post-operatively with regular transvaginal ultrasound scans and serial measurement of serum gonadotrophins, E2 and anti-Mϋllerian hormone (AMH) (Fig. 3). Serum AMH was measured using an automated assay (Roche Elecsys, sensitivity 0.07 pmol/L). Due to problematic climacteric symptoms, low-dose hormone replacement therapy was recommenced 5 weeks postoperatively, with 1 mg oral E2 daily. Her gonadotrophins fell, and a follicle of mean diameter 14 mm on the left ovary was observed 15 weeks postoperatively, at which time FSH was 11.2 IU/L, LH 13.4 IU/L and E2 891 pmol/L. She subsequently ovulated spontaneously with a confirmatory serum progesterone of 27.9 nmol/L 7 days later and menses a further week later. Hormone replacement therapy (HRT) was discontinued, but her menopausal symptoms returned; therefore, it was restarted 6 weeks later. She had a further spontaneous ovulation at 29 weeks postoperatively (peak E2 891 pmol/L followed by progesterone 34.9 nmol/L) (Fig. 4a and b). Natural conception occurred, and a single, viable intrauterine pregnancy was confirmed on transvaginal ultrasound scanning at 7 weeks gestation (Fig. 4c), with a corpus luteum visible on the left ovary. AMH became detectable at 21 weeks post-re-implantation and rose progressively thereafter, although remaining low.Fig. 3 Serum hormones were measured following re-implantation, with day 0 being the day of re-implantation. a Serum gonadotrophin (follicle stimulating hormone (FSH), luteinising hormone (LH) and estradiol (E2) levels. The grey boxes illustrate time periods on hormone replacement therapy (HRT). Corresponding progesterone rises occurred following the two E2 peaks denoted by black arrows, confirming ovulation. b Serum anti-Mϋllerian hormone (AMH) levels rose steadily from 21 weeks post-re-implantation\n\n\nFig. 4 Transvaginal ultrasound scan images post-re-implantation. a Two antral follicles on the left ovary seen at 29 weeks postoperatively. The larger follicle had a mean diameter of 15 mm and ovulation was confirmed by a progesterone rise 1 week later. b Longitudinal view of the uterus at 29 weeks post-re-implantation demonstrating an endometrial thickness of 7.9 mm. c Single viable intrauterine pregnancy at 7+3 weeks gestation by crown-rump length (CRL) measurement (white arrow). The yolk sac is denoted by the black arrow. A corpus luteum was seen on the left ovary\n\n\n\n\nThe pregnancy proceeded routinely, with normal ultrasound scans at 12, 20 and 28 weeks gestation. An elective Caesarean section was performed for maternal reasons (largely related to shortness of breath) at 36+4 weeks gestation with the delivery of a healthy male infant weighing 3.01 kg. Apgar scores were 9 at 1 min and 9 at 5 min, and cord blood gases were normal.\n\nDiscussion\nIn this case report, we describe the first incidence of ovarian cortex re-implantation with natural conception and successful pregnancy in the UK. The ovarian tissue had been exposed to non-sterilising chemotherapy, had been cryopreserved for 10 years and demonstrated an apparent reduced ovarian reserve on pathology. Yet, ovulation was detected within 15 weeks of the re-implantation, and a viable pregnancy was achieved after the second ovulation. That the pregnancy has occurred from a follicle within the grafted tissue appears highly likely due to the patient suffering POI, diagnosed clinically and biochemically, for 9 years prior to re-implantation, the presence of a dominant follicle at the site of re-implantation and a corresponding corpus luteum following ovulation.\n\nAlthough the patient reported initial improvement of menopausal symptoms in the weeks following replacement, HRT was later required for symptom relief, and it is notable that both ovulations occurred whilst taking oestrogen-only HRT. Oestrogen replacement increased the ovulation rate (and possibly pregnancy rate) in a randomised placebo-controlled trial in women with POI [11], with the effect confined to those with lower FSH concentrations during oestrogen treatment, probably reflecting less complete cessation of ovarian activity. Further RCTs are required to investigate the efficacy of this approach. Serum AMH remained undetectable following re-implantation for 20 weeks using a highly sensitive assay with limit of detection 0.07 pmol/L (0.01 ng/mL), then rose steadily over the next months until pregnancy. Thus, AMH remained undetectable until after the first ovulation but was thereafter consistently detectable, albeit at very low levels with a concentration of 1.8 pmol/L (0.25 ng/mL) at the time of conception. Using older assays, AMH has previously been reported to be generally undetectable post-re-implantation and therefore has not been considered valuable in monitoring ovarian function [12–14]. The present result therefore indicates that AMH may be of value in assessing the duration of function of ovarian transplants but requires the use of new, sensitive assays, although it must be recognised that AMH is not predictive of fecundability in young women [15].\n\nOur findings are in keeping with those of the other main centres where ovarian cortex cryopreservation is performed [9, 14, 16]. A study of 60 cases of re-implantation worldwide reported the restoration of ovarian function in 93 % of patients, with a correlation seen between resumption of menses and number of follicles in the re-implanted tissue [14], whilst a case series of 95 re-implantations performed by the FertiPROTEKT network reported ovarian activity at 1 year after replacement in 63 % of recipients with POI [16]. A period of 3.5 to 6.5 months is generally observed before FSH falls and E2 rises [14]. Conception rates of 29–33 % have been reported, with 75–82.5 % of these pregnancies resulting in a live birth [9, 16]. Furthermore, natural conception has occurred in more than half of the cases, as here, highlighting that assisted reproductive techniques are not necessary for most women [14]. An alternative approach is repeated cycles of ovarian stimulation and embryo cryopreservation [17] although this is very invasive and costly and therefore of limited application. The great majority of these pregnancies have occurred following slow freezing of the ovarian cortical pieces [9]; however, a recent study indicated that vitrification may have advantages [18] and, indeed, two pregnancies following re-implantation of vitrified ovarian cortex have been reported [19].\n\nThis case illustrates that cryopreserved ovarian tissue can be stored for long periods of time with maintenance of follicle growth potential and oocyte viability. The longest reported duration of storage resulting in pregnancy is 11 years, in a young woman with sickle cell anaemia whose ovarian tissue was cryopreserved aged 14 [20]. In the present case, she had previously received chemotherapy with vincristine and actinomycin D which have very low gonadotoxicity [21], but it is striking that pathological analysis of a biopsy of ovarian cortex showed the presence of only one primordial follicle despite her young age at that time. Assessment of ovarian reserve by ultrasound or serum AMH was not possible at that time. Furthermore, re-implantation of ovarian tissue results in loss of the majority of follicles within the tissue [22]. However, it is well recognised that the distribution of follicles within the ovary in not even [23–25].\n\nPreceding chemotherapy may affect graft function. The time to first ovulation in this case was more rapid than is generally observed in patients who had received chemotherapy prior to cryopreservation (less than 4 months in this case vs. 5.5–6.5 months [14]). This may not be related to her previous treatment; the rate of follicle activation increases with age and falling primordial follicle pool. The effect of cytotoxic treatments on ovarian reserve is variable and often difficult to predict, particularly as chemotherapy regimens frequently comprise a combination of drug classes. The alkylating agents used in her subsequent treatment, such as cyclophosphamide and melphalan (which are likely to have contributed to our patient’s POI, following her treatment for recurrence), are among the most toxic classes of chemotherapeutic agents [1]. However, a recent detailed analysis of childhood cancer survivors treated with chemotherapy without any possible effect of radiotherapy on gonadal function showed a risk of loss of fertility only with the highest doses of alkylating agent in females [26]. Furthermore, women who undergo a bone marrow transplant, as in this patient, are at extremely high risk of POI due to the requirement for highly toxic pre-conditioning regimens [27]. Previous chemotherapy is therefore important to consider when planning any form of fertility preservation procedure, with recent therapy potentially resulting in reduced viability of oocytes and in the longer term resulting in loss of ovarian reserve. However, this case highlights the likely importance of the patient’s young age (22 years old at tissue storage) and thus oocyte quality over low ovarian reserve in predicting successful conception. Indeed, the FertiPROTEKT case series demonstrated that re-implantation surgery was more successful in those patients who had their tissue cryopreserved at younger ages [16].\n\nWith regard to the surgical approach to re-implantation, several orthotopic strategies have been used (reviewed in [14]). In this case, we performed a similar procedure to that described by Sanchez-Serrano et al. [28] whereby the cortical pieces were inserted into a remaining ovary next to the medulla and sealed in place with a fibrin sealant. The pieces can also be sutured to the medulla, or placed in a subcortical area, although this was not performed here due to very high tissue friability and the availability of highly effective fibrin sealant. Another technique, required if the patient has no remaining ovaries, is the placing of ovarian pieces into a peritoneal window, preferably a vascular area, with the use of a sealant to keep the pieces adhered to the pelvic wall. Heterotopic re-implantations have also been performed. This method of transplantation has some advantages over orthotopic transplantation, including easier access for monitoring of graft function (reviewed in [14]); however, only one pregnancy has been reported as a result of the use of a heterotopic site (where the anterior abdominal wall was used) [29].\n\nThe average lifespan of ovarian tissue grafts appears to be 4–5 years [14] with much longer duration being reported in some women [13]. Five women have delivered at least twice from one re-implantation procedure to date [9]. Long-term ovarian function, comprising both fertility and hormone production can therefore be achieved; the latter is increasingly recognised to be of importance in the light of long-term adverse health effects of POI [30]. In this patient, ovarian function will be monitored post-pregnancy to assess the duration of the grafts, and half the stored tissue remains cryopreserved allowing the possibility of one or more further replacements. This case therefore adds to the growing evidence that ovarian tissue cryopreservation and later re-implantation are an important component of the fertility preservation repertoire, with the potential for restoration of fertility without the need for IVF and expensive medical interventions, and with the additional possibility of provision of long-term hormone production.\n\n\nCapsule The first re-implantation of cryopreserved ovarian cortex in the UK has resulted in restoration of ovarian function and natural conception, with detectable and rising AMH levels.\n\nThe authors are grateful to our Research Nurses, Joan Creiger and Anne Saunderson, for their help with the Fertility Preservation Programme, to the Laboratory team at Tissue and Cells Services, Scottish National Blood Transfusion Service for cryopreservation and storage of the tissue, to Prof. Alastair Williams for providing Fig. 1 and to Dr. Alastair Campbell for antenatal care of the patient.\n\nCompliance with ethical standards\nFunding\nThis work was supported in part by Medical Research Council UK grant G1100357 to RAA.\n\nConflict of interest\nThe authors declare that they have no conflict of interest.\n\nEthical approval\nAll procedures performed were in accordance with the ethical standards of the local research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\n\nInformed consent\nInformed consent was obtained from the participant in the case report.