article dict | reports listlengths 1 3.97k |
|---|---|
{
"abstract": "A 55-year-old man with end-stage emphysema underwent a right single-lung transplantation through a posterolateral thoracotomy. The fifth rib was divided and fused back using a biodegradable pin made of polylactide acid and hydroxyapatite. Two weeks postoperatively, he suffered from central vein catheter-related sepsis due to methicillin-sensitive Staphylococcus aureus. After being successfully treated for sepsis, he was discharged. However, 3 months later, computed tomography revealed multiple loculated abscesses in the chest wall and the right pleural space. Reoperative thoracotomy revealed abscesses mainly located around the fifth rib, where the pin was inserted. Both cultures of the abscess and the fifth rib were positive for methicillin-sensitive S. aureus, which suggested that the rib pin was the cause of the secondary infection. This case suggests the rib pins, even if they are biodegradable, could have a risk of infections side effect especially for the immunosuppressed patients.",
"affiliations": "Departments of Thoracic Surgery, Kyoto University, 54 Shogoin, Kawahara-cho, Sakyo-ku1, Kyoto, 606-8507, Japan.;Departments of Thoracic Surgery, Kyoto University, 54 Shogoin, Kawahara-cho, Sakyo-ku1, Kyoto, 606-8507, Japan. fengshic@kuhp.kyoto-u.ac.jp.;National Center for Geriatrics and Gerontology, Nagoya, Japan.;Departments of Thoracic Surgery, Kyoto University, 54 Shogoin, Kawahara-cho, Sakyo-ku1, Kyoto, 606-8507, Japan.;Departments of Thoracic Surgery, Kyoto University, 54 Shogoin, Kawahara-cho, Sakyo-ku1, Kyoto, 606-8507, Japan.;Departments of Thoracic Surgery, Kyoto University, 54 Shogoin, Kawahara-cho, Sakyo-ku1, Kyoto, 606-8507, Japan.;Departments of Thoracic Surgery, Kyoto University, 54 Shogoin, Kawahara-cho, Sakyo-ku1, Kyoto, 606-8507, Japan.;Departments of Thoracic Surgery, Kyoto University, 54 Shogoin, Kawahara-cho, Sakyo-ku1, Kyoto, 606-8507, Japan.",
"authors": "Goda|Yasufumi|Y|;Chen-Yoshikawa|Toyofumi F|TF|;Kusunose|Masaaki|M|;Hamaji|Masatsugu|M|;Motoyama|Hideki|H|;Hijiya|Kyoko|K|;Aoyama|Akihiro|A|;Date|Hiroshi|H|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s11748-017-0768-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1863-6705",
"issue": "66(3)",
"journal": "General thoracic and cardiovascular surgery",
"keywords": "Biodegradable rib pin; Chest wall abscess; Lung transplantation",
"medline_ta": "Gen Thorac Cardiovasc Surg",
"mesh_terms": "D000038:Abscess; D020341:Absorbable Implants; D001858:Bone Nails; D006801:Humans; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D016459:Prosthesis-Related Infections; D012272:Ribs; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus; D035441:Thoracic Wall; D013908:Thoracotomy; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101303952",
"other_id": null,
"pages": "175-178",
"pmc": null,
"pmid": "28315045",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Late-onset chest wall abscess due to a biodegradable rib pin infection after lung transplantation.",
"title_normalized": "late onset chest wall abscess due to a biodegradable rib pin infection after lung transplantation"
} | [
{
"companynumb": "JP-TEVA-2018-JP-879456",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Many Type 2 diabetic patients take metformin for its safety profile and lack of hypoglycemia. Although this drug is safe in those without renal dysfunction, lactic acidosis may rarely occur. Metformin-associated lactic acidosis is a potentially fatal yet rare diagnosis. Prompt recognition of even subtle symptoms can reduce mortality and preserve homeostasis.",
"affiliations": "Department of Emergency Medi-cine, North Shore University Health Systems, Evanston, Illinois.",
"authors": "Hevesy|Martin R|MR|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "United States",
"delete": false,
"doi": "10.1097/TME.0000000000000134",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1931-4485",
"issue": "39(1)",
"journal": "Advanced emergency nursing journal",
"keywords": null,
"medline_ta": "Adv Emerg Nurs J",
"mesh_terms": "D000140:Acidosis, Lactic; D000368:Aged; D003924:Diabetes Mellitus, Type 2; D003937:Diagnosis, Differential; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D008687:Metformin",
"nlm_unique_id": "101285075",
"other_id": null,
"pages": "26-30",
"pmc": null,
"pmid": "28141608",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metformin-Associated Lactic Acidosis: An Atypical Presentation.",
"title_normalized": "metformin associated lactic acidosis an atypical presentation"
} | [
{
"companynumb": "PHHY2017US027575",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": null,
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationn... |
{
"abstract": "This report describes a catastrophic bleeding following methotrexate treatment of cervical pregnancy and dramatic response to Bakri surgical obstetric silicone (SOS) balloon tamponade in controlling massive bleeding. A 42-year-old woman was diagnosed for cervical pregnancy with a viable fetus at 12 weeks by transvaginal ultrasound. Conservative treatment with intrafetal potassium chloride injection and systemic methotrexate were instituted. On the sixth day of therapy, catastrophic bleeding lead to hypovolemic shock. After resuscitation and blood transfusion, we attempt to control the bleeding with evacuation and curettage but was unsuccessful. Bakri SOS balloon tamponade was applied with immediate and effective response. Nevertheless, total abdominal hysterectomy was performed. In conclusion, conservative treatment of cervical pregnancy with systemic methotrexate could be catastrophic in some patients. Control of active bleeding with Bakri SOS balloon tamponade may possibly be helpful in case of uncontrolled bleeding in selected cases.",
"affiliations": "Department of Obstetrics and Gynecology, Chiang Mai University, Chiang Mai, Thailand.",
"authors": "Saeng-anan|Ubol|U|;Sreshthaputra|Opas|O|;Sukpan|Kornkanok|K|;Tongsong|Theera|T|",
"chemical_list": "D000020:Abortifacient Agents, Nonsteroidal; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000020:Abortifacient Agents, Nonsteroidal; D000032:Abortion, Therapeutic; D000328:Adult; D021721:Balloon Occlusion; D002584:Cervix Uteri; D004107:Dilatation and Curettage; D005260:Female; D006801:Humans; D008727:Methotrexate; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011271:Pregnancy, Ectopic; D016216:Ultrasonography, Prenatal; D014592:Uterine Hemorrhage",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "23929636",
"pubdate": "2013-08-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "22472336;20637109;16514619;21821998;19382285;19126514;18585712;21292258;18821465;17977172;8994238;15655698;22027230;21851040;20889136;17470585;17592059;8886714;16553188;19472784;10601926;15055783",
"title": "Cervical pregnancy with massive bleeding after treatment with methotrexate.",
"title_normalized": "cervical pregnancy with massive bleeding after treatment with methotrexate"
} | [
{
"companynumb": "PHHY2013TH130512",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "The efficacy of nonselective β-blocker and endoscopic procedures, such as endoscopic variceal ligation, as primary prophylaxis of variceal hemorrhage in cirrhotic adults was demonstrated by numerous controlled trials, but in pediatric population, few are the number of studies.\nThe objective of this study is to evaluate the primary prophylaxis with β-blocker in cirrhotic children and adolescents with portal hypertension.\nThis is a cohort study encompassing 26 cirrhotic patients. β-blocker prophylaxis was performed with propranolol. When contraindicated the use of β-blocker, or if side effects presents, the patients were referred to endoscopic therapy with band ligation. Patients were evaluated by endoscopy, and those who had varicose veins of medium and large caliber or reddish spots, regardless of the caliber of varices, received primary prophylaxis.\nOf the 26 patients evaluated, 9 (34.6%) had contraindications to the use of propranolol and were referred for endoscopic prophylaxis. Six (35.3%) of the 17 patients who received β-blocker (propranolol), had bled after a median follow-up time of 1.9 years. β-blockage dosage varied from 1 mg/kg/day to 3.1 mg/kg/day and seven (41.2%) patients had the propranolol suspended due to fail of the β-blockage or adverse effects, such as drowsiness, bronchospasm and hypotension. Patients who received endoscopic prophylaxis (elastic bandage) had no bleeding during the follow-up period.\nAll of the patients that had upper gastroinstestinal bleeding in this study were under propranolol prophylaxis. The use of propranolol showed a high number of contraindications and side effects, requiring referral to endoscopic prophylaxis. The endoscopic prophylaxis was effective in reducing episodes of bleeding.",
"affiliations": "Setor de Gastroenterologia Pediátrica, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil.;Setor de Gastroenterologia Pediátrica, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil.;Setor de Gastroenterologia Pediátrica, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil.;Departamento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil.;Setor de Gastroenterologia Pediátrica, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil.;Departamento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil.",
"authors": "Pimenta|Júlio Rocha|JR|;Ferreira|Alexandre Rodrigues|AR|;Bittencourt|Paulo Fernando Souto|PF|;Resende|Camilo Brandão de|CB|;Fagundes|Eleonora Druve Tavares|ED|;Silva|Isabela Maria Lopes da|IM|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D011433:Propranolol",
"country": "Brazil",
"delete": false,
"doi": "10.1590/S0004-28032016000400009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-2803",
"issue": "53(4)",
"journal": "Arquivos de gastroenterologia",
"keywords": null,
"medline_ta": "Arq Gastroenterol",
"mesh_terms": "D000293:Adolescent; D000319:Adrenergic beta-Antagonists; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D000075202:Contraindications; D016099:Endoscopy, Gastrointestinal; D004932:Esophageal and Gastric Varices; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D006975:Hypertension, Portal; D007223:Infant; D008026:Ligation; D008103:Liver Cirrhosis; D008297:Male; D011322:Primary Prevention; D011433:Propranolol; D016896:Treatment Outcome",
"nlm_unique_id": "15310600R",
"other_id": null,
"pages": "257-261",
"pmc": null,
"pmid": "27706456",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "EVALUATION OF PRIMARY PROPHYLAXIS WITH PROPRANOLOL AND ELASTIC BAND LIGATION IN VARICEAL BLEEDING IN CIRRHOTIC CHILDREN AND ADOLESCENTS.",
"title_normalized": "evaluation of primary prophylaxis with propranolol and elastic band ligation in variceal bleeding in cirrhotic children and adolescents"
} | [
{
"companynumb": "BR-FRESENIUS KABI-FK201608476",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROPRANOLOL HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "Lateral retropharyngeal lymph node (LRPLN) is located between the internal carotid artery and the prevertebral muscles. Metastasis to the LRPLN is frequent in nasopharyngeal cancer, but is rare in oral cancer. The prognosis of patients with oral cancer with LRPLN metastasis is usually poor. The present study reported a patient with LRPLN metastasis from squamous cell carcinoma of the upper gingiva, who survived for >7 years. Docetaxel, cisplatin and fluorouracil (TPF) therapy was performed as induction chemotherapy and it was planned to subsequently conduct chemoradiotherapy or surgery. As the tumor only exhibited a transient response to TPF, surgery was selected. Postoperatively, only radiotherapy was performed and a favorable outcome was achieved.",
"affiliations": "Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.;Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.;Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.;Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.;Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.;Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.;Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.;Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.;Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.",
"authors": "Yamazaki|Hiroshi|H|;Sasaki|Masashi|M|;Aoyama|Ken-Ichi|KI|;Suzuki|Takatsugu|T|;Denda|Yuya|Y|;Uchibori|Masahiro|M|;Nakanishi|Yasuhiro|Y|;Kojima|Rena|R|;Ota|Yoshihide|Y|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2017.1496",
"fulltext": "\n==== Front\nMol Clin OncolMol Clin OncolMCOMolecular and Clinical Oncology2049-94502049-9469D.A. Spandidos 10.3892/mco.2017.1496MCO-0-0-1496ArticlesLateral retropharyngeal lymph node metastasis from squamous cell carcinoma of the upper gingiva: A case report Yamazaki Hiroshi 12Sasaki Masashi 1Aoyama Ken-Ichi 12Suzuki Takatsugu 1Denda Yuya 1Uchibori Masahiro 1Nakanishi Yasuhiro 1Kojima Rena 12Ota Yoshihide 11 Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan2 Department of Oral and Maxillofacial Surgery, Tokai University Oiso Hospital, Kanagawa 259-0198, JapanCorrespondence to: Dr Hiroshi Yamazaki, Department of Oral and Maxillofacial Surgery, Tokai University Oiso Hospital, 21-1 Gakkyo, Oiso, Naka-gun, Kanagawa 259-0198, Japan, E-mail: osyamaza@is.icc.u-tokai.ac.jp1 2018 13 11 2017 13 11 2017 8 1 68 72 01 8 2017 09 11 2017 Copyright: © Yamazaki et al.2018This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Lateral retropharyngeal lymph node (LRPLN) is located between the internal carotid artery and the prevertebral muscles. Metastasis to the LRPLN is frequent in nasopharyngeal cancer, but is rare in oral cancer. The prognosis of patients with oral cancer with LRPLN metastasis is usually poor. The present study reported a patient with LRPLN metastasis from squamous cell carcinoma of the upper gingiva, who survived for >7 years. Docetaxel, cisplatin and fluorouracil (TPF) therapy was performed as induction chemotherapy and it was planned to subsequently conduct chemoradiotherapy or surgery. As the tumor only exhibited a transient response to TPF, surgery was selected. Postoperatively, only radiotherapy was performed and a favorable outcome was achieved.\n\nlateral retropharyngeal lymph nodemetastasisoral cancerinduction chemotherapy\n==== Body\nIntroduction\nThe lateral retropharyngeal lymph node (LRPLN) is located between the internal carotid artery and the prevertebral muscles. The LRPLN is most often seen anterior to the arch of C1, but is sometimes found at the level of the soft palate. The uppermost part of the LRPLN anterior to the atlas is known as the lymph node of Rouvière (1). Lateral retropharyngeal lymph node (LRPLN) metastasis from oral squamous cell carcinoma (OSCC) is rare and the prognosis is extremely poor (2–5). We report an unusual patient with LRPLN metastasis from squamous cell carcinoma of the upper gingiva and no progression for more than 7 years. Docetaxel, cisplatin and fluorouracil (TPF) therapy (6,7) was performed as induction chemotherapy and it was planned to subsequently conduct chemoradiotherapy or surgery. As the tumor only exhibited a transient response to TPF, surgery was selected. Postoperatively, only radiotherapy was performed and a favorable outcome was achieved.\n\nCase report\nA 56-year-old Japanese woman visited the outpatient clinic of the Department of Oral Surgery at Tokai University Hospital in 2009. She had a gingival ulcer near the right maxillary second molar. This molar had been extracted at another clinic 2 months previously, but healing of the socket was poor. A mobile lymph node measuring 1.5 cm was palpable in the right cervical region (Fig. 1). Her medical history included fatty liver with hepatic impairment and her performance status (ECOG) was Grade 0. A panoramic X-ray revealed bone destruction with an uneven margin of the right maxillary molar socket. Contrast CT scans showed a tumor with heterogeneous enhancement that spread from the right maxillary region through the maxillary sinus, and bone destruction with an uneven margin was observed. Enlarged lymph nodes with rim enhancement were seen in the right submandibular, superior internal jugular vein, and LRPLN regions (Fig. 2). PET/CT also demonstrated abnormal accumulation at the same sites. The SUVmax of the primary tumor was 17.2. Biopsy revealed squamous cell carcinoma and the diagnosis was upper gingival carcinoma T4aN2bM0: Stage IV A (Fig. 3).\n\nLaboratory tests gave the following results: WBC 8.6×103/µl (Seg+Stab 73.5%, lymphocytes 20.4%, monocytes 5.1%, eosinophils 0.8%, basophils 0.2%), RBC 3.93×106/µl, Hb 12.7 g/dl, Ht 37.3%, Plt 32.3×104/µl, AST 34 U/l, ALT 40 U/l, LDH 202 U/l, ALP 244 U/l, γ-GTP 62 U/l, BUN 13 mg/dl, Cre 0.6 mg/dl, TP 8.1 g/dl, Glu 103 mg/dl, TG 84 mg/dl, T-CHO 193 mg/dl, Na 141 mEq/l, K 4.1 mEq/l, Cl 107 mEq/l, and T-bil 0.4 mg/dl. Mild hepatic impairment was observed.\n\nThree courses of the induction chemotherapy were conducted with docetaxel (Taxotere, Sanofi-Aventis), cisplatin (CDDP), and fluorouracil (TPF) therapy (docetaxel at 60 mg/m2, CDDP at 60 mg/m2, and fluorouracil at 600 mg/m2) (6,7). At the end of the first course, CT demonstrated reduction in the size of the primary lesion and lymph nodes. However, repeat CT after 3 courses showed re-enlargement of metastatic lymph nodes, although the primary tumor was unchanged. There was only one adverse event of Grade 3 or higher during chemotherapy, which was leukopenia.\n\nThus, the primary tumor and LRPLN responded to the first course, but regrowth of the LRPLN was observed after 3 courses (Fig. 4). Similarly, the right submandibular lymph node initially decreased in size, but then showed regrowth. Therefore, she was judged to have progressive disease and it was decided to perform surgery. After induction of general anesthesia, surgery was started with tracheotomy followed by bilateral modified radical neck dissection. A midline lower lip incision was made and the mandibular swing approach was employed. The right maxilla was resected. From the dorsal region of the submandibular gland, fatty tissue was removed from the parapharyngeal space and it was explored in the cranial direction until the base of the skull was observed. The fascia of the superior constrictor muscle was detached. The internal carotid artery and vagus nerve were exposed, and were pulled aside using vascular tapes. Then the internal carotid artery, vagus nerve, and sympathetic nerves were dissected up to the base of the skull and fatty tissue was removed from the prevertebral fascia to complete dissection of the retropharyngeal space (Figs. 5 and 6). Postoperatively, only radiotherapy was administered (60 Gy). At 7 years after surgery, there has been no sign of relapse or metastasis. The patient has no difficulty with eating, swallowing, or speaking, and she returned to work postoperatively.\n\nHistopathological examination of resected specimens from the primary lesion indicated that the sites where tumor cells presumably had been present were replaced by fibrous tissue showing mild edema. Inflammatory cells (mainly lymphocytes) were observed at these sites, but no tumor cells were seen. Some LRPLN sections showed fibrosis and cyst formation within the structure of the lymph node, but proliferation of cancer cells was also observed and part of the capsule was involved. Tumor cells with enlarged, densely stained nuclei were observed, suggesting changes induced by chemotherapy (Fig. 7).\n\nThe present study was approved by the Institutional Review Board for Clinical Research of Tokai University (Kanagawa, Japan). Written informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nDiscussion\nThe LRPLN is located between the internal carotid artery and the prevertebral muscles. The LRPLN is most often seen anterior to the arch of C1, but is sometimes found at the level of the soft palate. The uppermost part of the LRPLN anterior to the atlas is known as the lymph node of Rouvière (1). The incidence of LRPLN metastasis is reported to be 29.1–88.6% in patients with nasopharyngeal cancer, 16–50% in those with oropharyngeal cancer, and 6–20% in those with hypopharyngeal cancer (1). The incidence is reported to be 0.6–1.4% in patients with OSCC (3,5), while it is 6.9–16% in patients with maxillary cancer and upper gingival cancer (4,8). Thus, compared with oral cancer at other sites, the incidence of LRPLN metastasis is high among patients with upper gingival cancer. At our institution, LRPLN metastasis was detected in 3 out of 57 patients with upper gingival cancer (5.2%) between 2003 and 2013. Umeda et al (4) discussed the route of LRPLN metastasis in patients with upper gingival cancer and they concluded that, similar to oral cancer at other sites, it occurs via the submandibular nodes and superior internal jugular nodes in upper gingival cancer (4). Lymph channels inside the maxilla also enter both of these lymph nodes. Furthermore, there may be a route unique to maxillary cancer that reaches the LRPLN from tumors adjacent to the anterior and posterior teeth, although it is more developed for the posterior teeth, which means that tumors growing posteriorly tend to metastasize to the LRPLN. Moreover, metastasis to the superior internal jugular lymph nodes could subsequently result in retrograde metastasis to the LRPLN. Therefore, it is considered that LRPLN metastasis from upper gingival cancer may be different to metastasis from other oral cancers.\n\nIn many reports about LRPLN metastasis from upper gingival cancer (2–5), it is stated that metastasis to this node occurred following resection of the primary tumor or secondary lymph node metastases and it is common for there to be multiple metastases to other lymph nodes (9). Accordingly, it seems that retrograde metastasis may often occur in patients with secondary lymph node metastasis.\n\nFor treatment of LRPLN metastasis, surgery is often considered in patients with hypopharyngeal cancer (10,11). Elective neck dissection and adjuvant radiotherapy are recommended. LRPLN metastasis tends to progress rapidly to involve the carotid sheath. Accordingly, the prognosis is usually quite poor when LRPLN metastasis is detected (2–4). Because there are not so many patients with oral cancer, including upper gingival cancer, evaluation of treatment outcomes has rarely been conducted.\n\nWhen a patient first presents with a tumor and LRPLN metastasis, curative treatment is attempted with chemoradiotherapy (CRT), radiotherapy alone, neo-adjuvant chemotherapy + surgery, or CRT + surgery + adjuvant CRT (5). Alternatively, chemotherapy is given alone as palliative therapy. Patients with secondary metastasis are often treated by radiotherapy alone or chemotherapy alone (5). LRPLN metastasis can only be detected by CT or MRI and many tumors are already non-resectable when detected, which means that radiotherapy or chemotherapy must be chosen.\n\nOn the other hand, there is a small group of patients in whom surgery is effective (3,4). Upper gingival cancer that grows posteriorly with metastasis in the deep cervical area is considered a high-risk tumor for LRPLN metastasis. Dissection of the parapharyngeal space and retropharyngeal space should be conducted and resection of the entire lesion together with the primary tumor should be considered (4,12). There have been no reports of a favorable outcome with current standard therapy or CRT according to the National Comprehensive Cancer Network (NCCN) strategy, in which surgery is followed by high-dose CDDP (100 mg/m2 on days 1, 22, and 43) (13). When LRPLN metastasis occurs, it may be debatable whether resection with a sufficient margin is feasible.\n\nIn the present case, induction chemotherapy was provided and it was planned to subsequently conduct CRT or surgery (cetuximab was not available in Japan in 2009). However, surgery was selected as the tumor only transiently responded to TPF therapy. Since TPF therapy had been conducted prior to surgery, postoperative radiotherapy was performed alone to improve tolerability and a favorable outcome was achieved. It is debatable whether our patient should be judged as resectable or non-resectable. Induction chemotherapy was reported to be ineffective for resectable OSCC (14,15). Standard therapy for non-resectable OSCC is CRT with high-dose CDDP (13), while induction chemotherapy with TPF therapy is also regarded as standard therapy in Europe (16). Among the regimens for induction chemotherapy, TPF therapy is considered to be the standard (17). On the other hand, a prospective Phase III study and a meta-analysis both failed to show an additive effect of induction chemotherapy (18–20), so re-appraisal of TPF therapy may be needed.\n\nIn conclusion, further discussion about whether treatment of LRPLN metastasis was appropriate in the present case seems to be warranted. Since LRPLN metastasis is rare among patients with oral cancer, a multicenter study will be needed to accumulate more cases.\n\nFigure 1. Oral findings at the initial examination: There is an ulcer adjacent to the right upper molar region.\n\nFigure 2. (A) Contrast CT (initial scan): The posterior part of the right maxilla is destroyed by tumor. The right LRPLN is enlarged and shows rim enhancement. (B) PET-CT finding: There is abnormal accumulation in the posterior part of the right maxilla and in the right LRPLN. (C) Contrast CT (initial scan): Metastasis to the right submandibular lymph nodes is observed. LRPLN, lateral retropharyngeal lymph node.\n\nFigure 3. Biopsy specimen (H&E staining). Well-differentiated squamous cell carcinoma. Magnification, ×100. H&E, haematoxylin and eosin.\n\nFigure 4. Contrast CT (before and after chemotherapy). (A) At the initial examination, (B) after 1 course of chemotherapy, there was a reduction in tumor size and (C) After 3 courses of chemotherapy, there was tumor regrowth.\n\nFigure 5. Surgical findings. (A) Intraoperative photograph (skin resection line). Partial resection of the right maxilla, bilateral modified radical neck dissection, right LRPLN dissection and reconstruction with a free skin flap were conducted. (B) Intraoperative photograph (right neck). The carotid sheath (common carotid artery and vagus nerve) (arrow A) and sympathetic nerves (arrow B) are demonstrated. (C) Intraoperative photograph (right neck). LRPLN metastasis is seen (at the forceps tip). LRPLN, lateral retropharyngeal lymph node.\n\nFigure 6. Resected specimens. (A) Resected maxillary tissue. (B) Dissected neck tissue.\n\nFigure 7. Histopathological findings (H&E staining). (A) A section of the primary tumor (magnification, ×40) shows fibrosis between bone tissues where the tumor may have been present. (B) Primary tumor (magnification, ×200). Inflammatory cells (mainly lymphocytes) were observed at these sites, but no tumor cells were seen. (C) LRPLN (magnification, ×40). Although fibrosis and cysts are present within the lymph node, proliferation of cancer cells is also observed. Part of the capsule is involved by the tumor. (D) LRPLN (magnification, ×400). Tumor cells with enlarged, densely stained nuclei were observed, suggesting changes induced by chemotherapy (arrow). H&E, haematoxylin and eosin; LRPLN, lateral retropharyngeal lymph node.\n==== Refs\nReferences\n1 Coskun HH Ferlito A Medina JE Robbins KT Rodrigo JP Strojan P Suárez C Takes RP Woolgar JA Shaha AR Retropharyngeal lymph node metastases in head and neck malignancies Head Neck 33 1520 1529 2011 10.1002/hed.21526 20737485 \n2 Kimura Y Hanazawa T Sano T Okano T Lateral retropharyngeal node metastasis from carcinoma of the upper gingiva and maxillary sinus AJNR Am J Neuroradiol 19 1221 1224 1998 9726457 \n3 Nishida M Yasuda S Murakami K Yamamura I Nagata Y Iizuka T Retropharyngeal lymph node metastases from oral cancer: A report of 2 patients J Oral Maxillofac Surg 63 410 412 2005 10.1016/j.joms.2004.04.035 15742298 \n4 Umeda M Shigeta T Takahashi H Kataoka T Oguni A Minamikawa T Shibuya Y Yokoo S Komori T Metastasis to the lateral retropharyngeal lymph node from squamous cell carcinoma of the oral cavity: Report of three cases Int J Oral Maxillofac Surg 38 1004 1008 2009 10.1016/j.ijom.2009.04.015 19467843 \n5 Tseng JR Ho TY Lin CY Lee LY Wang HM Liao CT Yen TC Clinical outcomes of patients with oral cavity squamous cell carcinoma and retropharyngeal lymph node metastasis identified by FDG PET/CT PLoS One 8 e79766 2013 10.1371/journal.pone.0079766 24244559 \n6 Vermorken JB Remenar E van Herpen C Gorlia T Mesia R Degardin M Stewart JS Jelic S Betka J Preiss JH Cisplatin, fluorouracil and docetaxel in unresectable head and neck cancer N Engl J Med 357 1695 1704 2007 10.1056/NEJMoa071028 17960012 \n7 Posner MR Hershock DM Blajman CR Mickiewicz E Winquist E Gorbounova V Tjulandin S Shin DM Cullen K Ervin TJ Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer N Engl J Med 357 1705 1715 2007 10.1056/NEJMoa070956 17960013 \n8 Watarai J Seino Y Kobayashi M Shindo M Kato T CT of retropharyngeal lymph node metastasis from maxillary carcinoma Acta Radiol 34 492 495 1993 10.3109/02841859309175391 8396404 \n9 Tauzin M Rabalais A Hagan JL Wood CG Ferris RL Walvekar RR PET-CT staging of the neck in cancers of the oropharynx: Patterns of regional and retropharyngeal nodal metastasis World J Surg Oncol 8 70 2010 10.1186/1477-7819-8-70 20712875 \n10 Amatsu M Mohri M Kinishi M Significance of retropharyngeal node dissection at radical surgery for carcinoma of the hypopharynx and cervical esophagus Laryngoscope 111 1099 1103 2001 10.1097/00005537-200106000-00031 11404628 \n11 Kamiyama R Saikawa M Kishimoto S Significance of retropharyngeal lymph node dissection in hypopharyngeal cancer Jpn J Clin Oncol 39 632 637 2009 10.1093/jjco/hyp080 19674993 \n12 Umeda M Minamikawa T Komatsubara H Ojima Y Shibuya Y Yokoo S Komori T En bloc resection of the primary tumour and cervical lymph nodes through the parapharyngeal space in patients with squamous cell carcinoma of the maxilla: A preliminary study Br J Oral Maxillofac Surg 43 17 22 2005 10.1016/j.bjoms.2004.10.003 15620769 \n13 Pfister DG Spencer S Brizel DM Burtness B Busse PM Caudell JJ Cmelak AJ Colevas AD Dunphy F Eisele DW Head and neck cancers, Version 2.2014. Clinical practice guidelines in oncology J Natl Compr Canc Netw 12 1454 1487 2014 10.6004/jnccn.2014.0142 25313184 \n14 Marta GN Riera R Bossi P Zhong LP Licitra L Macedo CR de Castro Junior G Carvalho AL William WN Jr Kowalski LP Induction chemotherapy prior to surgery with or without postoperative radiotherapy for oral cavity cancer patients: Systematic review and meta-analysis Eur J Cancer 51 2596 2603 2015 10.1016/j.ejca.2015.08.007 26318725 \n15 Lau A Li KY Yang WF Su YX Induction chemotherapy for squamous cell carcinomas of the oral cavity: A cumulative meta-analysis Oral Oncol 61 104 114 2016 10.1016/j.oraloncology.2016.08.022 27688112 \n16 Grégoire V Lefebvre JL Licitra L Felip E EHNS-ESMO-ESTRO Guidelines Working Group: Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 21 Suppl 5 v184 v186 2010 10.1093/annonc/mdq185 20555077 \n17 Teo M Karakaya E Young CA Dyker KE Coyle C Sen M Prestwich RJ The efficacy of induction chemotherapy with docetaxel, cisplatin and 5-fluorouracil combined with cisplatin concurrent chemoradiotherapy for locally advanced head and neck squamous cell carcinoma: A matched pair analysis Clin Oncol (R Coll Radiol) 25 647 653 2013 10.1016/j.clon.2013.07.007 23948462 \n18 Zhang L Jiang N Shi Y Li S Wang P Zhao Y Induction chemotherapy with concurrent chemoradiotherapy versus concurrent chemoradiotherapy for locally advanced squamous cell carcinoma of head and neck: A meta-analysis Sci Rep 5 10798 2015 10.1038/srep10798 26041604 \n19 Hitt R Grau JJ López-Pousa A Berrocal A García-Girón C Irigoyen A Sastre J Martínez-Trufero J Brandariz Castelo JA Verger E A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer Ann Oncol 25 216 225 2014 10.1093/annonc/mdt461 24256848 \n20 Budach W Bölke E Kammers K Gerber PA Orth K Gripp S Matuschek C Induction chemotherapy followed by concurrent radio-chemotherapy versus concurrent radio-chemotherapy alone as treatment of locally advanced squamous cell carcinoma of the head and neck (HNSCC): A meta-analysis of randomized trials Radiother Oncol 118 238 243 2016 10.1016/j.radonc.2015.10.014 26589131\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2049-9450",
"issue": "8(1)",
"journal": "Molecular and clinical oncology",
"keywords": "induction chemotherapy; lateral retropharyngeal lymph node; metastasis; oral cancer",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "68-72",
"pmc": null,
"pmid": "29399347",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": "26318725;8396404;24244559;25313184;20737485;26041604;20555077;17960012;17960013;23948462;27688112;24256848;11404628;9726457;15742298;20712875;15620769;19674993;26589131;19467843",
"title": "Lateral retropharyngeal lymph node metastasis from squamous cell carcinoma of the upper gingiva: A case report.",
"title_normalized": "lateral retropharyngeal lymph node metastasis from squamous cell carcinoma of the upper gingiva a case report"
} | [
{
"companynumb": "JP-ACCORD-063662",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "BACKGROUND\nRituximab is widely used as the first-line treatment for pemphigus patients. Since it depletes the B cells, it increases the risk of infections. Here, we evaluated the prophylactic efficacy of cotrimoxazole in decreasing the risk of Pneumocystis pneumonia (PCP) infection in the pemphigus patients treated with rituximab.\n\n\nMETHODS\nThe medical records of confirmed pemphigus patients receiving rituximab were evaluated in two groups; those who received cotrimoxazole as a prophylactic after rituximab and patients who only received rituximab without any prophylaxis. The occurrence of PCP infection was determined in each group and compared.\n\n\nRESULTS\nMedical records of 494 patients, including 301 women and 193 men, with the mean age of 46.74 years were analyzed. The phenotypes of the disease were mucocutaneous (n=364), mucosal (n=88) and cutaneous (n=42). Among them, 235 cases had received cotrimoxazole as a prophylaxis and 259 patients did not. The incidence of PCP in total patients was 2 (0.4%), 1 in each group. Accordingly, no significant difference was observed in the incidence of PCP between two groups (P=0.84). Also, no cotrimoxazole-related side effect was observed in the treated group.\n\n\nCONCLUSIONS\nIt seems that due to the low incidence of PCP in pemphigus patients treated with rituximab, prophylactic cotrimoxazole therapy is not necessary and it only increases the overall therapy cost and might cause cotrimoxazole-related adverse effects in some patients. However, regarding its probable beneficial effect in patients with long-term history of immunosuppressive therapy, more studies are required. This article is protected by copyright. All rights reserved.",
"affiliations": "Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.;Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran.",
"authors": "Faraji|Hannaneh|H|;Daneshpazhooh|Maryam|M|https://orcid.org/0000-0003-1020-8895;Ehsani|Amir Hooshang|AH|;Mahmoudi|Hamidreza|H|https://orcid.org/0000-0002-1890-1005;Tavakolpour|Soheil|S|https://orcid.org/0000-0002-6765-8830;Aryanian|Zeinab|Z|;Aslani|Saeed|S|;Khodaveisi|Hamidreza|H|;Balighi|Kamran|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/dth.15257",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1396-0296",
"issue": null,
"journal": "Dermatologic therapy",
"keywords": "Cotrimoxazole; Pemphigus; Pneumocystis pneumonia; Rituximab; side effects",
"medline_ta": "Dermatol Ther",
"mesh_terms": null,
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "e15257",
"pmc": null,
"pmid": "34890103",
"pubdate": "2021-12-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluating the risk-to-benefit ratio of using cotrimoxazole as a Pneumocystis pneumonia preventative intervention among pemphigus patients treated with rituximab: a retrospective study with 494 patients.",
"title_normalized": "evaluating the risk to benefit ratio of using cotrimoxazole as a pneumocystis pneumonia preventative intervention among pemphigus patients treated with rituximab a retrospective study with 494 patients"
} | [
{
"companynumb": "IR-LUPIN PHARMACEUTICALS INC.-2022-04338",
"fulfillexpeditecriteria": "2",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
... |
{
"abstract": "We have reported a case of a drug-drug interaction (DDI) involving warfarin and Δ-9-tetrahydrocannabinol (THC) that resulted in a supratherapeutic international normalized ratio (INR) level. The purpose of this case report is to highlight the possibility of a pharmacokinetic DDI between THC and warfarin.\n\n\n\nA 67-year-old Caucasian man suffering from chronic pain presented to a dispensary in Buffalo, NY, for a refill of his medical cannabis (MC). The patient asked to speak with the pharmacist, and during their discussion the patient stated that he had a supratherapeutic INR level of 5.2 measured at home with a self-test device. The patient had no evidence of bleeding, and administration of warfarin was held for 2 days before the INR level returned to a normal range. The supratherapeutic level occurred when the patient was self-titrating his dose of THC and scored an 8, or \"probable,\" on the Naranjo Adverse Drug Effect Probability Scale.\n\n\n\nWarfarin and cannabinoids such as THC are both metabolized by cytochrome P450 (CYP) isozymes present in the liver and gastrointestinal tract. In the case described, a dose increase of 7.35 mg THC preceded an INR elevation of 5.2, but did not result in any bleeding. These observations are suggestive of a DDI involving warfarin and THC. Clinicians involved with MC should have adequate knowledge of the drugs that act as substrates, inhibitors, and inducers of CYP enzymes, including the major cannabinoids.",
"affiliations": null,
"authors": "Brown|Geoffrey W|GW|;Bellnier|Terrance J|TJ|;Janda|Maria|M|;Miskowitz|Kyle|K|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin; D013759:Dronabinol",
"country": "United States",
"delete": false,
"doi": "10.1016/j.japh.2020.07.028",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1086-5802",
"issue": "61(1)",
"journal": "Journal of the American Pharmacists Association : JAPhA",
"keywords": null,
"medline_ta": "J Am Pharm Assoc (2003)",
"mesh_terms": "D000925:Anticoagulants; D013759:Dronabinol; D004347:Drug Interactions; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D014859:Warfarin",