\n==== Refs\nReferences\n1. Morgan S Anderson RA Gourley C Wallace WH Spears N How do chemotherapeutic agents damage the ovary? Hum Reprod Update 2012 18 5 525 35 10.1093/humupd/dms022 22647504 \n2. Loren AW Mangu PB Beck LN Brennan L Magdalinski AJ Partridge AH Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update J Clin Oncol 2013 31 19 2500 10 10.1200/JCO.2013.49.2678 23715580 \n3. Peate M Meiser B Hickey M Friedlander M The fertility-related concerns, needs and preferences of younger women with breast cancer: a systematic review Breast Cancer Res Treat 2009 116 2 215 23 10.1007/s10549-009-0401-6 19390962 \n4. Kondapalli LA Dillon KE Sammel MD Ray A Prewitt M Ginsberg JP Quality of life in female cancer survivors: is it related to ovarian reserve? Qual Life Res 2014 23 2 585 92 10.1007/s11136-013-0473-y 23881516 \n5. Anderson RA Mitchell RT Kelsey TW Spears N Telfer EE Wallace WH Cancer treatment and gonadal function: experimental and established strategies for fertility preservation in children and young adults Lancet Diabetes Endocrinol 2015 3 7 556 67 10.1016/S2213-8587(15)00039-X 25873571 \n6. Gosden RG Baird DT Wade JC Webb R Restoration of fertility to oophorectomized sheep by ovarian autografts stored at -196 degrees C Hum Reprod 1994 9 4 597 603 8046009 \n7. Anderson RA Wallace WH Baird DT Ovarian cryopreservation for fertility preservation: indications and outcomes Reproduction 2008 136 6 681 9 10.1530/REP-08-0097 18682546 \n8. Donnez J Dolmans MM Demylle D Jadoul P Pirard C Squifflet J Livebirth after orthotopic transplantation of cryopreserved ovarian tissue Lancet 2004 364 9443 1405 10 10.1016/S0140-6736(04)17222-X 15488215 \n9. Donnez J Dolmans MM Diaz C Pellicer A Ovarian cortex transplantation: time to move on from experimental studies to open clinical application Fertil Steril 2015 104 5 1097 8 10.1016/j.fertnstert.2015.08.005 26342246 \n10. Anderson RA McLaughlin M Wallace WH Albertini DF Telfer EE The immature human ovary shows loss of abnormal follicles and increasing follicle developmental competence through childhood and adolescence Hum Reprod 2014 29 1 97 106 10.1093/humrep/det388 24135076 \n11. Tartagni M Cicinelli E De Pergola G De Salvia MA Lavopa C Loverro G Effects of pretreatment with estrogens on ovarian stimulation with gonadotropins in women with premature ovarian failure: a randomized, placebo-controlled trial Fertil Steril 2007 87 4 858 61 10.1016/j.fertnstert.2006.08.086 17261285 \n12. Janse F Donnez J Anckaert E de Jong FH Fauser BC Dolmans MM Limited value of ovarian function markers following orthotopic transplantation of ovarian tissue after gonadotoxic treatment J Clin Endocrinol Metab 2011 96 4 1136 44 10.1210/jc.2010-2188 21289248 \n13. Andersen CY Silber SJ Bergholdt SH Jorgensen JS Ernst E Long-term duration of function of ovarian tissue transplants: case reports Reprod Biomed Online 2012 25 2 128 32 10.1016/j.rbmo.2012.03.014 22687323 \n14. Donnez J Dolmans MM Pellicer A Diaz-Garcia C Sanchez Serrano M Schmidt KT Restoration of ovarian activity and pregnancy after transplantation of cryopreserved ovarian tissue: a review of 60 cases of reimplantation Fertil Steril 2013 99 6 1503 13 10.1016/j.fertnstert.2013.03.030 23635349 \n15. Hagen CP Vestergaard S Juul A Skakkebaek NE Andersson AM Main KM Low concentration of circulating antimullerian hormone is not predictive of reduced fecundability in young healthy women: a prospective cohort study Fertil Steril 2012 98 6 1602 8 10.1016/j.fertnstert.2012.08.008 22959460 \n16. Van der Ven H Liebenthron J Beckmann M Toth B Korell M Krussel J Ninety-five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates Hum Reprod 2016 27378768 \n17. Oktay K, Bedoschi G, Pacheco F, Turan V, Emirdar V. First pregnancies, live birth, and in vitro fertilization outcomes after transplantation of frozen-banked ovarian tissue with a human extracellular matrix scaffold using robot-assisted minimally invasive surgery. Am J Obstet Gynecol. 2016;214(1):94 e1–9.\n18. Herraiz S Novella-Maestre E Rodriguez B Diaz C Sanchez-Serrano M Mirabet V Improving ovarian tissue cryopreservation for oncologic patients: slow freezing versus vitrification, effect of different procedures and devices Fertil Steril 2014 101 3 775 84 10.1016/j.fertnstert.2013.11.016 24359888 \n19. Suzuki N Yoshioka N Takae S Sugishita Y Tamura M Hashimoto S Successful fertility preservation following ovarian tissue vitrification in patients with primary ovarian insufficiency Hum Reprod 2015 30 3 608 15 10.1093/humrep/deu353 25567618 \n20. Demeestere I Simon P Dedeken L Moffa F Tsepelidis S Brachet C Live birth after autograft of ovarian tissue cryopreserved during childhood Hum Reprod 2015 30 9 2107 9 10.1093/humrep/dev128 26062556 \n21. Wallace WH Anderson RA Irvine DS Fertility preservation for young patients with cancer: who is at risk and what can be offered? Lancet Oncol 2005 6 4 209 18 10.1016/S1470-2045(05)70092-9 15811616 \n22. Baird DT Webb R Campbell BK Harkness LM Gosden RG Long-term ovarian function in sheep after ovariectomy and transplantation of autografts stored at -196 C Endocrinology 1999 140 1 462 71 9886858 \n23. Qu J Godin PA Nisolle M Donnez J Distribution and epidermal growth factor receptor expression of primordial follicles in human ovarian tissue before and after cryopreservation Hum Reprod 2000 15 2 302 10 10.1093/humrep/15.2.302 10655299 \n24. Schmidt KL Byskov AG Nyboe Andersen A Muller J Yding Andersen C Density and distribution of primordial follicles in single pieces of cortex from 21 patients and in individual pieces of cortex from three entire human ovaries Hum Reprod 2003 18 6 1158 64 10.1093/humrep/deg246 12773440 \n25. Gaytan F Morales C Leon S Garcia-Galiano D Roa J Tena-Sempere M Crowding and follicular fate: spatial determinants of follicular reserve and activation of follicular growth in the mammalian ovary PLoS One 2015 10 12 e0144099 10.1371/journal.pone.0144099 26642206 \n26. Chow EJ, Stratton KL, Leisenring WM, Oeffinger KC, Sklar CA, Donaldson SS et al. Pregnancy after chemotherapy in male and female survivors of childhood cancer treated between 1970 and 1999: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol. 2016. doi:10.1016/S1470-2045(16)00086-3.\n27. Meirow D Nugent D The effects of radiotherapy and chemotherapy on female reproduction Hum Reprod Update 2001 7 6 535 43 10.1093/humupd/7.6.535 11727861 \n28. Sanchez-Serrano M Crespo J Mirabet V Cobo AC Escriba MJ Simon C Twins born after transplantation of ovarian cortical tissue and oocyte vitrification Fertil Steril 2010 93 1 268 e11 3 10.1016/j.fertnstert.2009.09.046 \n29. Stern CJ Gook D Hale LG Agresta F Oldham J Rozen G First reported clinical pregnancy following heterotopic grafting of cryopreserved ovarian tissue in a woman after a bilateral oophorectomy Hum Reprod 2013 28 11 2996 9 10.1093/humrep/det360 24014608 \n30. ESHRE, Webber L, Davies M, Anderson R, Bartlett J, Braat D et al. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016. doi:10.1093/humrep/dew027.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1058-0468",
"issue": "33(12)",
"journal": "Journal of assisted reproduction and genetics",
"keywords": "AMH; Fertility preservation; Ovarian cortex re-implantation; Premature ovarian insufficiency",
"medline_ta": "J Assist Reprod Genet",
"mesh_terms": "D000328:Adult; D015925:Cryopreservation; D005260:Female; D059247:Fertility Preservation; D005718:Gametogenesis; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D050498:Live Birth; D009364:Neoplasm Recurrence, Local; D009865:Oocytes; D010053:Ovary; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D006113:United Kingdom; D009396:Wilms Tumor",
"nlm_unique_id": "9206495",
"other_id": null,
"pages": "1615-1620",
"pmc": null,
"pmid": "27639996",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9886858;25873571;10655299;26642206;27378768;15488215;24135076;15811616;22687323;17261285;25567618;26062556;26601616;27020005;26342246;23881516;23715580;12773440;22647504;11727861;8046009;19390962;22959460;19880105;21289248;27008889;23635349;24359888;18682546;24014608",
"title": "Re-implantation of cryopreserved ovarian cortex resulting in restoration of ovarian function, natural conception and successful pregnancy after haematopoietic stem cell transplantation for Wilms tumour.",
"title_normalized": "re implantation of cryopreserved ovarian cortex resulting in restoration of ovarian function natural conception and successful pregnancy after haematopoietic stem cell transplantation for wilms tumour"
} | [
{
"companynumb": "GB-SUN PHARMACEUTICAL INDUSTRIES LTD-2017RR-135974",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MELPHALAN"
},
"druga... |
{
"abstract": "Teriparatide, used for treatment of osteoporosis in patients at high risk of fracture risk, sometimes results in mild and transient hypercalcemia. There have been two recent reports of worsening dystrophic calcification in patients with autoimmune disorders following teriparatide treatment. We report a patient with severe osteoporosis and without a pre-existing autoimmune disorder, who developed symptomatic worsening of dystrophic calcification 4 months after teriparatide was initiated. Symptoms resolved within 1 week of teriparatide cessation.",
"affiliations": "Department of Endocrinology, St Vincent's Hospital, Sydney, Australia. thaw.htet@svha.org.au.;Department of Endocrinology, St Vincent's Hospital, Sydney, Australia.;Department of Endocrinology, St Vincent's Hospital, Sydney, Australia.;Department of Endocrinology, St Vincent's Hospital, Sydney, Australia.",
"authors": "Htet|T D|TD|;Eisman|J A|JA|;Elder|G J|GJ|;Center|J R|JR|",
"chemical_list": "D050071:Bone Density Conservation Agents; D019379:Teriparatide",
"country": "England",
"delete": false,
"doi": "10.1007/s00198-017-4330-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-941X",
"issue": "29(2)",
"journal": "Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA",
"keywords": "Dystrophic calcification; Osteoporosis; Teriparatide",
"medline_ta": "Osteoporos Int",
"mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D002114:Calcinosis; D003240:Connective Tissue Diseases; D018450:Disease Progression; D006801:Humans; D008297:Male; D010024:Osteoporosis; D019379:Teriparatide; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9100105",
"other_id": null,
"pages": "517-518",
"pmc": null,
"pmid": "29247298",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18422975;12839095;26992073;15942915;22840755;21679810;24438979;24292108;9777759;28431568",
"title": "Worsening of soft tissue dystrophic calcification in an osteoporotic patient treated with teriparatide.",
"title_normalized": "worsening of soft tissue dystrophic calcification in an osteoporotic patient treated with teriparatide"
} | [
{
"companynumb": "PHHY2017AU189573",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": "3",
"... |
{
"abstract": "OBJECTIVE\nPer-oral endoscopic myotomy (POEM) for achalasia is particularly appealing in the elderly because it is minimally invasive. However, data in patients aged ≥80 years are scarce. The aim of this study was to assess the clinical outcome of POEM in octogenarians.\n\n\nMETHODS\nThis was a multicenter retrospective study at 8 centers. Consecutive octogenarians with achalasia who underwent POEM between 2010 and 2016 were included. Rates of technical success (completion of myotomy), clinical response (Eckardt score ≤3), and adverse events (severity graded as per American Society for Gastrointestinal Endoscopy lexicon) were assessed.\n\n\nRESULTS\nA total of 76 patients (47.4% female, mean age 84 years) underwent POEM for treatment of achalasia: type I, 17.1%; type II, 35.5%; type III, 17.1%; and unspecified, 30.3%. Overall, 41.1% were treatment naïve, whereas others had previous botulinum toxin injection and/or pneumatic dilation. The mean (± standard deviation [SD]) age-adjusted Charlson comorbidity index score was 6.2 ± 2.4, with the majority of patients having American Society of Anesthesiologists Physical Status Classification System (ASA) scores of II/III. Technical success was 93.4%, with a median follow-up of 256 days. Fourteen adverse events occurred in 11 patients (14.5%). There were 3 inadvertent mucosotomies, 6 cases of symptomatic capnoperitoneum and/or capnomediastinum, 2 esophageal leaks, 1 cardiac arrhythmia, and 2 other). The severities of these adverse events were mild (78.6%), moderate (14.3%), and severe (7.1%). Clinical success was achieved in 90.8% of patients, with a mean (± SD) Eckardt score reduction from 7.0 ± 2.3 to 0.8 ± 0.1 (P < .001), a median follow-up of 256 days, and interquartile range of 66 to 547.\n\n\nCONCLUSIONS\nAlthough the rate of technical success may be somewhat lower and the rate of adverse events slightly higher than previously reported, our data suggest that POEM in octogenarians is safe and effective, supporting its role as a primary modality for achalasia in this patient population.",
"affiliations": "Department of Gastroenterology and Hepatology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.;Digestive Diseases Center, Showa University, Koto-Toyosu Hospital, Koto-Ku, Tokyo, Japan.;Department of Surgery, Section of Minimally Invasive Surgery, NorthShore University Health System, Evanston, Illinois, USA.;Division of Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, Florida, USA.;Division of Gastrointestinal and Minimally Invasive Surgery, The Oregon Clinic, Portland, Oregon, USA.;Digestive Physiology, Hospices Civils de Lyon and Lyon University, Lyon, France.;Baystate Medical Center, University of Massachusetts School of Medicine, Springfield, Massachusetts, USA.;Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong.;Digestive Diseases Center, Showa University, Koto-Toyosu Hospital, Koto-Ku, Tokyo, Japan.;Department of Surgery, Section of Minimally Invasive Surgery, NorthShore University Health System, Evanston, Illinois, USA.;Division of Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, Florida, USA.;Division of Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, Florida, USA.;Division of Gastrointestinal and Minimally Invasive Surgery, The Oregon Clinic, Portland, Oregon, USA.;Digestive Physiology, Hospices Civils de Lyon and Lyon University, Lyon, France.;Digestive Physiology, Hospices Civils de Lyon and Lyon University, Lyon, France.;Digestive Physiology, Hospices Civils de Lyon and Lyon University, Lyon, France.;Digestive Physiology, Hospices Civils de Lyon and Lyon University, Lyon, France.;Baystate Medical Center, University of Massachusetts School of Medicine, Springfield, Massachusetts, USA.;Digestive Endoscopy Unit, Humanitas Research Hospital, Rozzano, Milan, Italy.;Digestive Diseases Center, Showa University, Koto-Toyosu Hospital, Koto-Ku, Tokyo, Japan.;Digestive Diseases Center, Showa University, Koto-Toyosu Hospital, Koto-Ku, Tokyo, Japan.;Digestive Diseases Center, Showa University, Koto-Toyosu Hospital, Koto-Ku, Tokyo, Japan.;Department of Gastroenterology and Hepatology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.;Department of Gastroenterology and Hepatology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.;Department of Gastroenterology and Hepatology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.;Department of Gastroenterology and Hepatology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.;Department of Gastroenterology and Hepatology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.;Department of Gastroenterology and Hepatology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.;Digestive Endoscopy Unit, Humanitas Research Hospital, Rozzano, Milan, Italy.;Department of Gastroenterology and Hepatology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.",
"authors": "Chen|Yen-I|YI|;Inoue|Haruhiro|H|;Ujiki|Michael|M|;Draganov|Peter V|PV|;Colavita|Paul|P|;Mion|Francois|F|;Romanelli|John|J|;Chiu|Philip|P|;Balassone|Valerio|V|;Patel|Lava|L|;Abbas|Ali|A|;Yang|Dennis|D|;Dunst|Christy|C|;Pioche|Mathieu|M|;Roman|Sabine|S|;Rivory|Jérôme|J|;Ponchon|Thierry|T|;Desilets|David|D|;Maselli|Roberta|R|;Onimaru|Manabu|M|;Nakamura|Jun|J|;Hata|Yoshitaka|Y|;Hajiyeva|Gulara|G|;Ismail|Amr|A|;Ngamruengphong|Saowanee|S|;Bukhari|Majidah|M|;Chavez|Yamile Haito|YH|;Kumbhari|Vivek|V|;Repici|Alessandro|A|;Khashab|Mouen A|MA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.gie.2017.02.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-5107",
"issue": "87(4)",
"journal": "Gastrointestinal endoscopy",
"keywords": null,
"medline_ta": "Gastrointest Endosc",
"mesh_terms": "D000369:Aged, 80 and over; D016099:Endoscopy, Gastrointestinal; D004931:Esophageal Achalasia; D049630:Esophageal Sphincter, Lower; D005260:Female; D006801:Humans; D038622:Internationality; D008297:Male; D000074433:Myotomy; D011183:Postoperative Complications; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0010505",
"other_id": null,
"pages": "956-961",
"pmc": null,
"pmid": "28235595",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "An international multicenter study evaluating the clinical efficacy and safety of per-oral endoscopic myotomy in octogenarians.",
"title_normalized": "an international multicenter study evaluating the clinical efficacy and safety of per oral endoscopic myotomy in octogenarians"
} | [
{
"companynumb": "US-MERZ NORTH AMERICA, INC.-17MRZ-00109",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "INCOBOTULINUMTOXINA"
},
"druga... |
{
"abstract": "Flualprazolam is a designer benzodiazepine and novel psychoactive substance that is increasing in prevalence and appearing in forensic investigations. Flualprazolam was quantitatively confirmed in 197 blood samples from medicolegal death investigations and human performance cases reported between August 2019 and February 2020. Drug screening was performed using liquid chromatography-time-of-flight mass spectrometry and quantitative confirmation was performed using liquid chromatography-tandem mass spectrometry. A three-point standard addition protocol was implemented for quantitation in the absence of an available traditionally validated assay. In postmortem cases with quantitative results (n = 167), the mean (±standard deviation [SD]) flualprazolam concentration was 20 (±63) ng/mL, the median concentration was 8.2 ng/mL and the range of concentrations was 2.0-620 ng/mL. Four additional postmortem cases were reported positive (<2.0 ng/mL). In drug impaired driving cases (n = 22), the mean (±SD) flualprazolam concentration was 22 (±18) ng/mL, the median concentration was 14 ng/mL and the range of concentrations was 4.4 to 68 ng/mL. The four remaining cases were of unknown circumstances. This report details the most extensive dataset of flualprazolam intoxication cases reported to date. There was significant overlap in concentrations of flualprazolam between postmortem and DUID cases. Flualprazolam was commonly (83% of the time) found in combination with opioids (e.g. fentanyl). Toxicologists should consider quantitative flualprazolam results in the context of case history, observations, and/or other toxicological findings. Addition of flualprazolam to the scope of drug testing should be considered by all laboratories.",
"affiliations": "NMS Labs, 200 Welsh Road, Horsham, PA 19044, USA.;Center for Forensic Science Research and Education, Fredric Rieders Family Foundation, 2300 Stratford Ave, Willow Grove, PA 19090, USA.;NMS Labs, 200 Welsh Road, Horsham, PA 19044, USA.;NMS Labs, 200 Welsh Road, Horsham, PA 19044, USA.;NMS Labs, 200 Welsh Road, Horsham, PA 19044, USA.",
"authors": "Papsun|Donna M|DM|;Krotulski|Alex J|AJ|;Homan|Joseph|J|;Temporal|Keith D H|KDH|;Logan|Barry K|BK|",
"chemical_list": "C000657336:flualprazolam; D001569:Benzodiazepines; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkaa070",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "45(3)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D001569:Benzodiazepines; D002853:Chromatography, Liquid; D005283:Fentanyl; D053593:Forensic Toxicology; D006801:Humans; D015813:Substance Abuse Detection",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "226-232",
"pmc": null,
"pmid": "32542312",
"pubdate": "2021-03-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Flualprazolam Blood Concentrations in 197 Forensic Investigation Cases.",
"title_normalized": "flualprazolam blood concentrations in 197 forensic investigation cases"
} | [
{
"companynumb": "US-PFIZER INC-2021393174",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FENTANYL CITRATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe aim of this study was to assess the response rates (clinical and pathological ) with docetaxel and epirubicin combination chemotherapy and its effect on outcome.\n\n\nMETHODS\nWe retrospectively analysed locally advanced breast cancer (LABC) patients who received NACT from January 2008 to December 2012 in our tertiary care centre. LABC constituted 37% of all breast cancer cases and 120 patients fulfilled the eligibility criteria. The regimens used for NACT were, six cycles of DEC (docetaxel 75 mg/m2, epirubicin 75 mg/ m2, cyclophosphamide 500 mg/m2 on Day 1, 3 weekly) and a sequential regimen (4 cycles of FEC, 5-flurouracil 600 mg/m2, epirubicin 75 mg/m2, cyclophosphamide 600 mg/m2 followed by 4 cycles of docetaxel 85 mg/m2).\n\n\nRESULTS\nThe median age was 47 years (range 23-72). Ninety six ( 80 %) had T4 disease and 90% had clinically palpable lymph nodes at diagnosis. The median size of primary tumor at presentation was 5.9 cm. Hormone receptor positivity was seen in 55% and HER2/neu positivity, in 25%. Triple negative breast cancers constituted 25 % of the cases. The overall clinical response rate ( complete or partial ) was 85% and pathological complete responses were obtained in 15%. Four cases defaulted, 5 patients died of treatment related toxicity and 15% developed febrile neutropenia on DEC. The median duration of follow up was 22 months. The median time to relapse was 20 months and the 3 year relapse free and overall survival rates were 50% and 70% respectively.\n\n\nCONCLUSIONS\nLABC constituted 37% of all breast cancer cases at our institute. With NACT, pCR was seen in 15% of the cases. Sequential chemotherapy was better tolerated than concurrent anthracyline and taxane chemotherapy with a similar pCR.",
"affiliations": "Department of Medical Oncology, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India E-mail : ajaygogia@gmail.com.",
"authors": "Gogia|Ajay|A|;Raina|Vinod|V|;Deo|Suryanarayan Vishnu|SV|;Shukla|Nootan Kumar|NK|;Mohanti|Bidhu Kalyan|BK|;Sharma|Daya Nand|DN|",
"chemical_list": "D018943:Anthracyclines; D001952:Bridged-Ring Compounds; D043823:Taxoids; D000077143:Docetaxel; C080625:taxane; D015251:Epirubicin",
"country": "Thailand",
"delete": false,
"doi": "10.7314/apjcp.2014.15.5.1989",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1513-7368",
"issue": "15(5)",
"journal": "Asian Pacific journal of cancer prevention : APJCP",
"keywords": null,
"medline_ta": "Asian Pac J Cancer Prev",
"mesh_terms": "D000328:Adult; D000368:Aged; D018943:Anthracyclines; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D001952:Bridged-Ring Compounds; D000077143:Docetaxel; D015251:Epirubicin; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local; D012189:Retrospective Studies; D043823:Taxoids; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101130625",
"other_id": null,
"pages": "1989-92",
"pmc": null,
"pmid": "24716923",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Taxane and anthracycline based neoadjuvant chemotherapy for locally advanced breast cancer: institutional experience.",
"title_normalized": "taxane and anthracycline based neoadjuvant chemotherapy for locally advanced breast cancer institutional experience"
} | [
{
"companynumb": "IN-CIPLA (EU) LIMITED-2018IN10302",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional"... |
{
"abstract": "Mycoplasma salivarium is a rare agent of septic arthritis in immunocompromised patients. We report a case of septic arthritis due to Mycoplasma salivarium in a patient with B-cell chronic lymphocytic leukemia who underwent chemotherapy with rituximab and bendamustin. Therapy of arthritis due to Mycoplasma salivarium is difficult because there are almost no susceptibility data available. The present case illustrates that antimicrobial susceptibility of Mycoplasma strains is not necessarily predictable and that antibiotic therapy should therefore be guided by in vitro susceptibility testing.",
"affiliations": "Institute of Medical Microbiology and Hygiene, University Medical Centre Freiburg, Hermann-Herder-Straße 11, 79104 Freiburg, Germany. Electronic address: martin.buechsel@uniklinik-freiburg.de.;Department of Medical Oncology, Tumor Biology Center, Breisacher Straße 117, 79106 Freiburg, Germany.;Department of Medical Oncology, Tumor Biology Center, Breisacher Straße 117, 79106 Freiburg, Germany.;Institute of Medical Microbiology and Hygiene, University Medical Centre Freiburg, Hermann-Herder-Straße 11, 79104 Freiburg, Germany.;Institute of Medical Microbiology and Hygiene, University Medical Centre Freiburg, Hermann-Herder-Straße 11, 79104 Freiburg, Germany.",