"nlm_unique_id": "101176252",
"other_id": null,
"pages": "e57-e60",
"pmc": null,
"pmid": "32828704",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Δ-9-tetrahydrocannabinol dose increase leads to warfarin drug interaction and elevated INR.",
"title_normalized": "9 tetrahydrocannabinol dose increase leads to warfarin drug interaction and elevated inr"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-072853",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "The proof-of-concept of uterus transplantation, as a treatment for absolute uterine factor infertility, came with the first live birth after uterus transplantation, which took place in Sweden in 2014. This was after a live donor procedure, with laparotomy in both donor and recipient. In our second, ongoing trial we introduced a robotic-assisted laparoscopic surgery of the donor to develop minimal invasive surgery for this procedure. Here, we report the surgery and pregnancy behind the first live birth from that trial.\n\n\n\nIn the present study, within a prospective observational study, a 62-year-old mother was the uterus donor and her 33-year-old daughter with uterine absence as part of the Mayer-Rokitansky-Küster-Hauser syndrome, was the recipient. Donor surgery was mainly done by robotic-assisted laparoscopy, involving dissections of the utero-vaginal fossa, arteries and ureters. The last part of surgery was by laparotomy. Recipient laparotomy included vascular anastomoses to the external iliac vessels. Data relating to in vitro fertilization, surgery, follow up, obstetrics and postnatal growth are presented.\n\n\n\nThree in vitro fertilization cycles prior to transplantation gave 12 cryopreserved embryos. The surgical time of the donor in the robot was 360 minutes, according to protocol. The durations for robotic surgery for dissections of the utero-vaginal fossa, arteries and ureters were 30, 160 and 84 minutes, respectively. The remainder of donor surgery was by laparotomy. Recipient surgery included preparations of the vaginal vault, three end-to-side anastomoses (one arterial, two venous) on each side to the external iliacs and fixation of the uterus. Ten months after transplantation, one blastocyst was transferred and resulted in pregnancy, which proceeded uneventfully until elective cesarean section in week 36+1 . A healthy boy (Apgar 9-10-10) was delivered. Follow up of child has been uneventful for 12 months.\n\n\n\nThis is the first report of a live birth after use of robotic-assisted laparoscopy in uterus transplantation and is thereby a proof-of-concept of use of minimal invasive surgery in this new type of transplantation.",
"affiliations": "Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Department of Transplantation, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;STOCKHOLM IVF-EUGIN, Stockholm, Sweden.;Department of Transplantation, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Department of Transplantation, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Department of Anesthesiology and Intensive Care, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;STOCKHOLM IVF-EUGIN, Stockholm, Sweden.;Department of Clinical Pathology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.",
"authors": "Brännström|Mats|M|https://orcid.org/0000-0002-6081-9101;Dahm-Kähler|Pernilla|P|https://orcid.org/0000-0003-4678-1757;Kvarnström|Niclas|N|;Akouri|Randa|R|;Rova|Karin|K|;Olausson|Michael|M|;Groth|Klaus|K|;Ekberg|Jana|J|;Enskog|Anders|A|;Sheikhi|Mona|M|;Mölne|Johan|J|;Bokström|Hans|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/aogs.13853",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-6349",
"issue": "99(9)",
"journal": "Acta obstetricia et gynecologica Scandinavica",
"keywords": "human; infertility; pregnancy; robot; robotic-assisted laparoscopy; transplantation; uterus; uterus transplantation",
"medline_ta": "Acta Obstet Gynecol Scand",
"mesh_terms": "D000328:Adult; D005260:Female; D005307:Fertilization in Vitro; D006801:Humans; D007231:Infant, Newborn; D010535:Laparoscopy; D050498:Live Birth; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D011247:Pregnancy; D011446:Prospective Studies; D065287:Robotic Surgical Procedures; D014599:Uterus",
"nlm_unique_id": "0370343",
"other_id": null,
"pages": "1222-1229",
"pmc": null,
"pmid": "32196630",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Live birth after robotic-assisted live donor uterus transplantation.",
"title_normalized": "live birth after robotic assisted live donor uterus transplantation"
} | [
{
"companynumb": "SE-MYLANLABS-2020M1048403",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE SODIUM"
},
"drugadditional": nul... |
{
"abstract": "Cryptococcus neoformans is the most frequent cause of fungal meningitis in humans. Cryptococcus affects people of all ages and has a worldwide distribution. It is the fourth most common infection in AIDS (CD4 counts <100/mm3). Cases also occur in patients with other forms of immunosuppression and in apparently immunocompetent individuals. Chronic high-dose steroid may precipitate such an immunocompromised state and thus create susceptibility to fungal infections. In our case, we describe a 14-year-old boy who was on steroids for tubercular meningitis for a period of 8 weeks after which he developed cryptococcal meningitis. Attention is drawn to the increasing number of reported cases of this disease which have been associated with steroid therapy and this possibility should be remembered when investigating patients with tubercular meningitis especially if they are being treated with steroids.",
"affiliations": "Department of Internal Medicine, Maulana Azad Medical College, New Delhi, India.;Department of Medicine, Maulana Azad Medical College, New Delhi, India.;Department of Internal Medicine, Maulana Azad Medical College, New Delhi, India.;Department of Medicine, Maulana Azad Medical College, New Delhi, India.",
"authors": "Nidhi|Anand|A|;Meena|Alpana|A|;Sreekumar|Arjun|A|;Daga|Mradul Kumar|MK|",
"chemical_list": "D000935:Antifungal Agents; D005938:Glucocorticoids; D003907:Dexamethasone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-216496",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000293:Adolescent; D000935:Antifungal Agents; D003907:Dexamethasone; D003937:Diagnosis, Differential; D004359:Drug Therapy, Combination; D005938:Glucocorticoids; D018023:HIV Seronegativity; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D016919:Meningitis, Cryptococcal; D009894:Opportunistic Infections; D014391:Tuberculosis, Miliary",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28052943",
"pubdate": "2017-01-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11447704;16100437;19182676;23081814;24872723",
"title": "Corticosteroid-induced cryptococcal meningitis in patient without HIV.",
"title_normalized": "corticosteroid induced cryptococcal meningitis in patient without hiv"
} | [
{
"companynumb": "IN-BAUSCH-BL-2017-014953",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "STREPTOMYCIN\\STREPTOMYCIN SULFATE"
},
"druga... |
{
"abstract": "BACKGROUND\nEarly surgery improves the prognosis of elderly patients with hip fractures. However, many patients take antiplatelet and anticoagulant therapies for comorbidities. This study compared perioperative outcomes and 1-year mortality rates with early surgery in elderly patients with hip fractures taking or not taking these agents preoperatively.\n\n\nMETHODS\nAmong 418 patients undergoing surgery for hip fractures at our institution from 2014 to 2016, 266 patients over 65 years who had surgery within 48 hours of admission were enrolled. We excluded patients with high-energy injuries, multiple or pathological fractures, and patients undergoing osteosynthesis for femoral neck fractures. The study population was divided into those who underwent hemiarthroplasty for neck fractures and those who underwent osteosynthesis for trochanteric fractures. We also divided the population into patients receiving chronic anticoagulation therapy (medicated group: 19 hemiarthroplasty, 70 osteosynthesis) and patients not receiving anticoagulation therapy (non-medicated group: 47 hemiarthroplasty, 130 osteosynthesis). Comorbidities, intraoperative blood loss, estimated blood loss from admission to the first and seventh day after surgery, transfusions, length of stay, complications, and 1-year mortality rates were evaluated.\n\n\nRESULTS\nDiabetes mellitus and cerebrovascular disorders were significantly more common in the medicated group for both surgery types. In the osteosynthesis group, estimated blood loss on the first day was 710 ml in the medicated group and 572 ml in the non-medicated group (P = 0.015). In the hemiarthroplasty group, corresponding values were 668 and 480 ml, respectively (P = 0.016). Estimated blood loss on the seventh day, complications, length of stay and 1-year mortality rate were not increased significantly.\n\n\nCONCLUSIONS\nThe medicated group had an increase in estimated blood loss on the first day. However, there was no significant increase in transfusions, complications and 1-year mortality rates. Early surgery for elderly patients with hip fractures is recommended, even for those taking antiplatelet and anticoagulant agents.",
"affiliations": "Department of Orthopedic Surgery and Joint Reconstructive Surgery, Toyama Municipal Hospital, Toyama, Japan. Electronic address: style8772@yahoo.co.jp.;Department of Orthopedic Surgery and Joint Reconstructive Surgery, Toyama Municipal Hospital, Toyama, Japan.;Department of Orthopedic Surgery and Joint Reconstructive Surgery, Toyama Municipal Hospital, Toyama, Japan.;Department of Orthopedic Surgery and Joint Reconstructive Surgery, Toyama Municipal Hospital, Toyama, Japan.;Department of Orthopedic Surgery and Joint Reconstructive Surgery, Toyama Municipal Hospital, Toyama, Japan.;Department of Orthopedic Surgery and Joint Reconstructive Surgery, Toyama Municipal Hospital, Toyama, Japan.",
"authors": "Ueoka|Ken|K|;Sawaguchi|Takeshi|T|;Goshima|Kenichi|K|;Shigemoto|Kenji|K|;Iwai|Shintaro|S|;Nakanishi|Akira|A|",
"chemical_list": "D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors",
"country": "Japan",
"delete": false,
"doi": "10.1016/j.jos.2018.12.027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0949-2658",
"issue": "24(5)",
"journal": "Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association",
"keywords": null,
"medline_ta": "J Orthop Sci",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D016063:Blood Loss, Surgical; D004359:Drug Therapy, Combination; D005260:Female; D006620:Hip Fractures; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors; D019106:Postoperative Hemorrhage; D011300:Preoperative Care",
"nlm_unique_id": "9604934",
"other_id": null,
"pages": "830-835",
"pmc": null,
"pmid": "30709788",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The influence of pre-operative antiplatelet and anticoagulant agents on the outcomes in elderly patients undergoing early surgery for hip fracture.",
"title_normalized": "the influence of pre operative antiplatelet and anticoagulant agents on the outcomes in elderly patients undergoing early surgery for hip fracture"
} | [
{
"companynumb": "JP-DSJP-DSJ-2019-138015",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "EDOXABAN TOSYLATE"
},
"drugadditional": null,
... |
{
"abstract": "Data from clinical studies confirm the efficacy of switching to dolutegravir (DTG) plus rilpivirine (RPV) in selected patients.\n\n\n\nThe primary objective is to report the 96-week virological suppression in our cohort, assessing the durability of this strategy in complicated situations. The secondary objective is to describe the safety and metabolic profile.\n\n\n\nAll patients who had switched to DTG plus RPV between October 1, 2014, and September 30, 2015, were analyzed using a retrospective-prospective design, approved by ethics committees. Routine metabolic, immunological, and virological data were regularly sent to the coordinating center. Viral control was classified as HIV-1 RNA ≥50 copies/mL, 1 to 49 copies/mL, or undetectable (no virus detected [NVD]).\n\n\n\nWe followed 145 patients for a median of 101 weeks. The median age was 52 years; 31.7% were women, and 9.6% non-Caucasian; 50.3% had failed at least 1 antiretroviral regimen; and 15% had ≥50 copies/mL at baseline. The reasons for switching were as follows: simplification (51.7%), toxicity (36.5%), drug-drug interactions (6.9%), persistent low-level viremia (3.0%), nonadherence (2.1%), and viral failure (1.4%). By week 96, seven patients dropped out. At week 96, none had ≥50 HIV-1 RNA copies/mL, 138 (95.2%) had <50 copies/mL, and 123 (84.8%) had NVD. The low- to high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio decreased significantly ( P = 0.04). Of the 287 baseline altered laboratory parameters, 32.7% normalized by week 96. Serum glucose and total- and LDL-cholesterol normalization were statistically significant.\n\n\n\nSwitching to DTG plus RPV improved viral suppression and LDL-C/HDL-C ratio.",
"affiliations": "1 ASST Fatebenefratelli-Sacco, Milano, Italy.;1 ASST Fatebenefratelli-Sacco, Milano, Italy.;2 Careggi' Hospital, Firenze, Italy.;3 Policlinico San Matteo' Hospital, Pavia, Italy.;4 Università Cattolica del Sacro Cuore, Roma, Italy.;5 Azienda Ospedaliero-Universitaria di Perugia, Italy.;6 Amedeo di Savoia' Hospital, Torino, Italy.;7 San Martino' Hospital, Genova, Italy.;8 University of Catania, Italy.;1 ASST Fatebenefratelli-Sacco, Milano, Italy.;1 ASST Fatebenefratelli-Sacco, Milano, Italy.;1 ASST Fatebenefratelli-Sacco, Milano, Italy.",
"authors": "Capetti|Amedeo Ferdinando|AF|0000-0003-4633-1035;Cossu|Maria Vittoria|MV|;Sterrantino|Gaetana|G|;Barbarini|Giorgio|G|;Di Giambenedetto|Simona|S|;De Socio|Giuseppe Vittorio|GV|0000-0001-8774-4843;Orofino|GianCarlo|G|;Di Biagio|Antonio|A|;Celesia|Benedetto M|BM|;Rusconi|Stefano|S|0000-0002-0375-9990;Argenteri|Barbara|B|;Rizzardini|Giuliano|G|",
"chemical_list": "D019380:Anti-HIV Agents; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012367:RNA, Viral; C562325:dolutegravir; D000068696:Rilpivirine",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028018761600",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "52(8)",
"journal": "The Annals of pharmacotherapy",
"keywords": "HIV/AIDS; adverse drug reactions; antiretrovirals; drug utilization; metabolism; pharmacoeconomics",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D057915:Drug Substitution; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012367:RNA, Viral; D000068696:Rilpivirine",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "740-746",
"pmc": null,
"pmid": "29482352",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Dolutegravir Plus Rilpivirine as a Switch Option in cART-Experienced Patients: 96-Week Data.",
"title_normalized": "dolutegravir plus rilpivirine as a switch option in cart experienced patients 96 week data"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-184217",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RILPIVIRINE"
},
"dru... |
{
"abstract": "Opioids are increasingly prescribed and frequently involved in adverse drug events (ADEs). The underlying nature of opioid-related ADEs (ORADEs) is however understudied. This hampers our understanding of risks related to opioid use during hospitalisation and when designing interventions. Therefore, we provided a description of the nature of ORADEs.\n\n\n\nA post-hoc analysis of data collected during three retrospective patient record review studies (in 2008, 2011/2012 and 2015/2016).\n\n\n\nThe three record review studies were conducted in 32 Dutch hospitals.\n\n\n\nA total of 10 917 patient records were assessed by trained nurses and physicians.\n\n\n\nPer identified ORADE, we described preventability, type of medication error, attributable factors and type of opioids involved. Moreover, the characteristics of preventable and non-preventable ORADEs were compared to identify risk factors.\n\n\n\nOut of 10 917 patient records, 357 ADEs were identified, of which 28 (8%) involved opioids. Eleven ORADEs were assessed as preventable. Of these, 10 were caused by dosing errors and 4 probably contributed to patients' death. Attributable factors identified were mainly on patient and organisational levels. Morphine and oxycodone were the most frequently involved opioids. The risk for ORADEs was higher in elderly patients.\n\n\n\nOnly 8% of ADEs identified in our sample were related to opioids. Although the frequency is low, the risk of serious consequences is high. We recommend to use our findings to increase awareness among physicians and nurses. Future interventions should focus on safe dosing of opioids when prescribing and administering, especially in elderly patients.",
"affiliations": "Public and Occupational Health, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands b.schutijser@amsterdamumc.nl.;Public and Occupational Health, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands.;Medical Informatics, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands.;Public and Occupational Health, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands.;NIVEL, Utrecht, The Netherlands.;Public and Occupational Health, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands.;Public and Occupational Health, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands.",
"authors": "Schutijser|Bernadette Clara Francisca Maria|BCFM|0000-0002-8957-4590;Jongerden|Irene|I|;Klopotowska|Joanna Ewa|JE|0000-0002-9707-5740;Moesker|Marco|M|0000-0002-3546-760X;Langelaan|Maaike|M|;Wagner|Cordula|C|;de Bruijne|Martine|M|0000-0003-1838-1158",
"chemical_list": "D000701:Analgesics, Opioid; D010098:Oxycodone",
"country": "England",
"delete": false,
"doi": "10.1136/bmjopen-2020-038037",
"fulltext": "\n==== Front\nBMJ Open\nBMJ Open\nbmjopen\nbmjopen\nBMJ Open\n2044-6055 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\nbmjopen-2020-038037\n10.1136/bmjopen-2020-038037\nPharmacology and Therapeutics\n1506\n1723\nOriginal researchNature of adverse events with opioids in hospitalised patients: a post-hoc analysis of three patient record review studies\nhttp://orcid.org/0000-0002-8957-4590Schutijser Bernadette Clara Francisca Maria 1 Jongerden Irene 1 http://orcid.org/0000-0002-9707-5740Klopotowska Joanna Ewa 2 http://orcid.org/0000-0002-3546-760XMoesker Marco 1 Langelaan Maaike 3 Wagner Cordula 13 http://orcid.org/0000-0003-1838-1158de Bruijne Martine 1 1 Public and Occupational Health, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands\n2 Medical Informatics, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands\n3 NIVEL, Utrecht, The Netherlands\nCorrespondence to Bernadette Clara Francisca Maria Schutijser; b.schutijser@amsterdamumc.nl\n2020 \n30 9 2020 \n10 9 e03803726 2 2020 13 8 2020 18 8 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/.Objective\nOpioids are increasingly prescribed and frequently involved in adverse drug events (ADEs). The underlying nature of opioid-related ADEs (ORADEs) is however understudied. This hampers our understanding of risks related to opioid use during hospitalisation and when designing interventions. Therefore, we provided a description of the nature of ORADEs.\n\nDesign\nA post-hoc analysis of data collected during three retrospective patient record review studies (in 2008, 2011/2012 and 2015/2016).\n\nSetting\nThe three record review studies were conducted in 32 Dutch hospitals.\n\nParticipants\nA total of 10 917 patient records were assessed by trained nurses and physicians.\n\nOutcome measures\nPer identified ORADE, we described preventability, type of medication error, attributable factors and type of opioids involved. Moreover, the characteristics of preventable and non-preventable ORADEs were compared to identify risk factors.\n\nResults\nOut of 10 917 patient records, 357 ADEs were identified, of which 28 (8%) involved opioids. Eleven ORADEs were assessed as preventable. Of these, 10 were caused by dosing errors and 4 probably contributed to patients’ death. Attributable factors identified were mainly on patient and organisational levels. Morphine and oxycodone were the most frequently involved opioids. The risk for ORADEs was higher in elderly patients.\n\nConclusions\nOnly 8% of ADEs identified in our sample were related to opioids. Although the frequency is low, the risk of serious consequences is high. We recommend to use our findings to increase awareness among physicians and nurses. Future interventions should focus on safe dosing of opioids when prescribing and administering, especially in elderly patients.\n\npain managementadverse eventshealth & safetyquality in health carehttp://dx.doi.org/10.13039/501100002999Ministerie van Volksgezondheid, Welzijn en SportMonitor Zorggerelateerde Schade 2015-2018special-featureunlocked\n==== Body\nStrengths and limitations of this study\nThis study was based on data gathered during three national retrospective patient record review studies conducted in 2008, 2011/2012 and 2015/2016 within 32 Dutch hospitals.\n\nDuring all three studies, a broad and randomly selected sample of all hospital admissions of patients were reviewed to assess the nature and preventability of adverse drug events with opioids.\n\nOur study population was stratified, resulting in an over-representation of in-hospital deceased patients.\n\nThe low frequency of opioid-related adverse drug events limited a comparison of events over time among the three study periods.\n\nIntroduction\nOver the past decades, prescription of opioids has substantially increased worldwide.1 2 Moreover, the rise in addiction rates and deaths resulting from opioid overdoses has urged physicians to call out an opioid crisis.3 In the Netherlands, the prescription of oxycodone has increased almost fivefold over 10 years (from 96 000 users in 2008 to 485 000 users in 2018).4 This increase may however not only lead to more addiction but may also affect the number of opioid-related adverse drug events (ADEs) in hospitals.\n\nOpioids are frequently involved in ADEs5–7 and approximately in 2%–14% of all patients.8–12 ADEs are unintended injuries from a medical intervention related to drugs.13 Opioid-related ADEs (ORADEs) occur frequently, specifically in paediatric,7 14 palliative15 and surgical patients.10 11 16 ORADEs are often caused by errors such as omissions or incorrect dosing.7 14 15 17 In addition, approximately 11% of ORADEs among hospitalised patients cause severe or even fatal patient harm,18 and also due to the fast therapeutic effects of opioids. Besides these severe consequences, ORADEs lead to significantly higher healthcare costs.9 10 16\n\nOur current knowledge about the incidence of ORADEs and their underlying nature is mostly based on medication-related incident reports.7 14 15 17 However, a comprehensive patient chart review provides the most reliable information on ADEs in hospitals, while incident reports suffer from severe under-reporting.19 20 Furthermore, ORADE studies based on incident reports were usually conducted at one point in time or within one hospital or at a specific department.7 14 15 17 The few ORADE studies based on comprehensive patient chart review were mainly conducted within a surgical population.10 11 16\n\nTherefore, and also motivated by the opioid crisis, we have conducted an indepth analysis of ORADEs using data gathered during three consecutive national adverse event (AE) studies in the Netherlands in which patient record review was applied. To our knowledge, no such longitudinal multicentre study on ORADEs in a diverse inpatient population and using a comprehensive ADE detection method has been published. The aim of this study was to provide a detailed description of the underlying nature of ORADEs. By doing so, we hope to increase awareness and provide recommendations on how to prevent ORADEs in future hospitalised patients.\n\nMethods\nDesign and setting\nWe conducted a post-hoc analysis of data that were collected during three national retrospective patient record review studies conducted in 2008, 2011/2012 and 2015/2016. The aim of these studies was to identify AEs and ADEs in Dutch hospitals. A detailed description of the methodology used in these studies was previously published and comparable with other international AE studies.21 22 In summary, for the 2008 and 2011/2012 studies, a random sample of 20 hospitals participated. In 2015/2016, a new random sample of 19 hospitals were selected, of which 7 had previously participated in two of the earlier studies. Both samples were stratified for hospital type and representation of urban and rural areas. In 2008 and 2011/2012, 200 patient records per hospital were randomly selected for review: 100 records of discharged patients and 100 records of in-hospital deceased patients. The 2015/2016 study was limited to 150 in-hospital deceased patients per hospital because the frequency of preventable AEs remained unchanged for in-hospital deceased patients in both the 2008 and the 2011/2012 measurements.23–25 Records of patients younger than 1 year and of patients admitted at the departments of psychiatry and obstetrics were excluded because other expertise is necessary to detect AEs in these patients. The random selection of patient records was conducted by the participating hospitals with clear instructions of the researchers.\n\nReview procedure: AE studies\nDuring all three AE studies, selected patient records were reviewed for the occurrence of AEs, including ADEs. In figure 1, a schematic overview of the review process in the national studies and this study is presented. In summary, the review process consisted of two phases. In phase 1, the records were screened for potential AEs by trained independent nurses. When predefined triggers were found, indicating an AE might have occurred, the record was labelled for an indepth review by a trained independent physician. Independent means that the physicians and nurses never had an employment contract in the participating hospitals. The physicians were highly experienced and specialised in surgery, internal medicine or neurology, and during the record review studies they had access to all information on the electronic patient records. Besides, 10% of all patient records were reviewed by two physicians to determine inter-rater reliability. Validity of this scoring system has not been tested, but it has been used widely in AE studies for over 20 years and the ratings of the system did not change in that time.21–23 26–29 Prior to the study, both nurses and physicians had training sessions in which cases were discussed to enhance the quality and standardisation of the review process.\n\nFigure 1 Overview of the three Dutch adverse event studies and our study. ADE, adverse drug event; AE, adverse event.\n\nAn AE was defined by three criteria: (1) an unintended physical or mental injury; (2) the injury resulted in prolongation of hospital stay, temporary or permanent disability, or death; and (3) the injury was caused by healthcare management rather than the patient’s underlying disease.23 27 28 An AE was scored as caused by the healthcare (causality) if the likelihood score was equal to or greater than 4 based on a 6-point Likert scale, with (virtually) no evidence (1), slight to modest evidence (2), not likely but borderline (3), more likely but borderline (4), moderate to strong evidence (5), or (virtually) certain evidence (6) of management causation. The scoring system was used in all three record review studies and the physicians made the judgements about causality and preventability based on all the available information of the patient’s condition and taking into account the guidelines.\n\nIf an AE was identified, the independent physicians (hereafter: experts) assessed each AE on cause (diagnostic, surgery, non-invasive procedure, medication, other clinical activities, admission and other), preventability, possible contribution to death and attributable factors. The attributable factors were based on the taxonomy of the Eindhoven Classification Model and consisted of the main categories: technical, care, organisational, patient-related, violation and other.30 An AE was considered to be preventable when the care given fell below the current level of expected performance of practitioners or systems. Before the physicians answered the question about preventability, they were required to respond to 13 questions to add more structure to the review process (see online supplemental table 1), for example, if there was a complex medical history, if the patient had comorbidity and whether another physician would repeat this treatment. Preventability was also assessed on a 6-point Likert scale, with almost no evidence (1), slight to modest evidence (2), modest evidence but borderline (3), modest to strong evidence (4), strong evidence (5), or almost certain evidence (6) of preventability. A score of 4–6 indicated that the reviewer assessed the AE as having a greater than 50% chance of being potentially preventable.\n\n10.1136/bmjopen-2020-038037.supp1Supplementary data \n\n Furthermore, for each patient the following characteristics were registered: gender, age, length of hospital stay, urgency of admission, whether patients were terminally ill prior to the admission, the number of involved medical specialists, department of admission, type of procedure and comorbidity. The latter was divided into no, minor, moderate and severe comorbidity, and was assessed by the experts after careful review of the information on the patient record. Also, one organisational characteristic (type of hospital: university, tertiary teaching or general) and one AE characteristic (weekend or holiday at the time of the AE) were registered.\n\nWhen an AE was medication-related (ADE), the following additional characteristics were registered by the experts: name and type of medication involved, medication phase, a description of the ADE and whether the ADE possibly contributed to the patient’s death. The medication phases were classified into ordering, transcribing, dispensing, administering and monitoring.31 32 The possible contribution to the patient’s death was only registered for ORADEs, with ‘medication’ as a main cause of the event and not for ADEs with ‘medication’ as a subcause.\n\nAll data were entered into a national AE database specifically designed for these AE studies.\n\nReview procedure: ORADEs\nFor our study, we used the national AE database to identify ORADEs (figure 1). One researcher (BCFMS) conducted the screening of the database and retrieved several preselected variables: (1) AEs with the main classification cause ‘medication’ as well as AEs with ‘medication’ as a subcause; and (2) AEs with ‘analgesics’ as involved medication. Furthermore, two free-text fields were selected: the summary of the AEs and the preventability assessment. A second researcher (MM) independently double-checked the selection procedure.\n\nAll identified ORADEs were then classified by BCFMS on the type of opioids involved using the WHO Anatomical Therapeutic Chemical (WHO ATC) classification.33 For the preventable ORADEs, the type of medication error was classified according to a data-driven analysis of the free-text summaries of the ADEs. The classification of ORADEs was double-checked by two senior researchers (JEK and IJ) and any discrepancies were resolved by consensus.\n\nOutcomes\nTo provide insight into the nature of the ORADEs, each ORADE case was summarised by gender, age of the patient (categorised in steps of 10 years for privacy reasons), type of opioid involved, attributable factors and preventability. When the ORADE was preventable, then the type of medication error and medication phase were also described. Furthermore, in order to identify risk factors, we compared the outcome variables between preventable and non-preventable ORADEs.\n\nData analysis\nOnly descriptive statistics were used in this study. Descriptives are presented as median (age and length of hospital stay) or frequency (gender, comorbidity, type of opioids and attributable factors and so on). Patient and hospital characteristics are presented on the patient level and ORADE characteristics are presented on the AE level. Inter-rater reliability among nurses and physicians was addressed in terms of positive and negative agreement frequencies.34 All analyses were conducted using STATA V.14.1 and double-checked by a second researcher (MM) and a statistician (PS).\n\nPatient and public involvement\nPatients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.\n\nResults\nIn total, 10 917 records were screened during the three AE studies. The patient records of discharged and deceased patients were equally distributed among male and female patients. Most patients were hospitalised for a non-elective procedure (table 1). In 1150 patient records, at least one AE was detected, with a total of 1240 AEs. When detecting the predefined triggers, positive agreement between nurses varied between 76.0% and 91.5%. When detecting AEs, positive agreement between physicians varied between 53.4% and 63.3%. For assessing preventability, positive agreement between physicians varied between 71.4% and 73.3%. Overall, agreement frequencies were moderate. More detailed information about the inter-rater reliability is presented in online supplemental table 2.\n\n10.1136/bmjopen-2020-038037.supp2Supplementary data \n\n Table 1 Patient and hospital characteristics of all reviewed patient records, including adverse events per study period and discharge status\n\n\tStudy period and discharge status\t\n2008\t2011/2012\t2015/2016\t\nDischarged\tDeceased\tDischarged\tDeceased\tDeceased\t\nHospital characteristics*\t\n Patient records, n\t2016\t2007\t2023\t2025\t2846\t\n General hospital records, n (%)\t1013 (50)\t1015 (51)\t794 (39)\t813 (40)\t1197 (42)\t\n Tertiary teaching hospital records, n (%)\t608 (30)\t593 (30)\t822 (41)\t820 (40)\t1052 (37)\t\n Academic hospital records, n (%)\t395 (20)\t399 (20)\t407 (20)\t392 (19)\t597 (21)\t\nPatient characteristics*\t\n Male sex, n (%)\t999 (50)\t1067 (53)\t1027 (51)\t1062 (52)\t1524 (54)\t\n Age (years), median (IQR)\t62 (47–75)\t77 (67–84)\t63 (48–75)\t77 (68–84)\t77 (68–85)\t\n Length of stay (days), median (IQR)\t4 (2–8)\t7 (3–14)\t3 (2–7)\t6 (2–13)\t4 (1–11)\t\n Non-elective admission, n (%)\t1038 (51)\t1708 (85)\t1063 (53)\t1775 (88)\t2496 (88)\t\nAdmission department, n (%)\t\n Surgery\t481 (24)\t276 (14)\t472 (23)\t239 (12)\t340 (12)\t\n Cardiology\t290 (14)\t291 (15)\t272 (13)\t247 (12)\t360 (13)\t\n Internal medicine\t364 (18)\t599 (30)\t365 (18)\t597 (29)\t876 (31)\t\n Orthopaedics\t226 (11)\t33 (2)\t225 (11)\t26 (1)\t29 (1)\t\n Neurology\t150 (7)\t219 (11)\t133 (7)\t193 (10)\t269 (9)\t\n Lung diseases\t117 (6)\t259 (13)\t126 (6)\t300 (15)\t347 (12)\t\n Urology\t109 (5)\t18 (1)\t111 (5)\t28 (1)\t23 (1)\t\n Other\t279 (14)\t312 (16)\t319 (16)\t395 (20)\t602 (21)\t\nUnderwent invasive procedure, n (%)\t925 (46)\t423 (21)\t918 (45)\t403 (20)\t461 (16)\t\nAdverse event occurrence†‡\t\n AE, n (%)\t161 (8)\t351 (16)\t157 (8)\t259 (12)\t312 (10)\t\n ADE, n (% within population)\t37 (2)\t93 (4)\t40 (2)\t76 (4)\t111 (4)\t\n ADE, n (% within adverse event)\t37 (23)\t93 (27)\t40 (25)\t76 (29)\t111 (36)\t\n ORADE, n (% within population)\t1 (0)\t7 (0)\t2 (0)\t8 (0)\t10 (0)\t\n ORADE, n (% within ADEs)\t1 (3)\t7 (8)\t2 (5)\t8 (11)\t10 (9)\t\n*Presented on the patient record level.\n\n†Presented on the AE level.\n\n‡Total number of AEs: 1240; total number of ADEs: 357; total number of opioid-related ADEs: 28.\n\nADE, adverse drug event; AE, adverse event; ORADE, opioid-related adverse drug event.\n\nOpioid-related ADEs\nOf 1240 AEs, 357 (29%) were medication-related (ADEs). In 28 (8%) ADEs, opioids were involved. These ADEs are summarised in detail in table 2, and included 24 ADEs with ‘medication’ as a main cause and four ADEs with ‘medication’ as a subcause. The ORADEs occurred in 27 patients; one patient experienced two ORADEs. Most patients with ORADEs involved female patients (59%). The median age of the patients was 76 years (IQR: 66–83), and the median length of hospital stay was 7 days (IQR: 4–16). Most patients had moderate to significant comorbidity (70%) and had three medical specialists during the admission (78%) (table 3).\n\nTable 2 Descriptions of the 28 opioid-related adverse drug events divided into preventable and non-preventable\n\nCase\tDescription*\tPreventability score (1–6)† and type of error‡\t\nPreventable opioid-related ADEs\t\nCause: dosing errors\t\n1\tA man, 90–99 years, admitted with pain after a fall. Oxycodone for the pain was unintentionally prescribed twice instead of once and also administered twice (dose unknown). This resulted in drowsiness.\t6\n(prescribing error)\t\n2\tA man, 60–69 years, suffering from colon cancer and liver metastases, was admitted for optimising his analgesics medication. On returning from his weekend leave, he was diagnosed with oxycodone intoxication. During hospital stay, he received a too high dose of the opioid antagonist naloxone (1 mg instead of the ordered 0.4 mg), which caused confusion and agitation.\t6\n(administration error)\t\n3\tA woman, 70–79 years, admitted with a pelvic fracture after a fall. A too high dose (dose unknown) of oxycodone was prescribed and administered resulting in hypotension and drowsiness. Consequently, she needed to be transferred to the intensive care unit.\t5\n(prescribing error)\t\n4\tA woman, 80–89 years, admitted with malaise after a fall. During her admission she received a too high dose of morphine. In her patient record, the morphine was ordered as ‘as needed’ (PRN). In the medication list, the morphine was ordered ‘6 times a day’ (dose unknown). This resulted in drowsiness.\t5\n(prescribing error)\t\n5\tA woman, 70–79 years, admitted for a plastic surgery. A high dose of intravenous administered anaesthetic/pain medication (dose and medication type unknown) caused hypoventilation and a myocardial infarct. The myocardial infarct was discovered too late. She was resuscitated and ventilated. Her death was possibly caused by a hospital-acquired pneumonia.\t5\n(administration error)\t\n6\tA woman, 50–59 years, admitted due to an aspiration pneumonia, was administered morphine. The pump mode was set at 13 mL/hour instead of 8 mL/hour as ordered. This possibly resulted in an epileptic insult requiring ventilation.