"authors": "Büchsel|Martin|M|;Pletschen|Lars|L|;Fleiner|Michael|M|;Häcker|Georg|G|;Serr|Annerose|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D000069283:Rituximab; D002939:Ciprofloxacin; D000069461:Bendamustine Hydrochloride; D017291:Clarithromycin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-8893",
"issue": "86(1)",
"journal": "Diagnostic microbiology and infectious disease",
"keywords": "B-CLL; Mycoplasma salivarium; Rituximab; Septic arthritis; Susceptibility",
"medline_ta": "Diagn Microbiol Infect Dis",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D001170:Arthritis, Infectious; D000069461:Bendamustine Hydrochloride; D002939:Ciprofloxacin; D017291:Clarithromycin; D024881:Drug Resistance, Bacterial; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D009175:Mycoplasma Infections; D045804:Mycoplasma salivarium; D000069283:Rituximab",
"nlm_unique_id": "8305899",
"other_id": null,
"pages": "115-7",
"pmc": null,
"pmid": "27342785",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of septic arthritis caused by a Mycoplasma salivarium strain resistant towards Ciprofloxacin and Clarithromycin in a patient with chronic lymphatic leukemia.",
"title_normalized": "a case of septic arthritis caused by a mycoplasma salivarium strain resistant towards ciprofloxacin and clarithromycin in a patient with chronic lymphatic leukemia"
} | [
{
"companynumb": "PHHY2016DE163229",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": "1",
"drug... |
{
"abstract": "A 33-year-old man died after intentionally inhaling a gaseous mix of methyl acetylene (propyne) and propadiene (allene) commonly known as MAPP, which is used for soldering and welding. He was found with a plastic bag securely placed over his head and a cylinder of MAPP alongside his head. The cylinder had been vented into the bag using a flexible hose. A comprehensive toxicological analysis revealed only a trace of diphenhydramine in the liver and 0.02 mg/L of morphine in the urine. Analysis of blood by headspace gas chromatography (HS-GC) detected two unknown peaks. These were determined to be the components of MAPP gas. MAPP was quantitated in femoral blood (59.6 mg/L) and brain (43.6 mg/kg) using a HS-GC method. The cause of death was attributed to acute MAPP intoxication, and the manner was determined to be suicide. A discussion on the analytical and interpretive considerations commonly encountered when analyzing volatile compounds is also presented.",
"affiliations": "Department of Forensic Toxicology, Suffolk County Office of the Medical Examiner, Hauppauge, NY 11788-0099, USA. joseph.avella@suffolkcountyny.gov",
"authors": "Avella|Joseph|J|;Lehrer|Michael|M|",
"chemical_list": "D000466:Alkadienes; D000480:Alkynes; D005740:Gases; C022030:methylacetylene; C025947:propadiene",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1198",
"issue": "49(6)",
"journal": "Journal of forensic sciences",
"keywords": null,
"medline_ta": "J Forensic Sci",
"mesh_terms": "D000280:Administration, Inhalation; D000328:Adult; D000466:Alkadienes; D000480:Alkynes; D001923:Brain Chemistry; D002849:Chromatography, Gas; D005740:Gases; D006801:Humans; D008297:Male; D013405:Suicide",
"nlm_unique_id": "0375370",
"other_id": null,
"pages": "1361-3",
"pmc": null,
"pmid": "15568715",
"pubdate": "2004-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatality due to methyl acetylene-propadiene (MAPP) inhalation.",
"title_normalized": "fatality due to methyl acetylene propadiene mapp inhalation"
} | [
{
"companynumb": "US-PFIZER INC-2021670759",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE HYDROCHLORIDE"
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"abstract": "BACKGROUND\nOsteomyelitis is a rare problem in pregnancy but can present challenges for diagnosis and treatment. This case report describes a patient with a history of vulvar abscess who developed methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and osteomyelitis during pregnancy.\n\n\nMETHODS\nA 20-year-old woman, gravida 1, at 33 weeks' gestation, developed sepsis from MRSA bacteremia after a vulvar abscess drainage. She developed acute respiratory distress syndrome (ARDS) and was found to have osteomyelitis on her thoracic spine level 7. The diagnosis of osteomyelitis was based on clinical findings and magnetic resonance imaging. An emergent cesarean section was undertaken due to worsening ARDS. The osteomyelitis was treated with intravenous daptomycin with symptomatic improvement. However, back pain returned and the patient was readmitted and required a spinal brace and 6 weeks of intravenous vancomycin.\n\n\nCONCLUSIONS\nOsteomyelitis in pregnancy is a rare complication and a challenging diagnosis that requires a high index of suspicion. The treatment of osteomyelitis in pregnancy versus nonpregnancy is the same. This case is unique because this pregnant patient developed osteomyelitis secondary to a vulvar abscess.",
"affiliations": null,
"authors": "Nguyen|Loan N|LN|;Lopes|Carol|C|;Folk|John J|JJ|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0024-7758",
"issue": "60(7-8)",
"journal": "The Journal of reproductive medicine",
"keywords": null,
"medline_ta": "J Reprod Med",
"mesh_terms": "D000038:Abscess; D000328:Adult; D000900:Anti-Bacterial Agents; D005260:Female; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus; D010019:Osteomyelitis; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D012128:Respiratory Distress Syndrome; D013122:Spinal Diseases; D013203:Staphylococcal Infections; D013904:Thoracic Vertebrae; D014640:Vancomycin; D014845:Vulvar Diseases; D055815:Young Adult",
"nlm_unique_id": "0173343",
"other_id": null,
"pages": "362-4",
"pmc": null,
"pmid": "26380498",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Vertebral Osteomyelitis in Pregnancy from a Methicillin-resistant Staphylococcus Aureus Vulvar Abscess. A Case Report.",
"title_normalized": "vertebral osteomyelitis in pregnancy from a methicillin resistant staphylococcus aureus vulvar abscess a case report"
} | [
{
"companynumb": "US-ZYDUS-009753",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
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"drugadditio... |
{
"abstract": "Clinical trials showed limited benefit of anti-PD-1 (programmed cell death 1) monotherapy in pancreatic adenocarcinoma patients and immune-related adverse events caused by immune checkpoint inhibitors were rarely reported in pancreatic adenocarcinoma. Here, we report the first case of durable benefit along with systemic lupus erythematosus following immunotherapy in mismatch repair-proficient pancreatic cancer.\n\n\n\nWe describe a 57-year-old woman with resected stage ⅢB pancreatic cancer who underwent several lines of conventional chemotherapy after multiple lymph node metastases. When the disease progressed again, the patient received an off-label treatment with pembrolizumab (100 mg every 3 weeks). After four cycles of immunotherapy treatment, CA19-9 level rapidly decreased to normal and the lymph node metastases reduced dramatically in volume, demonstrating a partial response to the therapy by RECIST 1.1 criteria. She continued on pembrolizumab and a total of eight cycles of administration she had received. Her lesions showed consistent reduction in size even when the medication had been stopped. Actually the patient experienced durable benefit from anti-PD-1 therapy for more than 4 years and she is still in good condition without tumor relapses to date. Besides, she was diagnosed with systemic lupus erythematosus 2 months after the last dose of pembrolizumab. Molecular profiling identified two deleterious PALB2 alterations including a germline mutation (PALB2 c.3114-1G>A) and a somatic mutation (PALB2 c.2514+1G>C) in this patient, suggesting the potential of DNA homologous recombination deficiency. Multiplex immunohistochemistry and RNA-seq results revealed a brisk immune cell infiltration in her resected primary lesion. Additionally, humanleukocyte antigen (HLA) typing assay identified two previously reported systemic lupus erythematosus risk alleles HLA-DRB1*15:01 and HLA-DQB1*06:02 in this patient.\n\n\n\nThe deleterious mutations of PALB2 closely related to homologous recombination deficiency or alterations of DNA damage response and repair genes might be promising biomarkers for predicting efficacy of immune checkpoint inhibitors in pancreatic adenocarcinoma. Genetic correlation behind immunotherapy-induced systemic lupus erythematosus and associated mechanism remain to be elucidated.",
"affiliations": "Department of Oncology, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen Second People's Hospital, Shenzhen, China nanxue168@126.com zhhbao@ccmu.edu.cn.;Genecast Precision Medicine Technology Institute, Beijing, China.;Department of Oncology, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen Second People's Hospital, Shenzhen, China.;Genecast Precision Medicine Technology Institute, Beijing, China.;Department of Oncology, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen Second People's Hospital, Shenzhen, China.;Department of Radiology, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen Second People's Hospital, Shenzhen, China.;Department of Radiology, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen Second People's Hospital, Shenzhen, China.;Department of Oncology, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen Second People's Hospital, Shenzhen, China.;Department of Oncology, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen Second People's Hospital, Shenzhen, China.;Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China nanxue168@126.com zhhbao@ccmu.edu.cn.",
"authors": "Pang|Xionghao|X|;Qian|Juanjuan|J|;Jin|Hua|H|;Zhang|Lei|L|;Lin|Lin|L|;Wang|Yuli|Y|;Lei|Yi|Y|;Zhou|Zeqiang|Z|;Li|Meixiang|M|;Zhang|Henghui|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/jitc-2019-000463",
"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\njitc-2019-000463\n10.1136/jitc-2019-000463\nCase Report\n1506\n2518\nDurable benefit from immunotherapy and accompanied lupus erythematosus in pancreatic adenocarcinoma with DNA repair deficiency\nPang Xionghao 1 Qian Juanjuan 2 Jin Hua 1 Zhang Lei 2 Lin Lin 1 Wang Yuli 3 Lei Yi 3 Zhou Zeqiang 1 Li Meixiang 1 Zhang Henghui 4 \n1 \nDepartment of Oncology, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen Second People’s Hospital, Shenzhen, China\n\n\n2 \nGenecast Precision Medicine Technology Institute, Beijing, China\n\n\n3 \nDepartment of Radiology, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen Second People’s Hospital, Shenzhen, China\n\n\n4 \nInstitute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China\n\nCorrespondence to Dr Xionghao Pang; nanxue168@126.com; Dr Henghui Zhang, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Jingshundongjie8, Beijing, China; zhhbao@ccmu.edu.cnXP, JQ and HJ are joint first authors.\n\n\n2020 \n6 7 2020 \n8 2 e00046309 6 2020 © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.Background\nClinical trials showed limited benefit of anti-PD-1 (programmed cell death 1) monotherapy in pancreatic adenocarcinoma patients and immune-related adverse events caused by immune checkpoint inhibitors were rarely reported in pancreatic adenocarcinoma. Here, we report the first case of durable benefit along with systemic lupus erythematosus following immunotherapy in mismatch repair-proficient pancreatic cancer.\n\nCase presentation\nWe describe a 57-year-old woman with resected stage ⅢB pancreatic cancer who underwent several lines of conventional chemotherapy after multiple lymph node metastases. When the disease progressed again, the patient received an off-label treatment with pembrolizumab (100 mg every 3 weeks). After four cycles of immunotherapy treatment, CA19-9 level rapidly decreased to normal and the lymph node metastases reduced dramatically in volume, demonstrating a partial response to the therapy by RECIST 1.1 criteria. She continued on pembrolizumab and a total of eight cycles of administration she had received. Her lesions showed consistent reduction in size even when the medication had been stopped. Actually the patient experienced durable benefit from anti-PD-1 therapy for more than 4 years and she is still in good condition without tumor relapses to date. Besides, she was diagnosed with systemic lupus erythematosus 2 months after the last dose of pembrolizumab. Molecular profiling identified two deleterious PALB2 alterations including a germline mutation (PALB2 c.3114–1G>A) and a somatic mutation (PALB2 c.2514+1G>C) in this patient, suggesting the potential of DNA homologous recombination deficiency. Multiplex immunohistochemistry and RNA-seq results revealed a brisk immune cell infiltration in her resected primary lesion. Additionally, humanleukocyte antigen (HLA) typing assay identified two previously reported systemic lupus erythematosus risk alleles HLA-DRB1*15:01 and HLA-DQB1*06:02 in this patient.