\t5\n(administration error)\t\n7\tA man, 60–69 years, readmitted to the hospital due to a collapse at home. He was previously hospitalised for treatment of rib fractures and COPD Gold IV. At discharge, the doses of fentanyl and oxycodone had been significantly increased to 20 mg 4–6 times a day. Monitoring the effects of increasing these opioid doses was not conducted.\t4\n(prescribing error)\t\n8\tA woman, 80–89 years, admitted with osteoporosis, received at home 5 mg morphine two times per day for her back pain. The dosage was increased to subcutaneous 5 mg four times a day during hospital stay. Three days later, a paralytic ileus was discovered. A lower morphine dose was more appropriate for this elderly woman.\t4\n(prescribing error)\t\n9\tA woman, 80–89 years, admitted with abdominal pain due to kidney bleeding. She received morphine injections daily, varying from 2 to 6 subcutaneous injections of 2.5 mg per day along with transdermal fentanyl 12 μg hourly. Severe hypercapnia eventually caused her death.\t4\n(prescribing error)\t\n10\tA boy, 0–9 years, with Down syndrome, was acutely ill due to a laryngitis. He was difficult to ventilate and received antibiotics and sedatives including opioids. He was transferred to another hospital following detubation. Here, his methadone intake was reduced resulting in a delirium (dose unknown). Initially he improved, but one day unexpectedly he was found dead. It is unclear why this patient received methadone, but reducing the methadone intake may have been the problem.\t4\n(unknown)\t\nCause: incorrect decision making\t\n11\tA woman, 60–69 years, admitted for a laminectomy. Postoperatively she developed an ileus caused by severe constipation aggravated by administered morphine. Macrogol oral suspension (dose unknown) instead of an enema was given as treatment, which was insufficient to resolve, and the ileus and colon perforation occurred. Untreatable abdominal septic complications followed.\t4\n(unknown)\t\nNon-preventable opioid-related ADEs\t\n12\tA woman, 80–89 years, admitted due to total knee replacement. Postoperatively, drowsiness, hypotension and oliguria occurred, possibly caused by the epidural medication sufentanil (dose unknown). This may have led to a small asymptomatic myocardial infarct.\t3\n(administration error)\t\n13\tA man, 80–89 years, admitted with a perforated stomach ulcer and known stomach cancer. His extreme, not previously known, sensitivity to morphine postoperatively (dose unknown) resulted in recurrent apnoea.\t3\n(other error)\t\n14\tA woman, 60–69 years, suffering from lung cancer, was admitted with severe back and limb pain related to bone metastases. She was treated with transdermal fentanyl 300 μg/hour. This resulted in drowsiness and hypoventilation.\t2\n(prescribing error)\t\n15\tA woman, 80–89 years, known with breast cancer and multiple lung metastases. She received tramadol (dose unknown) for the pain, which have been stopped due to drowsiness.\t2\n(unknown)\t\n16\tA man, 70–79 years, admitted with severe heart failure. He received morphine 2.5 mg for the pain. As a result of increased, not previously known, sensitivity to morphine, his saturation dropped.\t2\n(other error)\t\n17\tA man, 90–99 years, admitted due to stroke and a lot of pain. The nurse administered 10% of the prescribed dose (dose unknown) of morphine on two occasions, which caused unnecessary suffering.\t2\n(administration error)\t\n18\tA man, 60–69 years, admitted for surgery due to an ileus. Postoperative complications included an exacerbation of COPD and hospital-acquired pneumonia after receiving morphine (dose unknown).\t2\n(unknown)\t\n19\tA woman, 60–69 years, admitted with a reoccurrence of drowsiness, hypoventilation and difficulties with waking up, which was the result of a dose of 5 mg of methadone being administered in the hospital.\t2\n(prescribing and administration error)\t\n20\tA woman, 60–69 years, had a blood pressure drop following the administration of morphine (dose unknown) in the recovery room.\t1\n(other error)\t\n21\tA woman, 70–79 years, admitted with pain related to severe Kahler disease. For the pain, she received opioids (unknown which type and dose). The opioids caused drowsiness, and because of the drowsiness she choked once. This caused pneumonia. The patient died during hospitalisation.\t1\n(other error)\t\n22\tA man, 70–79 years, received transdermal fentanyl and oxycodone 5 mg daily up to six times due to metastases in the hip. This caused apraxia and confusion.\t1\n(unknown)\t\n23\tA woman, 80–89 years, admitted for occlusion of an artery in her leg. She received a morphine infusion (0.5–1.0 mg/hour) causing hypoventilation with a good response to naloxone.\t1\n(administration error)\t\n24\tA man, 80–89 years, admitted due to obstructive laryngeal cancer, was prescribed anticoagulants. This resulted in haematoma, along with severe abdominal pain for which he received morphine (dose unknown), after which he died.\t1\n(other error)\t\n25\tA man, 60–69 years, admitted with an acute respiratory insufficiency due to pneumonia. He received methadone 20 mg two times per day, causing hypoventilation on two occasions. This needed to be treated with naloxone.\t1\n(prescribing error)\t\n26\tA woman, 80–89 years, suffered from pain due to rib fractures caused by resuscitation. She received sufentanil (dose unknown), which led to bronchospasm.\t1\n(unknown)\t\n27\tA woman, 70–79 years, admitted with pain related to breast cancer. During the admission, it became apparent that she had metastases along with femur and vertebral fractures. A high dose of morphine (dose unknown) was necessary to relieve her pain, which consequently resulted in a delirium.\t1\n(prescribing error)\t\n28\tA woman, 80–89 years, admitted due to a hip fracture and pain. For her restlessness and pain she was administered 1 mg morphine, which probably caused a reduced level of consciousness.\t1\n(other error)\t\n*Patients were categorised in age groups of 10 years to avoid traceability.\n\n†Preventability was scored on a 6-point Likert scale: 1=(almost) no evidence of preventability; 2=small indications for preventability; 3=preventability not very likely, less than 50% but ‘close call’; 4=preventability more than likely, more than 50% but ‘close call’; 5=strong indications for preventability; 6=(almost) certain indications of preventability.\n\n‡For the judgement on preventability and type of error, the experts had access to all information on the electronic patient record and therefore to the whole context in which ADEs occurred. The types of error were prescribing error, administration error, other error (eg, side effects) or unknown.\n\nADEs, adverse drug events; COPD, chronic obstructive pulmonary disease.\n\nTable 3 Characteristics of patients (n=27) with ORADEs (n=28)*\n\nPatient characteristics\t\nPatients with an ADE, n\t27\t\nMale sex, n (%)\t11 (41)\t\nAge, median years (IQR)\t76 (66–83)\t\nLength of stay, median days (IQR)\t7 (4–16)\t\nNon-elective admission, n (%)\t19 (70)\t\nTerminally ill prior to admission, n (%)\t6 (22)\t\nTotal number of medical specialists, n (%)\t\n 1\t4 (15)\t\n 2\t2 (7)\t\n 3\t21 (78)\t\nPrimary specialisation during admission, n (%)\t\n Surgical\t7 (26)\t\n Non-surgical\t20 (74)\t\nUnderwent invasive procedure, n (%)\t9 (33)\t\nComorbidity†, n (%)\t\n No comorbidity\t0 (0)\t\n Minor comorbidity\t3 (11)\t\n Moderate comorbidity\t5 (19)\t\n Significant comorbidity\t19 (70)\t\n*Presented on the patient level.\n\n†The level of comorbidity was assessed by the experts after careful review of the information on patient records.\n\nADE, adverse drug event; ORADEs, opioid-related adverse drug events.\n\nNature of ORADEs: preventability\nAccording to the experts, 11 (39%) out of the 28 ORADEs were considered as potentially preventable (table 4). Non-preventable (31%) ORADEs occurred slightly more during weekends and holidays than preventable ADEs (18%). Moreover, most preventable and non-preventable ORADEs occurred during day shifts (08:00–17:00).\n\nTable 4 Clinical context of ORADEs (n=28)*\n\nClinical context\tNon-preventable† ADEs (n=17)\tPreventable†\nADEs (n=11)\t\nType of hospital, n (%)\t\n University, ADEs\t1 (6)\t1 (9)\t\n Tertiary teaching, ADEs\t6 (35)\t4 (36)\t\n General, ADEs\t10 (59)\t6 (55)\t\nWeekend or national holiday (yes), n (%)\t5 (31)\t2 (18)\t\nTime, n (%)\t\n 08:00–17:00\t6 (35)\t5 (45)\t\n 17:00–23:00\t3 (18)\t0 (0)\t\n 23:00–08:00\t2 (12)\t3 (27)\t\n Cannot be assessed\t6 (35)\t3 (27)\t\nType of opioids (ATC code), n (%)\t\n Opioid anaesthetics (N01AH03)\t2 (12)\t1 (9)\t\n Natural opium alkaloids (N02AA)\t9 (53)\t8 (73)\t\n Natural opium alkaloids and phenylpiperidine derivatives (N02AA/N02AB, combination)\t1 (6)\t1 (9)\t\n Phenylpiperidine derivatives (N02AB)\t2 (12)\t0 (0)\t\n Other opioids (N02AX)\t1 (6)\t0 (0)\t\n Drugs used in opioid dependence (N07BC)\t2 (12)\t1 (9)\t\nAttributable factors‡, n (%)\t\n Technical\t0 (0)\t0 (0)\t\n Care-related\t3 (19)\t8 (80)\t\n Organisational\t2 (13)\t4 (40)\t\n Patient-related\t10 (63)\t6 (60)\t\n Violation\t0 (0)\t1 (10)\t\n Cannot be assessed\t3 (19)\t1 (10)\t\n Other\t1 (6)\t0 (0)\t\n*Presented on the adverse event level.\n\n†Preventability was scored on a 6-point Likert scale: 1=(almost) no evidence of preventability; 2=small indications for preventability; 3=preventability not very likely, less than 50% but ‘close call’; 4=preventability more than likely, more than 50% but ‘close call’; 5=strong indications for preventability; 6=(almost) certain indications of preventability. Not preventable ADEs were scored at 1–3; preventable ADEs were scored at 4–6.\n\n‡These variables were missing for two patients: one in the preventable group and one in the non-preventable group. Moreover, it was possible to select more than one option for this question.\n\nADE, adverse drug event; ATC, Anatomical Therapeutic Chemical; ORADE, opioid-related adverse drug event.\n\nNature of ORADEs: medication errors and phase\nOf the 11 potentially preventable ORADEs, 10 (91%) were caused by dosing errors, of which 6 were during the prescribing phase (cases 1, 3, 7, 8, 9 and 10) and 4 during the administration phase (cases 2, 4, 5 and 6) (table 2). Of the 10 dosing errors, 6 occurred in elderly patients (≥70 years) (cases 1, 3, 4, 5, 8 and 9) and 2 around patients’ discharge (cases 2 and 7). The remaining one preventable ORADE (case 11) was related to incorrect decision making. Finally, the experts assessed the consequences of the ORADEs (multiple options possible). In eight ORADEs, an intervention or extra treatment was needed, in two ORADEs the patients had a prolonged hospital stay, and four preventable ORADEs possibly contributed to the death of the patient (cases 5, 6, 8 and 9).\n\nNature of ORADEs: attributable factors\nThe attributable factors involved in ORADEs were care-related (knowledge, skills, monitoring, verification and coordination of care) and patient-related (comorbidity, age, a demanding patient or a patient with an intellectual disability) (table 4). Of preventable ORADEs, eight were care-related and six were patient-related. For non-preventable ORADEs, 3 were care-related and 10 were patient-related. However, in three of the cases of non-preventable ORADEs, the attributable factors could not be assessed by the experts due to insufficient information on the patient records.\n\nNature of ORADEs: medications involved\nOut of the 11 preventable ADEs, 8 occurred with opioids with ATC code N02AA, which are morphine and oxycodone (table 4). Non-preventable ORADEs occurred with opioids mainly with ATC code N02AA (morphine and oxycodone, 53%).\n\nDiscussion\nIn three national patient record studies with 4-year intervals, we found 28 ADEs caused by opioids. These ADEs correspond with 8% of all identified ADEs and 0.3% of all studied patient records. Of the 28 ORADEs, 11 (39%) were assessed as potentially preventable, involving mostly morphine and oxycodone. Dosing errors during the prescription and administration phase were the most common cause of preventable ORADEs and occurred most often in elderly patients. Four preventable ORADEs probably contributed to patients’ death. Finally, attributable factors for ADEs were mostly care-related and patient-related.\n\nIn this study, the percentage of ORADEs of all patient records (0.3%) was low, also in comparison with previously conducted ORADE studies that focused on large populations (11%–14%).10 11 16 However, two of these studies were based on large databases and all involved surgical patients who often receive opioids postoperatively. We focused on a broad hospitalised patient population, both surgical and non-surgical. Furthermore, the difference in ORADE occurrence might be explained by differences in the used ADE definition. For example, instead of using all ORADEs, that is, including side effects of opioids, in our study only ADEs that resulted in severe patient harm were included. This means that ADEs resulted in prolongation of hospital stay, temporary or permanent disability, or death. Furthermore, only ADEs with a causality likelihood score of equal or greater than 4 were included, which means that the experts indicated an ADE as having a greater than 50% chance of being caused by healthcare. Should we have selected the cases with causality likelihood scores of 1–3 as well, then we could determine at least 2500 additional cases on whether medication and opioids were related. However, we did not determine these 2500 cases, since we wanted to stay true to the definition of an AE (at least 4 on the 6-point Likert scale), and we did not consider it ethical to change the method of the study afterwards.\n\nIn line with previous studies,7 14 15 17 we found that dosing errors during prescribing and administering were the main cause of preventable ORADEs. Furthermore, 60% of the dosing errors in our study occurred in elderly patients (≥70 years). In general, prescribing medication for elderly patients is challenging since polypharmacy, multimorbidity, and altered pharmacokinetics and pharmacodynamics of drugs are often present. Besides, this population will rapidly increase in the upcoming years. Specifically related to opioids, physicians also need to be aware of the higher sensitivity of elderly patients to the effects of opioids,35 and balancing between minimising the risk of addiction and side effects while effectively relieving pain.36 37 Taking into account all these factors while prescribing demands a lot from physicians during their busy daily hospital practice. A clinical decision support system (CDSS) can help physicians in this complex task by showing warnings and advice during prescribing, for example showing the most appropriate choice of medication for a given condition and/or by providing dosing recommendations. CDSS has shown to effectively reduce prescribing errors among hospitalised elderly patients38 39 and errors with medications of which the therapeutic effects are fast, such as opioids.40 Furthermore, a CDSS can also be effective in predicting which patients are at risk for ORADEs. Using retrospective data from gastrointestinal surgical patients, Minkowitz et al\n41 developed a risk-scoring model to identify patients with a high risk for experiencing an ORADE based on their clinical and demographic profiles. If developed specifically for elderly inpatients, such a prediction model could help physicians in determining the most appropriate and safe pain management strategy for these vulnerable patients. Finally, a CDSS could also be used to identify patients who might be suitable for pre-emptive genotyping, which involves metabolic testing prior to prescribing.42 Patients with high levels of pain despite using high doses of pain medication or patients who experience severe side effects while using common dosing schedules may especially benefit from such an intervention.43\n\nAdministering opioids is a task usually conducted by nurses. The dosing errors in our study were mostly related to injectable opioids. Error-prone activities, such as calculating the concentration and administration rate,14 17 require that nurses have sufficient arithmetic knowledge and follow the protocol for safe preparation and administration of injectable medication. However, in daily practice, some nurses have math anxiety, and on average arithmetic knowledge of nursing students seems moderate.44 45 Besides, nurse compliance with protocols for safe administration of injectable medication is considered low (around 20%)46 47 and needs further attention. An intervention which might help to reduce dosing errors during opioid administration is the use of smart infusion pumps. These pumps have integrated medication libraries which allow nurses to set the pump automatically to the right administration rate during administration. By doing so, the administration rate of smart pumps can be seen as a double-check of the nurses’ own calculation. Smart pumps seem also effective in reducing programming errors.48 Furthermore, educational programmes for nurses about brand and generic names and pharmacology of opioids or side effects might increase their knowledge and awareness of risks related to dosing during the administration of opioids.49–51\n\nOverall, we think the ORADE frequency of 8% of all ADEs and 0.3% of all studied patient records found in our study is low and acceptable. However, although the frequency is low, the risk of serious consequences is high. Thus, new contributions to prevent ORADEs in future hospitalised patients need to be identified. Using the Safety-2 perspective may offer new opportunities to do so.52 In order to understand what happened when an adverse (drug) event occurred, it is also necessary to understand how work is done when the process goes well.53 Since healthcare processes have become more complex nowadays, it may be helpful to visualise the current variable practice of prescribing and administering opioids from a multistakeholder perspective.54\n\nStrengths and limitations\nOpioids are in the top 10 of drug types that cause fatal medication errors.8 Hence, focusing on the detailed description of the nature of ORADEs was important and necessary. Another strength of this study is that it was based on a comprehensive ADE detection method and conducted in a broad sample of all hospital admissions. Most previous studies, which described the nature of ORADEs, are based on medication-related incident reports. Furthermore, data were gathered over an extended period of time within a randomly selected sample of one-third of all Dutch hospitals.\n\nThis study also has some limitations. First, in all three AE studies, the population consisted of relatively many older and deceased patients. Therefore, it is not possible to generalise the results to all Dutch hospital population. To make the study sample more representative for the Dutch hospital population, weighting the results (ie, correcting for type of hospital, study period and discharge status) would be a solution which has been used in previous studies of our research group. However, since the total amount of ORADEs was low, we chose not to weight our results as this had little effect and makes interpretation difficult. Second, overall agreement frequencies between physicians were moderate. This could have led to different assessments or different scores if other experts were involved. This should be taken into account when interpreting our results. However, a previous review of studies focusing on assessing AEs showed also moderate to substantial inter-rater reliability.55 For this reason, patient records in all Dutch AE studies have been assessed by the same experts as much as possible, and over the years these experts have not become stricter or lenient in their judgement of AEs and their preventability.56 Third, due to this low number of ORADEs, it was not possible to compare the events over the three study periods. Therefore, we cannot conclude whether the low number is a positive finding and if the occurrence of ORADEs increased or decreased over time. Fourth, our post-hoc analysis was based on the information previously recorded by the experts in an AE database and on the assessment conducted by these physicians. Therefore, some information could be missing, and interpreting the assessment of preventability was difficult for us in one case, resulting in a non-preventable ORADE. Furthermore, this was also the reason that the harm could not be further categorised according to the National Coordinating Council for Medication Error Reporting and Prevention (NCCMERP) Index for Categorizing Medication Errors.57 Besides, the retrospective interpretation can also be biased by temporal views. The current opinion is that prescribing opioids should be minimised due to the harm of opioids, which is supported by updated guidelines.58 This view changed throughout the years and may not have been recognised 15 years ago, when the focus was mainly on alleviating suffering of pain. This change in opinion may have increased alertness when prescribing or administering opioids, which could have led to less ORADEs. However, our study showed that ORADEs still occur and publishing about them could serve as a method of increasing awareness.\n\nConclusion\nOnly 8% of ADEs identified in our sample were related to opioids, 0.3% of all studied patient records. Although the frequency is low, the risk of serious consequences is high. We recommend to use our findings to increase awareness among physicians and nurses. Future interventions should focus on safe dosing of opioids when prescribing and administering, especially in elderly patients.\n\nSupplementary Material\nReviewer comments\n Author's manuscript\n We would like to thank all participating hospitals and independent nurses and physicians for their cooperation during the data collection on the three Dutch adverse event studies. We also thank Peter Spreeuwenberg, MSc, for double-checking the statistical analyses, and Catherine Combee-Duffy, MANP, for improving the readability of this article.\n\nContributors: BCFMS, MM, JEK, ML, MdB and CW designed the study and developed the study protocol. BCFMS and MM organised the selection and classification of ORADEs. JEK and IJ double-checked this classification. BCFMS and MM performed statistical analyses and interpreted the analytical results. BCFMS, JEK and IJ wrote the manuscript. MdB and CW supervised the study. All authors made critical revisions and approved the final version of the manuscript.\n\nFunding: This study was funded by the Dutch Ministry of Health, Welfare and Sport, with project title Monitor Zorggerelateerde Schade 2015–2018.\n\nCompeting interests: None declared.\n\nPatient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.\n\nPatient consent for publication: Not required.\n\nEthics approval: The medical ethical committee of the Amsterdam UMC, Vrije Universiteit Amsterdam waived the requirement of informed consent (protocol numbers: 2005.146, 2009.130, 2016.282) as they found the scope of the study outside the Dutch Medical Research (Human Subjects) Act.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData availability statement: No data are available. All data relevant to the study are included in the article or uploaded as supplementary information.\n==== Refs\nReferences\n1 Schepens MHJ , Leusink M , de Vries SE , et al \n[Increase in opioid prescribing in extramural care in the Netherlands: assessment of use and prescription behaviour, based on claims data]\n. Ned Tijdschr Geneeskd \n2019 ;163 :D3854.31050276 \n2 Lyden J , Binswanger IA \nThe United States opioid epidemic\n. Semin Perinatol \n2019 ;43 :123 –31\n. 10.1053/j.semperi.2019.01.001 30711195 \n3 AMA \nPhysicians’ progress to reverse the nation’s opioid epidemic: American Medical Association\n, 2018 Available: https://www.ama-assn.org/sites/default/files/media-browser/public/physicians/patient-care/opioid-task-force-progress-report.pdf [Accessed 8 Aug 2018 ].\n4 Overheid.nl. Geneesmiddelenbeleid \nDen Haag, the Netherlands: Overheid.nl\n, 2019 Available: https://zoek.officielebekendmakingen.nl/kst-29477-537.html [Accessed 19 Mar 2019 ].\n5 Laatikainen O , Miettunen J , Sneck S , et al \nThe prevalence of medication-related adverse events in inpatients-a systematic review and meta-analysis\n. Eur J Clin Pharmacol \n2017 ;73 :1539 –49\n. 10.1007/s00228-017-2330-3 28871436 \n6 Mihajlovic S , Gauthier J , MacDonald E \nPatient characteristics associated with adverse drug events in hospital: an overview of reviews\n. Can J Hosp Pharm \n2016 ;69 :294 –300\n. 10.4212/cjhp.v69i4.1583 27621489 \n7 Mc Donnell C \nOpioid medication errors in pediatric practice: four years' experience of voluntary safety reporting\n. Pain Res Manag \n2011 ;16 :93 –8\n. 10.1155/2011/739359 21499584 \n8 Saedder EA , Brock B , Nielsen LP , et al \nIdentifying high-risk medication: a systematic literature review\n. Eur J Clin Pharmacol \n2014 ;70 :637 –45\n. 10.1007/s00228-014-1668-z 24671697 \n9 Kane-Gill SL , Rubin EC , Smithburger PL , et al \nThe cost of opioid-related adverse drug events\n. J Pain Palliat Care Pharmacother \n2014 ;28 :282 –93\n. 10.3109/15360288.2014.938889 25102043 \n10 Oderda GM , Gan TJ , Johnson BH , et al \nEffect of opioid-related adverse events on outcomes in selected surgical patients\n. J Pain Palliat Care Pharmacother \n2013 ;27 :62 –70\n. 10.3109/15360288.2012.751956 23302094 \n11 Kessler ER , Shah M , Gruschkus SK , et al \nCost and quality implications of opioid-based postsurgical pain control using administrative claims data from a large health system: opioid-related adverse events and their impact on clinical and economic outcomes\n. Pharmacotherapy \n2013 ;33 :383 –91\n. 10.1002/phar.1223 23553809 \n12 de Vries EN , Ramrattan MA , Smorenburg SM , et al \nThe incidence and nature of in-hospital adverse events: a systematic review\n. Qual Saf Health Care \n2008 ;17 :216 –23\n. 10.1136/qshc.2007.023622 18519629 \n13 Bates DW , Cullen DJ , Laird N , et al \nIncidence of adverse drug events and potential adverse drug events. Implications for prevention. ade prevention Study Group\n. JAMA \n1995 ;274 :29 –34\n.7791255 \n14 Doherty C , Mc Donnell C \nTenfold medication errors: 5 years' experience at a university-affiliated pediatric hospital\n. Pediatrics \n2012 ;129 :916 –24\n. 10.1542/peds.2011-2526 22473367 \n15 Heneka N , Shaw T , Rowett D , et al \nOpioid errors in inpatient palliative care services: a retrospective review\n. BMJ Support Palliat Care \n2018 ;8 :175 –9\n. 10.1136/bmjspcare-2017-001417 \n16 Shafi S , Collinsworth AW , Copeland LA , et al \nAssociation of opioid-related adverse drug events with clinical and cost outcomes among surgical patients in a large integrated health care delivery system\n. JAMA Surg \n2018 ;153 :757 –63\n. 10.1001/jamasurg.2018.1039 29799927 \n17 Dy SM , Shore AD , Hicks RW , et al \nMedication errors with opioids: results from a national reporting system\n. J Opioid Manag \n2007 ;3 :189 –94\n. 10.5055/jom.2007.0004 17957978 \n18 Cousins DH , Gerrett D , Warner B \nA review of medication incidents reported to the National reporting and learning system in England and Wales over 6 years (2005-2010)\n. Br J Clin Pharmacol \n2012 ;74 :597 –604\n. 10.1111/j.1365-2125.2011.04166.x 22188210 \n19 Noble DJ , Pronovost PJ \nUnderreporting of patient safety incidents reduces health care's ability to quantify and accurately measure harm reduction\n. J Patient Saf \n2010 ;6 :247 –50\n. 10.1097/PTS.0b013e3181fd1697 21500613 \n20 Yung H-P , Yu S , Chu C , et al \nNurses' attitudes and perceived barriers to the reporting of medication administration errors\n. J Nurs Manag \n2016 ;24 :580 –8\n. 10.1111/jonm.12360 26888342 \n21 Baker GR , Norton PG , Flintoft V , et al \nThe Canadian adverse events study: the incidence of adverse events among hospital patients in Canada\n. CMAJ \n2004 ;170 :1678 –86\n. 10.1503/cmaj.1040498 15159366 \n22 Brennan TA , Leape LL , Laird NM , et al \nIncidence of adverse events and negligence in hospitalized patients. Results of the Harvard medical practice study I\n. N Engl J Med \n1991 ;324 :370 –6\n. 10.1056/NEJM199102073240604 1987460 \n23 Baines RJ , Langelaan M , de Bruijne MC , et al \nChanges in adverse event rates in hospitals over time: a longitudinal retrospective patient record review study\n. BMJ Qual Saf \n2013 ;22 :290 –8\n. 10.1136/bmjqs-2012-001126 \n24 Langelaan M , De Bruijne MC , Baines RJ , et al \nDutch adverse event study 2011/2012 Utrecht: NIVEL/EMGO+\n, 2013 Available: https://www.nivel.nl/sites/default/files/bestanden/monitor_zorggerelateerde_schade_2011_2012.pdf [Accessed 12 Dec 2018 ].\n25 Baines RJ , Langelaan M , de Bruijne MC , et al \nIs researching adverse events in hospital deaths a good way to describe patient safety in hospitals: a retrospective patient record review study\n. BMJ Open \n2015 ;5 :e007380. 10.1136/bmjopen-2014-007380 \n26 Vincent C , Neale G , Woloshynowych M \nAdverse events in British hospitals: preliminary retrospective record review\n. BMJ \n2001 ;322 :517 –9\n. 10.1136/bmj.322.7285.517 11230064 \n27 Zegers M , de Bruijne MC , Wagner C , et al \nAdverse events and potentially preventable deaths in Dutch hospitals: results of a retrospective patient record review study\n. Qual Saf Health Care \n2009 ;18 :297 –302\n. 10.1136/qshc.2007.025924 19651935 \n28 Damen NL , Baines R , Wagner C , et al \nMedication-Related adverse events during hospitalization: a retrospective patient record review study in the Netherlands\n. Pharmacoepidemiol Drug Saf \n2017 ;26 :32 –9\n. 10.1002/pds.4037 27193415 \n29 Baines R , Langelaan M , de Bruijne M , et al \nHow effective are patient safety initiatives? A retrospective patient record review study of changes to patient safety over time\n. BMJ Qual Saf \n2015 ;24 :561 –71\n. 10.1136/bmjqs-2014-003702 \n30 van Vuren W , Shea CE , van der Schaaf TW \nThe development of an incident analysis tool for the medical field . Eindhoven : Eindhoven University of Technology , 1997 .\n31 Morimoto T , Sakuma M , Matsui K , et al \nIncidence of adverse drug events and medication errors in Japan: the JADE study\n. J Gen Intern Med \n2011 ;26 :148 –53\n. 10.1007/s11606-010-1518-3 20872082 \n32 WHO \nMedication errors: technical series on safer primary care . Geneva : World Health Organization , 2016 \nhttp://apps.who.int/iris/bitstream/handle/10665/252274/9789241511643-eng.pdf?sequence=1\n33 WHO \nATC/DDD index\n, 2017 Available: https://www.whocc.no/atc_ddd_index/?code=N02A [Accessed 10 Jul 2018 ].\n34 de Vet HCW , Mokkink LB , Terwee CB , et al \nClinicians are right not to like Cohen's κ\n. BMJ \n2013 ;346 :f2125. 10.1136/bmj.f2125 23585065 \n35 Huang AR , Mallet L \nPrescribing opioids in older people\n. Maturitas \n2013 ;74 :123 –9\n. 10.1016/j.maturitas.2012.11.002 23201325 \n36 Aronson JK \nBalanced prescribing - principles and challenges\n. Br J Clin Pharmacol \n2012 ;74 :566 –72\n. 10.1111/j.1365-2125.2012.04413.x 22950551 \n37 Wallwork RS , Chipidza FE , Stern TA \nObstacles to the prescription and use of opioids\n. Prim Care Companion CNS Disord \n2016 ;18 \n10.4088/PCC.15f01900 \n38 Scott IA , Pillans PI , Barras M , et al \nUsing EMR-enabled computerized decision support systems to reduce prescribing of potentially inappropriate medications: a narrative review\n. Ther Adv Drug Saf \n2018 ;9 :559 –73\n. 10.1177/2042098618784809 30181862 \n39 Clyne B , Bradley MC , Hughes C , et al \nElectronic prescribing and other forms of technology to reduce inappropriate medication use and polypharmacy in older people: a review of current evidence\n. Clin Geriatr Med \n2012 ;28 :301 –22\n. 10.1016/j.cger.2012.01.009 22500545 \n40 Durieux P , Trinquart L , Colombet I , et al \nComputerized advice on drug dosage to improve prescribing practice\n. Cochrane Database Syst Rev \n2008 ;3 :CD002894.\n41 Minkowitz HS , Scranton R , Gruschkus SK , et al \nDevelopment and validation of a risk score to identify patients at high risk for opioid-related adverse drug events\n. J Manag Care Spec Pharm \n2014 ;20 :948 –58\n. 10.18553/jmcp.2014.20.9.948 25166294 \n42 Hinderer M , Boeker M , Wagner SA , et al \nIntegrating clinical decision support systems for pharmacogenomic testing into clinical routine - a scoping review of designs of user-system interactions in recent system development\n. BMC Med Inform Decis Mak \n2017 ;17 :81. 10.1186/s12911-017-0480-y 28587608 \n43 Agarwal D , Udoji MA , Trescot A \nGenetic testing for opioid pain management: a primer\n. Pain Ther \n2017 ;6 :93 –105\n. 10.1007/s40122-017-0069-2 28409480 \n44 Simonsen BO , Daehlin GK , Johansson I , et al \nDifferences in medication knowledge and risk of errors between graduating nursing students and working registered nurses: comparative study\n. BMC Health Serv Res \n2014 ;14 :580. 10.1186/s12913-014-0580-7 25413244 \n45 Williams B , Davis S \nMaths anxiety and medication dosage calculation errors: a scoping review\n. Nurse Educ Pract \n2016 ;20 :139 –46\n. 10.1016/j.nepr.2016.08.005 27589091 \n46 Schilp J , Boot S , de Blok C , et al \nProtocol compliance of administering parenteral medication in Dutch hospitals: an evaluation and cost estimation of the implementation\n. BMJ Open \n2014 ;4 :e005232. 10.1136/bmjopen-2014-005232 \n47 Schutijser B , Klopotowska JE , Jongerden I , et al \nNurse compliance with a protocol for safe injectable medication administration: comparison of two multicentre observational studies\n. BMJ Open \n2018 ;8 :e019648. 10.1136/bmjopen-2017-019648 \n48 Ohashi K , Dalleur O , Dykes PC , et al \nBenefits and risks of using smart pumps to reduce medication error rates: a systematic review\n. Drug Saf \n2014 ;37 :1011 –20\n. 10.1007/s40264-014-0232-1 25294653 \n49 Murnion BP , Gnjidic D , Hilmer SN \nPrescription and administration of opioids to hospital in-patients, and barriers to effective use\n. Pain Med \n2010 ;11 :58 –66\n. 10.1111/j.1526-4637.2009.00747.x 19930113 \n50 Jho HJ , Kim Y , Kong KA , et al \nKnowledge, practices, and perceived barriers regarding cancer pain management among physicians and nurses in Korea: a nationwide multicenter survey\n. PLoS One \n2014 ;9 :e105900. 10.1371/journal.pone.0105900 25144641 \n51 AlReshidi N , Long T , Darvill A \nA systematic review of the impact of educational programs on factors that affect nurses' post-operative pain management for children\n. Compr Child Adolesc Nurs \n2018 ;41 :9 –24\n. 10.1080/24694193.2017.1319432 28548542 \n52 Furniss D , Lyons I , Franklin BD , et al \nProcedural and documentation variations in intravenous infusion administration: a mixed methods study of policy and practice across 16 Hospital trusts in England\n. BMC Health Serv Res \n2018 ;18 :270. 10.1186/s12913-018-3025-x 29636034 \n53 Hollnagel E , Wears R , Braithwaite J \nFrom safety-I to safety-II: a white paper. The resilient healthcare net: published simultaneously by the University of southern Denmark, University of Florida, USA, and Australia . Macquarie University , 2015 .\n54 Clay-Williams R , Hounsgaard J , Hollnagel E \nWhere the rubber meets the road: using FRAM to align work-as-imagined with work-as-done when implementing clinical guidelines\n. Implement Sci \n2015 ;10 :125. 10.1186/s13012-015-0317-y 26319404 \n55 Hanskamp-Sebregts M , Zegers M , Vincent C , et al \nMeasurement of patient safety: a systematic review of the reliability and validity of adverse event detection with record review\n. BMJ Open \n2016 ;6 :e011078. 10.1136/bmjopen-2016-011078 \n56 Baines RJ \nIntra-rater agreement in adverse event studies: stability of assessment of adverse events over time\n, 2018 Available: https://www.nivel.nl/sites/default/files/bestanden/Proefschrif_Rebecca_Baines_Monitoring_adverse_events_in_hospitals.pdf [Accessed 26 Jun 2020 ].\n57 Hartwig SC , Denger SD , Schneider PJ \nSeverity-indexed, incident report-based medication error-reporting program\n. Am J Hosp Pharm \n1991 ;48 :2611 –6\n. 10.1093/ajhp/48.12.2611 1814201 \n58 Verenso \nRichtlijn Pijn.Herkenning en behandeling van pijn bij kwetsbare ouderen. Utrecht\n, 2016 Available: https://www.verenso.nl/_asset/_public/Richtlijnen_kwaliteit/richtlijnen/database/VER-003-32-Richtlijn-Pijn-deel2-v5LR.pdf [Accessed 20 Jun 2020 ].\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2044-6055",
"issue": "10(9)",
"journal": "BMJ open",
"keywords": "adverse events; health & safety; pain management; quality in health care",
"medline_ta": "BMJ Open",
"mesh_terms": "D000368:Aged; D000701:Analgesics, Opioid; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D009293:Opioid-Related Disorders; D010098:Oxycodone; D012189:Retrospective Studies",
"nlm_unique_id": "101552874",
"other_id": null,
"pages": "e038037",
"pmc": null,
"pmid": "32998923",
"pubdate": "2020-09-30",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "23585065;1987460;23201325;23302094;23293136;30181862;25294653;28871436;27589091;22500545;23553809;26888342;28587608;7791255;19651935;11230064;26150548;28548542;24671697;28409480;25102043;27193415;21500613;27550650;22473367;17957978;19930113;31050276;22950551;1814201;25550289;29307863;29306893;25413244;26319404;27621489;30711195;27247832;15159366;26159451;25166294;22188210;21499584;29636034;25144641;18646085;20872082;18519629;29799927",
"title": "Nature of adverse events with opioids in hospitalised patients: a post-hoc analysis of three patient record review studies.",
"title_normalized": "nature of adverse events with opioids in hospitalised patients a post hoc analysis of three patient record review studies"
} | [
{
"companynumb": "NL-ALKEM LABORATORIES LIMITED-NL-ALKEM-2020-06667",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXYCODONE HYDROCHLORIDE"
},
... |
{
"abstract": "Fungal infections caused by Paecilomyces species are rare. Although most cases of human infection occur in immunocompromised patients, this species is also being increasingly recognized as a pathogen in immunocompetent individuals. Paecilomyces variotii and P. lilacinus are the most common pathogens in humans. P. variotii infection usually manifests as peritonitis, pneumonia or endophthalmitis. We present the case of an 84-year-old immunocompromised patient with interstitial lung disease, who developed pulmonary mycetoma with isolation of P. variotii in bronchoalveolar lavage fluid culture. We found one similar case in the literature, but Paecilomyces species was not identified. Therefore, this is the first described case of pulmonary mycetoma caused by P. variotii.\nPaecilomyces are rare causes of fungal infection in humans and occur more frequently in immunocompromised patients.Paecilomyces variotii is one of the most common pathogens of this species and is associated with peritonitis, pneumonia, osteomyelitis, endophthalmitis and fungaemia.To the date, pulmonary mycetoma caused by P. variotii has been described in only one patient in the literature.",