\n\nConclusions\nThe deleterious mutations of PALB2 closely related to homologous recombination deficiency or alterations of DNA damage response and repair genes might be promising biomarkers for predicting efficacy of immune checkpoint inhibitors in pancreatic adenocarcinoma. Genetic correlation behind immunotherapy-induced systemic lupus erythematosus and associated mechanism remain to be elucidated.\n\nbiomarkerstumorgastrointestinal neoplasmsimmunotherapytumor microenvironmentcase reportsNational Key Sci-Tech Special Project of China2018ZX10302207special-featureunlocked\n==== Body\nIntroduction\nPancreatic adenocarcinoma (PAAD) is one of the most refractory malignancies with poor prognosis after radical surgery. In recent years, immune checkpoint blockade-based immunotherapies have gained encouraging success in multiple solid tumors, however, single-agent immune checkpoint inhibitors (CPIs) fail to elicit efficacy in PAAD patients except pembrolizumab in certain individuals with mismatch repair deficiency.1 2 There is little known about whether there are other biomarkers for predicting response to CPI treatment in PAAD. It should be noted that 3.9% to 9.7% of pancreatic ductal adenocarcinoma individuals carry pathogenic/likely pathogenic germline alterations, especially those alterations involved in homologous recombination deficiency (HRD) or DNA damage response and repair (DDR) genes including BRCA1/2, PALB2, ATM, etc.3 4 Moreover, the deleterious DDR gene variants have revealed the potential of predicting responsiveness to anti-PD-1 (programmed cell death 1)/PD-L1 (programmed death-ligand 1) therapy in bladder urothelial carcinoma5 and non-small cell lung cancer patients,6 whereas there are few reports of survival benefit in PAAD patients receiving CPIs.\n\nAs the increasing prevalence of CPI treatment in solid tumors, the special feature of side effects, that is, the immune related adverse events (irAEs), have gained wide attention. The diverse irAEs bring challenges in management of cancer patients during immunotherapy treatment. On the other hand, studies have found that certain irAEs are associated with improved response and prognosis in cancer patients treated with CPIs.7 8 In general, it is vital to explore the underlying mechanisms of irAEs, especially genetic factors.9\n\n\nHere we report an exceptional case of recurrent PAAD individual with microsatellite stability (MSS)/proficient mismatch repair who experienced durable survival benefit (more than 4 years) along with systemic lupus erythematosus (SLE) after receiving pembrolizumab. Two deleterious PALB2 mutations including a germline mutation in combination with several humanleukocyte antigen (HLA) class II risk loci for SLE identified in this patient may account for her outcomes under CPI treatment.\n\nCase presentation\nA 57-year-old Chinese woman was diagnosed with a stage ⅢB moderately-differentiated pancreatic adenocarcinoma (figure 1A) and underwent distal pancreatectomy and en-bloc splenectomy in September 2014. Eight months later, a follow-up contrast-enhanced CT scan revealed enlargement of her multiple abdominal lymph nodes. Then the patient was treated with two cycles of chemotherapy with gemcitabine (1200 mg) plus paclitaxel liposome (180 mg) on days 1 and 8, every 3 weeks. However, the re-examination of CT demonstrated progression of disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST, V.1.1). Next, she started receiving docetaxel (110 mg) intravenously on days 1, plus tegafur (50 mg, two times per day) orally on days 1 to 14, every 3 weeks. CT scan showed a partial response (PR) following six cycles of the chemotherapy. In November 2015, docetaxel was discontinued and tegafur regimen was used for maintenance chemotherapy. After two cycles of tegafur monotherapy, a follow-up CT scan showed the PD again. CT imaging revealed the presence of retroperitoneal lymph node metastases with two nodes of 2.4×2.1 cm and 2.9×1.7 cm, respectively, as well as abdominal para-aortic lymph node metastasis with a node of 2.4×2.2 cm. Whereafter, this patient decided to pursue an off-label use of pembrolizumab (100 mg, every 3 weeks) on January 21, 2016. Fortunately, radiological results demonstrated a PR after four cycles of immunotherapy. Moreover, her serum level of CA19-9 rapidly dropped down to normal (below 37 U/mL) (figure 1B). Next, she continued to receive another four cycles of pembrolizumab with the same dosage and administration as before and durable benefit was observed (figure 1C). Notably, after her last cycle of pembrolizumab treatment in July 2016, the adverse effects started to appear, characterized by allergic dermatitis, fever, nausea and vomiting. In September 2016, she was diagnosed with SLE based on her clinical features and autoantibody in serum, positive antinuclear antibody of 1:320 titer (speckled patterns) and antibodies to Sjögren’s-syndrome-related antigen A (SS-A). Subsequently, she was administrated with hydroxychloroquine (200 mg, daily) to control SLE until March 2019. In the meantime, her recurrent tumor lesions of retroperitoneal nodes achieved near complete remission and the para-aortic nodes maintained a reduced size. This patient has neither history of autoimmune disease nor family history of cancer. Her whole disease course and clinical outcomes were summarized in figure 1D. From initiation of the immunotherapy to date, the patient experienced durable survival benefit of more than 4 years, and she had a good performance status when this case report was revised.\n\nFigure 1 Clinical course of the patient. (A) Histological characteristic of the moderately differentiated adenocarcinoma of the pancreas (hematoxylin-eosin stain; original magnification×400). (B) Serum CA19-9 levels during and after treatment with pembrolizumab (red arrow indicates the last dose of pembrolizumab). (C) Representative contrast-enhanced CT images of the abdomen in venous phase, showing patient’s recurrent lymph node lesions during and after treatment with pembrolizumab. A 2.5-month follow-up scan demonstrated partial response of the disease. (the top row: retroperitoneal lymph nodes; the bottom row: abdominal para-aortic lymph node; lesions are marked by red triangle). (D) Time line of clinical events. PD, progressive disease; PR, partial response.\n\nMethods\nTo identify the involvement of genomic features as well as tumor immune microenvironment signature in this unexpected response to immune checkpoint blockade and underlying genetic association with pembrolizumab-induced systemic lupus erythematosus. We performed molecular analyzes of the patient’s resected primary tumor tissue, paracancerous tissue and peripheral blood sample in a College of American Pathologists accredited laboratory (GeneCast Biotechnology Co, Beijing) with consent of the patient.\n\nTumor immune microenvironment was examined by multiplex immunohistochemistry (mIHC) and RNA sequencing. Two resected tumor tissue sections were used for mIHC staining: one for anti-CD3 (clone LN10), anti-CD8 (clone SP16), anti-PD-1 (clone UMAB199); the other for anti-CD4 (clone UMAB64), anti-CD68 (clone KP1), anti-CD163 (clone 10D6); all the primary antibodies were from ZSGB-BIO, Beijing, China. The stained slides were scanned using the PerkinElmer Vectra and analyzed by inForm Advanced Image Analysis software (PerkinElmer, Massachusetts, USA). Positive cells were defined as cells with true immunofluorescence signal detected and with right expression pattern. More than 12 fields per slide were selected to calculate the number, percentage and density of positive cells under the 200×magnification. Mean percentage of specific positive cells in all nucleated cells of the tumor stroma from the selected fields was used for analyzes. RNA sequencing based gene expression profiling was performed on resected tumor tissue and paracancerous tissue by the Oncomine Immune Response Research Assay (Thermo Fisher Scientific, USA). Gene expression levels of approximately 400 genes relevant to oncology and immunology were analyzed. Five immune signatures were defined to represent T cell-inflamed features, including T cell markers (CD2, CD3D, CD3E, CD4, CD40LG, CD8A and CD8B), cytolytic markers (GNLY, GZMA, GZMB and PRF1), IFN-γ signature (CXCL10, CXCL9, HLA-DRA, IDO1, IFNG and STAT1), HLA molecules and chemokines. The signature scores were calculated by averaging the log10 transformed expression value of the involved genes.\n\nGenetic analyzes were used to explore the mechanism of immunotherapy response and the induced autoimmune disease. HLA genotyping of the peripheral blood lymphocytes was performed via PCR amplification with sequence based typing methodology and DNA sequencing analysis of resected tumor and peripheral blood sample was performed using next generation sequencing of a customized gene panel, including 543 cancer related genes.\n\nPD-L1 expression and mismatch repair protein expression were also examined with regular methods. For more details of the experimental methods, please see the online additional file 1. No statistical test was performed as there is only one patient and we did not investigate the differences between samples.\n\n10.1136/jitc-2019-000463.supp1Supplementary data \n\n\n\n Results\nTargeted sequencing results show a common driver mutation KRAS p.G12V (8.72%) along with two splicing mutations of DDR gene PALB2 in her resected primary lesion (online supplementary table S1). No alterations of other major driver genes (ie, TP53, CDKN2A, SMAD4) in PAAD were identified. Of note, both of the two PALB2 mutations are viewed as likely pathogenic based on ClinVar database, suggesting the probable deficiency of DNA homologous recombination. Among them, PALB2 c.3114–1G>A was a germline mutation simultaneously detected in her peripheral blood cells, while PALB2 c.2514+1G>C (8.32%) was a somatic mutation (figure 2A).\n\nFigure 2 \nPALB2 mutations and immunologic characteristics of the patient. (A) Schematic representation of PALB2 gene with the two splicing mutations indicated. (B) Immune response signature scores of primary tumor and matched paracancerous tissue. (C) Quantitative distribution of tumor infiltrated T cell and macrophage in the stroma of the primary tumor. (D) Distribution of PD-1 expression on CD3 or CD8 positive T cells and CD163 expression on CD68 positive macrophages in stroma. (E and F) Representative histological images of the resected tumor stained by multiplex immunofluorescence, showing the brisk immune cell infiltration in tumor microenvironment. Original magnification×200. HLA, human leukocyte antigen; PD-1, programmed cell death 1.\n\nTumor immune microenvironment signature of this patient was examined by expression profiling of 395 immune related genes and analysis of immune cell subsets in situ by mIHC. Compared with paracancerous tissue, higher expression levels of cytolytic markers, T cell markers, IFN-γ signature, chemokines as well as HLA molecules were observed in cancer tissue, demonstrating a T cell-inflamed tumor microenvironment (figure 2B). Global expression levels of 35 pre-set gene function signatures were also evaluated and immune signature scores of 21 functional pathways are at least 1.5-fold differentially changed in cancer tissue relative to paracancerous tissue, most of which are favorable for antitumor immune (online supplementary figure S1). In consistent with the expression profiling results, there were relatively high infiltration degrees of CD3 or CD8 positive T cells in stroma of cancer specimen examined by multiplex immunohistochemistry (figure 2C–F). Cytotoxic T cells (CD8+) and helper T cells (CD4+) account for about 10% of all cells in tumor stroma, respectively, and macrophages (CD68+) has a proportion of 4% (figure 2C). Moreover, exhausted or inhibitory cells such as PD-1 positive CD3 or CD8 T cells or CD68+ CD163+ cells were also explored, each accounts for tiny proportion in corresponding immune cell subset (figure 2D; online supplementary figure S2), indicating good activity and antitumor potential of the tumor infiltrating lymphocytes or macrophages. Collectively, primary tumor of this pancreatic patient has a favorable baseline immune microenvironment.