"affiliations": "Internal Medicine Department, Hospital de Egas Moniz, Lisbon, Portugal.;Pulmonology Department, Hospital de Egas Moniz, Lisbon, Portugal.;Internal Medicine Department, Hospital de Egas Moniz, Lisbon, Portugal.;Internal Medicine Department, Hospital de Egas Moniz, Lisbon, Portugal.",
"authors": "Marques|Diogo Paixão|DP|;Carvalho|Joana|J|;Rocha|Sara|S|;Domingos|Raquel|R|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2019_001040",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2019_0010401040-1-7131-1-10-20190214ArticlesA Case of Pulmonary Mycetoma Caused by Paecilomyces variotii Marques Diogo Paixão 1Carvalho Joana 2Rocha Sara 1Domingos Raquel 1\n1 Internal Medicine Department, Hospital de Egas Moniz, Lisbon, Portugal\n2 Pulmonology Department, Hospital de Egas Moniz, Lisbon, Portugal2019 20 2 2019 6 2 00104031 12 2018 09 1 2019 © EFIM 20192019This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseFungal infections caused by Paecilomyces species are rare. Although most cases of human infection occur in immunocompromised patients, this species is also being increasingly recognized as a pathogen in immunocompetent individuals. Paecilomyces variotii and P. lilacinus are the most common pathogens in humans. P. variotii infection usually manifests as peritonitis, pneumonia or endophthalmitis. We present the case of an 84-year-old immunocompromised patient with interstitial lung disease, who developed pulmonary mycetoma with isolation of P. variotii in bronchoalveolar lavage fluid culture. We found one similar case in the literature, but Paecilomyces species was not identified. Therefore, this is the first described case of pulmonary mycetoma caused by P. variotii.\n\nLEARNING POINTS\nPaecilomyces are rare causes of fungal infection in humans and occur more frequently in immunocompromised patients.\n\nPaecilomyces variotii is one of the most common pathogens of this species and is associated with peritonitis, pneumonia, osteomyelitis, endophthalmitis and fungaemia.\n\nTo the date, pulmonary mycetoma caused by P. variotii has been described in only one patient in the literature.\n\nPaecilomyces variotiimycetomaimmunosuppressioninterstitial lung disease\n==== Body\nINTRODUCTION\nPaecilomyces is a ubiquitous worldwide fungus that lives in the soil, decaying plants, wood and some food products[1]. These filamentous fungi are able to grow under stressful conditions such as hot or dry environments, which may contribute to their potential pathogenic nature[2]. Fungal infections caused by Paecilomyces species are uncommon[3]. Most cases of human infection occur in immunocompromised individuals, as well as following trauma or surgical procedures such as intraocular lens implantation[3]. However, Paecilomyces infection in immunocompetent patients have been increasingly reported in the literature[3,4].\n\nWe present the case of an immunocompromised 84-year-old man with interstitial lung disease who developed pulmonary mycetoma caused by Paecilomyces variotii.\n\nCASE DESCRIPTION\nAn 84-year-old man presented to the Emergency Department complaining of productive cough and low-grade fever for the last few days.\n\nHis past medical history included arterial hypertension, atrial fibrillation, ischaemic heart disease and nummular eczema. Nine years before admission he had presented to the pulmonology outpatient clinic with a few months’ history of dry cough, fatigue and exertional dyspnoea. A chest CT scan had revealed subpleural bibasilar interlobular septal thickening (Fig. 1).\n\nBronchoalveolar lavage fluid showed 42% lymphocytes with a diminished CD4/CD8 ratio. He had a history of previous exposure to birds but denied any other occupational or recreational exposures. A lung biopsy was not performed because of the high surgical risk. A diagnosis of probable chronic hypersensitivity pneumonitis—bird fancier’s lung—was established and he was treated with corticosteroids but subsequently failed to completely avoid contact with birds. Despite maintaining treatment with prednisone 7.5 mg/day because of his nummular eczema, over the following years he showed steady clinical and radiological deterioration.\n\nAt presentation in the Emergency Department, he was febrile (38.2ºC), with tachypnoea at rest and a peripheral oxygen saturation at room air of 81%; remaining vital signs were stable. Lung auscultation revealed bilateral crackles in lower lobes. There were no other relevant physical findings. Laboratory evaluation showed raised inflammatory markers (leucocyte count 19,400/μl with an absolute neutrophil count of 17,070/μl, C-reactive protein 6.8 mg/dl), D-dimer 0.3 μg/ml and N-terminal-pro BNP 542 pg/ml. A chest radiograph showed a bibasilar reticular pattern without parenchymal consolidation or pleural effusion (Fig. 2). A diagnosis of acute tracheobronchitis was made and antibiotic therapy with levofloxacin was started. The patient was admitted to the Internal Medicine Department.\n\nDuring the patient’s hospital stay there was clinical improvement upon antibiotic therapy. A follow-up chest CT scan revealed a reticular pattern with traction bronchiectasis, honeycombing and multiple cystic lesions with a subpleural and basal predominance, some of which had a crescent-air sign, suggestive of mycetoma (Fig. 3).\n\nA bronchoscopy was performed and the bronchoalveolar lavage fluid culture isolated P. variotii. Antifungal susceptibility testing showed a low minimal inhibitory concentration (MIC) to posaconazole and amphotericin B (0.02 μg/ml and 0.06 μg/ml, respectively) and a high MIC to voriconazole (>32 μg/ml). Serum and bronchoalveolar lavage galactomannan antigen detection was negative, as well as routine blood and sputum cultures. Given the context of immunosuppression and interstitial lung disease, a 6-week course of antifungal therapy with posaconazole was started. The patient was discharged after 7 days of antibiotic therapy.\n\nSix days after hospital discharge, the patient was readmitted with nosocomial pneumonia. He was treated empirically with piperacillin-tazobactam and linezolid and maintained posaconazole. Nevertheless, he developed worsening respiratory failure and was later transferred to the intensive care unit where high-flow oxygen therapy was instituted. The patient refused mechanical ventilation. Despite completing a 14-day course of antibiotics he showed no clinical improvement, with progressive worsening of dyspnoea and respiratory failure eventually leading to death.\n\nDISCUSSION\nP. variotii and P. lilacinus are the most common pathogens of the Paecilomyces species[1,3,5]. Clinical manifestations of P. variotii infection include peritonitis, pneumonia, osteomyelitis, skin and soft tissue infections and fungaemia. P. variotii pneumonia is rare, with only a few cases reported in the literature[1]. Symptoms usually include productive cough, pleuritic chest pain and fever, which are mostly indistinguishable from those of pneumonia due to other bacterial or fungal causes[1]. Chest imaging abnormalities include hilar lymphadenopathy, confluent and patchy opacities and cavities[1]. The patient described in the present case did not seem to fall into this category since he showed clinical improvement with antibiotic therapy and the cystic lesions described in the chest CT scan were likely to secondary to progressive parenchymal fibrosis with architectural distortion.\n\nThe CT scan performed during the patient’s hospital stay showed an air-crescent sign in some cystic lesions, suggestive of pulmonary mycetoma. Most pulmonary mycetomas are caused by Aspergillus, although Zygomycetes and Fusarium species have also been reported[3]. To our knowledge, only one case has been described in the literature of pulmonary mycetoma caused by Paecilomyces species[3]. Gutiérrez et al. described a case in which Paecilomyces was isolated by DNA sequencing techniques from a transthoracic needle aspiration culture of a large pulmonary mycetoma in an immunocompetent patient[3]. However, the clinical strain was not identified. Therefore, to our knowledge, the present case is the only example of P. variotii pulmonary mycetoma in a patient with interstitial lung disease.\n\nUnlike P. lilacinus, P. variotii is usually susceptible to most antifungal agents apart from voriconazole and ravuconazole[1,4,5]. Therefore, posaconazole or amphotericin B are usually good alternatives to treat this infection[4,5]. Correct species identification and antifungal susceptibility testing are crucial to guide appropriate therapy. Since treatment guidelines are lacking, duration of treatment must be tailored according to clinical response.\n\nMost cases of pulmonary aspergilloma require surgery; however, surgery was not a suitable option for this patient due to the high surgical risk and multifocal distribution of mycetomas. Unfortunately, this patient died even though he was treated with appropriate antifungal and antibacterial therapy. This was probably due to the severity of his underlying conditions, particularly the lung disease.\n\nIn conclusion, P. variotii is a rare but increasingly common cause of infection in both immunocompromised and immunocompetent individuals. Although it is very rare, this case shows that Paecilomyces species can also be aetiological agents of pulmonary mycetoma.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nFigure 1 Initial chest CT scan revealing interlobular and intralobular septal thickening predominantly in a basal subpleural location\n\nFigure 2 Chest radiograph showing a bilateral reticular pattern predominantly involving the lower lung zones and subpleural lung regions, suggestive of extensive fibrosis\n\nFigure 3 Follow up chest CT scan showing extensive lung fibrosis with multiple cystic lesions, some of which have a typical air-crescent sign suggestive of mycetoma (arrow)\n==== Refs\nREFERENCES\n1 Steiner B Aquino VR Paz AA Silla LM Zavascki A Goldani LZ Paecilomyces variotii as an emergent pathogenic agent of pneumonia Case Rep Infect Dis 2013 2013 273848 \n2 Houbraken J Verweij PE Rijs AJ Borman AM Samson RA Identification of Paecilomyces variotii in clinical samples and settings J Clin Microbiol 2010 48 2754 2761 20519470 \n3 Gutiérrez F Masiá M Ramos J Elía M Mellado E Cuenca-Estrella M Pulmonary mycetoma caused by an atypical isolate of Paecilomyces species in an immunocompetent individual: case report and literature review of Paecilomyces lung infections Eur J Clin Microbiol Infect Dis 2005 24 607 611 16187056 \n4 Feldman R Cockerham L Buchan BW Lu Z Huang AM Treatment of Paecilomyces variotii pneumonia with posaconazole: case report and literature review Mycoses 2016 59 746 750 27401982 \n5 Aguilar C Pujol I Sala J Guarro J Antifungal susceptibilities of Paecilomyces species Antimicrob Agents Chemother 1998 42 1601 1604 9660991\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2284-2594",
"issue": "6(2)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Paecilomyces variotii; immunosuppression; interstitial lung disease; mycetoma",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "001040",
"pmc": null,
"pmid": "30931270",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "16187056;20519470;23819077;27401982;9660991",
"title": "A Case of Pulmonary Mycetoma Caused by Paecilomyces variotii.",
"title_normalized": "a case of pulmonary mycetoma caused by paecilomyces variotii"
} | [
{
"companynumb": "PT-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-208545",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "Gemcitabine application for patients with impaired renal function or undergoing haemodialysis will increase if the efficacy and safety are proved as the treatment for pancreatic cancer of these patients. However, there is no guideline about the usage of gemcitabine in patients with impaired renal function or haemodialysis. We report the case of a 70-year-old man with advanced pancreatic cancer undergoing haemodialysis. After discontinuation of 100% or 80% dosage, 60% dose of gemcitabine was administered biweekly. Serum carbohydrate antigen 19-9 and carcinoembryonic antigen levels were marked by slight variations and abdominal computed tomography (CT) showed the tumour size hardly changed. We administered gemcitabine for the patient 14 times in total, and he survived over 8 months from the definitive diagnosis. These findings confirm the efficacy and safety of treatment with a biweekly 60% dose of gemcitabine for patients with advanced pancreatic cancer undergoing haemodialysis in the face of dose modification.",
"affiliations": null,
"authors": "Takakura|Kazuki|K|;Koido|Shigeo|S|;Takahara|Akitaka|A|;Odahara|Shunichi|S|;Mitobe|Jimi|J|;Matsudaira|Hiroshi|H|;Tsukinaga|Shintaro|S|;Yukawa|Toyokazu|T|;Matsumoto|Kei|K|;Nagatsuma|Keisuke|K|;Uchiyama|Kan|K|;Kajihara|Mikio|M|;Ohkusa|Toshifumi|T|;Tajiri|Hisao|H|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "England",
"delete": false,
"doi": "10.1179/1973947813Y.0000000150",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-009X",
"issue": "26(6)",
"journal": "Journal of chemotherapy (Florence, Italy)",
"keywords": "Dose modification; Gemcitabine,; Haemodialysis,; Pancreatic cancer,",
"medline_ta": "J Chemother",
"mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D006801:Humans; D008297:Male; D010190:Pancreatic Neoplasms; D006435:Renal Dialysis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8907348",
"other_id": null,
"pages": "369-72",
"pmc": null,
"pmid": "24621160",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Long-term management of gemcitabine in a patient with advanced pancreatic cancer undergoing haemodialysis.",
"title_normalized": "long term management of gemcitabine in a patient with advanced pancreatic cancer undergoing haemodialysis"
} | [
{
"companynumb": "JP-PFIZER INC-2019179769",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Atypical hemolytic uremic syndrome is a rare group of disorders that have in common underlying complement amplifying conditions. These conditions can accelerate complement activation that results in a positive feedback cycle. The known triggers for complement activation can be diverse and include, infection, autoimmune disease, and malignancy. Recent reports suggest that certain autoimmune and rheumatological triggers of complement activation may result in atypical hemolytic uremic syndrome that does not resolve despite treating the underlying disorder. Specifically, patients with systemic lupus erythematosus and microangiopathic hemolysis may not respond to treatment of their underlying rheumatological trigger but responded to complement blockade.\nWe report two patients with inflammatory bowel disease complicated by development of atypical hemolytic uremic syndrome. In both cases, patients were on treatment for inflammatory bowel disease, that was not well controlled/flaring at the time. The first patient is a male who developed Crohn's disease and microangiopathic hemolysis at age 5 and was treated with eculizumab successfully. Discontinuation of the medication led to multiple relapses, and the patient currently is being treated with eculizumab and has normal hematological and stable renal parameters. The second patient is a 49-year-old female with Ulcerative Colitis treated with 6-Mercaptopurine. She developed acute kidney injury and microangiopathic hemolysis. Prompt diagnosis and treatment with eculizumab resulted in the recovery of kidney injury along with a complete hematological response.\nThese two cases are the fifth and sixth patients to be published in the literature with atypical hemolytic uremic syndrome and inflammatory bowel disease treated with complement blockade. This confirms that C5 complement blockade is effective in treating complement mediated thrombotic microangiopathy/atypical hemolytic uremic syndrome when it is triggered in patients with inflammatory bowel disease.",
"affiliations": "1Department of Medicine, Division of Nephrology, UCLA David Geffen School of Medicine, Room 7-155, Factor Bldg. 700 Tiverton Ave, Los Angeles, CA 90095 USA.;3Department of Medicine, Division of Hematology Oncology, Cedars Sinai Medical Center, Los Angeles, USA.;4Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Cedars Sinai Medical Center, Los Angeles, USA.;1Department of Medicine, Division of Nephrology, UCLA David Geffen School of Medicine, Room 7-155, Factor Bldg. 700 Tiverton Ave, Los Angeles, CA 90095 USA.;1Department of Medicine, Division of Nephrology, UCLA David Geffen School of Medicine, Room 7-155, Factor Bldg. 700 Tiverton Ave, Los Angeles, CA 90095 USA.;5Department of Medicine, Division of Digestive Diseases, UCLA David Geffen School of Medicine, Los Angeles, USA.;6Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, USA.;6Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, USA.;1Department of Medicine, Division of Nephrology, UCLA David Geffen School of Medicine, Room 7-155, Factor Bldg. 700 Tiverton Ave, Los Angeles, CA 90095 USA.",
"authors": "Hanna|Ramy M|RM|0000-0003-1807-8909;Merin|Noah|N|;Burwick|Richard M|RM|;Abdelnour|Lama|L|;Selamet|Umut|U|;Yanny|Beshoy|B|;Bui|Patrick|P|;Fouad|Mary|M|;Kurtz|Ira|I|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12959-019-0207-7",
"fulltext": "\n==== Front\nThromb JThromb JThrombosis Journal1477-9560BioMed Central London 20710.1186/s12959-019-0207-7Case ReportSuccessful use of eculizumab to treat atypical hemolytic uremic syndrome in patients with inflammatory bowel disease http://orcid.org/0000-0003-1807-8909Hanna Ramy M. 310-206-6741rhannamd81@yahoo.comrmhanna@mednet.ucla.edu 12Merin Noah 3Burwick Richard M. 4Abdelnour Lama 1Selamet Umut 1Yanny Beshoy 5Bui Patrick 6Fouad Mary 6Kurtz Ira 171 0000 0000 9632 6718grid.19006.3eDepartment of Medicine, Division of Nephrology, UCLA David Geffen School of Medicine, Room 7-155, Factor Bldg. 700 Tiverton Ave, Los Angeles, CA 90095 USA 2 0000 0001 0668 7243grid.266093.8Department of Medicine, Division of Nephrology, University of California Irvine School of Medicine, Irvine CA, USA 3 0000 0001 2152 9905grid.50956.3fDepartment of Medicine, Division of Hematology Oncology, Cedars Sinai Medical Center, Los Angeles, USA 4 0000 0001 2152 9905grid.50956.3fDepartment of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Cedars Sinai Medical Center, Los Angeles, USA 5 0000 0000 9632 6718grid.19006.3eDepartment of Medicine, Division of Digestive Diseases, UCLA David Geffen School of Medicine, Los Angeles, USA 6 0000 0000 9632 6718grid.19006.3eDepartment of Medicine, UCLA David Geffen School of Medicine, Los Angeles, USA 7 0000 0000 9632 6718grid.19006.3eUCLA Brain Research Institute, Los Angeles, USA 9 9 2019 9 9 2019 2019 17 1824 6 2019 31 7 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAtypical hemolytic uremic syndrome is a rare group of disorders that have in common underlying complement amplifying conditions. These conditions can accelerate complement activation that results in a positive feedback cycle. The known triggers for complement activation can be diverse and include, infection, autoimmune disease, and malignancy. Recent reports suggest that certain autoimmune and rheumatological triggers of complement activation may result in atypical hemolytic uremic syndrome that does not resolve despite treating the underlying disorder. Specifically, patients with systemic lupus erythematosus and microangiopathic hemolysis may not respond to treatment of their underlying rheumatological trigger but responded to complement blockade.\n\nCase presentations\nWe report two patients with inflammatory bowel disease complicated by development of atypical hemolytic uremic syndrome. In both cases, patients were on treatment for inflammatory bowel disease, that was not well controlled/flaring at the time. The first patient is a male who developed Crohn’s disease and microangiopathic hemolysis at age 5 and was treated with eculizumab successfully. Discontinuation of the medication led to multiple relapses, and the patient currently is being treated with eculizumab and has normal hematological and stable renal parameters. The second patient is a 49-year-old female with Ulcerative Colitis treated with 6-Mercaptopurine. She developed acute kidney injury and microangiopathic hemolysis. Prompt diagnosis and treatment with eculizumab resulted in the recovery of kidney injury along with a complete hematological response.\n\nConclusions\nThese two cases are the fifth and sixth patients to be published in the literature with atypical hemolytic uremic syndrome and inflammatory bowel disease treated with complement blockade. This confirms that C5 complement blockade is effective in treating complement mediated thrombotic microangiopathy/atypical hemolytic uremic syndrome when it is triggered in patients with inflammatory bowel disease.\n\nKeywords\nAtypical hemolytic uremic syndromeComplementComplement blockadeThrombotic MicroangiopathyInflammatory bowel diseaseCrohn’s colitis/Crohn’s diseaseUlcerative colitisNational Institutes of Health (US)R01-DK077162Kurtz Ira issue-copyright-statement© The Author(s) 2019\n==== Body\nKey points\n\nIBD can trigger aHUS, and in both cases, we report patients received eculizumab and other biologic agents for IBD concurrently.\n\nWe report the 5th and 6th cases of complement mediated TMA/aHUS in IBD patients (1 with UC and 1 with CD), with successful resolution of aHUS with complement blockade.\n\nWe report prevention of relapse with ongoing complement blockade in one case.\n\n\n\n\nBackground\nAtypical Hemolytic Uremic Syndrome (aHUS), is a syndrome resulting from complement activation. The causes of complement activation are numerous, and the genetics are diverse. In affected patients, a latent susceptibility becomes unmasked by a complement amplifying condition resulting in Thrombotic Microangiopathy (TMA) [1]. New research is revealing complement biology as having a role in microangiopathic hemolysis and endothelial dysfunction in many rheumatological diseases [1]. Recent publications by Park et al. disclose that ongoing microangiopathic hemolysis stemming from rheumatological conditions like systemic lupus erythematosus can be treated with eculizumab when more traditional immunosuppression has failed [2, 3]. Microangiopathic hemolysis due to Antiphospholipid antibody syndrome and catastrophic antiphospholipid antibody syndrome (CAPS) variant has also been successfully treated with complement blockade [4].\n\nThe final common pathway of a positive feedback complement activation loop is the etiologic feature of aHUS, despite the various triggers [1]. In most cases, a strong genetic susceptibility is unmasked by the presence of a strong temporary, or a milder but lingering complement amplifying condition [1]. Indeed, some cases of aHUS can be self-limiting (due to hypertension, post-partum aHUS), and others can be due to slow ongoing complement activation (C3 glomerulopathy, and chronic hypertension due to occult TMA) [1].\n\nInflammatory bowel disease (IBD), resulting in Crohn’s Disease (CD) and Ulcerative Colitis (UC) as clinical phenotypes, is one such group of complement amplifying conditions [5]. As with other autoimmune diseases, first-line treatment has always focused on suppression of the immune system to eliminate inflammation and clinical symptoms. In the current literature, there are three published case reports and one abstract detailing patients with IBD and aHUS treated with eculizumab [6–10].\n\nWe report two additional cases of patients with IBD and aHUS treated with eculizumab. Patient 1 is a 19-year-old male with CD who was treated with eculizumab at age 5 and had multiple relapses off the drug. He was maintained on eculizumab with near-normal renal and hematological parameters for 14 years. Patient 2 is a 49-year-old female with UC who developed severe aHUS and was promptly treated with eculizumab resulting in normalization of renal and hematological parameters.\n\nCase presentations\nPatient 1\nThe first patient is a 19-year-old Caucasian male who presented for the continuation of complement blockade therapy with eculizumab. He was diagnosed with CD at age 5 and started on per rectum steroid therapy with budesonide and mesalamine therapy. He did require continuous infusions of adalimumab then infliximab for control of his disease. During the initial episode of colitis/CD in 2005, he was noted to have thrombocytopenia, hemolytic anemia, schistocytes with elevations in lactate dehydrogenase. The ADAMTS13 level was not available early on in the time of his diagnosis. Though Shiga toxin was not found in stool, vitamin B12 levels was 781 nanogram (ng)/mL, red blood cell (RBC) folate levels were within normal limits 981 nanomoles/L excluding other known TMA causes at that time. Rheumatolgoic serologies like anti nuclear antibody (ANA), anti double stranded DNA (dsDNA), anti ribonucleic protein smith (RNP-smith), anti cardiolipin (anti CL), dilute russell viper venom time assay (DRVVT), and anti phospholipid antibody (anti APL Ab) studies were all negative during initial workup.\n\nAs the scientific understanding of aHUS developed, it was decided that eculizumab would be initiated on an experimental basis with institutional review board approval (in a health system in Florida). He underwent a several-month course of eculizumab with clinical response. Following discontinuation of the medication, the patient suffered a relapse a few months later. Therapy was reinitiated and was subsequently weaned off successfully. Complement testing found a high level of C5 convertase function with high soluble membrane attack complex that improved with eculizumab use.\n\nIn April 2010 the patient had a severe flare of his underlying CD despite ongoing use of adalimumab, his disease remained poorly controlled clinically. He had a concomitant serum creatinine elevation peaking at 3.13 mg/dL in 04/2010 (baseline of 0.57 mg/dL 08/2009) with a drop in hemoglobin from 12.9 g/L baseline in 08/2009 to 7.6 g/L in 03/2010. The total bilirubin concentration was not elevated but increased from a baseline of 0.1 (mg/dL) in 03/2010 to 0.8 (mg/dL) in 04/2010 during the flare. Lactate dehydrogenase (LDH) was significantly elevated at 2223 Units/L in 4/2010 and decreased after that. The platelets had decreased by ~ 50% from 366,000/uL at baseline in 02/2010 to 187,000/uL in 4/2010. ADAMTS 13 activity level was within normal limits at 44% ruling out ADAMTS13 deficiency and thrombotic thrombocytopenic purpura (TTP). Prothrombin time (PT) was 11 s with an International Normalized Ratio (INR) was 1, and activated partial thromboplastin time (aPTT) was 39 s both within normal. Fibrinogen levels were high at 471 mg/dL, and a D-dimer was high at 6.17 microgram/mL as expected in an inflammatory condition. Absolute reticulocyte count was in the upper limit of normal / slightly elevated at 2.92%.\n\nSince the patient had an established aHUS diagnosis, eculizumab was promptly reintroduced at 900 mg (infusion dose) each week with normalization of the platelet count and LDH levels, and improvement of the serum Cr to 1 mg/dL. The patient received eculizumab (1200 mg infusions) every two weeks for 8.5 years continually after this aHUS relapse. The patient had already received appropriate meningococcal vaccinations from prior courses and was aware of the risks and benefits of pharmacological complement blockade. He has not had any issues with meningitis or other infections linked to eculizumab. Clinically, his IBD symptoms slowly improved with use of ongoing adalimumab and steroid therapy for CD/IBD along with eculizumab use for aHUS.\n\nThe effect of this regimen was the maintenance on his aHUS was the maintenance of normal hematological parameters and renal function with current serum Cr of 1 mg/dL, hemoglobin of 10–12 g/L, and LDH within normal limits. The patient has agreed to continue lifelong eculizumab in this case given his two prior relapses. No antibodies against complement factors were found, and no mutations were found. Only 60% of patients with aHUS have detectable mutations, and in some cases, the mutations can be present but are currently unknown [11]. Figure 1 details laboratory findings in patient 1 and his course during his last flare in 2010.Fig. 1 Laboratory tests for patient one as a function of time. Abbreviations: dL, deciliter; g, gram; L, liter; LDH, lactate dehydrogenase; mg, milligram; uL, microliter\n\n\n\nPatient 2\nThe second patient is a 49-year-old Caucasian female with a history of UC treated with six mercaptopurine (6MP), and steroids per rectum [budesonide]. She developed a flare of ulcerative colitis symptoms, along with increased platelet count from 322,000 platelets/uL (09/2018) to 622,000 platelets/uL (10/2018). This was a reactive thrombocytosis that occurred initially, and was clinically concomitant with a flare despite treatment with budesonide and 6MP.Her serum Cr at baseline was 0.51 mg/dL, and her hemoglobin was 13.1 g/L. She presented to the emergency department one month after the start of this flare with weakness and was found to have a decreased hemoglobin concentration of 4.3 g/L, serum Cr of 3.2 mg/dL, LDH of 1000 units/L, and schistocytes on the peripheral smear. Her platelets had droped from baseline of 322,000 platelets/ul and more recent peak of 622,000 platelets/ul to 83,000 platelets/ul; this level dropped further to 43,000 plateltes/ul at a nadir 11/17/2018. These findings and the hemolysis suggested thrombotic microangiopathy like aHUS as the likely diagnosis over 6-mercaptopurine bone marrow toxicity which was another possibility. Vitamin B12 level was normal at 769 ng/mL, serum folate level was also normal at 12.9 ng/mL. PT was 13 s with an INR of 1.3, aPTT was slightly elevated at 39 s. Fibrinogen levels were high normal range at 313 mg/dL, with an elevated D-dimer 3.28 microgram/mL. Rheumatologic serologies (ANA, anti dsDNA, anti RNP sm, anti CL, DRVVT, APL Ab) were all negative. Reticulocyte counts were obtained at 2% (normal), and one result was 3% which is slightly elevated, and not expected in bone marrow toxicity.\n\nThe finding of an ADAMTS13 level of 80.8% suggested that the cause of TMA was not TTP. The patient was transferred back to a quaternary care center, and then eculizumab was started after meningococcal vaccination. The patient agreed to the risks and benefits of complement blockade in the absence of waiting the requisite two weeks for development of meningococcal antibody titers after immunization, and antibiotic prophylaxis with penicillin-based antibiotics was provided.\n\nThe serum Cr, platelets, hemoglobin, LDH all improved quickly and normalized (Fig. 2). The patient required hemodialysis for ~ 1 week and was weaned off. Eculizumab was administered at a given dose of 900 mg weekly infusions. The patient was discharged on 1200 mg infusions of eculizumab every other week with normal lab parameters. She is currently undergoing genetic testing at the University of Iowa laboratory to look for autoantibodies and genetic mutations. The response to eculizumab and the clinical course are typical for aHUS and diagnostic.Fig. 2 Laboratory results for patient two as a function of time. Abbreviations: dL, deciliter; g, gram; L, liter; LDH, lactate dehydrogenase; mg, milligram; uL, microliter\n\n\n\nDiscussion and conclusions\nWe report a series of two patients with two variants of IBD presented with a very rare association with aHUS. The pathophysiology of aberrant complement activation does not require a specific trigger, and like rheumatological diseases, gastroenterological autoimmune disease like IBD can also trigger complement activation in susceptible individuals [1]. Interestingly, both patients had poorly controlled IBD at the time of aHUS diagnosis. The patients’ IBD (CD case 1, UC case 2), was eventually well controlled with intensive IBD therapy, alongside complement blockade for aHUS.\n\nThe lack of finding a complement mutation in patient 1 who had a relapsing course is suggestive of either: 1) a new complement mutation that has not been previously reported; 2) background gene effect. The two known classes of complement mutations are complement factor mutations resulting in auto-activation or increased activation of complement (factor B, factor I), and loss of function mutations resulting in decreased ability of self-cells to disarm complement proteins (like membrane cofactor protein, etc.) [11]. Other complement proteins interact with the complement cascade that when mutated can also affect complement function. For example, vitronectin is the newest genetic defect described that has been linked to aHUS [11, 12].\n\nIn addition to four other published case, we report the fifth and sixth cases of IBD associated aHUS successfully treated with eculizumab. Table 1 summarizes previous case reports in the literature and our current cases that highlight the infrequent association between IBD (CD and UC) and aHUS [6–10].Table 1 aHUS Cases Associated with Inflammatory Bowel Disease\n\nReference #\tn\tPt age\tPt gender\tUC/CD\tCreatinine improvement (Y/N)\tTMA resolution (Y/N)\tAb/Mutation found?\t\nCase Reports\t\n Beers [6] [abstract]\t1\t19\tF\tIBD**\tY\tY\tCFH Auto-Ab & HZ CF1/CFH3 Del\t\n Webb [7]\t1\t16\tM\tUC\tY\tY\t\nHZ MTHFR mutation***\n\t\n Viada Bris [8, 9]*\t1\t15\tF\tUC\tNT\tNT\tHZ CFH, HZ MCP\t\n Green H [10]\t1\t27\tF\tUC\tY\tY\tCFH Auto-Ab\t\n Hanna et.al. Case 1\t(1/2)\t19\tM\tCD\tY\tY\tNo clear mutation found****\t\n Hanna et.al. Case 2\t(2/2)\t49\tF\tUC\tY\tY\tTesting not completed\t\nAb antibody, CD Crohn’s disease, CF1 complement factor 1, CF3 complement factor 3, CFH complement factor H, HZ heterozygous, MCP membrane cofactor protein, MTHFR methylenetetrahydrofolate reductase gene/protein product, n number, N no, NT not treated, Pt patient, UC ulcerative colitis, Y yes. *8, 9 describe same case. ** IBD is only stated, it is not otherwise specified whether UC/CD.***Heterozygous MTHFR mutations are not generally thought to cause aHUS, therefore a known causative mutation was not found in Webb et.al. [7]. ****Early on in Case 1 a borderline positive C3 nephritic factor antibody was found and complement testing revealed a high level of soluble membrane attack complex\n\n\n\nAbbreviations\n6MPSix mercaptopurine\n\nADAMTS13A Disintegrin and Metalloproteinase Thrombospondin Motif # 13, member 1\n\naHUSAtypical Hemolytic Uremic Syndrome\n\nANAAnti Nuclear Antibody\n\nanti APL AbAnti Phospholipid Antibody\n\nanti CLAnti Cardiolipin\n\naPTTActivated Partial Thromboplastin Time\n\nCAPSCatastrophic Antiphospholipid Antibody Syndrome\n\nCDCrohn’s Disease\n\nCrCreatinine\n\ndLDeciliter\n\nDRVVTDilute Russell Viper Venom Time Assay\n\ndsDNAAnti Double Stranded DNA\n\nIBDInflammatory bowel disease\n\nINR International Normalized Ratio\n\nLLiter\n\nLDHLactate Dehydrogenase\n\nmgMilligram\n\nmicroliteruL\n\nmLMilliliter\n\nngNanogram\n\nPTProthrombin Time\n\nRBCRed blood cell\n\nRNP-smith,Anti Ribonucleic protein Smith\n\nTMAThrombotic Microangiopathy\n\nTTP.Thrombotic Thrombocytopenic Purpura\n\nUCUlcerative Colitis\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nIK is supported in part by funds from the NIH (R01-DK077162), the Allan Smidt Charitable Fund, the Factor Family Foundation, and the Ralph Block Family Foundation.\n\nAuthors’ contributions\nRMH, directed manuscript writing as first author. NM, assisted in writing case 2 and revised text of manuscript. RB, assisted in the background and with case 2. LA, assisted in writing case 1. US, helped with case 1 and figures. BY, edited case with oversight of gastrointestinal portions of introduction and conclusion. PB, assisted in making figures. MF, edited text and compiled references. IK, edited text of manuscript as senior author. All authors read and approved the final manuscript.\n\nAuthors’ information\nRamy M, Hanna MD FASN FACP Is an assistant Professor and nephrology consultant at UCLA David Geffen School of Medicine with expertise in complement mediated renal disorders.\n\nNoah Merin MD PhD is an assistant professor and hematology / oncology consultant at Cedars Sinai Medical Center with expertise in complement mediated diseases.\n\nRichard Burwick MD MPH is an associate professor and maternal fetal medicine consultant at Cedars Sinai Medical Center with key expertise in pre-eclampsia and complement mediated disorders during pregnancy.\n\nIra Kurtz MD is a long term-NIH funded investigator, and the division chief of nephrology at UCLA.\n\nFunding\nIK is supported in part by funds from the NIH (R01-DK077162), the Allan Smidt Charitable Fund, the Factor Family Foundation and the Ralph Block Family Foundation.\n\nSponsorship: This work was not sponsored.\n\nAvailability of data and materials\nNot applicable, no data.\n\nEthics approval and consent to participate\nNot applicable, this was discussed with UCLA IRB and determined not to constitute human research material and not to need an institutional review board application.\n\nConsent for publication\nConsent for publication has been obtained in writing by authors from patients and has been documented in health record.\n\nCompeting interests\nRMH, NM, and RB belong to the 2018 and 2019 Alexion Pharmaceuticals speaker’s Bureau and received honoraria for speaking and consulting.\n==== Refs\nReferences\n1. Hanna R, Marina B, Vandross A et.al. Atypical hemolytic uremic syndrome and complement blockade: established and emerging uses of complement activation. Curr Opin Nephrol Hypertens 2019, 28:000–000 DOI: 10.1097/MHN.0000000000000499.\n2. Park MHCN Ulmer S Weitz IC Complement-mediated thrombotic microangiopathy associated with lupus nephritis Blood Advances 2018 2 2090 2094 10.1182/bloodadvances.2018019596 30131343 \n3. Park MHWI Effective treatment of thrombotic Microangiopathy associated with lupus nephritis with Eculizumab: a series of 8 cases Blood. 2017 130 1043 10.1182/blood-2017-02-768234 \n4. Hanna RMHM Larson B Lopez EA Wilson J Hendifar A Thrombotic Microangiopathy due to catastrophic antiphospholipid antibody syndrome confirmed on skin biopsy and treated with Eculizumab J Onco Nephrol 2017 1 2 \n5. Bianchi L, Gaiani F, Vincenzi F, et.al. Hemolytic uremic syndrome: differential diagnosis with the onset of inflammatory bowel diseases. Acta Biomed 2018;89(9-S):153–157. (Review).\n6. Beers K Zarrabi K Yezina N Atypical HUS in a patient with inflammatory bowel disease Am J Kidney Dis 2017 69 4 A1 A105 \n7. Webb TN Griffiths H Miyashita Y Atypical hemolytic uremic syndrome and chronic ulcerative colitis treated with Eculizumab Int J Med Pharm Case Reports Int J Med Pharm Case Reports 2015 4 5 105 112 10.9734/IJMPCR/2015/18771 27135055 \n8. Viada Bris JF, Velasco Rodríguez-Belvís M, de Lucas Collantes C. Et.al. Ulcerative colitis and atypical hemolytic-uremic syndrome: an unusual but potentially life-threating life complication. Inflamm Bowel Dis. 2018 Jun 20.\n9. Viada Bris JF, Velasco Rodríguez-Belvís M, de Lucas Collantes C, et.al. Ulcerative Colitis and Atypical Hemolytic-Uremic Syndrome: An Unusual But Potentially Life-threatening Complication Inflamm Bowel Dis • Volume 00, Number 00, Month 2018 (letter to the editor).\n10. Green H Harari E Davidovits M Atypical HUS due to factor H antibodies in an adult patient successfully treated with eculizumab Ren Fail 2014 36 7 1119 1121 10.3109/0886022X.2014.917574 24828571 \n11. Rodriguez de Cordoba S Hidalgo MS Pinto S Et.al. Genetics of atypical hemolytic uremic syndrome (aHUS) Semin Thromb Hemost 2014 40 4 422 430 10.1055/s-0034-1375296 24799305 \n12. Bu F, Zhang Y, Wang K, et.al. Genetic analysis of 400 patients refines understanding and implicates a new gene in atypical hemolytic uremic syndrome. J Am Soc Nephrol 2018;29(12):2809–2819.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1477-9560",
"issue": "17()",
"journal": "Thrombosis journal",
"keywords": "Atypical hemolytic uremic syndrome; Complement; Complement blockade; Crohn’s colitis/Crohn’s disease; Inflammatory bowel disease; Thrombotic Microangiopathy; Ulcerative colitis",
"medline_ta": "Thromb J",
"mesh_terms": null,
"nlm_unique_id": "101170542",
"other_id": null,
"pages": "18",
"pmc": null,
"pmid": "31516395",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "24799305;24828571;27135055;30131343;30377230;30561409;30865166",
"title": "Successful use of eculizumab to treat atypical hemolytic uremic syndrome in patients with inflammatory bowel disease.",
"title_normalized": "successful use of eculizumab to treat atypical hemolytic uremic syndrome in patients with inflammatory bowel disease"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-19-05214",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BUDESONIDE"
},
"d... |
{
"abstract": "Cytomegalovirus (CMV) infections can induce severe complications in immunosuppressed patients. Currently, ganciclovir represents the preferred treatment option; however, in patients with resistance or toxicity related to ganciclovir, the therapeutic options are limited.Cellular immunity plays an important role in the control of viral infections. Adoptive T-cell therapy can contribute to recovering immunological function in immunosuppressed patients. Selective T-cell depletion targeting CD45RA enhances early T-cell recovery and can represent a salvage therapy. In this study, an immunocompromised non-transplanted patient with CMV disease and toxicity to conventional therapy was successfully treated by adoptive transfer of CD45RA-depleted T-cells.",
"affiliations": "Division of Infectious Diseases, Clínica Universidad de Navarra, Pamplona, Spain.;Immunology and Immunotherapy Department, Clínica Universidad de Navarra, Pamplona, Spain.;Hematology Service and Cell Therapy Area, Clínica Universidad de Navarra, Pamplona, Spain.;Immunology and Immunotherapy Department, Clínica Universidad de Navarra, Pamplona, Spain.;Division of Infectious Diseases, Clínica Universidad de Navarra, Pamplona, Spain.;Immunology and Immunotherapy Department, Clínica Universidad de Navarra, Pamplona, Spain.",
"authors": "Yuste|Jose R|JR|;López-Díaz de Cerio|Ascensión|A|;Rifón|Jose|J|;Moreno|Cristina|C|;Panizo|María|M|;Inogés|Susana|S|",
"chemical_list": "D004279:DNA, Viral; D007074:Immunoglobulin G; D017493:Leukocyte Common Antigens",
"country": "England",
"delete": false,
"doi": "10.3851/IMP3307",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1359-6535",
"issue": "24(4)",
"journal": "Antiviral therapy",
"keywords": null,
"medline_ta": "Antivir Ther",
"mesh_terms": "D000368:Aged; D003586:Cytomegalovirus Infections; D004279:DNA, Viral; D046148:Donor Selection; D005434:Flow Cytometry; D006801:Humans; D016867:Immunocompromised Host; D007074:Immunoglobulin G; D016219:Immunotherapy, Adoptive; D017493:Leukocyte Common Antigens; D008297:Male; D013601:T-Lymphocytes; D014019:Tissue Donors; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "9815705",
"other_id": null,
"pages": "313-319",
"pmc": null,
"pmid": "30912764",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Adoptive T-cell therapy with CD45RA-depleted donor in the treatment of cytomegalovirus disease in immunocompromised non-transplant patients.",
"title_normalized": "adoptive t cell therapy with cd45ra depleted donor in the treatment of cytomegalovirus disease in immunocompromised non transplant patients"
} | [
{
"companynumb": "ES-ROCHE-2549710",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BENDAMUSTINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Neurological involvement of sarcoidosis is a rare condition, and its occurrence in the context of transplantation is exceptional. Moreover, treatment can be challenging. We report the unusual case of a patient transplanted with a kidney for end-stage renal disease secondary to sarcoidosis who experienced a neurological recurrence of the disease under immunosuppressive treatment, translating in behavioural aggressiveness, social withdrawal and weight loss. He relapsed thrice under corticosteroids but responded finally to infliximab. This case highlights the potential of sarcoidosis to recur neurologically after kidney transplantation despite immunosuppressive treatment. Also, treatment of relapsing neurosarcoidosis can be challenging and may benefit from TNF-α blockers.",
"affiliations": "Division of Nephrology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.;Division of Nephrology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.;Division of Radiology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.;Division of Neurology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.;Division of Nephrology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.;Division of Nephrology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.;Division of Nephrology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.",
"authors": "Hanset|Nicolas|N|https://orcid.org/0000-0002-8914-8209;Tsevi|Mawufemo Yawovi|MY|;Duprez|Thierry|T|;Ivanoiu|Adrian|A|;Devresse|Arnaud|A|;Demoulin|Nathalie|N|;Kanaan|Nada|N|https://orcid.org/0000-0001-7903-8631",
"chemical_list": "D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1080/17843286.2019.1664093",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1784-3286",
"issue": "76(2)",
"journal": "Acta clinica Belgica",
"keywords": "Neurosarcoidosis; TNF-alpha blockers; immunosuppression; kidney transplantation; sarcoidosis",
"medline_ta": "Acta Clin Belg",
"mesh_terms": "D002493:Central Nervous System Diseases; D006801:Humans; D000069285:Infliximab; D016030:Kidney Transplantation; D008297:Male; D009364:Neoplasm Recurrence, Local; D012507:Sarcoidosis",
"nlm_unique_id": "0370306",
"other_id": null,
"pages": "149-151",
"pmc": null,
"pmid": "31486719",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Infliximab for relapsing neurosarcoidosis recurring after kidney transplantation: a case report.",
"title_normalized": "infliximab for relapsing neurosarcoidosis recurring after kidney transplantation a case report"
} | [
{
"companynumb": "BE-MYLANLABS-2021M1065567",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",... |
{
"abstract": "Patients with relapsed and refractory multiple myeloma have poor prognosis. A recent analysis of patients with relapsed and refractory multiple myeloma who were refractory to both proteasome inhibitors and immunomodulatory drugs showed the median overall survival of 9 months only. Daratumumab is the first-in-class human monoclonal antibody against CD38 cells which was studied in phase I/II trials for treatment of these patients with relapsed refractory multiple myeloma. It showed an overall response rate of 36% and a median overall survival (OS) of 17 months in these patients. We report a case of 40-year-old man with immunoglobulin D (IgD) multiple myeloma whose disease was refractory to at least 5 different chemotherapy regimens including proteasome inhibitors and immunomodulatory drugs. The clinical studies assessing daratumumab did not include any patients with IgD myeloma which is a rare form of multiple myeloma and to our knowledge is the first study reporting use of daratumumab in IgD myeloma.",
"affiliations": "Department of Medicine, University of Arizona, Tucson, AZ, USA.;Banner University Medical Center Tucson, Department of Hematology Oncology, University of Arizona, Tucson, AZ, USA.;Banner University Medical Center Tucson, Department of Hematology Oncology, University of Arizona, Tucson, AZ, USA.;Department of Medicine, University of Arizona, Tucson, AZ, USA.;Department of Medicine, University of Arizona, Tucson, AZ, USA; Banner University Medical Center Tucson, Department of Hematology Oncology, University of Arizona, Tucson, AZ, USA.",
"authors": "Husnain|Muhammad|M|;Kurtin|Sandra|S|;Barkett|Nikki|N|;Riaz|Irbaz Bin|IB|;Agarwal|Amit|A|0000-0002-7342-4969",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2016/2490168",
"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi Publishing Corporation 2775237610.1155/2016/2490168Case ReportRefractory IgD Multiple Myeloma Treated with Daratumumab: A Case Report and Literature Review Husnain Muhammad \n1\nKurtin Sandra \n2\nBarkett Nikki \n2\nRiaz Irbaz Bin \n1\nhttp://orcid.org/0000-0002-7342-4969Agarwal Amit \n1\n\n2\n\n*\n1Department of Medicine, University of Arizona, Tucson, AZ, USA2Banner University Medical Center Tucson, Department of Hematology Oncology, University of Arizona, Tucson, AZ, USA*Amit Agarwal: aagarwal@uacc.arizona.eduAcademic Editor: Josep M. Ribera\n\n2016 26 9 2016 2016 24901685 6 2016 29 8 2016 Copyright © 2016 Muhammad Husnain et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Patients with relapsed and refractory multiple myeloma have poor prognosis. A recent analysis of patients with relapsed and refractory multiple myeloma who were refractory to both proteasome inhibitors and immunomodulatory drugs showed the median overall survival of 9 months only. Daratumumab is the first-in-class human monoclonal antibody against CD38 cells which was studied in phase I/II trials for treatment of these patients with relapsed refractory multiple myeloma. It showed an overall response rate of 36% and a median overall survival (OS) of 17 months in these patients. We report a case of 40-year-old man with immunoglobulin D (IgD) multiple myeloma whose disease was refractory to at least 5 different chemotherapy regimens including proteasome inhibitors and immunomodulatory drugs. The clinical studies assessing daratumumab did not include any patients with IgD myeloma which is a rare form of multiple myeloma and to our knowledge is the first study reporting use of daratumumab in IgD myeloma.\n==== Body\n1. Introduction\nThe conventional treatment options in relapsed multiple myeloma include hematopoietic cell transplantation (HCT) or trial of the previously tried chemotherapy regimens. Several new drugs such as Panobinostat (first-in-class histone deacetylase inhibitor), daratumumab (the first monoclonal antibody), ixazomib (the first oral proteasome inhibitor), and Elotuzumab (the first-in-class immunostimulatory agent) have been approved in the past year [1–4]. However, there is limited experience with the use of these novel drugs in the real life clinical setting and there are no published reports of real life experience with these drugs since their approval. Daratumumab has shown promising results in clinical trials in the setting of relapsed refractory multiple myeloma but most of the patients in clinical trials were IgG, IgA, or Bence Jones proteins multiple myeloma. There is little data regarding daratumumab role in the setting of IgD multiple myeloma. We present a case of Immunoglobulin D (IgD) multiple myeloma which was refractory to at least five different regimens and finally responded when treated with daratumumab.\n\n2. Case Presentation\nA 40-year-old man with a known diagnosis of Immunoglobulin D (IgD) lambda multiple myeloma presented with relapsed multiple myeloma (MM). He first presented in September 2007 with the chief complaint of cough and left sided abdominal pain. Physical examination was significant for splenomegaly. His labs were significant for pancytopenia. A bone marrow biopsy in September 2007 was significant for 100% cellularity and sheets of atypical cells positive for CD138 and lambda light chains consistent with multiple myeloma. Protein electrophoresis showed a monoclonal spike (M spike) and an elevated IgD level of 190 mg/L. A diagnosis of IgD multiple myeloma was made and he was initially started on dexamethasone and later in October 2007 thalidomide was added to his regimen. Patient had intermittent lapses in his thalidomide treatment because of his insurance issues and his IgD level slowly kept rising. In July 2008 his IgD level was found to be 293 mg/L. A bone marrow biopsy performed in July 2008 was significant for 5% plasma cells by immunohistochemistry. He was continued on dexamethasone and thalidomide. A repeat bone marrow biopsy in July 2009 showed 40% plasma cells. At that point bortezomib was added to his regimen to reduce his tumor burden and he was referred for autologous peripheral blood stem cell transplantation (PBSCT). Patient only took 50 mg of thalidomide instead of usual 100 mg. His repeat bone marrow biopsy in February 2010 showed persistent multiple myeloma with 20% monoclonal plasma cells with overall cellularity of 60%. In March 2010 his IgD level increased up to 531 mg/L. At that point his thalidomide dose was increased to 200 mg daily. Patient was having issues with compliance. Eventually, he underwent autologous peripheral blood stem cell transplant (PBSCT) on January 2011 after 6 cycles of salvage CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) chemotherapy. He was transplanted with stable disease with his pretransplant IgD level of 112 mg/L. He did not receive maintenance therapy and only 10 months after transplant there was evidence of myeloma progression with IgD level increasing to over 500 mg/L in October 2011. Patient at that point chose to pursue alternative therapies and was lost to follow-up. He presented again in April 2012 with severe lower back pain and an IgD level of 4020 mg/L. He was immediately started on pulse dose dexamethasone and lenalidomide was added in May 2012 (25 mg daily for 21 of 28 days). His IgD level decreased to 60 mg/L in November 2012 consistent with a very good partial response (VGPR) and he underwent a second autologous PBSCT in January 2013. His posttransplant course was complicated by some chemotherapy associated nausea, diarrhea, and neutropenic fever. He recovered well and was discharged home in stable condition. His day 100 bone marrow biopsy in April 2013 showed 20–40% plasma cells and an IgD level of 107 mg/L consistent with disease progression. Patient was restarted on lenalidomide 25 mg daily and had an initial response with a decrease in his IgD, which nadired at about 23.9 mg/L in June 2013 but his IgD quickly began to rise again.\n\nDespite lenalidomide and dexamethasone, his IgD continued to rise to as high as 500 mg/L and at that point he was started on Pomalidomide in December 2013. He completed 2 cycles of Pomalidomide and dexamethasone but his disease continued to progress so he was switched to bortezomib, Pomalidomide, and dexamethasone in September 2014 for about 4-5 months and later carfilzomib, Pomalidomide, and dexamethasone for an additional 5 months from January 2015 to May 2015 without much improvement. He was started on bortezomib, Panobinostat, and dexamethasone in July 2015 but could not tolerate this regimen. He was deemed to be unsuitable for allogeneic stem cell transplant by his insurance. He was requiring PRBC transfusion twice a week to maintain his hemoglobin to >7. He was not a candidate for clinical trials because of his cytopenias. At that point we decided to treat him with daratumumab. His pretreatment IgD levels in December 2015 were 4000 mg/L and came down drastically to 5 mg/L in May 2016 after 5 cycles of daratumumab showing very good partial response (Figure 1). During his first infusion, he developed a grade 3 infusion reaction. His other side effects to medication were transient neutropenia and E. coli and Giardia diarrhea for which he was treated with antibiotics. His transfusion requirements which had been very high throughout his disease course requiring multiple transfusions with packed red blood cells (PRBCs) also came down dramatically with stable hemoglobin levels after the start of daratumumab (Figure 2). Patient continues on daratumumab, with his last IgD level at 12 mg/L in June 2016.\n\n3. Discussion\nMultiple myeloma is a plasma cell neoplasm with an incidence of 6.3 cases per 100,000 persons per year in United States [5, 6]. The treatment outcome and overall survival have significantly improved after the use of novel agents and autologous stem cell transplant for multiple myeloma [1]. However, for patients who are refractory to these agents, the prognosis remains poor with overall survival (OS) of 9 months only [7]. This clearly demonstrates the need for additional agents with novel mechanisms of actions. In the past decade, many new potential therapeutic targets have been identified, including histone deacetylation, proteasome activity, mammalian target of rapamycin, and targetable surface receptors such as SLAMF-7, CD38, and CD40 [1, 2, 8]. Monoclonal antibodies in particular present a new exciting approach. Two new monoclonal antibodies daratumumab (anti-CD38) and Elotuzumab (anti-SLAMF-7) have been approved by FDA for relapsed refractory multiple myeloma [9].\n\nCD38 is a transmembrane glycoprotein that is highly expressed on multiple myeloma cells and at low levels on normal lymphoid and myeloid cells [10, 11]. It functions as an ectoenzyme involved in regulating intracytoplasmic concentration of calcium and the catabolism of extracellular nucleotides. Daratumumab, an IgG1-k fully human anti-CD38 monoclonal antibody, exerts its cytotoxic effect through a number of mechanisms after binding to CD38, including antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated phagocytosis (ADCP), and the direct induction of apoptosis [12, 13]. Moreover, an immunomodulatory effect of daratumumab was also recently described [14]. The safety of daratumumab was investigated in a dose-escalation phase I/II trial of 104 patients with relapsed or refractory multiple myeloma. The most common adverse events were grade 3 or 4 pneumonia and thrombocytopenia. The overall response rate was 36% in the cohort that received 16 mg per kilogram and 10% in the cohort that received 8 mg per kilogram. In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months [11]. In another open label phase II trial (SIRIUS) 106 patients with multiple myeloma who had failed at least three lines of treatment including a proteasome inhibitor and immunomodulatory drugs were treated with daratumumab [15]. Two dose levels 8 mg/kg and 16 mg/kg were evaluated. Daratumumab was well tolerated and there were no discontinuations due to drug-related treatment emergent adverse effects. Infusion reactions were seen in 45 (42%) patients but these were mostly grades 1 and 2 with five patients reporting grade 3 and none with grade 4 infusion reaction. Other side effects included fatigue (40%) and anemia (33%). Patients treated with daratumumab showed 29% overall response with a median time to first response of one month. The estimated median progression-free and overall survival rates were 3.7 and 17.5 months, respectively [15].\n\nTwo phase III trials [16] are evaluating patients with relapsed or refractory disease; one is comparing daratumumab plus bortezomib and dexamethasone with bortezomib and dexamethasone (NCT02136134) [16], and the other is comparing daratumumab plus lenalidomide and dexamethasone with lenalidomide and dexamethasone (NCT02076009) [16]. The final results of these studies are awaited but the CASTOR trial (Velcade/dex versus Dara/Velcade/dex) was stopped early because at an interim analysis the study met its end point with a very impressive hazard ratio of 0.39 favoring the daratumumab arm. The POLLUX study (Rev/dex versus Dara/Rev/dex) has also shown similarly impressive results with a hazard ratio of 0.37 favoring the Dara arm. Two additional phase III studies are being performed in patients with previously untreated multiple myeloma; one is comparing daratumumab plus bortezomib, melphalan, and prednisone with bortezomib, melphalan, and prednisone (NCT02195479), and the other is evaluating daratumumab plus lenalidomide and dexamethasone with lenalidomide and dexamethasone (NCT02252172) [17].\n\n4. Conclusions\nDespite significant progress in the treatment of multiple myeloma, the disease remains incurable in a vast majority of patients. The approval of promising new agents will undoubtedly improve outcomes for myeloma patients. Daratumumab is a monoclonal antibody that is now approved for treatment of multiple myeloma patients and has shown significant response in the real world setting. Our case illustrates the potential of a dramatic response using monoclonal antibodies in patients that are heavily pretreated and having a very meaningful impact towards their outcome.\n\nCompeting Interests\nAmit Agarwal is on the speaker's bureau for Janssen pharmaceutical. The other authors declare that there is no conflict of interest related to this publication of this article.\n\nFigure 1 IgD levels over the course of 6 years of treatment.\n\nFigure 2 Transfusion requirements prior to starting daratumumab and after daratumumab.\n==== Refs\n1 Ito S. Novel agents in multiple myeloma treatment Rinsho Ketsueki 2015 56 10 2066 2073 26458446 \n2 El-Amm J. Tabbara I. A. Emerging therapies in multiple myeloma American Journal of Clinical Oncology 2015 38 3 315 321 10.1097/coc.0b013e3182a4676b 2-s2.0-84930761105 23934133 \n3 Afifi S. Michael A. Lesokhin A. Immunotherapy: a new approach to treating multiple myeloma with daratumumab and elotuzumab Annals of Pharmacotherapy 2016 50 7 555 568 10.1177/1060028016642786 27083916 \n4 Poh A. Multiple myeloma gets three new drugs Cancer Discovery 2016 6 1 p. 4 \n5 Smith A. Howell D. Patmore R. Jack A. Roman E. Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network British Journal of Cancer 2011 105 11 1684 1692 10.1038/bjc.2011.450 2-s2.0-81955165195 22045184 \n6 Siegel R. L. Miller K. D. Jemal A. Cancer statistics, 2016 CA: A Cancer Journal for Clinicians 2016 66 1 7 30 10.3322/caac.21332 2-s2.0-84954400636 26742998 \n7 Daratumumab improves overall survival in multiple myeloma American Health & Drug Benefits 2016 9, article 14 \n8 Ocio E. M. Richardson P. G. Rajkumar S. V. New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG) Leukemia 2014 28 3 525 542 10.1038/leu.2013.350 2-s2.0-84895784261 24253022 \n9 Kuroda J. Nagoshi H. Shimura Y. Taniwaki M. Elotuzumab and daratumumab: emerging new monoclonal antibodies for multiple myeloma Expert Review of Anticancer Therapy 2013 13 9 1081 1088 10.1586/14737140.2013.829641 2-s2.0-84896527916 24053207 \n10 Laubach J. P. Richardson P. G. CD38-targeted immunochemotherapy in refractory multiple myeloma: a new horizon Clinical Cancer Research 2015 21 12 2660 2662 10.1158/1078-0432.ccr-14-3190 2-s2.0-84930319546 25878332 \n11 Lokhorst H. M. Plesner T. Laubach J. P. Targeting CD38 with daratumumab monotherapy in multiple myeloma The New England Journal of Medicine 2015 373 13 1207 1219 10.1056/nejmoa1506348 2-s2.0-84942436321 26308596 \n12 Van Der Veer M. S. De Weers M. Van Kessel B. The therapeutic human CD38 antibody daratumumab improves the anti-myeloma effect of newly emerging multi-drug therapies Blood Cancer Journal 2011 1 10, article e41 10.1038/bcj.2011.42 2-s2.0-84864061825 \n13 Overdijk M. B. Verploegen S. Bögels M. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma mAbs 2015 7 2 311 321 10.1080/19420862.2015.1007813 2-s2.0-84924546237 25760767 \n14 Khagi Y. Mark T. M. Potential role of daratumumab in the treatment of multiple myeloma OncoTargets and Therapy 2014 7 1095 1100 10.2147/ott.s49480 2-s2.0-84902982435 24971019 \n15 Lonial S. Weiss B. M. Usmani S. Z. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial The Lancet 2016 387 10027 1551 1560 10.1016/s0140-6736(15)01120-4 2-s2.0-84953325096 \n16 Palumbo A. Dimopoulos M. A. Reece D. E. Twin randomized studies of daratumumab (DARA; D) plus standard of care (lenalidomide/dexamethasone or bortezomib/dexamethasone [DRd or DVd]) versus Rd or Vd alone in relapsed or refractory multiple myeloma (MM): 54767414MMY3003 (Pollux) and 54767414MMY3004 (Castor) Proceedings of the 2015 ASCO Annual Meeting 2015 \n17 Mateos M.-V. Cavo M. Jakubowiak A. J. A randomized open-label study of bortezomib, melphalan, and prednisone (VMP) versus daratumumab (DARA) plus VMP in patients with previously untreated multiple myeloma (MM) who are ineligible for high-dose therapy: 54767414MMY3007 (Alcyone) Journal of Clinical Oncology 2015 33 supplement, abstract TPS8608 Proceedings of the ASCO Annual Meeting\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2016()",
"journal": "Case reports in oncological medicine",
"keywords": null,
"medline_ta": "Case Rep Oncol Med",
"mesh_terms": null,
"nlm_unique_id": "101581035",
"other_id": null,
"pages": "2490168",
"pmc": null,
"pmid": "27752376",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "22829073;26458446;26658418;25878332;27083916;25760767;26308596;22045184;23934133;26778538;24971019;27014408;26742998;24053207;24253022",
"title": "Refractory IgD Multiple Myeloma Treated with Daratumumab: A Case Report and Literature Review.",
"title_normalized": "refractory igd multiple myeloma treated with daratumumab a case report and literature review"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-16-02742",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
... |
{
"abstract": "Increasing numbers of patients are now offered immunotherapy as part of their cancer treatment. These treatments, while often very effective, have a wide range of adverse effects that are distinct from those of traditional chemotherapy regimens. Thyroid disease, dermatological disease, colitis and pneumonitis are some of the most commonly reported immune side effects. We present a case of life-threatening de novo autoimmune haemolytic anaemia (AIHA) complicated by immune cholangitis induced by pembrolizumab. An 81-year-old woman with metastatic melanoma completed a two-year course of pembrolizumab in August 2018 and six weeks later presented to hospital with jaundice. Admission haemoglobin (Hb) was 91 g/L, rapidly decreasing to 31 g/L, at which point she required admission to the intensive care unit. AIHA is a rare but potentially life-threatening complication of checkpoint inhibitors and should be considered in patients presenting with anaemia during or after immunotherapy treatment.",
"affiliations": "Haematology Department, Buckinghamshire Healthcare NHS Trust, Aylesbury, UK harriet.williams3@nhs.net.;Haematology Department, Buckinghamshire Healthcare NHS Trust, Aylesbury, UK.",
"authors": "Williams|Harriet|H|http://orcid.org/0000-0002-8009-9236;Aitchison|Robin|R|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C582435:pembrolizumab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-232505",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(12)",
"journal": "BMJ case reports",
"keywords": "haematology (drugs and medicines); haematology (incl blood transfusion); oncology; skin cancer; unwanted effects/adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D000744:Anemia, Hemolytic, Autoimmune; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D002761:Cholangitis; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008545:Melanoma; D009362:Neoplasm Metastasis; D012878:Skin Neoplasms",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31811095",
"pubdate": "2019-12-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29340837;26115796;30790338;28239468;30528137;30715153;7165009;29669775;29924973;27472273;30347480;28317087;26765102;26795275;30228268;25891173;28881921;30677306",
"title": "Pembrolizumab-induced autoimmune haemolytic anaemia and cholangitis.",
"title_normalized": "pembrolizumab induced autoimmune haemolytic anaemia and cholangitis"
} | [
{
"companynumb": "GB-009507513-2001GBR001170",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Molecular targeted therapies are becoming ubiquitous in cancer treatment. These drugs may cause gastrointestinal toxicities including perforation, pneumatosis, enteritis, colitis and fistula formation. Knowledge of these complications and their management enables early radiological identification and appropriate intervention, reducing patient morbidity and mortality.",
"affiliations": "Department of Imaging, Dana-Farber Cancer Institute, Boston, MA, USA.",
"authors": "Thornton|E|E|;Howard|S A|SA|;Jagannathan|J|J|;Krajewski|K M|KM|;Shinagare|A B|AB|;O'Regan|K|K|;Cleary|J M|JM|;Ramaiya|N H|NH|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1259/bjr/19815818",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1285",
"issue": "85(1018)",
"journal": "The British journal of radiology",
"keywords": null,
"medline_ta": "Br J Radiol",
"mesh_terms": "D000368:Aged; D003092:Colitis; D005260:Female; D005759:Gastroenteritis; D006801:Humans; D007410:Intestinal Diseases; D007412:Intestinal Fistula; D007416:Intestinal Perforation; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009369:Neoplasms; D011006:Pneumatosis Cystoides Intestinalis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0373125",
"other_id": null,
"pages": "1420-6",
"pmc": null,
"pmid": "22674709",
"pubdate": "2012-10",
"publication_types": "D016428:Journal Article",
"references": "19482548;16710025;21208844;20380333;21576636;20524036;20382413;17962908;18024857;21357780;21188500;20525992;21245693",
"title": "Imaging features of bowel toxicities in the setting of molecular targeted therapies in cancer patients.",
"title_normalized": "imaging features of bowel toxicities in the setting of molecular targeted therapies in cancer patients"
} | [
{
"companynumb": "US-PFIZER INC-2017419858",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SUNITINIB MALATE"
},
"drugadditional": "1",
... |
{
"abstract": "To examine the effect of disease-modifying antirheumatic drug (DMARD) therapy on hepatotoxicity among patients with rheumatoid arthritis (RA) and hepatitis C virus (HCV) infection.\n\n\n\nWe identified biologic and nonbiologic treatment episodes of patients with RA using the 1997-2011 national data from the US Veterans Health Administration. Eligible episodes had HCV infection (defined by detectable HCV RNA) and subsequently initiated a new biologic or nonbiologic DMARD. Cohort entry required a baseline alanine aminotransferase (ALT) < 66 IU/l and quantifiable HCV RNA within 90 days prior to starting biologic/DMARD therapy. The primary outcome of interest was hepatotoxicity, defined as ALT elevation ≥ 100 IU/l or increase in HCV RNA of 1 log or more, and was examined within the first year of biologic/DMARD use. Results were reported as the cumulative incidence of treatment episodes achieving predefined hepatotoxicity at 3, 6, and 12 months after biologic/DMARD initiation.\n\n\n\nRA patients with HCV (n = 748) were identified and contributed 1097 biologic/DMARD treatment episodes. Overall, ALT elevations were uncommon, with 37 (3.4%) hepatotoxicity events occurring within 12 months. Treatment episodes with biologic DMARD demonstrated more frequency of hepatotoxicity than did nonbiologic DMARD (4.8% vs 2.3%, p = 0.03). Among treatment episodes involving hepatotoxicity events, the majority occurred within 6 months of DMARD initiation (29/37, 78%).\n\n\n\nIn US veterans with HCV and RA receiving biologic and nonbiologic DMARD, the frequency of hepatotoxicity (ALT ≥ 100 IU/l) was low, with a higher frequency observed in treatment episodes with current biologic use.",
"affiliations": "From the Veterans Affairs (VA) Medical Center; Department of Medicine, Division of Infectious Diseases, University of Mississippi Medical Center, Jackson, Mississippi; Birmingham VA Medical Center (VAMC); Department of Medicine, Division of Rheumatology, University of Alabama at Birmingham; Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama; VA Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, Nebraska; Oregon Health Sciences University, Portland, Oregon, USA. Mary.burton2@va.gov.;From the Veterans Affairs (VA) Medical Center; Department of Medicine, Division of Infectious Diseases, University of Mississippi Medical Center, Jackson, Mississippi; Birmingham VA Medical Center (VAMC); Department of Medicine, Division of Rheumatology, University of Alabama at Birmingham; Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama; VA Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, Nebraska; Oregon Health Sciences University, Portland, Oregon, USA.;From the Veterans Affairs (VA) Medical Center; Department of Medicine, Division of Infectious Diseases, University of Mississippi Medical Center, Jackson, Mississippi; Birmingham VA Medical Center (VAMC); Department of Medicine, Division of Rheumatology, University of Alabama at Birmingham; Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama; VA Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, Nebraska; Oregon Health Sciences University, Portland, Oregon, USA.;From the Veterans Affairs (VA) Medical Center; Department of Medicine, Division of Infectious Diseases, University of Mississippi Medical Center, Jackson, Mississippi; Birmingham VA Medical Center (VAMC); Department of Medicine, Division of Rheumatology, University of Alabama at Birmingham; Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama; VA Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, Nebraska; Oregon Health Sciences University, Portland, Oregon, USA.;From the Veterans Affairs (VA) Medical Center; Department of Medicine, Division of Infectious Diseases, University of Mississippi Medical Center, Jackson, Mississippi; Birmingham VA Medical Center (VAMC); Department of Medicine, Division of Rheumatology, University of Alabama at Birmingham; Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama; VA Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, Nebraska; Oregon Health Sciences University, Portland, Oregon, USA.;From the Veterans Affairs (VA) Medical Center; Department of Medicine, Division of Infectious Diseases, University of Mississippi Medical Center, Jackson, Mississippi; Birmingham VA Medical Center (VAMC); Department of Medicine, Division of Rheumatology, University of Alabama at Birmingham; Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama; VA Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, Nebraska; Oregon Health Sciences University, Portland, Oregon, USA.;From the Veterans Affairs (VA) Medical Center; Department of Medicine, Division of Infectious Diseases, University of Mississippi Medical Center, Jackson, Mississippi; Birmingham VA Medical Center (VAMC); Department of Medicine, Division of Rheumatology, University of Alabama at Birmingham; Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama; VA Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, Nebraska; Oregon Health Sciences University, Portland, Oregon, USA.;From the Veterans Affairs (VA) Medical Center; Department of Medicine, Division of Infectious Diseases, University of Mississippi Medical Center, Jackson, Mississippi; Birmingham VA Medical Center (VAMC); Department of Medicine, Division of Rheumatology, University of Alabama at Birmingham; Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama; VA Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, Nebraska; Oregon Health Sciences University, Portland, Oregon, USA.",
"authors": "Burton|Mary Jane|MJ|;Curtis|Jeffrey R|JR|;Yang|Shuo|S|;Chen|Lang|L|;Singh|Jasvinder A|JA|;Mikuls|Ted R|TR|;Winthrop|Kevin L|KL|;Baddley|John W|JW|",
"chemical_list": "D018501:Antirheumatic Agents; D001688:Biological Products",
"country": "Canada",
"delete": false,
"doi": "10.3899/jrheum.160983",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0315-162X",
"issue": "44(5)",
"journal": "The Journal of rheumatology",
"keywords": "ANTIRHEUMATIC AGENTS; CHRONIC HEPATITIS C; RHEUMATOID ARTHRITIS; VETERANS HEALTH",
"medline_ta": "J Rheumatol",
"mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D001688:Biological Products; D005260:Female; D006526:Hepatitis C; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014728:Veterans",
"nlm_unique_id": "7501984",
"other_id": null,
"pages": "565-570",
"pmc": null,
"pmid": "28250142",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": null,
"title": "Safety of Biologic and Nonbiologic Disease-modifying Antirheumatic Drug Therapy in Veterans with Rheumatoid Arthritis and Hepatitis C Virus Infection.",
"title_normalized": "safety of biologic and nonbiologic disease modifying antirheumatic drug therapy in veterans with rheumatoid arthritis and hepatitis c virus infection"
} | [
{