\n\nAdditionally, PD-L1 (SP142 staining) was absent and four mismatch repair proteins (MLH1, MSH2, MSH6 and PSM2) were proficient in this patient’s tumor (online supplementary figure S3). Likewise, her microsatellite instability status was MSS (online supplementary figure S4). Given the close relationship of HLA alleles with the susceptibility to SLE,10 we performed HLA genotyping of normal DNA from her peripheral blood cells. Not surprisingly, two SLE risk alleles HLA-DRB1*15:01 and HLA-DQB1*06:02 previously reported in the Eastern Asians11 were identified. Besides, there were some other HLA alleles potentially related to SLE in this patient (table 1).\n\nTable 1 Human leukocyte antigen alleles of the patient\n\nHLA loci\tAllele\tAssociation with SLE susceptibility\tPopulation (reference)\t\nHLA-A\tA*02:01\t–\tNA\t\nA*11:01\tUncertain\tMalays and Chinese18\n\t\nHLA-B\tB*15:01\t–\tNA\t\nB*54:01\t–\tNA\t\nHLA-C\tC*03:03\t–\tNA\t\nC*01:02\t–\tNA\t\nHLA-DQ\tDQB1*05:01\tRisk factor\tChinese Taiwan19\n\t\n\nDQB1*06:02\n\tRisk factor\tEastern Asians11\n\nEuropean10 20\n\nSaudis21\n\t\nHLA-DR\tDRB1*01:01\t–\tNA\t\n\nDRB1*15:01\n\tRisk factor\tEastern Asians11\n\nChinese Taiwan19 22\n\nJapanese23\n\nKoreans24\n\nEuropean10 20\n\t\nHLA-DP\tDPB1*04:02\t–\tNA\t\nDPB1*05:01\tUncertain\tJapanese25\n\t\nAlleles in bold font are considered to be more likely to increase the risk of SLE.\n\n–, unknown; HLA, human leukocyte antigen; NA, not available; SLE, systemic lupus erythematosus.\n\nDiscussion and conclusions\nThe pancreatic ductal adenocarcinoma patients with HRD have shown association with enhanced expression of antitumor immunity related molecules and active immune status in previous research,12 which is in agreement with our findings of this pancreatic cancer patient harboring deleterious PALB2 mutations. There were obviously higher levels of cytolytic markers in her resected cancer tissue than in paracancerous tissue as well as more infiltrates of CD8+ T cells in tumor stroma. Correspondingly, she responded well to CPI treatment with pembrolizumab and achieved more than 4-year survival benefit. It should be noted that this individual had paired deleterious mutations of PALB2, each one for germline and somatic, while about half of PAAD patients arising from pathogenic germline alterations of homologous recombination (HR) genes lack somatic variants of HR genes (‘second hit’) in their tumors and these patients may not be true HRD.13 Theoretically, co-occurrence of germline and somatic HR gene alterations might bring about higher number of tumor-specific neoantigens along with relatively activated immune environment.12 Given this, we speculated that this patient’s paired PALB2 mutations probably contributed to her exceptional good outcomes after pembrolizumab treatment, although to our knowledge there are hardly any clinical studies reporting HR gene variants as predictive biomarkers for CPI monotherapy in PAAD patients to date.\n\nDuring cancer immunotherapy, irAEs consisting of rash, colitis, pneumonitis, and so on, are not uncommon as the increasing clinical use of CPIs.14 Nonetheless, secondary lupus erythematosus following CPI treatment is fairly rare. In terms of mechanism, two aforementioned known HLA class Ⅱ (HLA-Ⅱ) germline alleles susceptible to SLE in combination with the exposure to pembrolizumab may jointly lead to the unusual adverse event of this patient. The two SLE risk alleles HLA-DRB1*15:01 and HLA-DQB1*06:02 might confer a high level of immunity to this patient or even put her in a pre-autoimmunity state. As an external factor, CPI could just trigger the development of SLE. Interestingly, a substantial association between the development of irAEs and survival benefit from anti-PD-1/PD-L1 antibodies has been recently identified in 1747 patients.8 In addition, it was previously reported that among five efficacy evaluable cancer patients with the occurrence of lupus erythematosus after receiving CPIs, three individuals had complete or partial remission and two of them were treated with pembrolizumab.15 It is impressive that CPI showed remarkable efficacy in this patient with HRD pancreatic cancer carrying two SLE risk alleles, which may inspire future investigation of the intrinsic correlation between efficacy and side effects of checkpoint inhibitors in tumors. Predictive biomarkers of immunotherapy-related toxicity are worth studying, like autoantibodies16 or genetic factors.9\n\n\nNotably, the duration of exposure to pembrolizumab in this PAAD patient was just 6 months (100 mg, every three weeks). However, she gained lasting survival benefit along with lupus erythematosus until now. In consideration of the potential role of HLA-Ⅱ molecules in immunotherapy,17 it is plausible that her specific HLA-Ⅱ genotype perhaps not only involves in irAEs but also is beneficial for CPI treatment.\n\nIn summary, DNA repair deficiency characterized by deleterious germline and somatic alterations of PALB2 as well as certain HLA-Ⅱ germline alleles related to lupus erythematosus may be promising biomarkers for anti-PD-1/PD-L1 therapy in PAAD patients.\n\nThe authors wish to gratefully acknowledge the patient and her family for allowing us to publish her clinical case.\n\nContributors: XP, JQ and HJ contributed equally to this work and are co-first authors. XP and JQ had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analyzes. XP, JQ and HJ designed the study. LL, ZZ, and ML collected the data. YW and YL performed radiological data analysis and provided the imaging figures. JQ, HJ, LL, ZZ and ML analyzed the data. JQ drafted the manuscript. XP was the main treating physician. LZ, XP and HZ contributed to the interpretation of the results and critical revision of the manuscript for important intellectual content. All authors have read and approved the final version manuscript. XP and HZ are the study guarantors.\n\nFunding: This work was supported by grants from the National Key Sci-Tech Special Project of China (No. 2018ZX10302207).\n\nCompeting interests: None declared.\n\nPatient consent for publication: Obtained.\n\nEthics approval: This study was approved by the Research Ethics Committee of Shenzhen Second People's Hospital (Shenzhen, China), and the patient gave informed written consent.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 \nHenriksen A , Dyhl-Polk A , Chen I , et al \nCheckpoint inhibitors in pancreatic cancer\n. Cancer Treat Rev \n2019 ;78 :17 –30\n. 10.1016/j.ctrv.2019.06.005 \n31325788 \n2 \nLe DT , Durham JN , Smith KN , et al \nMismatch repair deficiency predicts response of solid tumors to PD-1 blockade\n. Science \n2017 ;357 :409 –13\n. 10.1126/science.aan6733 \n28596308 \n3 \nShindo K , Yu J , Suenaga M , et al \nDeleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma\n. J Clin Oncol \n2017 ;35 :3382 –90\n. 10.1200/JCO.2017.72.3502 \n28767289 \n4 \nYurgelun MB , Chittenden AB , Morales-Oyarvide V , et al \nGermline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer\n. Genet Med \n2019 ;21 :213 –23\n. 10.1038/s41436-018-0009-5 \n29961768 \n5 \nTeo MY , Seier K , Ostrovnaya I , et al \nAlterations in DNA damage response and repair genes as potential marker of clinical benefit from PD-1/PD-L1 blockade in advanced urothelial cancers\n. J Clin Oncol \n2018 ;36 :1685 –94\n. 10.1200/JCO.2017.75.7740 \n29489427 \n6 \nRicciuti B , Cheng ML , Recondo G , et al \nDNA damage response gene alterations are associated with high tumor mutational burden and clinical benefit from programmed death 1 axis inhibition in non-small cell lung cancer\n. J Clin Oncol \n2019 ;37 :9077\n10.1200/JCO.2019.37.15_suppl.9077 \n\n7 \nLo JA , Fisher DE , Flaherty KT \nPrognostic significance of cutaneous adverse events associated with pembrolizumab therapy\n. JAMA Oncol \n2015 ;1 :1340 –1\n. 10.1001/jamaoncol.2015.2274 \n26270186 \n8 \nMaher VE , Fernandes LL , Weinstock C , et al \nAnalysis of the association between adverse events and outcome in patients receiving a programmed death protein 1 or programmed death ligand 1 antibody\n. J Clin Oncol \n2019 ;37 :2730 –7\n. 10.1200/JCO.19.00318 \n31116675 \n9 \nKhan Z , Hammer C , Guardino E , et al \nMechanisms of immune-related adverse events associated with immune checkpoint blockade: using germline genetics to develop a personalized approach\n. Genome Med \n2019 ;11 :39. 10.1186/s13073-019-0652-8 \n31221204 \n10 \nTeruel M , Alarcón-Riquelme ME \nThe genetic basis of systemic lupus erythematosus: what are the risk factors and what have we learned\n. J Autoimmun \n2016 ;74 :161 –75\n. 10.1016/j.jaut.2016.08.001 \n27522116 \n11 \nMolineros JE , Looger LL , Kim K , et al \nAmino acid signatures of HLA class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in eastern Asians\n. PLoS Genet \n2019 ;15 :e1008092. 10.1371/journal.pgen.1008092 \n31022184 \n12 \nConnor AA , Denroche RE , Jang GH , et al \nAssociation of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma\n. JAMA Oncol \n2017 ;3 :774 –83\n. 10.1001/jamaoncol.2016.3916 \n27768182 \n13 \nWood LD , Yurgelun MB , Goggins MG \nGenetics of familial and sporadic pancreatic cancer\n. Gastroenterology \n2019 ;156 :2041 –55\n. 10.1053/j.gastro.2018.12.039 \n30660730 \n14 \nThompson JA , Schneider BJ , Brahmer J , et al \nManagement of Immunotherapy-Related toxicities, version 1.2019\n. J Natl Compr Canc Netw \n2019 ;17 :255 –89\n. 10.6004/jnccn.2019.0013 \n30865922 \n15 \nMichot J-M , Fusellier M , Champiat S , et al \nDrug-induced lupus erythematosus following immunotherapy with anti-programmed death-(ligand) 1\n. Ann Rheum Dis \n2019 ;78 :e67. 10.1136/annrheumdis-2018-213677 \n29858173 \n16 \nde Moel EC , Rozeman EA , Kapiteijn EH , et al \nAutoantibody development under treatment with Immune-Checkpoint inhibitors\n. Cancer Immunol Res \n2019 ;7 :6 –11\n. 10.1158/2326-6066.CIR-18-0245 \n30425107 \n17 \nAlspach E , Lussier DM , Miceli AP , et al \nMHC-II neoantigens shape tumour immunity and response to immunotherapy\n. Nature \n2019 ;574 :696 –701\n. 10.1038/s41586-019-1671-8 \n31645760 \n18 \nMohd-Yusuf Y , Phipps ME , Chow SK , et al \nHLA-A*11 and novel associations in Malays and Chinese with systemic lupus erythematosus\n. Immunol Lett \n2011 ;139 :68 –72\n. 10.1016/j.imlet.2011.05.001 \n21658414 \n19 \nLu LY , Ding WZ , Fici D , et al \nMolecular analysis of major histocompatibility complex allelic associations with systemic lupus erythematosus in Taiwan\n. Arthritis Rheum \n1997 ;40 :1138 –45\n. 10.1002/art.1780400619 \n9182925 \n20 \nGraham RR , Ortmann W , Rodine P , et al \nSpecific combinations of HLA-DR2 and DR3 class II haplotypes contribute graded risk for disease susceptibility and autoantibodies in human SLE\n. Eur J Hum Genet \n2007 ;15 :823 –30\n. 10.1038/sj.ejhg.5201827 \n17406641 \n21 \nAl-Motwee S , Jawdat D , Jehani GS , et al \nAssociation of HLA-DRB1*15 and HLADQB1*06 with SLE in Saudis\n. Ann Saudi Med \n2013 ;33 :229 –34\n. 10.5144/0256-4947.2013.229 \n23793423 \n22 \nPan CF , Wu CJ , Chen HH , et al \nMolecular analysis of HLA-DRB1 allelic associations with systemic lupus erythematous and lupus nephritis in Taiwan\n. Lupus \n2009 ;18 :698 –704\n. 10.1177/0961203308101955 \n19502265 \n23 \nShimane K , Kochi Y , Suzuki A , et al \nAn association analysis of HLA-DRB1 with systemic lupus erythematosus and rheumatoid arthritis in a Japanese population: effects of *09:01 allele on disease phenotypes\n. Rheumatology \n2013 ;52 :1172 –82\n. 10.1093/rheumatology/kes427 \n23407388 \n24 \nBang S-Y , Choi J-Y , Park S , et al \nBrief report: influence of HLA-DRB1 susceptibility alleles on the clinical subphenotypes of systemic lupus erythematosus in Koreans\n. Arthritis Rheumatol \n2016 ;68 :1190 –6\n. 10.1002/art.39539 \n26663868 \n25 \nFurukawa H , Oka S , Shimada K , et al \nAssociation of increased frequencies of HLA-DPB1*05:01 with the presence of anti-Ro/SS-A and anti-La/SS-B antibodies in Japanese rheumatoid arthritis and systemic lupus erythematosus patients\n. PLoS One \n2013 ;8 :e53910. 10.1371/journal.pone.0053910 \n23320107\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2051-1426",
"issue": "8(2)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "biomarkers; case reports; gastrointestinal neoplasms; immunotherapy; tumor; tumor microenvironment",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D049914:DNA Repair-Deficiency Disorders; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008180:Lupus Erythematosus, Systemic; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D059016:Tumor Microenvironment",
"nlm_unique_id": "101620585",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32636238",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "31325788;23407388;30865922;23320107;27768182;30425107;30660730;26270186;23793423;31022184;28767289;27522116;26663868;9182925;29961768;31221204;31116675;19502265;31645760;17406641;29489427;29858173;28596308;21658414",
"title": "Durable benefit from immunotherapy and accompanied lupus erythematosus in pancreatic adenocarcinoma with DNA repair deficiency.",
"title_normalized": "durable benefit from immunotherapy and accompanied lupus erythematosus in pancreatic adenocarcinoma with dna repair deficiency"
} | [
{
"companynumb": "CN-009507513-2007CHN008975",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe mechanism by which ocular surface squamous neoplasia (OSSN) responds to topical interferon-alpha-2b (IFNα2b) is not known. We report the cases of 3 immunosuppressed patients whose tumors did not respond to topical IFNα2b therapy. The purpose of this series is to shed light on potential mechanisms of IFNα2b in OSSN.\n\n\nMETHODS\nRetrospective case series of 3 immunosuppressed patients whose biopsy-proven OSSN did not respond to topical IFNα2b treatment.\n\n\nRESULTS\nThree white, immunosuppressed males (mean age 70 years, range 66-76) were diagnosed with OSSN. Topical IFNα2b 1 million units/mL was administered 4 times a day and used for a mean of 5 months (range 2-7 mo) without an adequate response. All patients were then switched to 5-fluorouracil. Successful eradication of OSSN was achieved in 2 cases, and improvement of OSSN in another. The latter patient was switched to mitomycin-C with subsequent resolution of OSSN.\n\n\nCONCLUSIONS\nThese cases suggest that an intact immune system may be an important link between IFNα2b therapy and tumor resolution. As such, topical IFNα2b may not be an optimal choice for patients with underlying immunosuppression. It may be more effective in this patient population to switch to a non-immune-modulating therapy such as 5-fluorouracil or mitomycin-C.",
"affiliations": "*Department of Ophthalmology, Miami Veterans Affairs Medical Center; †Bascom Palmer Eye Institute, University of Miami, Miami, FL; and ‡Jackson Memorial Hospital, Miami, FL.",
"authors": "Ashkenazy|Noy|N|;Karp|Carol L|CL|;Wang|Gaofeng|G|;Acosta|Carolina Mercado|CM|;Galor|Anat|A|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D007155:Immunologic Factors; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D009883:Ophthalmic Solutions; D011994:Recombinant Proteins; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000001153",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3740",
"issue": "36(4)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": "D000287:Administration, Topical; D000368:Aged; D000964:Antimetabolites, Antineoplastic; D002294:Carcinoma, Squamous Cell; D003230:Conjunctival Neoplasms; D003316:Corneal Diseases; D005134:Eye Neoplasms; D005472:Fluorouracil; D006801:Humans; D016867:Immunocompromised Host; D007155:Immunologic Factors; D007165:Immunosuppression Therapy; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008297:Male; D009883:Ophthalmic Solutions; D011994:Recombinant Proteins; D012189:Retrospective Studies; D012307:Risk Factors; D017211:Treatment Failure",
"nlm_unique_id": "8216186",
"other_id": null,
"pages": "506-510",
"pmc": null,
"pmid": "28129301",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25834312;9194740;15778602;26911188;19493859;18161743;25764160;24654456;21061793;22391814;22694104;9505174;15057887;23570381;12724731",
"title": "Immunosuppression as a Possible Risk Factor for Interferon Nonresponse in Ocular Surface Squamous Neoplasia.",
"title_normalized": "immunosuppression as a possible risk factor for interferon nonresponse in ocular surface squamous neoplasia"
} | [
{
"companynumb": "US-CELGENEUS-USA-20170403827",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nGlucocorticoids are regarded as first-line therapy in the management of hypercalcemia associated with sarcoidosis. However, prolonged glucocorticoid therapy leads to metabolic abnormalities, Cushingoid habitus, and impairment of bone health. This study demonstrates the efficacy and glucocorticoid-sparing effect of zoledronic acid in sarcoid hypercalcemia.\n\n\nMETHODS\nWe present three patients with sarcoid hypercalcemia. They were successfully managed with oral glucocorticoids for many months. However, all patients developed adverse effects of glucocorticoids. When tapering of glucocorticoids was attempted, hypercalcemia recurred. Zoledronic acid was administered in order to control hypercalcemia and to allow tapering of glucocorticoids.\n\n\nRESULTS\nFollowing zoledronic acid administration, serum calcium level normalised and glucocorticoids could be discontinued in all the three patients. Normocalcemia was maintained for an average of 18 months after a single infusion. Sarcoidosis remained in remission in all the three patients.\n\n\nCONCLUSIONS\nZoledronic acid should be studied as a potential first-line agent for sarcoid hypercalcemia. Furthermore, disease-modifying effects of zoledronic acid in sarcoidosis should be investigated.",
"affiliations": "Division of Endocrinology and Diabetes, Medanta-The Medicity, Sector 38, Gurgaon, Haryana, 122001, India. drshafikuchay@gmail.com.;Division of Endocrinology and Diabetes, Medanta-The Medicity, Sector 38, Gurgaon, Haryana, 122001, India.;Division of Endocrinology and Diabetes, Medanta-The Medicity, Sector 38, Gurgaon, Haryana, 122001, India.;Division of Endocrinology and Diabetes, Medanta-The Medicity, Sector 38, Gurgaon, Haryana, 122001, India.;Division of Internal Medicine, Medanta-The Medicity, Sector-38, Gurgaon, Haryana, 122001, India.;Division of Endocrinology and Diabetes, Medanta-The Medicity, Sector 38, Gurgaon, Haryana, 122001, India.",
"authors": "Kuchay|Mohammad Shafi|MS|;Mishra|Sunil Kumar|SK|;Bansal|Beena|B|;Farooqui|Khalid Jamal|KJ|;Sekhar|Lalitha|L|;Mithal|Ambrish|A|",
"chemical_list": "D004164:Diphosphonates; D005938:Glucocorticoids; D007093:Imidazoles; D000077211:Zoledronic Acid",
"country": "England",
"delete": false,
"doi": "10.1007/s11657-017-0360-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "12(1)",
"journal": "Archives of osteoporosis",
"keywords": "Adverse effects; Glucocorticoids; Hypercalcemia; Sarcoidosis; Zoledronic acid",
"medline_ta": "Arch Osteoporos",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D004164:Diphosphonates; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D006934:Hypercalcemia; D007093:Imidazoles; D008875:Middle Aged; D012507:Sarcoidosis; D000077211:Zoledronic Acid",
"nlm_unique_id": "101318988",
"other_id": null,
"pages": "68",
"pmc": null,
"pmid": "28726113",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Glucocorticoid sparing effect of zoledronic acid in sarcoid hypercalcemia.",
"title_normalized": "glucocorticoid sparing effect of zoledronic acid in sarcoid hypercalcemia"
} | [
{
"companynumb": "IN-CONCORDIA PHARMACEUTICALS INC.-E2B_00008316",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugad... |
{
"abstract": "Inflammatory bowel disease is associated with an increased likelihood of developing lymphoma. However, it is still controversial if this risk may be attributed to the disease itself or rather represents an effect of immunosuppressive treatment. Although tumor necrosis factor alpha (TNFα) is a key cytokine for cancer immunosurveillance, the potential relationship between anti-TNFα agents and the pathogenesis of lymphoproliferative disorders remains unclear. Here, we describe the case of a patient with severe perianal Crohn's disease, treated with infliximab monotherapy, whose unusual presentation with acute groin pain required surgical intervention and led to the diagnosis of diffuse large B-cell lymphoma. However, 10 months after this episode, treatment with infliximab was restarted because the patient continued with refractory and disabling perianal disease. Currently, with a follow-up of 36 months, under infliximab 10 mg/kg every 4 weeks, he maintains mild perianal Crohn's disease and persists in sustained clinical and imaging remission of the lymphoproliferative disorder.",
"affiliations": "Gastroenterology Department, Centro Hospitalar de Lisboa Central, Lisbon, Portugal. carlosfbernardes@gmail.com.;Gastroenterology Department, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.;Gastroenterology Department, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.;Gastroenterology Department, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.;Gastroenterology Department, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.",
"authors": "Bernardes|Carlos|C|http://orcid.org/0000-0003-0567-9780;Russo|Pedro|P|;Carvalho|Diana|D|;Saiote|Joana|J|;Ramos|Jaime|J|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha; D011239:Prednisolone; D000069285:Infliximab",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-017-0802-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "11(1)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Anti-TNFα; Crohn’s disease; Inflammatory bowel disease; Infliximab; Lymphoma; Lymphoproliferative disorder",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D003424:Crohn Disease; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D011239:Prednisolone; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "48-52",
"pmc": null,
"pmid": "29168104",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18349407;11677199;10774465;18368468;26896086;22890223;20953706;21165742;23891975;26988544;23978954;14687024;24419748;23006945;20210767;15958773;23399737;21183450;21658658;19137269;23721759;19837455;28261018;12687538;27924643;15880596;20332773;22470604;21885875",
"title": "Safe use of infliximab for the treatment of severe perianal Crohn's disease after diagnosis and treatment of lymphoma.",
"title_normalized": "safe use of infliximab for the treatment of severe perianal crohn s disease after diagnosis and treatment of lymphoma"
} | [
{
"companynumb": "PT-JNJFOC-20180226846",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "1",
"... |
{
"abstract": "Paragangliomas are relatively rare chromaffin cell tumors which may be cured through resection. Patients with paragangliomas may develop metastatic diseases. There is no consensus regarding refractory chemotherapy for treatment of metastatic disease. In this report, we presented a case of a 43-year-old woman who was admitted to the hospital with a history of episodic headaches, diaphoresis, and weakness. Elevated plasma catecholamine levels and a right paraaortic mass were observed on computed tomography. The mass was excised, and a diagnosis of paraganglioma was confirmed. After 20 months of follow-up, local recurrence and metastases were detected in the thorax, abdomen, and skeletal system. Plasma and urinary catecholamine levels were high. Chemotherapy was administered, and no improvement was observed. Therefore, following this palliative conventional chemotherapy, sorafenib was administered for three months, and, finally, positron emission tomography showed that the patient's lesions had completely regressed.",
"affiliations": "Department of Medical Oncology, University of Cukurova Faculty of Medicine, Adana, Turkey.;Department of Medical Oncology, University of Cukurova Faculty of Medicine, Adana, Turkey.;Department of Medical Oncology, University of Cukurova Faculty of Medicine, Adana, Turkey.;Department of Medical Oncology, University of Cukurova Faculty of Medicine, Adana, Turkey.;Department of Pathology, University of Cukurova Faculty of Medicine, Adana, Turkey.;Department of Pathology, University of Cukurova Faculty of Medicine, Adana, Turkey.",
"authors": "Gunaldi|Meral|M|;Kara|Ismail Oguz|IO|;Duman|Berna Bozkurt|BB|;Afsar|Cigdem Usul|CU|;Ergin|Melek|M|;Avci|Arbil|A|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.4143/crt.2013.093",