"companynumb": "US-ROCHE-1938166",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Solid organ transplant patients are at heightened risk of several cancers compared to the general population. Secondary to a higher number of procedures and better survival after transplantation, cancer is a rising health concern in this situation. Limited data exist for lung cancer (LC) after renal transplantation. We report here the most important series of renal transplant recipients with lung cancer.\n\n\n\nRetrospective study of all cases of LC diagnosed in three French Renal Transplant Units from 2003 to 2012. A control group consisted of non-transplant patients with LC matched with the cases for age (<30; 30-50; 50-65; >65 years), gender and diagnosis date. We recruited two controls for each case.\n\n\n\nThirty patients (median age 60 years; range 29-85; male/female ratio 80/20%) with LC were analysed. LC incidence was 1.89/1000 person-years over the period 2008-2012. All patients were former or active smokers (median 30 pack-years). Transplanted patients had significantly more comorbidities, mainly cardiovascular disease. The median interval of time from kidney transplantation (KT) to diagnosis of LC was 7 years (range 0.5-47 years). LC was incidentally diagnosed in 40%. Most patients (70%) had advanced LC (stage III or IV) disease. Stage of LC at diagnosis was similar in cases and controls. Surgery and chemotherapy were proposed to the same proportion of patients. In cases, mortality was cancer related in 87% and median survival time after diagnosis was 24 months. Survival was not significantly different between the 2 groups.\n\n\n\nDespite frequent medical and radiological examinations, diagnosis of LC is usually made at an advanced stage and the overall prognosis remains poor.",
"affiliations": "Respiratory Diseases Department, Foch Hospital, Suresnes, France.;Respiratory Diseases Department, Foch Hospital, Suresnes, France.;Respiratory Diseases Department, Foch Hospital, Suresnes, France; Faculté des Sciences de la vie UPRES EA 220, Versailles Saint-Quentin University, Versailles, France.;Renal Transplantation Unit, Necker-Enfants Malades Hospital, Paris, France.;Respiratory Diseases Department, Bichat Hospital, Paris, France.;Nephrology Department, Foch Hospital, Suresnes, France.;Renal Transplantation Unit, Necker-Enfants Malades Hospital, Paris, France; Paris VI René Descartes University, Paris, France.;Renal Transplantation Unit, Necker-Enfants Malades Hospital, Paris, France.;Respiratory Diseases Department, Foch Hospital, Suresnes, France.;Thoracic Surgery Department, Foch Hospital, Suresnes, France.;Radiology Department, Foch Hospital, Suresnes, France.;Respiratory Diseases Department, Foch Hospital, Suresnes, France.;Nephrology Department, Foch Hospital, Suresnes, France.;Thoracic Surgery Department, Foch Hospital, Suresnes, France.;Oncology Department, Foch Hospital, Suresnes, France.;Nephrology Department, Foch Hospital, Suresnes, France.;Department of Pathology, Foch Hospital, Suresnes, France.;Thoracic Surgery Department, Foch Hospital, Suresnes, France.;Respiratory Diseases Department, Foch Hospital, Suresnes, France.;Thoracic Surgery Department, Foch Hospital, Suresnes, France.;Department of Pathology, Foch Hospital, Suresnes, France.;Renal Transplantation Unit, Necker-Enfants Malades Hospital, Paris, France; Paris VI René Descartes University, Paris, France.;Respiratory Diseases Department, Foch Hospital, Suresnes, France.;Respiratory Diseases Department, Foch Hospital, Suresnes, France. Electronic address: e.catherinot@hopital-foch.org.",
"authors": "Rousseau-Gazaniol|Claire|C|;Fraboulet|Séverine|S|;Couderc|Louis-Jean|LJ|;Kreis|Henri|H|;Borie|Raphaël|R|;Tricot|Leila|L|;Anglicheau|Dany|D|;Martinez|Frank|F|;Doubre|Hélène|H|;Bonnette|Pierre|P|;Mellot|François|F|;Massiani|Marie-Ange|MA|;Pelle|Gaëlle|G|;Sage|Edouard|E|;Moisson|Patricia|P|;Delahousse|Michel|M|;Zemoura|Leila|L|;Chapelier|Alain|A|;Hamid|Abdul Monem|AM|;Puyo|Philippe|P|;Longchampt|Elisabeth|E|;Legendre|Christophe|C|;Friard|Sylvie|S|;Catherinot|Emilie|E|",
"chemical_list": null,
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.lungcan.2017.07.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "111()",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "Kidney transplantation; Lung cancer; Thoracic malignancies; Thoracic surgery",
"medline_ta": "Lung Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D016030:Kidney Transplantation; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011159:Population Surveillance; D012189:Retrospective Studies; D066027:Transplant Recipients",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "96-100",
"pmc": null,
"pmid": "28838407",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Lung cancer in renal transplant recipients: A case-control study.",
"title_normalized": "lung cancer in renal transplant recipients a case control study"
} | [
{
"companynumb": "PHHY2017FR116390",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drug... |
{
"abstract": "Rifampin is commonly used for the treatment of tuberculosis and staphylococcal infections, as well as for prevention of infection in cardiac valve and bone surgeries. We report a case of profound hypotension after anesthesia induction with propofol in a patient who was treated with two 600 mg doses of rifampin for prophylaxis of infection before surgery. In a retrospective case-control study of 75 patients, we confirmed this potentially serious drug-drug interaction. After rifampin, there was a significant and prolonged arterial blood pressure reduction when patients received propofol, but not thiopental.",
"affiliations": "Department of Anesthesia and Critical Care, Massachusetts General Hospital, GRJ-4-416, 55 Fruit St., Boston, MA 02114-2696, USA.",
"authors": "Mirzakhani|Hooman|H|;Nozari|Ala|A|;Ehrenfeld|Jesse M|JM|;Peterfreund|Robert|R|;Szabo|Michele|M|;Walsh|John L|JL|;Jiang|Yandong|Y|;Sandberg|Warren|W|;Rosow|Carl|C|;Wang|Jingping|J|",
"chemical_list": "D000904:Antibiotics, Antitubercular; D012293:Rifampin; D015742:Propofol",
"country": "United States",
"delete": false,
"doi": "10.1213/ANE.0b013e318292cbd0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-2999",
"issue": "117(1)",
"journal": "Anesthesia and analgesia",
"keywords": null,
"medline_ta": "Anesth Analg",
"mesh_terms": "D000328:Adult; D000368:Aged; D000771:Anesthesia, Intravenous; D000904:Antibiotics, Antitubercular; D016022:Case-Control Studies; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007022:Hypotension; D008297:Male; D008875:Middle Aged; D015742:Propofol; D012189:Retrospective Studies; D012293:Rifampin; D016896:Treatment Outcome",
"nlm_unique_id": "1310650",
"other_id": null,
"pages": "61-4",
"pmc": null,
"pmid": "23687230",
"pubdate": "2013-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case report: profound hypotension after anesthetic induction with propofol in patients treated with rifampin.",
"title_normalized": "case report profound hypotension after anesthetic induction with propofol in patients treated with rifampin"
} | [
{
"companynumb": "PHHY2013US103593",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN\\HYDROCODONE BITARTRATE"
},
"drugadditio... |
{
"abstract": "BACKGROUND\nIn patients with various autoimmune and rheumatic diseases, a drug-induced lupus-like syndrome (DILS) has been reported with the use of adalimumab, cerrolizumab pegol, etanercept, and infliximab.\n\n\nOBJECTIVE\nTo review clinical characteristics of patients who develop tumor necrosis factor (TNF) alpha antagonist-induced lupus-like syndrome (TAILS) and review implications for further TNF alpha antagonist therapy.\n\n\nMETHODS\nWe describe a 62-year-old woman with rheumatoid arthritis who developed a pruritic photo-distributed rash two months after the initiation of etanercept therapy. Her skin biopsy showed lupus erythematosus, and she had positive serum ANA, anti-Sjogren's syndrome A (SSA)/Ro, and anti-Sjogren's syndrome B (SSB)/La antibodies. Her symptoms resolved after discontinuation of the drug, topical and systemic corticosteroids, and hydroxychloroquine sulfate. Subsequently, her rheumatoid arthritis was treated with golimumab for six months without recurrence of skin lesions. Published reports of individuals who have developed TAILS and those who have continued treatment with alternative TNF alpha antagonists are reviewed.\n\n\nRESULTS\nTAILS is most commonly associated with the use of etanercept and infliximab. It occurs most often in women in the fifth decade of life. Onset of symptoms ranges from less than one month to more than four years. Syndrome-associated cutaneous lesions and induction of autoantibodies are common. There is no definitively established mechanism of pathogenesis. Treatment can include discontinuation of the drug, corticosteroids, immunosuppressives, and hydroxychloroquine sulfate. To date, 10 patients with TAILS have continued therapy with an alternative TNF alpha antagonist without recurrence of lupus symptoms.\n\n\nCONCLUSIONS\nDevelopment of a DILS after one TNF alpha antagonist does not preclude continued treatment with an alternative TNF alpha antagonist.",
"affiliations": "The Medical School, Baylor College of Medicine, Houston, TX, USA.",
"authors": "Williams|Victoria L|VL|;Cohen|Philip R|PR|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols; D006886:Hydroxychloroquine; C529000:golimumab; D000069285:Infliximab; D000068800:Etanercept; D000068582:Certolizumab Pegol",
"country": "England",
"delete": false,
"doi": "10.1111/j.1365-4632.2011.04871.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-9059",
"issue": "50(5)",
"journal": "International journal of dermatology",
"keywords": null,
"medline_ta": "Int J Dermatol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D000068582:Certolizumab Pegol; D000068800:Etanercept; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D000069285:Infliximab; D008180:Lupus Erythematosus, Systemic; D008875:Middle Aged; D011092:Polyethylene Glycols; D018124:Receptors, Tumor Necrosis Factor; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "0243704",
"other_id": null,
"pages": "619-25",
"pmc": null,
"pmid": "21506984",
"pubdate": "2011-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "TNF alpha antagonist-induced lupus-like syndrome: report and review of the literature with implications for treatment with alternative TNF alpha antagonists.",
"title_normalized": "tnf alpha antagonist induced lupus like syndrome report and review of the literature with implications for treatment with alternative tnf alpha antagonists"
} | [
{
"companynumb": "US-PFIZER INC-202200579383",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ETANERCEPT"
},
"drugadditional": "1",
... |
{
"abstract": "Multiple factors such as vitamin K consumption, drug interactions, herbs interactions, disease states, and alcohol intake affect international normalized ratio (INR) values and thus warfarin dosing. These variables have been described in general and for all patients in the literature. In contrast, the factors that affect INR control in a specific population are rarely studied. Being aware of these factors contributes a lot in maintaining an INR control and avoiding the supratherapeutic or subtherapeutic anticoagulation and the associated risks of hemorrhage or thromboembolism. The aim of this study is to recognize the specific population factors in Jordanian patients that interrupt INR control. Such recognition provides clinical pharmacists managing the anti-coagulation clinic (ACC) with necessary tools and predictors of dose adjustment, nontarget INR handling, and points to add on to the educational session. A total of 2788 patients were referred to the first clinical pharmacists managed ACC at Queen Alia Heart Institute-the only official referral hospital for cardiac patients in Jordan-for education and monitoring between November 1, 2013, and November 1, 2016. We evaluated specific population factors that interrupt INR control using a pretested, structured clinical data collection form. The patients were followed up regularly for achieving target INR (TINR). For patients who were not achieving TINR, the possible cause was examined thoroughly by reviewing the patient's medical file for recent medication intake, comorbidities, and laboratory results. Then the patients or their caregiver were asked direct questions regarding their diet, food supplements, cigarette smoking, shisha smoking, alcohol intake, herbs, and complementary medicine use and compliance, in addition to performing pharmacogenetic testing (polymorphisms of vitamin K-epoxide reductase complex [VKORC1] and cytochrome P450 2C9 [CYP2C9] genes) in special cases. For a total of 2788 patients, 89 488 INR values were included in the study. Of all, 20 365 (22.8%) were non-TINR values, 13 145 (14%) were subtherapeutic, and 7220 (8.1%) were supratherapeutic. All patients included in the study had a non-TINR at least 3 times (n = 65, 2.3%) and as frequent as 50 times (n = 21, 0.8%) during the study period. Non-TINR values ranged from 1 to 11. Serious side effects reported in 7 patients with uncontrolled INR, 6 were bleeding, which required hospitalization (2 upper gastrointestinal [GI] bleeding, 3 nasal bleeding, and 1 eye bleeding), 1 was cerebrovascular accident (CVA thrombolytic). Factors that interrupted INR control in our population, arranged in descending sequence, were concurrent medication use 46.9% (mainly Salicylates and Amiodarone), smoking cigarettes and shisha 17% (represented the most frequent single factor that caused non-TINR in the present study), a nonbalanced dietary vitamin K intake 16.88% caused changes in INR (lower) was related to an increase in the intake of vitamin K-rich food, were noticed to be much more in the spring season in Jordan (end of March and April mainly), herbal supplements 15.02%; Hawthorn (Crataegus, الزعرور) is an herb that lives widely in Jordan, and shockingly we found that it is used very commonly in our ACC patients and corresponded to an elevated INR <8 in 11 patients, and serious bleeding events that required hospitalization in 2 cases), noncompliance 1.49%, comorbid diseases 1%, malabsorption 0.53%, alcohol intake 0.39%, and VKORC1 A/G and CYP2C9 *1*1 genotype 0.15%. The analysis of factors that interrupted with INR control in our patients were both predicted and distinctive; most of these factors were reported previously by other researchers. On the other hand, many of the previously reported factors were not frequently detected in our patients, and the frequency of each of the realized factors was contributed differently to non-TINR in our population. Alarming factors causing non-TINR detected in our study include smoking both cigarettes and shisha, herbal use (Hawthorn and Ginseng), increased intake of vitamin K rich food in the spring season, and concurrent medication use (Salicylates, Amiodarone, Ciprofloxacin, nonsteroidal anti-inflammatory drugs [NSAIDS], Azithromycin, Clarithromycin: although the use of these drugs is mandatory sometimes, it can be replaced by an alternative, eg, antibiotics or monitored closely together with warfarin).",
"affiliations": "1 Queen Alia Heart Institute, King Hussein Medical Center (KHMC), Royal Medical Services (RMS), Amman, Jordan.;1 Queen Alia Heart Institute, King Hussein Medical Center (KHMC), Royal Medical Services (RMS), Amman, Jordan.;2 Anti-Coagulation Clinic, Queen Alia Heart Institute, King Hussein Medical Center (KHMC), Royal Medical Services (RMS), Amman, Jordan.;2 Anti-Coagulation Clinic, Queen Alia Heart Institute, King Hussein Medical Center (KHMC), Royal Medical Services (RMS), Amman, Jordan.;3 Prince Iman Center for Research and Laboratory Sciences, King Hussein Medical Center (KHMC), Royal Medical Services (RMS), Amman, Jordan.",
"authors": "Al-Momany|Nairooz H|NH|;Makahleh|Zeid M|ZM|;Al-Omari|Nadia A|NA|;Al-Sarayreh|Hana A|HA|;Momani|Rawan O|RO|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants",
"country": "United States",
"delete": false,
"doi": "10.1177/1076029619870252",
"fulltext": "\n==== Front\nClin Appl Thromb HemostClin. Appl. Thromb. HemostCATspcatClinical and Applied Thrombosis/Hemostasis1076-02961938-2723SAGE Publications Sage CA: Los Angeles, CA 3140912310.1177/107602961987025210.1177_1076029619870252Original ArticleAnalysis of Factors That Interrupt With INR Control in the First\nAnticoagulation Clinic Monitoring Jordanian Patients Al-Momany Nairooz H. MSc1Makahleh Zeid M. MD, MRCS1Al-Omari Nadia A. MSc2Al-Sarayreh Hana A. BCs2Momani Rawan O. MCs3\n1 Queen Alia Heart Institute, King Hussein Medical Center (KHMC), Royal\nMedical Services (RMS), Amman, Jordan\n2 Anti-Coagulation Clinic, Queen Alia Heart Institute, King Hussein Medical\nCenter (KHMC), Royal Medical Services (RMS), Amman, Jordan\n3 Prince Iman Center for Research and Laboratory Sciences, King Hussein\nMedical Center (KHMC), Royal Medical Services (RMS), Amman, JordanNairooz H. Al-Momany, Anti-Coagulation Clinic at\nQueen Alia Heart Institute, King Hussein Medical Center (KHMC), Royal Medical Services\n(RMS), Amman 11953, Jordan. Email: nmomany@yahoo.com14 8 2019 Jan-Dec 2019 25 10760296198702529 5 2019 14 7 2019 22 7 2019 © The Author(s) 20192019SAGE Publications Inc. unless otherwise noted.\nManuscript content on this site is licensed under Creative Commons\nLicensesThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits\nnon-commercial use, reproduction and distribution of the work without further permission\nprovided the original work is attributed as specified on the SAGE and Open Access pages\n(https://us.sagepub.com/en-us/nam/open-access-at-sage).Multiple factors such as vitamin K consumption, drug interactions, herbs interactions,\ndisease states, and alcohol intake affect international normalized ratio (INR) values and\nthus warfarin dosing. These variables have been described in general and for all patients\nin the literature. In contrast, the factors that affect INR control in a specific\npopulation are rarely studied. Being aware of these factors contributes a lot in\nmaintaining an INR control and avoiding the supratherapeutic or subtherapeutic\nanticoagulation and the associated risks of hemorrhage or thromboembolism. The aim of this\nstudy is to recognize the specific population factors in Jordanian patients that interrupt\nINR control. Such recognition provides clinical pharmacists managing the anti-coagulation\nclinic (ACC) with necessary tools and predictors of dose adjustment, nontarget INR\nhandling, and points to add on to the educational session. A total of 2788 patients were\nreferred to the first clinical pharmacists managed ACC at Queen Alia Heart Institute—the\nonly official referral hospital for cardiac patients in Jordan—for education and\nmonitoring between November 1, 2013, and November 1, 2016. We evaluated specific\npopulation factors that interrupt INR control using a pretested, structured clinical data\ncollection form. The patients were followed up regularly for achieving target INR (TINR).\nFor patients who were not achieving TINR, the possible cause was examined thoroughly by\nreviewing the patient’s medical file for recent medication intake, comorbidities, and\nlaboratory results. Then the patients or their caregiver were asked direct questions\nregarding their diet, food supplements, cigarette smoking, shisha smoking, alcohol intake,\nherbs, and complementary medicine use and compliance, in addition to performing\npharmacogenetic testing (polymorphisms of vitamin K–epoxide reductase complex [VKORC1] and\ncytochrome P450 2C9 [CYP2C9] genes) in special cases. For a total of 2788 patients, 89 488\nINR values were included in the study. Of all, 20 365 (22.8%) were non-TINR values, 13 145\n(14%) were subtherapeutic, and 7220 (8.1%) were supratherapeutic. All patients included in\nthe study had a non-TINR at least 3 times (n = 65, 2.3%) and as frequent as 50 times (n =\n21, 0.8%) during the study period. Non-TINR values ranged from 1 to 11. Serious side\neffects reported in 7 patients with uncontrolled INR, 6 were bleeding, which required\nhospitalization (2 upper gastrointestinal [GI] bleeding, 3 nasal bleeding, and 1 eye\nbleeding), 1 was cerebrovascular accident (CVA thrombolytic). Factors that interrupted INR\ncontrol in our population, arranged in descending sequence, were concurrent medication use\n46.9% (mainly Salicylates and Amiodarone), smoking cigarettes and shisha 17% (represented\nthe most frequent single factor that caused non-TINR in the present study), a nonbalanced\ndietary vitamin K intake 16.88% caused changes in INR (lower) was related to an increase\nin the intake of vitamin K-rich food, were noticed to be much more in the spring season in\nJordan (end of March and April mainly), herbal supplements 15.02%; Hawthorn (Crataegus,\nالزعرور) is an herb that lives widely in Jordan, and shockingly we found that it is used\nvery commonly in our ACC patients and corresponded to an elevated INR <8 in 11\npatients, and serious bleeding events that required hospitalization in 2 cases),\nnoncompliance 1.49%, comorbid diseases 1%, malabsorption 0.53%, alcohol intake 0.39%, and\nVKORC1 A/G and CYP2C9 *1*1 genotype 0.15%. The analysis of factors that interrupted with\nINR control in our patients were both predicted and distinctive; most of these factors\nwere reported previously by other researchers. On the other hand, many of the previously\nreported factors were not frequently detected in our patients, and the frequency of each\nof the realized factors was contributed differently to non-TINR in our population.\nAlarming factors causing non-TINR detected in our study include smoking both cigarettes\nand shisha, herbal use (Hawthorn and Ginseng), increased intake of vitamin K rich food in\nthe spring season, and concurrent medication use (Salicylates, Amiodarone, Ciprofloxacin,\nnonsteroidal anti-inflammatory drugs [NSAIDS], Azithromycin, Clarithromycin: although the\nuse of these drugs is mandatory sometimes, it can be replaced by an alternative, eg,\nantibiotics or monitored closely together with warfarin).\n\nanticoagulantsINR controlfactors affecting INR controlanti-coagulation clinicwarfarinwarfarin interactionscover-dateJanuary-December 2019\n==== Body\nBackground\nAnticoagulation clinics (ACC) have been widely used since 5 decades for anticoagulation\nmanagement in many countries. In 2013, the first ACC has been established in the Royal\nMedical Services (RMS) at Queen Alia Heart Institute (QAHI), Amman, Jordan. The beneficial\noutcomes of oral anticoagulation therapy are dependent on achieving and maintaining an\noptimal international normalized ratio (INR) therapeutic range, with minimal adverse events\nlike bleeding and thrombosis. There is ongoing evidence that better outcomes are achieved\nwhen anticoagulation is managed by a pharmacist with expertise in anticoagulation management\nrather than usual care by physicians.1–5 Our clinic protocol was prepared in consensus between the managing clinical\npharmacists and the referring physicians and approved by the RMS higher medical committee\n(Online Appendix 1).\n\nThe main goals of the clinic were to assist physicians in improving the quality of care\nprovided to their patients on anticoagulation therapy and assuring that these services\nimprove patients’ therapeutic outcomes, reduce complications of anticoagulation therapy,\nprovide patient education on disease state and drug therapy, and reduce\nhospitalizations.\n\nSince its establishment, the clinic has provided primary care of educational sessions and\nINR monitoring for about 3000 patients. This considerable number of patients served as a\ndatabase for anticoagulation research in Jordan.\n\nThe American College of Chest Physicians recommends INR ranges between 2.0 and 3.0 for most\nindications and between 2.5 and 3.5 for patients with certain mechanical heart valves (MFVs).6,7 Multiple factors such as vitamin K consumption, drug interactions, herbs\ninteractions, disease states, and alcohol intake affect INR values and thus warfarin dosing.8 These variables have been described in general and for all patients in the\nliterature. In contrast, the factors that affect INR control in a specific population are\nrarely studied. Being aware of these factors highly contributes in maintaining INR control\nand avoiding the supratherapeutic or subtherapeutic anticoagulation and the associated risks\nof hemorrhage or thromboembolism.\n\nThe aim of this study is to recognize specific population factors (Jordanian patients) that\ninterrupt INR control. Such recognition provides clinical pharmacists managing the ACC with\nthe necessary tools and predictors of dose adjustment, nontherapeutic INR handling, and\npoints to add to the educational session.\n\nMethods\nPatients, Setting, and Study Design\nPatients enrolled in the present study were referred to our ACC by their treating\nphysicians at QAHI between September 2013 and May 2017. Eligible patients were outpatients\non maintenance warfarin dose for any indication. We excluded patients referred to the\nclinic for initialization of therapy (warfarin was not initialized at hospital mostly;\natrial fibrillation [AF] patients) and patients post warfarin dose interruption (due to\nsurgery, dental, or any invasive procedure that requires dose interruption) until they\nachieved target INR. Queen Alia Heart Institute is the only official referral hospital for\ncardiac patients in Jordan performing all types of interventional catheterization and\ncardiac surgeries for all age groups. Patients were enrolled in the study if informed\nconsent was obtained from the patient or his/her representative. The study was approved by\nthe Career Ethics Committee, the equivalent of an institutional review board in Jordan, in\nthe RMS.\n\nData Collection\nGenerally, the study evaluated specific population predictors that interrupt INR control.\nData were collected from the patients’ verbal self-reports, files, medication sheets, and\nprescriptions. The deduced causes were documented in a special excel form prepared by\nresearchers (Table 1). The\nform had been pretested on a small pilot scale (n = 10) and subsequently modified to\nensure that the data would provide valid information. The entire clinical data collection\nform is available from the authors upon request.\n\nTable 1. Summary of Clinical Data Collection Form.\n\nPatient’s name\tAge\tGender\tComorbidities\tWarfarin indication\tTarget INR\tNon TINR value/values\tPossible cause/causes of non-TINR value\t\n\n\t\n\t\n\t\n\t\n\t\n\t\t\t\n\t\t\n\t\t\n\t\t\n\t\t\t\t\t\t\t\t\nAll parts of the form were completed by the authors (N.H.A.-M., a clinical pharmacist;\nN.A.A.-O., a clinical pharmacist; and Z.M.M., a cardiac surgeon) who work at QAHI. For all\npatients who were monitored in the clinic, an INR test was performed on each visit\n(frequency of visits is determined according to the clinic protocol; Online Appendix\n1).\n\nDetection of Specific Population Factors That Interrupt INR Control\nOn their first clinic appointment, all patients or their caregivers received a 45-minute\neducational session and printed booklet regarding warfarin indication, mechanism of\naction, target INR, INR monitoring, side effects, drug–warfarin interactions,\nfood–warfarin interactions, and duration for treatment.\n\nThe patients were followed up regularly for achieving target INR (TINR). For patients who\nwere not achieving TINR, the possible causes were examined thoroughly byReviewing patients medical file for recent medication intake, comorbidities, and\nlaboratory results\n\nAsking the patients or their caregiver direct questions regarding their diet or\nfood supplements, cigarette smoking, shisha smoking, alcohol intake, herbs and\ncomplementary medicine use, and compliance\n\nFor warfarin-resistant or warfarin-sensitive patientsThose with frequent supratherapeutic INR plus recurrent bleeding (considered\nWarfarin sensitive if they required a warfarin dose of ≤21 mg/week to achieve\nTINR value)\n\nThose with frequent subtherapeutic INR despite dose increase (considered\nWarfarin resistant if they required a warfarin dose of >105 mg/week without\nachieving TINR value) We considered going further by performing\npharmacogenetic testing (polymorphisms of vitamin K–epoxide reductase complex\n[VKORC1] and cytochrome P450 2C9 [CYP2C9] genes) for both (a) and (b) groups\nand by adopting Osinbowale et al algorithm (Figure 1) as a reference to determine the\ntype of resistance pattern for group (b).9 For patients who were not achieving TINR, we did dose adjustment\naccording to Figures 2\nand 3.\n\n\n\n\n\n\n\nFigure 1. Algorithm for evaluating suspected warfarin resistance modified from Osinbowale et\nal.\n\nFigure 2. The protocol of altering maintenance warfarin dose to achieve target INR. Altering\nCoumadin/warfarin dosage to achieve INR of 2 to 3.\n\nFigure 3. The protocol of altering maintenance warfarin dose to achieve target INR. Altering\nwarfarin dosage to achieve INR of 2.5 to 3.5.\n\nLaboratory Devices and Methods\nOral anticoagulant therapy was mandated by the prothrombin time, that is, evaluated using\nan automated method over STAGO coagulometric unit in the QAHI laboratory. To calculate\nINR, there was a blood coagulation (clotting) test.\n\nGenomic DNA was extracted within 1 week of blood collection using the commercially\navailable Wizard GenomicDNA Purification Kit (Promega Corporation, Madison, Wisconsin)\naccording to the manufacturer’s instructions. After extraction, the DNA was diluted in\n96-well plates using an automated robotic system to achieve concentrations of 20 ng/L\n(50-500 L). Concentrations were confirmed with the Nano-Drop ND-100 (Thermo Scientific,\nWilmington, Delaware). Genotyping was carried out by means of the MassARRAY®\nsystem (iPLEX GOLD; Sequenom, San Diego, California).\n\nStatistical Analysis\nAll data were coded, entered, and analyzed using SPSS for Windows, version 14.0 (SPSS\nInc, Chicago, Illinois). Frequency and percentages were calculated and presented.\n\nResults\nBetween November 1, 2013, and November 1, 2016, 2788 patients were referred to our ACC for\neducation and monitoring. During the study period, 95 260 INR values were obtained for all\npatients referred to the clinic. After the application of inclusion and exclusion criteria,\n89 488 INR values were included in the study; 20 365 (22.8%) were non-TINR values; 13\n145(14%) were subtherapeutic; 7220 (8.1%) were supratherapeutic. All patients included in\nthe study had a non-TINR at least 3 times (n = 65, 2.3%) and as frequent as 50\ntimes (n = 21, 0.8%) during the study period. Non-TINR values ranged from 1\nto11. Serious side effects reported in 7 patients with uncontrolled INR, 6 were bleeding\nthat required hospitalization (2 upper GI bleeding, 3 nasal bleeding, and 1 eye bleeding), 1\nwas CVA (thrombolytic). Patients’ characteristics are presented in Table 2.10\n\n\nTable 2. Characteristics for Patients Enrolled in the Study.\n\nCharacteristic\tN = 2788\t\nMean [SD] (range) age in years\t46 [29.3] (5-81)\t\nMale, % (n)\t65% (1812)\t\nPatient weighta\n\t\n Underweight (BMI ≤ 18.5)\t4.4% (122)\t\n Normal weight (BMI = 18.5–24.9)\t40.3% (1123)\t\n Overweight (BMI = 25–29.9)\t38% (1059)\t\n Obese (BMI ≥ 30)\t17.4% (484)\t\n Current smoking, % (n)\t20.0% (557)\t\n Diabetes mellitus, % (n)\t38.3% (1068)\t\n 3 medical diagnoses or more, % (n)\t29.5% (822)\t\nIndication of warfarin\t\t\n AF\t15.4% (430)\t\n MHV\t83% (2314)\t\n Othersb\n\t1.6% (45)\t\nAbbreviations: AF, atrial fibrillation; SD, standard deviation.\n\n\na BMI (Body Mass Index) = weight in kilograms divided by height in squared meters.10\n\n\n\nb Deep vein thrombosis, pulmonary embolism, recurrent stroke.\n\nFactors that interrupt INR control were stratified and coded. Then the frequency of each\nfactor was calculated. Factors that interrupted INR control in our population arranged in\ndescending sequence are concurrent medication use 46.9% (mainly Salicylates and Amiodarone),\ndiet and herbal supplements 31.9%, smoking 17%, noncompliance 1.49%, comorbid diseases 1%,\nmalabsorption 0.53%, alcohol intake 0.39%, and VKORC1 A/G and CYP2C9 *1*1 genotype 0.15%.\nRealized factors are presented in Table\n3.\n\nTable 3. Factors Interrupt With INR Control.\n\nRealized cause of non-TINR value\tFrequency, (n/20365), %\t\nConcurrent medication use\t(9550/20 365), 46.9%\t\n Salicylates\t(3361/20 365), 16.5%\t\n Amiodarone\t(2447/20 365), 12%\t\n Ciprofloxacin\t(927/20 365), 4.6%\t\n NSAIDS\t(705/20 365), 3.5%\t\n Azithromycin\t(609/20 365), 3%\t\n Clarithromycin\t555/20 365, 2.7%\t\n Carbamazepine\t413/20 365, 2%\t\n Levofloxacin\t215/20 365, 1 %\t\n Metronidazol\t120/20 365 0.6%\t\n Multivitamins (containing Vit K)\t100/20 365, 0.49%\t\n Allopurinol\t50/20 365, 0.25%\t\n Thyroxin\t22/20 365, 0.1%\t\n Phenytoin\t18/20 365, 0.09%\t\n Fluconazole\t8/20 365, 0.04%\t\nSmoking\t3466/20 365, 17%\t\n Cigarettes\t3005/20 365, 14.7%\t\n Shisha\t461, 2.3%\t\nDiet and herbal supplements\t6495/20 365, 31.9%\t\n Nonbalanced vitamin K diet\t3437/20 365, 16.88%\t\nHerbal supplements\t3058/20 365, 15.02%\t\n Hawthorn (Crataegus, الزعرور)\t866/20 365, 4.25%\t\n Ginseng\t732/20 365, 3.59%\t\n Garlic\t602/20 365, 2.96%\t\n Ginger\t466/20 365, 2.29%\t\n Fish oil\t236/20 365, 1.16%\t\n Tamarind (التمر الهندي)\t95/20 365, 0.47%\t\n Liquorice\t31/20 365, 0.15%\t\n Green tea\t30/20 365, 0.15%\t\nNoncompliance\t303/20 365, 1.49%\t\nComorbid diseases (cerebrovascular, renal, gastrointestinal, and duodenal\nulcers)\t203/20 365, 1.00%\t\nMalabsorption\t107/20 365, 0.53%\t\nAlcohol intake\t80/20 365, 0.39%\t\nGenetic polymorphism\t30/20 365, 0.15%\t\nUnknown\t131/20 365, 0.64%\t\nAbbreviations: INR, international normalized ratio; NSAIDS, nonsteroidal\nanti-inflammatory drug; TINR, target INR.\n\nDiscussion\nThe present study identified the most common factors that interrupt INR control in our\npopulation. All of our patients experienced non-TINR values during the study period either\nsub- or supratherapeutic. Warfarin dose was adjusted according to the ACC protocol.\nGenerally, the identified factors are well known from previous studies. But its frequency in\ncausing non-TINR was specific to our population. Concurrent medication use represented the\nmost frequent cause for non-TINR (46.9%), particularly Salicylates and Amiodarone (16.5%,\n12%). The use of both drugs is very common among our patients, since most of them are\ncardiac patients; AF and MHV (Table\n2). The aspirin–warfarin interaction is well known and described thoroughly in the literature.11–13 In a meta-analysis of randomized controlled trials, the risk of major bleeding was\ncalculated to be about 1.5 times higher in combination therapy with aspirin and warfarin\nthan with warfarin alone.13 In such cases, we have 2 options (to take in consensus with the treating physician):\neither to stop aspirin for individual cases such as patients with stable coronary artery\ndisease or at risk of coronary disease, where the benefit of adding aspirin is not\nsubstantial and continuing warfarin alone may be the preferred strategy; or to keep both\naspirin and warfarin if the cardiovascular benefit outweighs the increased risk of bleeding\nin patients presenting with an acute coronary syndrome or those with MHVs or coronary stents.14 If the decision is to continue on both drugs, then based on the results of the\ncurrent study, the dose of warfarin should be decreased before starting aspirin and then\ntitrated accordingly. Patients should also be educated for the interaction and the need to\ndo dose adjustment (under the monitoring of ACC) if aspirin is interrupted. Similarly, the\nwarfarin amiodarone interaction represented a main factor of non-TINR. This is a well-known\ninteraction as well.15,16 Saleh found in his study that Amiodarone use was associated with 3.29-fold increases\nthe likelihood of receiving a low warfarin dose.16 The findings of our study encouraged extra precautions in dealing with patients on\nwarfarin–amiodarone combination such as, alarming the patient regarding the interaction, the\nneed to adjust warfarin dose while changing amiodarone dose or before discontinuing it, and\nthe need to comply to both medications as any noncompliance to amiodarone may interrupt INR\ncontrol.\n\nOther warfarin drug interactions were also detected as factors that interrupted INR control\nin our study (Table 3).\nCiprofloxacin was remarkably the cause of non-TINR (4.6%) and levofloxacin to a less extent\n(1%), but it caused a serious bleeding event in 1 of the 6 bleeding cases that required\nhospitalization. This high percentage is explained by the considerable number of\ncardiosurgical patients who were discharged on ciprofloxacin. This interaction has been\nreported by previous studies to be clinically significant.16–19 Based on the findings of our study, the infection control team at QAHI restricted the\nprescription of ciprofloxacin (or other quinolones) and warfarin to cases where\nciprofloxacin (or quinolones) is the only antibiotic option and advised to monitor patients\non this drug combination more frequently.\n\nOut of 6 serious bleeding events that were detected in the study, 4 were related to drug\ncombination: 2 cases (warfarin, aspirin, NSAID) for at least 6 days and lead to upper GI\nbleeding, 1 case (warfarin, aspirin, clopidogrel), and lead to eye and continuous nasal\nbleeding and the above mentioned (warfarin, levofloxacin) lead to recent surgical site\nbleeding. Smoking represented the most frequent single factor that caused non-TINR in the\npresent study.\n\nA systematic review and metanalysis of 13 studies assessing the interaction between smoking\nand warfarin reported that smoking may potentially increase warfarin clearance, leading to\nreduced warfarin effects.20 Smoking cigarettes can have a significant impact on warfarin therapy. Although there\nis no reported interaction between nicotine and warfarin, the other chemical compounds that\nare absorbed into the body from the smoke have an effect on the liver. The liver makes more\nenzymes to eliminate the toxic substances and, in the process, eliminates more warfarin. The\nend result of this process is an increase in warfarin requirements for someone who has\nstarted smoking. Warfarin management can also be problematic in patients who stop smoking.\nEx-smokers should be monitored carefully after quitting because their warfarin requirements\nwill likely be lower. Patients with a known recent smoking history who develop an unstable\nINR pattern should be questioned about smoking relapses, since starting and stopping smoking\ncan cause warfarin requirements to vary.21\n\n\nBesides cigarettes smoking there is shisha smoking that has emerged as a significant cause\nof non-TINR in the present study. Generally, shisha smoking is considered as dangerous as\ncigarette smoking or even more. But its effect on warfarin dosing is not studied yet. We\nfound that monitoring patients smoking shisha is even worse than cigarettes smoking;\npatients who smoke shisha occasionally consider themselves nonsmokers unless they are asked\ndirectly about shisha. In addition, the nonconsistent pattern of smoking shisha makes it\nvery difficult to maintain TINR, moreover smoking shisha the day just before performing INR\ntest caused a sharp drop in the test (much more than smoking cigarettes). Smoking generally\nis an alarming phenomenon in Jordanian population, and the high percentage of smoking in our\ncardiac patients study sample (20.0%) rings the bell for the urgent need of a national\nawareness program and smoking cessation strategies.\n\nDiet and herbal supplements were responsible for 31.9% of non-TINR during the study period.\nNon balanced dietary vitamin K intake corresponded to 16.88% of non-TINR despite the\ndetailed educational session and the printed booklet that shows the daily allowed amount of\nvitamin K-rich food in serving size and that stresses on the need to take a consistent\namount of vitamin K daily. The changes in INR (low) that is related to increased intake of\nvitamin K-rich food were noticed to be much more in the spring season in Jordan (end of\nMarch and April mainly), which is due to the increased consumption of seasonal leafy\nvegetables in spring such as spinach, hibiscus, hedge mustard, and parsley.\n\nThe effect of gross changes in vitamin K intake on anticoagulation is a classic. Since the\nearly years of warfarin use, countless case reports and case series have described decreased\nanticoagulant response due to sudden excessive vitamin K intake. The causes were usually\nvitamin K rich, vegetable-based, weight reducing diets and food supplements or multivitamins.22–25 Excessive anticoagulation has also been described after unrecorded dietary\nmodification or discontinuation of multivitamin use.25,26\n\n\nHerbal supplements corresponded to 15.02% of non-TINR—mainly high. Hawthorn (Crataegus,\nالزعرور) is an herb that lives widely in Jordan. It is well known in traditional and\nalternative medicine, and it is claimed to be a treatment for cardiovascular diseases and to\nprevent heart attacks and clots. Shockingly, we found that it is used very commonly in our\nACC patients. It was corresponded to an elevated INR <8 in 11 patients, and serious\nbleeding events that required hospitalization in 2 cases. Ginseng use was also associated\nwith elevated INR <8 in 2 patients. Herbs–warfarin interactions are well studied, and\nmany herbs are well known to interact with warfarin. Ge et al in their updates on the\nclinical evidenced herb–warfarin interactions found that among 38 herbs, Cannabis,\nChamomile, Cranberry, Garlic, Ginkgo, Grapefruit, Lycium, Red clover, and St. John’s wort\nwere evaluated to have major severity interaction with warfarin.27\n\n\nTherefore, we provide our patients with a printed table of the herbs to avoid or the\nmaximum amount they can use. Hawthorn was not among the list in the beginning, but since we\nreported the bleeding events and the elevated INR, we added it to the list of herbs to avoid\nand we now ask patients routinely if they use it.\n\nNoncompliance, comorbid diseases, malabsorption, alcohol intake, genetic polymorphism were\nalso corresponded to the causes of non-TINR values in our study population. Those factors\nare well studied previously, and our results are consistent with previous studies.28,29\n\n\nAlthough genetic variants in both CYP2C9 and VKORC1 enzymes are known to affect INR\ncontrol, we did not do genetic-guided therapy routinely since it is a burden on the system;\ninstead we did it for selected patients (n = 2) in whom we could not achieve therapeutic INR\ncontrol despite the high warfarin dose (105 and 122.5 mg). Warfarin-sensitive patients with\nincreased bleeding risk may also be candidates for genetic study. In a study that has been\ndone at our ACC by other genetics researchers, Al-Eitan et al confirmed a genetic\nassociation of the CYP2C9*3 and VKORC1 rs10871454, rs8050894, rs9934438, and rs17708472\nsingle-nucleotide polymorphisms with warfarin sensitivity. This study also found an\nassociation between CYP2C9 andVKORC1 genetic haplotype blocks and warfarin sensitivity.30\n\n\nThe genetic report for our 2 warfarin resistance patients suggested that the VKORC1-1639 GG\nand the wild-type CYP2C9*1*1 genotypes are associated with the high-dose requirement for\nwarfarin therapy, and that VKORC1-1639 GG is responsible for warfarin resistance and failure\nin our patients.\n\nIn 2007, the Food and Drug Administration (FDA) added pharmacogenetic information to the\nwarfarin package insert, presumably in recognition of the fact that genetic variations in\nthe CYP2C9 and VKORC1 genes contribute significantly to the variability in dose requirements\nfor warfarin. However, the FDA did not propose a specific method for using genetic\ninformation to predict the dose required in individual patients.31 The review by Limdi et al32 did not find supporting evidence to suggest that genotype-guided therapy will improve\nanticoagulant control and prevent or reduce the risk of hemorrhagic or thromboembolic\ncomplications. In any case, it would be both reasonable and prudent to use CYP2C9 and VKORC1\ngenotypes as part of diagnostic efforts to understand unusual responses to standard medical care.33\n\n\nLimitations\nThe realized factors corresponded to non-TINR depended to some extent on a patient’s\nstory and explanations regarding their lifestyle. So some factors may be missed out or not\ntold or exaggerated. In the future, one can consider finding more reliable tools of\ndetecting factors related to patient’s behavior and practice.\n\nConclusion\nThe analysis of the realized factors that interrupted with INR control in our patients were\nboth predicted and distinctive; most of these factors were reported previously by other\nresearchers. On the other hand, many of the previously reported factors were not frequently\ndetected in our patients and the frequency of each of the realized factors was contributed\ndifferently to non-TINR in our population. Alarming factors causing non-TINR detected in our\nstudy include smoking both cigarettes and shisha, herbal use (Hawthorn and Ginseng),\nincreased intake of vitamin K-rich food in the spring season, and concurrent medication use\n(Salicylates, Amiodarone, Ciprofloxacin, NSAIDS, Azithromycin, Clarithromycin: although the\nuse of these drugs is mandatory sometimes, it can be replaced by an alternative, eg,\nantibiotics or monitored closely together with warfarin).\n\nSupplemental Material\nSupplemental Material, ACC_PROTOCOL_AND_PRINTED_BOOKLET_revision - Analysis of\nFactors That Interrupt With INR Control in the First Anticoagulation Clinic Monitoring\nJordanian Patients\nClick here for additional data file.\n\nSupplemental Material, ACC_PROTOCOL_AND_PRINTED_BOOKLET_revision for Analysis of Factors\nThat Interrupt With INR Control in the First Anticoagulation Clinic Monitoring Jordanian\nPatients by Nairooz H. Al-Momany, Zeid M. Makahleh, Nadia A. Al-Omari, Hana A. Al-Sarayreh\nand Rawan O. Momani in Clinical and Applied Thrombosis/Hemostasis\n\n Authors’ Note: All authors contributed equally to concept and design, data collection and\ninterpretation, and writing and revision of the manuscript.\n\nAcknowledgments\nThe authors would like to thank all the physicians and nurses working at Queen Alia Heart\nInstitute (QAHI) who helped us in patient recruitment and data collection.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research,\nauthorship, and/or publication of this article.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research,\nauthorship, and/or publication of this article: This study was funded by the Royal Medical\nServices.\n\nSupplemental Material: Supplemental material for this article is available online.\n==== Refs\nReferences\n1 \nBaker WL Cios DA Sander SD Coleman CI \nMeta-analysis to assess the quality of warfarin control in\natrial fibrillation patients in the United States . J Manag Care\nPharm .\n2009 ;15 (3 ):244 –252 .19326955 \n2 \nChamberlain MA Sageser NA Ruiz D \nComparison of anticoagulation clinic patient outcomes with\noutcomes from traditional care in a family medicine clinic . J Am\nBoard Fam Pract .\n2001 ;14 (1 ):16 –21 .11206689 \n3 \nChiquette E Amato MG Bussey HI \nComparison of an anticoagulation clinic with usual medical\ncare: anticoagulation control, patient outcomes, and health care costs .\nArch Intern Med .\n1998 ;158 (15 ):1641 –1647 .9701098 \n4 \nvan Walraven C Jennings A Oake N Fergusson D Forster AJ \nEffect of study setting on anticoagulation control, a\nsystematic review and meta regression . Chest .\n2006 ;129 (5 ):1155 –1166 .16685005 \n5 \nLevi M Richard Hobbs FD Jacobson AK \net al.\nImproving antithrombotic management in patients with atrial fibrillation:\ncurrent status and perspectives . Sem Thromb Hemost .\n2009 ;35 (6 ):527 –542 .\n6 \nAnsell J Hirsh J Hylek E Jacobson A Crowther M Palareti G \nPharmacology and management of the vitamin k antagonists:\nAmerican College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th\nEdition) . Chest .\n2008 ;133 (suppl\n6 ):160S –198S .18574265 \n7 \nSalem DN O’Gara PT Madias C Pauker SG \nValvular and structural heart disease: American College of\nChest Physicians Evidence-Based Clinical Practice Guidelines (8th\nEdition) . Chest .\n2008 ;133 (suppl\n6 ):593S –629S .18574274 \n8 \nNeel S \nEssential warfarin knowledge In:\nGulseth M , ed. Managing Anticoagulation Patients in the Hospital: The\nInpatient Anticoagulation Service . Bethesda, MD :\nAmerican Society of Health-System Pharmacists ;\n2007 ;133 –175 .\n9 \nOsinbowale O Al Malki M Schade A Bartholomew JR \nAn algorithm for managing warfarin\nresistance . Cleve Clin J Med .\n2009 ;76 (12 ):724 –730 .\n(published Online First: Epub Date) [PubMed] \n19952297 \n10 \nLacy CF Armstrong LL Goldman MP Lance LL \nDrug Information Handbook 2006-2007 . 15th\ned \nWashington, D.C : The\nAmerican Pharmaceutical Association ;\n2006 .\n11 \nSteinberg BA Kim S Piccini JP \net al.\nUse and associated risks of concomitant aspirin therapy with oral\nanticoagulation in patients with atrial fibrillation: insights from the Outcomes\nRegistry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF)\nRegistry . Circulation .\n2013 ;128 (7 ):721 –728 .23861512 \n12 \nRothberg MB Celestin C Fiore LD Lawler E Cook JR \nWarfarin plus aspirin after myocardial infarction or the\nacute coronary syndrome: meta-analysis with estimates of risk and\nbenefit . Ann Intern Med .\n2005 ;143 (4 ):241 –250 .16103468 \n13 \nDentali F Douketis JD Lim W Crowther M \nCombined aspirin-oral anticoagulant therapy compared with\noral anticoagulant therapy alone among patients at risk for cardiovascular disease: a\nmeta-analysis of randomized trials . Arch Intern Med .\n2007 ;167 (2 ):117 –124 .17242311 \n14 \nMadhwal S Lincoff AM Rolston DDK \nShould patients on long-term warfarin take aspirin for\nheart disease? \nClev Clin J Med .\n2008 ;75 (3 ):206 –208 .\n15 \nHeimark LD Wienkers L Kunze K \net al.\nThe mechanism of the interaction between amiodarone and warfarin in\nhumans . Clin Pharmacol Ther .\n1992 :51 (14 ):398 –407 .1563209 \n16 \nSaleh MI \nClinical predictors associated with warfarin\nsensitivity . Am J Ther .\n2015 ;23 (6 ):e1690 –e1694 .\n10.1097/MJT.0000000000000248 .\n17 \nBayer Corporation . Product Information:\nCipro (Ciprofloxacin) . West Haven, Conn :\nBayer Corporation ;1997 .\n18 \nJolson HM Tanner LA Green L Grasela TH Jr \nAdverse reaction reporting of interaction between warfarin\nand fluoroquinolones . Arch Intern Med .\n1991 ;151 (5 ):1003 –1004 .1842668 \n19 \nBianco TM Bussey HI Farnett LE Linn WO Roush MK Wong YW \nPotential warfarin-ciprofloxacin interaction in patients\nreceiving long-term anticoagulation . Pharmacotherapy .\n1992 ;12 (6 ):435 –439 .1492006 \n20 \nNathisuwan S Dilokthornsakul P Chaiyakunapnik N \net al.\nAssessing evidence of interaction between smoking and warfarin: a\nsystematic review and meta-analysis . Chest .\n2011 ;139 (5 ):1130 –119 .21540214 \n21 \nAnna DG \nSmoking affects warfarin therapy .\npharmacytimes.com/publications/issue/2007-05-6496.\n22 \nQureshi GD Reinders TP Swint JJ Slate MB \nAcquired warfarin resistance and weight-reducing\ndiet . Arch Intern Med .\n1981 :141 (4 ):507 –509 .7212893 \n23 \nWalker FB \n4th Myocardial infarction after diet-induced warfarin\nresistance . Arch Intern Med .\n1984 ;144 (10 ):2089 –2090 .6486994 \n24 \nOren B Shvartzman P \nUnsuspected source of vitamin K in patients treated with\nanticoagulants: a case report . Fam Pract .\n1989 ;6 (2 ):151 –152 .2663579 \n25 \nKurnik D Lubetsky A Loebstein R Almog S Halkin H \nMultivitamin supplements may affect warfarin\nanticoagulation in susceptible patients . Ann\nPharmacother .\n2003 ;37 (11 ):1603 –1606 .14565795 \n26 \nChow WH Chow TC Tse TM Tai YT Lee WT \nAnticoagulation instability with life-threatening\ncomplication after dietary modification . Postgrad Med\nJ .\n1990 ;66 (780 ):855 –857 .\nPMC free article .2099431 \n27 \nGe B Zhang Z Zuo Z \nUpdates on the clinical evidenced herb-warfarin\ninteractions . Evid Based Complement Alternat Med .\n2014 ;2014 :957362 .\n28 \nDharmarajan L Dharmarajan TS \nPrescribing warfarin appropriately to meet patient safety\ngoals . Am Health Drug Benefits .\n2008 ;1 (6 ):26 –32 .\n29 \nAgeno W Gallus AS Wittkowsky A Crowther M Hylek EM Palareti G \nOral anticoagulant therapy: antithrombotic therapy and\nprevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based\nClinical Practice Guidelines . Chest .\n2012 ;141 (suppl\n2 ):e44S –e88S .22315269 \n30 \nAl-Eitan LN Almasri AY Khasawneh RH \nImpact of CYP2C9 and VKORC1 polymorphisms on warfarin\nsensitivity and responsiveness in Jordanian cardiovascular patients during the\ninitiation therapy . Genes (Basel) .\n2018 ;9 (12 ):E578 \ndoi:10.3390/genes9120578 .30486437 \n31 \nThe International Warfarin Pharmacogenetic\nConsortium ; Klein TE Altman RB Eriksson N \net al.\nEstimation of the warfarin dose with clinical and pharmacogenetic\ndata . N Engl J Med .\n2009 ;360 :753 –764 .19228618 \n32 \nLimdi NA Veenstra DL \nWarfarin pharmacogenetics .\nPharmacotherapy .\n2009 ;28 :1084 –1097 .\n33 \nYenny Y \nWarfarin: do we need genotype-based dose\nprediction ? Univ Med .\n2010 ;29 (3 ):1 –3 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1076-0296",
"issue": "25()",
"journal": "Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis",
"keywords": "INR control; anti-coagulation clinic; anticoagulants; factors affecting INR control; warfarin; warfarin interactions",
"medline_ta": "Clin Appl Thromb Hemost",
"mesh_terms": "D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants; D016903:Drug Monitoring; D005260:Female; D006470:Hemorrhage; D029001:Herbal Medicine; D006801:Humans; D019934:International Normalized Ratio; D007597:Jordan; D008297:Male; D008875:Middle Aged; D012907:Smoking; D000075387:Smoking Water Pipes; D013923:Thromboembolism",
"nlm_unique_id": "9508125",
"other_id": null,
"pages": "1076029619870252",
"pmc": null,
"pmid": "31409123",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "17242311;19952297;30486437;25830869;6486994;25126243;24790635;18752379;18383929;23861512;9701098;21540214;19228618;16685005;18574274;16103468;22315269;19787556;2099431;19326955;1563209;2663579;11206689;18574265;7212893;1842668;14565795;1492006",
"title": "Analysis of Factors That Interrupt With INR Control in the First Anticoagulation Clinic Monitoring Jordanian Patients.",
"title_normalized": "analysis of factors that interrupt with inr control in the first anticoagulation clinic monitoring jordanian patients"
} | [
{
"companynumb": "JO-ACCORD-152696",
"fulfillexpeditecriteria": "1",
"occurcountry": "JO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "Acute liver failure is a rare but life-threatening medical emergency. Despite advancements in medical management, mortality rates of acute liver failure remain high. Currently, liver transplant is the only definitive therapeutic option available. High-volume plasma exchange has been shown to increase transplant-free survival in patients with acute liver failure before liver transplant. However, the occurrence of infectious complications in patients who receive this treatment has not been well studied. We report 2 cases of severe opportunistic infections occurring within 30 days of transplant in patients who underwent high-volume plasma exchange before liver transplant.",
"affiliations": "From the Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.",
"authors": "Park|Ga Eun|GE|;Peck|Kyong Ran|KR|;Kim|Jong Man|JM|;Kwon|Choon Hyuck David|CHD|;Joh|Jae-Won|JW|;Cho|Duck|D|;Sinn|Dong Hyun|DH|",
"chemical_list": "D000935:Antifungal Agents; D000998:Antiviral Agents; D007166:Immunosuppressive Agents",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2018.0071",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "18(3)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D000998:Antiviral Agents; D003586:Cytomegalovirus Infections; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D055744:Invasive Pulmonary Aspergillosis; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D008297:Male; D009894:Opportunistic Infections; D010951:Plasma Exchange; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "392-395",
"pmc": null,
"pmid": "30696393",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Infectious Complications in Patients Who Received High-Volume Plasma Exchange Prior to Liver Transplant: A Case Report.",
"title_normalized": "infectious complications in patients who received high volume plasma exchange prior to liver transplant a case report"
} | [
{
"companynumb": "KR-JNJFOC-20200704135",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "Reference concentrations are needed to evaluate postmortem toxicology results and usually femoral blood is the specimen of choice. However, brain tissue has been suggested as a viable alternative specimen, since postmortem blood concentrations can be difficult to interpret due to postmortem redistribution, among other factors. Here we present reference concentrations of postmortem brain and femoral blood of the nitrobenzodiazepines clonazepam, flunitrazepam, and nitrazepam that are of particular interest since they commonly are converted to their corresponding 7-aminometabolites in the postmortem situation. The drugs and metabolites were quantified in both matrices using LC-MS-MS in 69 cases. In 63 cases the compounds were judged not to have been of significance for the death (C cases), whereas they were considered to have been a contributing factor in 6 cases (B cases). No cases were observed with a nitrobenzodiazepine being the sole cause of death (A cases). The brain-blood ratios for clonazepam and nitrazepam were 5.5 and 4.7, respectively, while the brain-blood ratios for the 7-aminometabolites ranged from 0.4 to 0.5. Flunitrazepam only occurred as the 7-aminometabolite. A positive correlation between brain and blood concentrations was found with Spearman's rank correlation coefficients (rs) ranging from 0.77 to 0.96. The measured femoral blood concentrations agree with literature values, but only few brain concentrations were available for comparison. The drug-metabolite ratios for clonazepam and nitrazepam were 10-12 times higher in brain than in blood. The pre-analytical variation in brain of 5.9% was fairly low, suggesting that brain tissue is a useful alternative to blood. The reported brain and femoral blood concentrations serve as reference values in postmortem investigations.",
"affiliations": "Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Frederik V's Vej 11, DK-2100 Copenhagen Ø, Denmark. Electronic address: louise.skov@hotmail.com.;Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Frederik V's Vej 11, DK-2100 Copenhagen Ø, Denmark. Electronic address: karen.holm@sund.ku.dk.;Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Frederik V's Vej 11, DK-2100 Copenhagen Ø, Denmark. Electronic address: Kristian.linnet@sund.ku.dk.",
"authors": "Skov|Louise|L|;Holm|Karen Marie Dollerup|KM|;Linnet|Kristian|K|",
"chemical_list": "C020860:7-aminoclonazepam; D002998:Clonazepam; D005445:Flunitrazepam; D009567:Nitrazepam",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2016.09.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "268()",
"journal": "Forensic science international",
"keywords": "Femoral blood; Human brain; Nitrobenzodiazepines; Postmortem reference concentrations; Pre-analytical variation",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D001923:Brain Chemistry; D002853:Chromatography, Liquid; D002998:Clonazepam; D005260:Female; D005445:Flunitrazepam; D053593:Forensic Toxicology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009567:Nitrazepam; D011180:Postmortem Changes; D012016:Reference Values; D053719:Tandem Mass Spectrometry; D055815:Young Adult",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "39-45",
"pmc": null,
"pmid": "27685474",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Nitrobenzodiazepines: Postmortem brain and blood reference concentrations.",
"title_normalized": "nitrobenzodiazepines postmortem brain and blood reference concentrations"
} | [
{
"companynumb": "DK-ROCHE-1840392",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Cerebral aspergillosis is a rare and highly fatal infection that mainly affects immunocompromised patients. We report on a case of a heart transplanted Caucasian man, who arrived at our hospital because of the onset of diplopy. We performed a broad diagnostic work-up: the brain MRI showed a single ring-enhancing thalamo-mesencephalic area suggestive of abscess lesion; cerebrospinal fluid (CSF) analysis disclosed galactomannan and beta-D-glucan antigens. Thus the antifungal therapy was immediately started. We decided to discontinue the therapy 16 months later because of severe hepatic toxicity, given that the patient was persistently asymptomatic, brain imaging showed a progressive resolution of the abscess area and CSF antigen analysis was persistently negative. The follow-up at three months was unchanged.",
"affiliations": "Sezione di Malattie Infettive, Dipartimento di Patologia, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico G.B. Rossi; Sezione di Neurologia Clinica, Dipartimento di Scienze Neurologiche e del Movimento, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico G.B. Rossi; Sezione di Cardiochirurgia, Dipartimento Cardiovascolare e Toracico, Azienda Ospedaliera Universitaria Integrata di Verona, Ospedale Civile Maggiore, Verona, Italy.;Sezione di Malattie Infettive, Dipartimento di Patologia, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico G.B. Rossi; Sezione di Neurologia Clinica, Dipartimento di Scienze Neurologiche e del Movimento, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico G.B. Rossi; Sezione di Cardiochirurgia, Dipartimento Cardiovascolare e Toracico, Azienda Ospedaliera Universitaria Integrata di Verona, Ospedale Civile Maggiore, Verona, Italy.;Sezione di Malattie Infettive, Dipartimento di Patologia, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico G.B. Rossi; Sezione di Neurologia Clinica, Dipartimento di Scienze Neurologiche e del Movimento, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico G.B. Rossi; Sezione di Cardiochirurgia, Dipartimento Cardiovascolare e Toracico, Azienda Ospedaliera Universitaria Integrata di Verona, Ospedale Civile Maggiore, Verona, Italy.;Sezione di Malattie Infettive, Dipartimento di Patologia, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico G.B. Rossi; Sezione di Neurologia Clinica, Dipartimento di Scienze Neurologiche e del Movimento, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico G.B. Rossi; Sezione di Cardiochirurgia, Dipartimento Cardiovascolare e Toracico, Azienda Ospedaliera Universitaria Integrata di Verona, Ospedale Civile Maggiore, Verona, Italy.;Sezione di Malattie Infettive, Dipartimento di Patologia, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico G.B. Rossi; Sezione di Neurologia Clinica, Dipartimento di Scienze Neurologiche e del Movimento, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico G.B. Rossi; Sezione di Cardiochirurgia, Dipartimento Cardiovascolare e Toracico, Azienda Ospedaliera Universitaria Integrata di Verona, Ospedale Civile Maggiore, Verona, Italy.;Sezione di Malattie Infettive, Dipartimento di Patologia, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico G.B. Rossi; Sezione di Neurologia Clinica, Dipartimento di Scienze Neurologiche e del Movimento, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico G.B. Rossi; Sezione di Cardiochirurgia, Dipartimento Cardiovascolare e Toracico, Azienda Ospedaliera Universitaria Integrata di Verona, Ospedale Civile Maggiore, Verona, Italy.;Sezione di Malattie Infettive, Dipartimento di Patologia, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico G.B. Rossi; Sezione di Neurologia Clinica, Dipartimento di Scienze Neurologiche e del Movimento, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico G.B. Rossi; Sezione di Cardiochirurgia, Dipartimento Cardiovascolare e Toracico, Azienda Ospedaliera Universitaria Integrata di Verona, Ospedale Civile Maggiore, Verona, Italy.;Sezione di Malattie Infettive, Dipartimento di Patologia, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico G.B. Rossi; Sezione di Neurologia Clinica, Dipartimento di Scienze Neurologiche e del Movimento, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico G.B. Rossi; Sezione di Cardiochirurgia, Dipartimento Cardiovascolare e Toracico, Azienda Ospedaliera Universitaria Integrata di Verona, Ospedale Civile Maggiore, Verona, Italy.;Sezione di Malattie Infettive, Dipartimento di Patologia, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico G.B. Rossi; Sezione di Neurologia Clinica, Dipartimento di Scienze Neurologiche e del Movimento, Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico G.B. Rossi; Sezione di Cardiochirurgia, Dipartimento Cardiovascolare e Toracico, Azienda Ospedaliera Universitaria Integrata di Verona, Ospedale Civile Maggiore, Verona, Italy.",
"authors": "Mazzaferri|Fulvia|F|;Adami|Irene|I|;Tocco|Pierluigi|P|;Cazzadori|Angelo|A|;Merighi|Mara|M|;Forni|Alberto|A|;Storato|Silvia|S|;Ferrari|Sergio|S|;Concia|Ercole|E|",
"chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B; D065819:Voriconazole",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1124-9390",
"issue": "23(1)",
"journal": "Le infezioni in medicina",
"keywords": null,
"medline_ta": "Infez Med",
"mesh_terms": "D061605:Administration, Intravenous; D000368:Aged; D000666:Amphotericin B; D000935:Antifungal Agents; D001228:Aspergillosis; D001230:Aspergillus; D001922:Brain Abscess; D004359:Drug Therapy, Combination; D016027:Heart Transplantation; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008636:Mesencephalon; D013788:Thalamus; D013997:Time Factors; D016896:Treatment Outcome; D065819:Voriconazole",
"nlm_unique_id": "9613961",
"other_id": null,
"pages": "51-5",
"pmc": null,
"pmid": "25819052",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Thalamo-mesencephalic aspergillus abscess in a heart transplant subject: a case report and literature review.",
"title_normalized": "thalamo mesencephalic aspergillus abscess in a heart transplant subject a case report and literature review"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-133850",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "Autoimmune manifestations (AIM) are reported in up to 10-30% of myelodysplastic syndromes (MDS) patients; this association is not well defined. We present herein a retrospective chart review of single center MDS patients for AIM, a case discussion and a literature review. Of 252 MDS patients examined, 11 (4.4%) had AIM around MDS diagnosis. International Prognostic Scoring System scores were: low or intermediate (int)-1 (n=7); int-2 or high (n=4). AIM were: culture negative sepsis (n=7); inflammatory arthritis (n=3); vasculitis (n=4); sweats; pericarditis; polymyalgia rheumatica (n=2 each); mouth ulcers; pulmonary infiltrates; suspicion for Behcet's; polychondritis and undifferentiated (n=1 each). AIM treatment and outcome were: prednisone +/- steroid sparing agents, n=8, ongoing symptoms in 5; azacitidine (n=3), 2 resolved; and observation, n=1, ongoing symptoms. At a median follow up of 13 months, seven patients are alive. In summary, 4.4% of MDS patients presented with concomitant AIM. MDS should remain on the differential diagnosis of patients with inflammatory symptoms.",
"affiliations": "Departments of Medicine, St. Paul's Hospital and the University of British Columbia , Vancouver, BC, Canada.;Departments of Hematology, St. Paul's Hospital and the University of British Columbia , Vancouver, BC, Canada.;Departments of Hematology, St. Paul's Hospital and the University of British Columbia , Vancouver, BC, Canada.",
"authors": "Williamson|Bradley T|BT|;Foltz|Lynda|L|;Leitch|Heather A|HA|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4081/hr.2016.6480",
"fulltext": "\n==== Front\nHematol RepHematol RepHRHematology Reports2038-83222038-8330PAGEPress Publications, Pavia, Italy 10.4081/hr.2016.6480Case ReportAutoimmune Syndromes Presenting as a Paraneoplastic Manifestation of Myelodysplastic Syndromes: Clinical Features, Course, Treatment and Outcome Williamson Bradley T. 1Foltz Lynda 2Leitch Heather A. 21 Departments of Medicine, St. Paul’s Hospital and the University of British Columbia, Vancouver, BC, Canada2 Departments of Hematology, St. Paul’s Hospital and the University of British Columbia, Vancouver, BC, CanadaSt. Paul’s Hospital and the University of British Columbia, 440-1144 Burrard Street, Vancouver V6Z 2A5, BC, Canada. +1.604.684.5794 - +1.604.684.5705. hleitch@providencehematology.comContributions: BTW reviewed the charts and wrote the paper; LMF, critically revised the paper; HAL, supervised the chart review, revised the paper and performed statistical analyses.\n\nConflict of interest: BTW was supported by a Summer Studentship from Celgene. LMF has consulted for Novartis and Janssen; has received research funding from Novartis, Incyte, Gilead and Promedior; and has received honoraria from Novartis. HAL has received research funding and honoraria from Novartis, Celgene and Alexion; has received an educational grant from Celgene; and is a member of the Exjade Speaker’s Bureau.\n\nPoster presentation: Norman Bethune Symposium, Vancouver, BC, November 13, 2014. Canadian Conference on MDS, Banff, AB, September 12-13, 2014.\n\n10 5 2016 10 5 2016 8 2 648020 2 2016 30 4 2016 02 5 2016 ©Copyright B.T. Williamson et al.2016Licensee 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.Autoimmune manifestations (AIM) are reported in up to 10-30% of myelodysplastic syndromes (MDS) patients; this association is not well defined. We present herein a retrospective chart review of single center MDS patients for AIM, a case discussion and a literature review. Of 252 MDS patients examined, 11 (4.4%) had AIM around MDS diagnosis. International Prognostic Scoring System scores were: low or intermediate (int)-1 (n=7); int-2 or high (n=4). AIM were: culture negative sepsis (n=7); inflammatory arthritis (n=3); vasculitis (n=4); sweats; pericarditis; polymyalgia rheumatica (n=2 each); mouth ulcers; pulmonary infiltrates; suspicion for Behcet’s; polychondritis and undifferentiated (n=1 each). AIM treatment and outcome were: prednisone +/- steroid sparing agents, n=8, ongoing symptoms in 5; azacitidine (n=3), 2 resolved; and observation, n=1, ongoing symptoms. At a median follow up of 13 months, seven patients are alive. In summary, 4.4% of MDS patients presented with concomitant AIM. MDS should remain on the differential diagnosis of patients with inflammatory symptoms.\n\nKey words\nAutoimmunemyelodysplastic syndromesHDS\n==== Body\nIntroduction\nThe myelodysplastic syndromes (MDS) are clonal hematopoietic disorders of ineffective hematopoiesis and risk of acute myeloid leukemia (AML) progression.1 Prognosis is determined by the International Prognostic Scoring System (IPSS) and other scores.2 Mutations in the pluripotent hematopoietic stem cell occur in MDS, with disruption of RNA splicing, ribosomal proteins, telomeres, microRNA expression, and DNA methylation.3-6 Reports suggest an association between MDS and immune dysregulation.7 Cytokine dysregulation and impaired cellular immunity have been noted in MDS initiation, development, and progression.8 Autoimmune (AI) symptoms have been reported in up to 10-30% of MDS patients.9-11 Patients with AI disorders or receiving immunosuppressive agents are more likely to be diagnosed with MDS.12\n\nParaneoplastic inflammatory syndromes concomitant with MDS diagnosis have also been reported.9,13-15 To better understand the incidence and outcomes of patients with MDS and AI disorders, we conducted a retrospective chart review of patients with MDS, looking for symptoms of AI disorders.\n\nMaterials and Methods\nMyelodysplastic syndromes patients were identified from a single-center MDS database. Charts were reviewed for the presence of autoimmune manifestations (AIM) within a 3-year period prior to or following the diagnosis of MDS, treatment and outcome. Patients with a longstanding history of connective tissue disorders were excluded. The term culture negative sepsis was used to describe fevers or drenching sweats with a negative workup for infectious and other causes such as drug fevers. Although these symptoms may be a manifestation of systemic vasculitis, the latter term was reserved for patients with biopsyproven vasculitis. Cases that are illustrative of AIM were selected for presentation.\n\nSurvival analyses were conducted by the log-rank method using SPSS for Windows, version 20. This review was conducted in accordance with the requirements of the institutional Research Ethics Board.\n\nResults\nOf 252 MDS patients, eleven (4.4%) had AIM presenting at or shortly before MDS diagnosis. Baseline and MDS characteristics, treatment and outcome are shown in Table 1. Eight patients were documented to have had a workup by the rheumatology service, and seven were followed regularly by rheumatology; all rheumatology-assigned diagnoses of autoimmune diseases are listed in Table 1.\n\nOf seven patients with culture negative sepsis, all underwent an extensive workup for infectious causes, five by the Infectious Diseases service. Three received intravenous antibiotics with no improvement. Other causes of fevers, such as medications, were considered but none identified. All seven had at least one bone marrow aspirate and biopsy performed during a symptomatic episode, with no hemophagocytosis seen. Four of these patients had 3 bone marrows performed, and one had more than ten done in two countries over a period of more than 7 years. Two patients had ferritin levels done; the maximum level was 1200 ng/mL. None of the patients had splenomegaly on physical examination, and one underwent CT scanning of the abdomen because of abdominal pain; the spleen was normal on imaging.\n\nAt a median follow up of 13 (4-87) months, seven patients are alive, six with stable MDS and one is undergoing allogeneic myeloablative hematopoietic stem cell transplantation (HSCT). Four patients died; causes were: MDS progression, n=2; infection, n=1; and unknown, n=1.\n\nOf four patients with int-2 or high IPSS risk MDS, three were treated with azacitidine. One patient receiving azacitidine did not respond, there was one early infectious death, and the third is undergoing HSCT.\n\nOverall survival (OS) analyses were performed comparing MDS patients with AIM to those without AIM. The OS of seven lower IPSS risk patients with AIM were compared to 204 lower risk MDS diagnosed over the same time period. The median follow up of all lower risk patients was 27.3 (0.5-161) months. There was no significant difference in OS between groups; all seven (100%) patients with AIM are alive compared to 166 (78.7%) patients without AIM, and the median OS was not reached at 43 months compared to 78.8 months, respectively (P=NS).\n\nOf higher IPSS risk patients, we restricted the analysis to patients diagnosed since azacitidine was available in Canada and compared three patients with AIM receiving azacitidine to 29 patients without AIM, but also receiving azacitidine. The median follow up of this group was 7.3 (0.5-46) months. There was no significant difference in OS between groups (P=NS).\n\nOf eight patients receiving immunosuppression for AIM, one died of AML progression at 4 months, one died of progressive (higher IPSS risk) MDS in the context of stopping azacitidine at 6 months, and one died suddenly of unknown causes 32 months from MDS diagnosis. The remaining five patients had stable MDS at a median of 14 (5-23) months from MDS diagnosis. Four of these patients were followed by Rheumatology and the fifth was given immunosuppressive medications by emergency room physicians for pericarditis. Both patients with systemic vasculitis had this diagnosis made on biopsy, one on open lung biopsy, and one on skin biopsy. Only one patient, without biopsy proven vasculitis but with culture negative sepsis, had anti-neutrophil cytoplasmic antibody (ANCA) levels done, which were negative.\n\nPatient #1\nA 31 year-old woman presented with fatigue and cytopenias. White blood cell (WBC) count was 3.9×109/L, neutrophils 1.8×109/L, hemoglobin (Hb) 125 g/L and platelet count (PLTS) 100×109/L. Peripheral blood morphology showed macrocytosis. Antinuclear antibody (ANA) was positive at a 1:320 dilution. She did not fulfill criteria for systemic lupus erythematosus (SLE) and was observed. Neutropenia and thrombocytopenia persisted and mild anemia developed (Hb 119 g/L). A bone marrow aspirate and biopsy (BMBx) showed erythroid dysplasia, 1% blasts and trisomy 8. A diagnosis of refractory cytopenia with unilineage dysplasia (RCUD) was made and the IPSS was int-1. The patient declined HSCT and yearly BMBx’s remained stable. Within one year of MDS diagnosis, she developed a rash to sun exposure. She experienced culture negative fevers and mouth ulcers suspicious for Behcet’s disease. Symptoms are ongoing 9.75 years from MDS diagnosis despite the use of non-steroidal anti-inflammatory medications. AIM nearly completely abated during three pregnancies.\n\nPatient #2\nA 77 year-old man presented with fatigue. Hb was 127 g/L, neutrophils 1.8×109/L, and PLTS 133×109/L. ANA titer was 1:80. A BMBx showed trilineage dysplasia, <5% blasts and a normal male karyotype. A diagnosis of refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS) was made and the IPSS was int-1.