"fulltext": "\n==== Front\nCancer Res TreatCancer Res TreatCRTCancer Research and Treatment : Official Journal of Korean Cancer Association1598-29982005-9256Korean Cancer Association 2503657710.4143/crt.2013.093crt-2013-093Case ReportA New Approach to the Treatment of Metastatic Paraganglioma: Sorafenib Gunaldi Meral MD1Kara Ismail Oguz PhD1Duman Berna Bozkurt MD1Afsar Cigdem Usul MD1Ergin Melek PhD2Avci Arbil MD21 Department of Medical Oncology, University of Cukurova Faculty of Medicine, Adana, Turkey2 Department of Pathology, University of Cukurova Faculty of Medicine, Adana, TurkeyCorrespondence: Meral Gunaldi, MD Department of Medical Oncology, University of Cukurova Faculty of Medicine, 01330, Saricam-Adana, Turkey Tel: 90-505-218-0300 Fax: 90-322-338-7072 E-mail: meralgunaldi@gmail.com10 2014 18 7 2014 46 4 411 414 13 6 2013 20 8 2013 Copyright © 2014 by the Korean Cancer Association2014This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Paragangliomas are relatively rare chromaffin cell tumors which may be cured through resection. Patients with paragangliomas may develop metastatic diseases. There is no consensus regarding refractory chemotherapy for treatment of metastatic disease. In this report, we presented a case of a 43-year-old woman who was admitted to the hospital with a history of episodic headaches, diaphoresis, and weakness. Elevated plasma catecholamine levels and a right paraaortic mass were observed on computed tomography. The mass was excised, and a diagnosis of paraganglioma was confirmed. After 20 months of follow-up, local recurrence and metastases were detected in the thorax, abdomen, and skeletal system. Plasma and urinary catecholamine levels were high. Chemotherapy was administered, and no improvement was observed. Therefore, following this palliative conventional chemotherapy, sorafenib was administered for three months, and, finally, positron emission tomography showed that the patient’s lesions had completely regressed.\n\nExtra-adrenal paragangliomaNeoplasm metastasisSorafenibPheochromocytomasTyrosine kinase inhibitor\n==== Body\nIntroduction\nParagangliomas (PGLs), which were first described in 1886 [1], are chromaffin cell tumors that develop from sympathetic and parasympathetic ganglia throughout the abdomen, head and neck area [2]. Some PGLs are inherited, and occur as sporadic tumors. Some hereditary syndromes can be linked to development of PGLs. These syndromes may be von Hippel-Lindau syndrome (VHL) and multiple endocrines neoplasia type 2, and are associated with impaired NF1, RET proto-oncogene or VHL gene expression [3].\n\nIn PGL diagnosis, measurement of plasma and urinary metanephrine levels has been used as an effective method. Untreated PGL could have devastating results due to myocardial infarction, severe hypertension, stroke and/or arrhythmia caused by catecholamine excess [2].\n\nAlthough PGL has been considered as a ten percentage disease (10% metastatic, 10% familial, 10% recurring, 10% extra-adrenal, 10% occurring in children), up-to-date diagnostic techniques illustrate that this rule of 10% does not indeed accurately describe the disease. PGL patients, with 0-36%, may develop metastatic disease. The familial percentage has been revised to approximately 30% [4]. Extra-adrenal PGLs are reported in patients with a range of 15-20% [2]. In general, PGLs are curable, yet, once a patient presents with metastases, the treatment options become limited.\n\nCase Report\nIn this report, we present the case of a 43-year-old woman with a history of episodic headaches, diaphoresis, and weakness. Hypertensive and tachycardic episodes were also diagnosed. Detailed family history revealed no unexplained or incompletely explained sudden death. She had elevated plasma and urinary metanephrine/catecholamine levels (Table 1), and a right paraaortic mass (9×9.5 cm) was observed on computed tomography (CT). Preoperatively, α- and β-adrenergic receptor blockers were administered. Following successful resection of the tumor, plasma and 24-hour urinary catecholamine levels were normalized. The mass was excised and diagnosis of PGL was confirmed; synaptophysin and chromogranin were positive (Fig. 1). In postoperative follow-up, the patient's blood pressure and catecholamine levels were normalized.\n\nAfter 20 months, positron emission tomography (PET) showed local recurrence, and metastases were detected in the thorax, abdomen, and skeletal system (Fig. 2). Plasma catecholamine levels were high (Table 1). An anthracycline plus CVD regimen (adriamycine 7 mg/m2, dacarbazine 400 mg/m2, cyclophosphamide 500 mg/m2, vincristine 1.4 mg/m2) on days 1 and 2, and zoledronic acid (4 mg) every 21 days were administered, and no improvement was observed on PET following a treatment of six cycles.\n\nFour months following termination of chemotherapy, calculated plasma and 24-hour urinary catecholamine levels were above normal range. Therefore, sorafenib tosylate (400 mg twice daily) was administered for three months due to recurred-progressive disease. The patient’s plasma and 24-hour urinary catecholamine levels finally decreased, and PET/CT showed that metastatic lesions had regressed after 12 weeks (Table 1, Fig. 3). In addition, the patient’s symptoms decreased. After 64-week treatment with sorafenib, distance and cerebral metastasis occurred, and the patient died.\n\nDiscussion\nPGLs, also called extra-adrenal pheochromocytomas, may develop anywhere from sympathetic/parasympathetic nerve cells to major arteries in the body, with 85-90% of occurrence in the abdomen. These tumors, hypersecreting catecholamines, can be observed in any region from the skull to the pelvis. Although metastatic PGLs (mPGLs) have no reliable markers, they can be characterized as being over 5-cm in mass, invading adjacent structures, and spreading to other organs [2].\n\nOptions for treatment of mPGLs include palliative tumor resection, ablation, reduction of tumor burden and excess of catecholamine related symptoms, and cytotoxic hemotherapy or targeted agents [5,6].\n\nThe benefits of CVD, the most widely used chemotherapeutic regimen [2], appear to be rather short-termed, and exclude an increase in patients' survival [6]. In a recent case study, another chemotherapeutic agent, temozolomide, was reported to yield positive effects prior to tumor resection [7]. Regarding post tumor removal, treatment with targeted radiotherapeutics may yield significant benefits, the most frequent being treatment with 131I-MIBG. The results here suggested that there was a symptomatic response in as many as 67-98% of patients; an observable tumor shrinkage in 27-47%; and a decrease in secretion in 45-67% [2].\n\nSo far, treatment with multiple tyrosine kinase inhibitors (mTKI) like sunitinib, to which five patients showed a partial response and one patient showed clinical improvement, appears to be the most effective approach [8-11]. Sunitinib, an oral multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity, targets platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), KIT, and FLT3. Duration of response on sunitinib was 24, 40, 40, 24, 4, and 24 weeks, respectively, in all patients.\n\nPhosphatidylinositide 3-kinase/ Akt/ mammalian target of rapamycin (mTOR) pathway in the pathogenesis of malignant neuroendocrine tumors includes pheochromocy-toma. Everolimus is a compound that inhibits mTOR signalling. Treatment with everolimus, as targeted therapy, was attempted, however, no significant benefits were obtained in four patients [12].\n\nImatinib does not appear to be useful for treatment of mPGLs; progression was reported in two patients who were administered this drug [13].\n\nSorafenib, a mTKI, is used in treatment of advanced renal cell and hepatocellular carcinomas. It is an inhibitor of RAF kinase, c-KIT, FLT-3, RET, VEGFRs (VEGFR-2, VEGFR-3), and PDGFR (PDGFR-β). It reduces activation of MEK and MAP kinase, and causes inhibition of cell proliferation, invasion, migration, and tumor growth.\n\nIn our case, the patient obtained clinical and laboratory benefits from sorafenib by showing a truly complete response after a three-month therapy. Response duration of sorafenib was 64 weeks in this case. Considering other cases in which sunitinib was administered, this period is quite important. Sorafenib may have potential for treatment of mPGLs since it targets several cellular pathways, one of which is VEGFR-2, -3, and possibly others. High vascularization is usually a common characteristic in almost all metastatic diseases [2]. Since this is the case, sorafenib may prove to be beneficial in inhibiting vascularization. In addition, expression of the RET gene mutation is known to be the most frequent type in familial PGLs [3]. Sorafenib may also be an active agent in inhibition of the RET protooncogene for familial PGLs.\n\nTo the best of our knowledge, in the literature, there are no cases with mPGLs subjected to treatment utilizing sorafenib. Because the options for treatment of mPGLs are rather limited, sorafenib may prove to be a very effective agent. The result we obtained with our case is very exciting, yet there is still a need for comprehensive research investigating reliability of this drug in treatment of patients with mPGLs.\n\nConflict of interest relevant to this article was not reported.\n\nFig. 1. Zellballen arrangement of the chief cells with peripherally layered sustentacular cells and a prominent capillary network around each group is noted (H&E staining, ×200).\n\nFig. 2. Positron emission tomography-computed tomography shows metastases.\n\nFig. 3. Positron emission tomography-computed tomography image obtained three months later, after onset of sorafenib therapy, shows regression of all metastases.\n\nTable 1. Plasma and urinary catecholamine levels of patients\n\n\tPreoperative\tPostoperative\tAfter 20 months\tPostchemotherapy\tAfter sorafenib\t\nPlasma\t\t\t\t\t\t\n Epinephrine (< 60 pg/mL)\t9\t0.3\t14\t10\t11\t\n Norepinephrine (120-680 pg/mL)\t206\t2.7\t2,700\t2,100\t97\t\n Dopamine (< 87 pg/mL)\t1,700\t150\t2,071\t1,800\t250\t\nUrinary\t\t\t\t\t\t\n Vanil mandelic acid (3.3-6.5 mg/day)\t46\t0.8\t25\t16.8\t8.2\t\n Metanephrine (< 350 μg/day)\t166\t46\t214\t109\t105\t\n Normetanephrine (< 450 μg/day)\t1,900\t500\t2,800\t2,599\t600\n==== Refs\nReferences\n1 Frankel F Ein Fall von doppelseitigem, vollig latent verlaufenen Nebennierentumor und gleichzeitiger Nephritis mit Veranderungen am Circulationsapparat und Retinitis Virchows Arch 1886 103 244 63 \n2 Fliedner SM Lehnert H Pacak K Metastatic paraganglioma Semin Oncol 2010 37 627 37 21167381 \n3 Krawczyk A Hasse-Lazar K Pawlaczek A Szpak-Ulczok S Krajewska J Paliczka-Cieslak E Germinal mutations of RET, SDHB, SDHD, and VHL genes in patients with apparently sporadic pheochromocytomas and paragangliomas Endokrynol Pol 2010 61 43 8 20205103 \n4 O’Riordain DS Young WF Jr Grant CS Carney JA van Heerden JA Clinical spectrum and outcome of functional extraadrenal paraganglioma World J Surg 1996 20 916 21 8678971 \n5 Lehnert H Mundschenk J Hahn K Malignant pheochromocytoma Front Horm Res 2004 31 155 62 14674310 \n6 Zografos GN Vasiliadis G Farfaras AN Aggeli C Digalakis M Laparoscopic surgery for malignant adrenal tumors JSLS 2009 13 196 202 19660215 \n7 Kulke MH Stuart K Enzinger PC Ryan DP Clark JW Muzikansky A Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors J Clin Oncol 2006 24 401 6 16421420 \n8 Joshua AM Ezzat S Asa SL Evans A Broom R Freeman M Rationale and evidence for sunitinib in the treatment of malignant paraganglioma/pheochromocytoma J Clin Endocrinol Metab 2009 94 5 9 19001511 \n9 Jimenez C Cabanillas ME Santarpia L Jonasch E Kyle KL Lano EA Use of the tyrosine kinase inhibitor sunitinib in a patient with von Hippel-Lindau disease: targeting angiogenic factors in pheochromocytoma and other von Hippel-Lindau disease-related tumors J Clin Endocrinol Metab 2009 94 386 91 19017755 \n10 Park KS Lee JL Ahn H Koh JM Park I Choi JS Sunitinib, a novel therapy for anthracycline- and cisplatin-refractory malignant pheochromocytoma Jpn J Clin Oncol 2009 39 327 31 19264767 \n11 Cirillo F Metastatic paraganglioma and treatment with sunitinib: a case report Tumori 2010 96 1022 7 21388069 \n12 Druce MR Kaltsas GA Fraenkel M Gross DJ Grossman AB Novel and evolving therapies in the treatment of malignant phaeochromocytoma: experience with the mTOR inhibitor everolimus (RAD001) Horm Metab Res 2009 41 697 702 19424940 \n13 Gross DJ Munter G Bitan M Siegal T Gabizon A Weitzen R The role of imatinib mesylate (Glivec) for treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R Endocr Relat Cancer 2006 13 535 40 16728580\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1598-2998",
"issue": "46(4)",
"journal": "Cancer research and treatment",
"keywords": "Extra-adrenal paraganglioma; Neoplasm metastasis; Pheochromocytomas; Sorafenib; Tyrosine kinase inhibitor",
"medline_ta": "Cancer Res Treat",
"mesh_terms": null,
"nlm_unique_id": "101155137",
"other_id": null,
"pages": "411-4",
"pmc": null,
"pmid": "25036577",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article",
"references": "16728580;19017755;19001511;21388069;14674310;20205103;21167381;19660215;19264767;8678971;16421420;19424940",
"title": "A new approach to the treatment of metastatic paraganglioma: sorafenib.",
"title_normalized": "a new approach to the treatment of metastatic paraganglioma sorafenib"
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"activesubstancename": "VINCRISTINE"
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