\n\nSix months after MDS diagnosis he developed progressive stiffness of the thighs, shoulders and neck. Workup revealed a positive rheumatoid factor (RF), C-reactive protein (CRP) of 44.2 mg/L (>7 mg/L indicates inflammation) and erythrocyte sedimentation rate (ESR) of 34 mm/hr (upper limit of normal 10 mm/hr). He was diagnosed with rheumatoid arthritis (RA) with a polymyalgia rheumatica (PMR)-type onset. He received 40 mg prednisone daily with near complete resolution of symptoms, and was transitioned to hydroxychloroquine and methotrexate.\n\nPatient #3\nA 70 year-old man presented with a Hb of 82 g/L. A BMBx showed erythroid dysplasia with ring sideroblasts, no increase in blasts, and deletion of chromosome 7. A diagnosis of refractory anemia with ring sideroblasts (RARS) was made and IPSS was int-1. He received blood transfusion support.\n\nFor 12 months prior to MDS diagnosis, he experienced intermittent swelling around the eyes and ears, fatigue and arthralgias. Five months after MDS diagnosis, he developed a skin rash; biopsy showed leukocytoclastic vasculitis. He received 50 mg prednisone daily, with marked improvement, allowing a taper to 10 mg daily, which controlled symptoms. He died suddenly thirty-two months from MDS diagnosis.\n\nPatient #4\nA 66 year-old man presented with pancytopenia. WBC count was 2.5×109/L, neutrophils 0.3×109/L, Hb 129 g/L, and PLTS 143×109/L. The ANA was 1:160. A BMBx was non-diagnostic. Five months later, he developed widespread myalgias and swelling of the hands. He was diagnosed with PMR and inflammatory arthritis not otherwise specified (NOS). Six months later, he developed hyperkeratotic patches on the scalp and hands. Skin biopsies showed a connective tissue disorder NOS. The diagnosis was amended to mixed connective tissue disorder, and he received azathioprine, hydroxychloroquine and prednisone. Five months later, the ESR was 64 mm/hr.\n\nThree months later, he experienced three episodes of culture negative sepsis. After an additional two months, dysplastic features in neutrophil precursors were seen. A repeat BMBx showed <1% blasts, increased cellularity and remained non-diagnostic. Cytogenetic analysis was normal male karyotype. Eight months from the second BMBx, the diagnosis was amended to MDS following a review of the previous BMBx at our center. The IPSS was low risk. Five months later, a third BMBx indicated no MDS progression, and cytogenetics remained normal.\n\nThis patient has ongoing arthritic symptoms. Following 15 months of treatment with immunosuppressive medications, culture negative fevers have not recurred.\n\nPatient #5\nA 39-year-old man presented with drenching sweats and chest pain, the latter diagnosed as pericarditis and treated with aspirin and colchicine. One week later, he developed abdominal pain suspicious for Behcet’s disease. A CBCD revealed a Hb of 110 g/L and a leukoerythroblastic picture. WBC count was 5.9×109/L, neutrophils 1.1×109/L, PLTS decreased (count unavailable due to clumping). A BMBx showed multilineage dysplasia, ring sideroblasts, 4% blasts and a complex karyotype. A diagnosis of RCMD-RS was made and the IPSS was int-2. He was initiated on azacitidine. Four months later, he developed culture-negative sepsis, three episodes in total. He also had a widespread, recurrent petechial rash without significant thrombocytopenia. A second BMBx one month after cycle two of azacitidine showed no MDS progression. He received four cycles of azacitidine in total with hematologic improvement in all lineages. He continues to suffer from fatigue and episodes of pericarditis; however, the other symptoms abated. He is undergoing HSCT.\n\nDiscussion and Conclusions\nReports suggest an association between AI manifestations and MDS, including: acute systemic vasculitis; chronic AI syndromes; connective tissue disorders; immune-mediated cytopenias; and serological abnormalities.9,13-21 Inflammatory syndromes may precede or follow the diagnosis of MDS.9,19,22\n\nCytokines implicated in MDS include tumor necrosis factor alpha (TNF-a) and transforming growth factor beta (TGF-b), which result in upregulation of proinflammatory and myelosuppressive cytokines, respectively.23,24 Interferon regulatory factor-1 (IRF-1) is involved in activities including inflammatory responses, and IRF mRNA was increased in MDS patients with AIM.10 Immune cells that may be involved in AIM include natural killer (NK) cells and regulatory T-cells.25,26\n\nThe prognostic impact of AIM in MDS is a matter of debate. In one study, the median survival of MDS patients with no AIM was 25 months compared to 9 months in patients with AIM.9 Acute vasculitis had a particularly poor prognosis, with a median survival of only 6 months. However, this study did not take into account the IPSS score. In another study that considered IPSS score and treatment, patients with AIM (n=13) did not have an inferior prognosis to those without (n=57).10 We separated our patients into lower IPSS risk, and higher risk receiving azacitidine, and compared the outcomes of those with and without AIM. In both instances we did not find a significant difference in OS between groups, though small numbers limits interpretation of these analyses. Supportive treatment of AIM in MDS requires careful consideration, as immunosuppressive medications (ISM) may increase infectious risk and exacerbate cytopenias. In one study, however, 26 of 27 of MDS patients with AIM responded favorably to ISM but only 6 experienced sustained AIM remission.27 There are reports of MDS progression with immunosuppression,28 but on the other hand, immunosuppressive therapy such as anti-thymocyte globulin (ATG) and cyclosporine may result in responses in some MDS patients.7 Given the uncertain safety of ISM for the treatment of AIM in MDS, these medications should be used with caution and patients monitored closely.\n\nTreatment of MDS may improve AIM. In one series of 22 patients with AIM receiving azacitidine for MDS, 19 (86%) had an AIM response within 3-6 azacitidine cycles, allowing discontinuation of ISM.29 Azacitidine is thought to act in this regard by increasing the number of FOXP3+ regulatory T-cells and inhibiting CD4+ T-cells.13,30\n\nIn six patients with AIM in MDS relapsed or refractory to steroid treatment, 5 had a response to lenalidomide, with 3 complete remissions.31 There are reports, however, implicating lenalidomide in increased AIM.32 Lenalidomide modulates the function of NK cells, monocytes, dendritic cells, and T-cells, and increases cytokines involved in attenuating inflammatory responses.25,26\n\nThe findings in our patients are consistent with other reports, with AIM occurring concomitant with MDS diagnosis in 4.4%, in patients with a median age of 68 years, 9 of 11 having adverse karyotype, and present in all IPSS risk groups.9-11,16,33 Though this percentage is lower than in previous reports, we restricted the analysis to patients presenting with AIM around the time of MDS diagnosis and excluded patients with longstanding autoimmune disorders.\n\nIn conclusion, MDS should remain on the differential diagnosis of patients undergoing work up for AIM. Similarly, MDS patients with AIM should be identified as symptoms may respond to therapy with immunosuppressive medications or specific MDS treatments.\n\nTable 1. Autoimmune manifestations of myelodysplastic syndromes in 11 patients: clinical features, treatment and outcome.\n\nCharacteristic\tN (%) /Median (range)\t\nAge (years)\t68 (34-84)\t\nGender (male)\t7(64)\t\nFAB* or WHO MDS diagnosis\t\n RCUD\t2\t\n RCMD-RS\t2\t\n RA\t1\t\n RARS\t1\t\n RCMD\t1\t\n RAEB-t°\t1\t\n MDS-NOS\t1\t\n CMML-2\t1\t\nIPSS risk\t\n Low\t3\t\n Intermediate-1\t4\t\n Intermediate-2\t3\t\n High\t1\t\nIPSS cytogenetics group\t\n Good\t6\t\n Intermediate\t2\t\n Poor\t3\t\nSignificant conditions\t\n No\t8\t\n Yes#\t3\t\nMDS treatment\t\n Observation\t5\t\n Supportive care§\t3\t\n Azacitidine\t3\t\nMDS outcome\t\n Stable\t6\t\n Good response\t1\t\n Died^\t4\t\nAutoimmune manifestation (AIM)\t\n Culture negative sepsis\t7\t\n Inflammatory arthritis\t3\t\n Systemic vasculitis\t2\t\n Cutaneous vasculitis\t1\t\n Polymyalgia rheumatica\t2\t\n Connective tissue disorder NOS\t2\t\n Polychondritis\t1\t\n Pericarditis\t2\t\nAIM months in relation to MDS diagnosis\t1 (-38-34)\t\nSerological abnormalities\t\n Positive ANA\t6\t\n Elevated CRP\t5\t\n Elevated ESR\t2\t\n Monoclonal paraprotein\t1\t\n Positive RF\t1\t\nAIM treatment\t\n Observation\t3\t\n Prednisone\t8$\t\n Methotrexate\t4\t\n Hydroxychloroquine\t4\t\n Azathioprine\t2\t\n Gold\t1\t\n Chlorambucil\t2\t\n Dapsone\t1\t\nAIM outcome\t\n Resolution of all symptoms\t3\t\n Partial resolution of symptoms\t4\t\n Persistent symptoms\t4\t\nANA, anti-nuclear antibody; CMML; chronic myelomonocytic leukemia; CRP, C-reactive protein; EB-t; excess blasts in transformation; ESR, erythrocyte sedimentation rate; FAB, French-American-British; IPSS, International Prognostic Scoring System; MD, multilineage dysplasia; MDS, myelodysplastic syndrome; NOS, not otherwise specified; RA, refractory anemia; RS, ring sideroblasts; RF, rheumatoid factor; t-, treatment related; UD, Unilineage dysplasia.\n\n*According to era of MDS diagnosis\n\n°t-MDS\n\n#myasthenia gravis and systemic lupus erythematosus; psoriatic arthritis, polychondritis and vasculitis; well-controlled HIV infection; n=1 each. The course of the HIV-positive patient has been published in detail (Williamson BT & Leitch HA, 2016).\n\n§Erythropoietin, n=2; red blood cell transfusions + iron chelation therapy, n=1.\n\n^MDS progression, n=2; complications of treatment, n=1; unknown cause, n=1.\n\n$7 in combination with other agents.\n==== Refs\nReferences\n1. Ades L Itzykson R Fenaux P. \nMyelodysplastic syndromes . Lancet \n2014 ;383 :2239 -52 .24656536 \n2. Greenberg P Cox C LeBeau MM \nInternational scoring system for evaluating prognosis in myelodysplastic syndromes . Blood \n1997 ;89 :2079 -88 .9058730 \n3. Will B Zhou L Vogler TO \nStem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations . Blood \n2012 ;120 :2076 -86 .22753872 \n4. Gadji M Adebayo Awe J \nProfiling three-dimensional nuclear telomeric architecture of myelodysplastic syndromes and acute myeloid leukemia defines patient subgroups . Clin Cancer Res \n2012 ;18 :3293 -304 .22539801 \n5. Rhyasen GW Starczynowski DT \nDeregulation of microRNAs in myelodysplastic syndrome . Leukemia \n2012 ;26 :13 -22 .21852786 \n6. del Rey M O’Hagan K Dellett M \nGenome-wide profiling of methylation identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes . Leukemia \n2013 ;27 :610 -8 .22936014 \n7. Sloand EM Wu CO Greenberg P \nFactors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy . J Clin Oncol \n2008 ;26 :2505 -11 .18413642 \n8. Zeng W Miyazato A Chen G \nInterferon-gamma-induced gene expression in CD34 cells: identification of pathologic cytokine-specific signature profiles . Blood \n2006 ;107 :167 -75 .16131564 \n9. Enright H Jacob HS Vercellotti G \nParaneoplastic autoimmune phenomena in patients with myelodysplastic syndromes: response to immunosuppressive therapy . Br J Haematol \n1995 ;91 :403 -8 .8547082 \n10. Giannouli S Voulgarelis M Zintzaras E \nAutoimmune phenomena in myelodysplastic syndromes: a 4-yr prospective study . Rheumatology (Oxford) \n2004 ;43 :626 -32 .14983106 \n11. de Hollanda A Beucher A Henrion D \nSystemic and immune manifestations in myelodysplasia: a multicenter retrospective study . Arthritis Care Res (Hoboken) \n2011 ;63 :1188 -94 .21584947 \n12. Anderson LA Pfeiffer RM Landgren O \nRisks of myeloid malignancies in patients with autoimmune conditions . Br J Cancer \n2009 ;100 :822 -8 .19259097 \n13. Frietsch JJ Dornaus S Neumann T \nParaneoplastic inflammation in myelodysplastic syndrome or bone marrow failure: case series with focus on 5-azacytidine and literature review . Eur J Haematol \n2014 ;93 :247 -59 .24635656 \n14. Bouali F Berrah A Si Ahmed-Bouali D \n[Immunological abnormalities in myelodysplastic syndromes. Prospective study (series of 40 patients)] . Rev Med Interne \n2005 ;26 :777 -83 . [Article in French ].16203055 \n15. Mekinian A Braun T Decaux O \nInflammatory arthritis in patients with myelodysplastic syndromes: a multicenter retrospective study and literature review of 68 cases . Medicine (Baltimore) \n2014 ;93 :1 -10 .24378738 \n16. Castro M Conn DL Su WP Garton JP \nRheumatic manifestations in myelodysplastic syndromes . J Rheumatol \n1991 ;18 :721 -7 .1865418 \n17. Hamblin TJ \nImmunological abnormalities in myelodysplastic syndromes . Semin Hematol \n1996 ;33 :150 -62 .8722685 \n18. Ramakrishna R Chaudhuri K Sturgess A Manoharan A. \nHaematological manifestations of primary Sjogren’s syndrome: a clinicopathological study . Q J Med \n1992 ;83 :547 -54 .1484932 \n19. Hebbar M Brouillard M Wattel E \nAssociation of myelodysplastic syndrome and relapsing polychondritis: further evidence . Leukemia \n1995 ;9 :731 -3 .7723411 \n20. Sokol RJ Hewitt S Booker DJ \nErythrocyte autoantibodies, autoimmune haemolysis, and myelodysplastic syndromes . J Clin Pathol \n1989 ;42 :1088 -91 .2584409 \n21. Okamoto T Okada M Mori A \nCorrelation between immunological abnormalities and prognosis in myelodysplastic syndrome patients . Int J Hematol \n1997 ;66 :345 -51 .9401280 \n22. Ahn JK Cha HS Koh EM \nBehcet’s disease associated with bone marrow failure in Korean patients: clinical characteristics and the association of intestinal ulceration and trisomy 8 . Rheumatology (Oxford) \n2008 ;47 :1228 -30 .18550640 \n23. Stirewalt DL Mhyre AJ Marcondes M \nTumour necrosis factor-induced gene expression in human marrow stroma: clues to the pathophysiology of MDS? \nBr J Haematol \n2008 ;140 :444 -53 .18162123 \n24. Zhou L Nguyen AN Sohal D \nInhibition of the TGF-beta receptor I kinase promotes hematopoiesis in MDS . Blood \n2008 ;112 :3434 -43 .18474728 \n25. McDaniel JM Pinilla-Ibarz J Epling-Burnette PK \nMolecular action of lenalidomide in lymphocytes and hematologic malignancies . Adv Hematol \n2012 ;2012 :513702 .22888354 \n26. Castelli R Cassin R Cannavo A Cugno M. \nImmunomodulatory drugs: new options for the treatment of myelodysplastic syndromes . Clin Lymphoma Myeloma Leuk \n2013 ;13 :1 -7 .23153925 \n27. Enright H Miller W. \nAutoimmune phenomena in patients with myelodysplastic syndromes . Leuk Lymphoma \n1997 ;24 :483 -9 .9086438 \n28. Kwong YL Au WY Liang RH \nAcute myeloid leukemia after azathioprine treatment for autoimmune diseases: association with -7/7q . Cancer Genet Cytogenet \n1998 \n15 ;104 :94 -7 .9666800 \n29. Fraison JB Mekinian A Grignano E \nEfficacy of azacitidine (AZA) in autoimmune and inflammatory disorders (AID) associated with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) . Blood \n2015 ;126 :1695 .26239089 \n30. Aggarwal S van de Loosdrecht AA Alhan C \nRole of immune responses in the pathogenesis of low-risk MDS and high-risk MDS: implications for immunotherapy . Br J Haematol \n2011 ;153 :568 -81 .21488861 \n31. Takeoka Y Miura A Nakamura K \nA detailed analysis of myelodysplastic syndrome complicated by autoimmune or inflammatory disorders: a possible efficacy of low-dose lenalidomide . Blood \n2014 ;124 :3256 .\n32. Montefusco V Galli M Spina F \nAutoimmune diseases during treatment with immunomodulatory drugs in multiple myeloma: selective occurrence after lenalidomide . Leuk Lymphoma \n2014 :1 -6 .\n33. Mekinian A Grignano E Braun T \nSystemic inflammatory and autoimmune manifestations associated with myelodysplastic syndromes and chronic myelomonocytic leukaemia: a French multicentre retrospective study . Rheumatology (Oxford) \n2016 ;55 :291 -300 .26350487\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2038-8322",
"issue": "8(2)",
"journal": "Hematology reports",
"keywords": "Autoimmune; HDS; myelodysplastic syndromes",
"medline_ta": "Hematol Rep",
"mesh_terms": null,
"nlm_unique_id": "101556723",
"other_id": null,
"pages": "6480",
"pmc": null,
"pmid": "27499837",
"pubdate": "2016-05-10",
"publication_types": "D002363:Case Reports",
"references": "26350487;1484932;9401280;7723411;8547082;24378738;24635656;21852786;21488861;2584409;22539801;18550640;9666800;18474728;19259097;24656536;16203055;1865418;9086438;14983106;18162123;22936014;9058730;8722685;22888354;16131564;18413642;22753872;24730540;23153925;21584947",
"title": "Autoimmune Syndromes Presenting as a Paraneoplastic Manifestation of Myelodysplastic Syndromes: Clinical Features, Course, Treatment and Outcome.",
"title_normalized": "autoimmune syndromes presenting as a paraneoplastic manifestation of myelodysplastic syndromes clinical features course treatment and outcome"
} | [
{
"companynumb": "CA-CELGENEUS-CAN-2016063363",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "COLCHICINE"
},
"drugadditional": null,
... |
{
"abstract": "Abiraterone is an inhibitor of androgen biosynthesis indicated for the treatment of metastatic castration-resistant prostate cancer. Common side effects include diarrhea, edema, hypokalemia, hypertension, and liver function test abnormalities. We report a case of rhabdomyolysis developing in association with the use of abiraterone. Following discontinuation of abiraterone, creatine kinase concentrations decreased gradually throughout the duration of the hospitalization.",
"affiliations": "Southeast Missouri Hospital, Cape Girardeau, MO, USA.;Southeast Missouri Hospital, Cape Girardeau, MO, USA.",
"authors": "Moore|Donald C|DC|;Moore|Andrew|A|",
"chemical_list": "D000701:Analgesics, Opioid; D000736:Androstenes; D018931:Antineoplastic Agents, Hormonal; D009020:Morphine; D000072478:Cytochrome P450 Family 17; D003402:Creatine Kinase; C089740:abiraterone; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1177/1078155215620921",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "23(2)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Abiraterone; rhabdomyolysis; toxicity",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000701:Analgesics, Opioid; D000736:Androstenes; D018931:Antineoplastic Agents, Hormonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D003248:Constipation; D003402:Creatine Kinase; D000072478:Cytochrome P450 Family 17; D004359:Drug Therapy, Combination; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D008875:Middle Aged; D009020:Morphine; D009325:Nausea; D059408:Pain Management; D011241:Prednisone; D064129:Prostatic Neoplasms, Castration-Resistant; D012206:Rhabdomyolysis; D014839:Vomiting",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "148-151",
"pmc": null,
"pmid": "26637407",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Abiraterone-induced rhabdomyolysis: A case report.",
"title_normalized": "abiraterone induced rhabdomyolysis a case report"
} | [
{
"companynumb": "US-MYLANLABS-2017M1014215",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ROSUVASTATIN"
},
"drugadditional": null,
... |
{
"abstract": "To demonstrate the effect of intravitreal bevacizumab (IVB) on the size and vascularity of the fibro-vascular complex with the optical coherence tomography angiography (OCTA) before pars plana vitrectomy (PPV).\nObservational case series of three eyes with active diabetic fibro-vascular complex and tractional retinal detachment (TRD) who underwent IVB (1.25 mg/0.05 ml) two days before proceeding to PPV. OCTA was carried out prior to IVB, two days after IVB and six weeks after PPV.\nOCTA showed a reduction in the size and calibre of the diabetic fibro-vascular complex two days after IVB in all the cases. Consequently, there was less traumatic dissection of the fibro-vascular membranes during PPV and thus reduced chances of intraoperative and postoperative vitreous cavity bleeding. One case showed mild hemorrhage in the posterior vitreous on the second day post-injection which implies the increased traction caused by IVB.\nIn this case series, we have used OCTA to demonstrate how IVB is highly effective in reducing the vascularity of diabetic fibro-vascular membranes. This finding also suggests that the use of IVB before PPV in the management of diabetic TRD could also be much shorter than the advocated standard practice of one week in most institutions.",
"affiliations": "Manchester Royal Eye Hospital, Manchester University Hospital NHS Foundation Trust, Manchester, UK.;Manchester Royal Eye Hospital, Manchester University Hospital NHS Foundation Trust, Manchester, UK.;Manchester Royal Eye Hospital, Manchester University Hospital NHS Foundation Trust, Manchester, UK.;Manchester Vision Regeneration Lab, Manchester University Hospital NHS Foundation Trust, Manchester, UK.;Manchester Royal Eye Hospital, Manchester University Hospital NHS Foundation Trust, Manchester, UK.;Manchester Royal Eye Hospital, Manchester University Hospital NHS Foundation Trust, Manchester, UK.",
"authors": "Ch'ng|Soon Wai|SW|;Papayannis|Alessandro|A|;Stringa|Francesco|F|;Tsamis|Emmanouil|E|;Stanga|Paulo|P|;Jalil|Assad|A|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1016/j.joco.2018.06.001",
"fulltext": "\n==== Front\nJ Curr OphthalmolJ Curr OphthalmolJournal of Current Ophthalmology2452-2325Elsevier S2452-2325(18)30063-510.1016/j.joco.2018.06.001ArticleThe effect of bevacizumab before vitrectomy for diabetic tractional retinal detachment demonstrated on optical coherence tomography angiography Ch'ng Soon Wai soon.ch'ng@nhs.netab∗Papayannis Alessandro abStringa Francesco abTsamis Emmanouil bcStanga Paulo abdJalil Assad aba Manchester Royal Eye Hospital, Manchester University Hospital NHS Foundation Trust, Manchester, UKb Manchester Vision Regeneration Lab, Manchester University Hospital NHS Foundation Trust, Manchester, UKc Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UKd Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK∗ Corresponding author. soon.ch'ng@nhs.net21 6 2018 9 2018 21 6 2018 30 3 276 279 20 3 2018 25 5 2018 2 6 2018 © 2018 Iranian Society of Ophthalmology. Production and hosting by Elsevier B.V.2018Iranian Society of OphthalmologyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo demonstrate the effect of intravitreal bevacizumab (IVB) on the size and vascularity of the fibro-vascular complex with the optical coherence tomography angiography (OCTA) before pars plana vitrectomy (PPV).\n\nMethods\nObservational case series of three eyes with active diabetic fibro-vascular complex and tractional retinal detachment (TRD) who underwent IVB (1.25 mg/0.05 ml) two days before proceeding to PPV. OCTA was carried out prior to IVB, two days after IVB and six weeks after PPV.\n\nResults\nOCTA showed a reduction in the size and calibre of the diabetic fibro-vascular complex two days after IVB in all the cases. Consequently, there was less traumatic dissection of the fibro-vascular membranes during PPV and thus reduced chances of intraoperative and postoperative vitreous cavity bleeding. One case showed mild hemorrhage in the posterior vitreous on the second day post-injection which implies the increased traction caused by IVB.\n\nConclusions\nIn this case series, we have used OCTA to demonstrate how IVB is highly effective in reducing the vascularity of diabetic fibro-vascular membranes. This finding also suggests that the use of IVB before PPV in the management of diabetic TRD could also be much shorter than the advocated standard practice of one week in most institutions.\n\nKeywords\nBevacizumabDiabetic tractional retinal detachmentOCTAVitreous hemorrhage\n==== Body\nIntroduction\nTractional retinal detachment (TRD) is a leading cause of vision loss in patients with proliferative diabetic retinopathy (PDR).1 Pars plana vitrectomy (PPV) is a successful surgical procedure for the complications of PDR such as TRD2; nevertheless, postoperative vitreous hemorrhage (VH) represents a significant complication occurring in 20%–30% of cases.3, 4 It has been hypothesized that VH tends to occur after PPV for diabetic TRD because of difficulty of hemostasis during surgery, neovascularization stimulated by the sclerotomy site, and residual contracting vitreous.5, 6 Intravitreal bevacizumab (IVB), an inhibitor of vascular endothelial growth factor, performed one to twenty days before vitrectomy has been reported to prevent recurrent VH after vitrectomy for PDR by reducing neovascular activity.7 The use of IVB has also been shown to reduce overall surgical time and diminish overall intraoperative complications.8 Optical coherence tomography angiography (OCTA) is a new and promising imaging modality that depict retinal vascular changes and capillary non-perfusion in DR patients.9 Regression of neovascularization around the optic disc has been shown on OCTA to occur as early as 24 hours after a single IVB administration.10 Therefore, we have used the OCTA technology to demonstrate the effectiveness of IVB changes on the active proliferative fibro-vascular network in a series of patients prior to PPV surgery for diabetic TRD.\n\nCase report\nThree diabetic patients with similar characteristics of active PDR, TRD, and VH were selected. All OCTA enface images were qualitatively reviewed by two independent graders for the size of the retinal fibro-vascular complexes. In all the OCTA images acquired two days after the IVB, a decrease in the reflectivity and the volume of all the retinal fibro-vascular complexes was noticed in all patients with an inter-reviewer agreement of 100%. Patients were imaged with the Deep Range Imaging (DRI) Triton® SS (Swept Source) OCTA (Topcon Corp., Tokyo, Japan) as follows:• Immediately before IVB 1.25 mg/0.05 ml\n\n• On the second morning after the injection prior to the PPV\n\n• Six weeks after PPV once the gas tamponade (if used) had been absorbed\n\n\n\nTopcon IMAGEnet i-base (Topcon Corp., Tokyo, Japan) semi-automated segmentation software demonstrated the findings through the vitreo-retinal segmentation or outer vitreous segmentation. Raster-pattern retinal scans were obtained through the macula, the optic disc, and areas of possible new vessels in the mid-peripheral retina using scanning patterns of 6 × 6 mm in all patients. During the OCT examination, the choroid and the retina were positioned at the lower border of the image plane and as necessary to achieve a full depth visualization of the new vessel processes in the vitreous cavity. During vitreoretinal or vitreous segmentation analysis, the vitreous was segmented semi-automatically after modifying the reference planes and manipulating the depth of the boundaries to optimize the visualization of new vessel features in the cortical vitreous. OCTA images obtained were then automatically segmented to show the neovascular changes above the internal limiting membrane, the superficial neurovascular plexus, or any other tissular layer that could be arbitrary set as the lower segmentation boundary. The superior boundary was set in the depth of the vitreous cavity in order to obtain full visualization of the new vessels performed.11 The same boundaries were evaluated before and after the IVB and PPV in all the patients.\n\nFig. 1 is a 45-year-old female, Fig. 2 is a 55-year-old male, and Fig. 3 is a 30-year-old female. There was absence of reflectivity of retinal fibro-vascular complexes after four to eight weeks from PPV in all three eyes following PPV. VH occurred in one patient two days after IVB (Fig. 2). No VH or postoperative RD was evident in all patients after six weeks from PPV. No intraoperative complications were observed during the PPV. There was no significant bleeding from the segmentation and delamination of the fibro-vascular complex during the PPV.Fig. 1 From the left to the right: Swept-source optical coherence tomography angiography (SS OCTA) (top) and B Scan SS OCT images (bottom) before intravitreal bevacizumab (IVB), two days after IVB and 6 weeks after pars plana vitrectomy (PPV). Red arrow indicates the superior edge of the fibro-vascular membrane before and 2 days after IVB (with the contraction of the membrane).\n\nFig. 1Fig. 2 From left to right: Optical coherence tomography angiography (OCTA) of the fibro-vascular complex and B Scan Swept-source optical coherence tomography angiography (SS OCTA) of the fibro-vascular complex. From top to bottom: before intravitreal bevacizumab (IVB), two days from IVB and 6 weeks from pars plana vitrectomy (PPV). Note the reduced size and branching of the vascular complex after IVB (red arrow) and the mild hemorrhage in the posterior vitreous on the second day post-injection (yellow arrow) implying the increased traction caused by IVB.\n\nFig. 2Fig. 3 From left to right: fundus image of the area of active proliferative retinal vessel and optical coherence tomography angiography (OCTA) of the fibro-vascular complex. From top to bottom: before intravitreal bevacizumab (IVB) and two days after IVB (with the decrease size of the active proliferative retinal vessel).\n\nFig. 3\n\nDiscussion\nSmith and Steel7 investigated the use of anti-VEGF for prevention of postoperative vitreous cavity hemorrhage (POVCH) for PDR and concluded in their Cochrane review that the use of pre or intraoperative bevacizumab lowers the incidence of early POVCH with no local or systemic complications of IVB. However, the effect on late POVCH was uncertain. Different authors have advocated different timelines for IVB use, from one day to three weeks pre-PPV, including some who give IVB at the end of PPV.7 A long delay from IVB to PPV also increases the change of progression in pre-existing TRD. These clinical findings influenced our decision to choose a shorter timeframe to proceed to PPV after the IVB. Our observational study has demonstrated that IVB can be effective as early as two days to take effect and this is confirmed with the OCTA findings. An early sign of increased traction was seen in one case. This increased traction was manifested through hemorrhage in the posterior hyaloid face due to the pulling effect on the fibro-vascular membranes. Alternatively, the mechanical effect of the IVB in the vitreous cavity and the mixing of pre-existing epi-retinal blood with the vitreous could also explain the blood in the posterior vitreous. Despite the evidence that anti-VEGFs reduce early POVCH, there is an argument against its use in all diabetic vitrectomies, especially those with fibrotic TRDs where it can be counterproductive. In our case series, IVB was given only before PPV for ‘vascular’ TRDs and not before other ‘routine’ diabetic PPV. It was highly effective in our case series by reducing vascularity of diabetic membranes, which in turn lead to an increased ease of surgical dissection and reduced chances of POVCH. Considering that worsening of fibrosis and traction is mostly seen after a week based on previous studies, performing PPV earlier after IVB can be considered an ideal compromise. Inherently, this case series has its obvious limitations which are the small sample size and lack of control group. However, the encouraging result from this case series using OCTA provides a platform for a randomized, controlled trial to confirm the optimum time frame for the use of IVB in diabetic TRD before PPV.\n\nDeclaration of interest: All authors have no conflict of interest in the production of this manuscript. There are no external funders that have played a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Professor Paulo Stanga receives a variety of consultancy, research funding, lecture fees and/or travel expenses from Allergan Plc, Bausch & Lomb Inc, Bayer AG, ExcelLens Inc, Novartis AG, Optos Plc, Second Sight Medical Products Inc, Thrombogenics Inc and Topcon Corp.\n\nPeer review under responsibility of the Iranian Society of Ophthalmology.\n==== Refs\nReferences\n1 Rice T.A. Michels R.G. Rice E.F. Vitrectomy for diabetic traction retinal detachment involving the macula Am J Ophthalmol 95 1 1983 22 33 6185000 \n2 Ho T. Smiddy W.E. Flynn H.W. Vitrectomy in the management of diabetic eye disease Surv Ophthalmol 37 3 1992 190 202 1475753 \n3 Blankenship G.W. Management of vitreous cavity hemorrhage following pars plana vitrectomy for diabetic retinopathy Ophthalmology 93 1 1986 39 44 2419815 \n4 Yorston D. Wickham L. Benson S. Bunce C. Sheard R. Charteris D. Predictive clinical features and outcomes of vitrectomy for proliferative diabetic retinopathy Br J Ophthalmol 92 3 2008 365 368 18303158 \n5 Novak M.A. Rice T.A. Michels R.G. Auer C. Vitreous hemorrhage after vitrectomy for diabetic retinopathy Ophthalmology 91 12 1984 1485 1489 6521989 \n6 Lewis H. Abrams G.W. Williams G.A. Anterior hyaloidal fibrovascular proliferation after diabetic vitrectomy Am J Ophthalmol 104 6 1987 607 613 2446501 \n7 Smith J.M. Steel D.H. Anti-vascular endothelial growth factor for prevention of postoperative vitreous cavity hemorrhage after vitrectomy for proliferative diabetic retinopathy Cochrane Database Syst Rev 8 2015 CD008214 \n8 Zhang Z.H. Liu H.Y. Hernandez-Da Mota S.E. Vitrectomy with or without preoperative intravitreal bevacizumab for proliferative diabetic retinopathy: a meta-analysis of randomized controlled trials Am J Ophthalmol 156 1 2013 106 115 23791371 \n9 Ishibazawa A. Nagaoka Takahashi A. Omae T. Optical coherence tomography angiography in diabetic retinopathy: a prospective pilot study Am J Ophthalmol 160 1 2015 35 44 25896459 \n10 Falavarjani K.G. Habibi A. Khorasani M.A. Anvari P. Sadda S.R. Time course of changes in optic disk neovascularization after a single intravitreal bevacizumab injection Retina 2018 Feb 19 (Epub ahead of print) \n11 Stanga P.E. Papayannis A. Tsamis E. New findings in diabetic maculopathy and proliferative disease by swept-source optical coherence tomography angiography Dev Ophthalmol 56 2016 113 121 27023703\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2452-2325",
"issue": "30(3)",
"journal": "Journal of current ophthalmology",
"keywords": "Bevacizumab; Diabetic tractional retinal detachment; OCTA; Vitreous hemorrhage",
"medline_ta": "J Curr Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101678509",
"other_id": null,
"pages": "276-279",
"pmc": null,
"pmid": "30197961",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports",
"references": "6521989;25896459;2446501;29466258;6185000;27023703;26250103;1475753;23791371;18303158;2419815",
"title": "The effect of bevacizumab before vitrectomy for diabetic tractional retinal detachment demonstrated on optical coherence tomography angiography.",
"title_normalized": "the effect of bevacizumab before vitrectomy for diabetic tractional retinal detachment demonstrated on optical coherence tomography angiography"
} | [
{
"companynumb": "GB-ROCHE-2152475",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "A 76-year-old Japanese woman was admitted due to uncontrolled cellulitis of the right lower leg. She had deep vein thrombosis on the right limb. Moreover, she had a long history of rheumatoid arthritis treated with corticosteroids. Skin biopsy and lumbar puncture were performed to diagnose disseminated cryptococcosis. She was administered antifungal agents (liposomal amphotericin B and 5-fluorocytosine). On treatment day 14, debridement was performed, and cryptococcosis was controlled. However, she developed toxic megacolon due to Clostridioides difficile infection (CDI). On day 32, she was transferred to the intensive care unit due to severe acidosis and acute kidney injury secondary to CDI-related toxic megacolon. Vancomycin, metronidazole, and tigecycline were administered for treatment of CDI. After several weeks of intensive care, toxic megacolon was improved, but renal replacement therapy was discontinued according to the patient's will. On day 73, she died of renal failure. We experienced a complex of rare diseases, Cryptococcus neoformans cellulitis and Clostridioides difficile-related toxic megacolon. Both diseases were presumed to be the result of corticosteroid and methotrexate use. Hence, careful monitoring is required when treating immunocompromised hosts to reduce the risk of developing complications.",
"affiliations": "Department of Clinical Infectious Diseases, Aichi Medical University Hospital, Nagakute, Aichi, Japan; Department of Infection Control and Prevention, Aichi Medical University Hospital, Nagakute, Aichi, Japan.;Division of Nephrology and Rheumatology, Department of Internal Medicine, Aichi Medical University Hospital, Nagakute, Aichi, Japan.;Department of Plastic Surgery, Aichi Medical University Hospital, Nagakute, Aichi, Japan.;Department of Dermatology, Aichi Medical University Hospital, Nagakute, Aichi, Japan.;Department of Clinical Infectious Diseases, Aichi Medical University Hospital, Nagakute, Aichi, Japan; Department of Infection Control and Prevention, Aichi Medical University Hospital, Nagakute, Aichi, Japan.;Department of Clinical Infectious Diseases, Aichi Medical University Hospital, Nagakute, Aichi, Japan; Department of Infection Control and Prevention, Aichi Medical University Hospital, Nagakute, Aichi, Japan.;Division of Nephrology and Rheumatology, Department of Internal Medicine, Aichi Medical University Hospital, Nagakute, Aichi, Japan.;Department of Infection Control and Prevention, Aichi Medical University Hospital, Nagakute, Aichi, Japan.;Department of Infection Control and Prevention, Aichi Medical University Hospital, Nagakute, Aichi, Japan.;Department of Infection Control and Prevention, Aichi Medical University Hospital, Nagakute, Aichi, Japan.;Department of Infection Control and Prevention, Aichi Medical University Hospital, Nagakute, Aichi, Japan.;Department of Clinical Infectious Diseases, Aichi Medical University Hospital, Nagakute, Aichi, Japan; Department of Infection Control and Prevention, Aichi Medical University Hospital, Nagakute, Aichi, Japan.;Department of Infection Control and Prevention, Aichi Medical University Hospital, Nagakute, Aichi, Japan.;Division of Nephrology and Rheumatology, Department of Internal Medicine, Aichi Medical University Hospital, Nagakute, Aichi, Japan.;Department of Clinical Infectious Diseases, Aichi Medical University Hospital, Nagakute, Aichi, Japan; Department of Infection Control and Prevention, Aichi Medical University Hospital, Nagakute, Aichi, Japan. Electronic address: mikamo@aichi-med-u.ac.jp.",
"authors": "Koizumi|Yusuke|Y|;Kachi|Asako|A|;Tsuboi|Kenji|K|;Muto|Jun|J|;Watanabe|Hiroki|H|;Asai|Nobuhiro|N|;Nobata|Hironobu|H|;Shiota|Arufumi|A|;Kato|Hideo|H|;Sakanashi|Daisuke|D|;Hagihara|Mao|M|;Yamagishi|Yuka|Y|;Suematsu|Hiroyuki|H|;Banno|Shogo|S|;Mikamo|Hiroshige|H|",
"chemical_list": "D000890:Anti-Infective Agents; D007166:Immunosuppressive Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2018.12.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "25(5)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Acute renal failure; Cutaneous ulcer; Immunocompromised host; Meningitis; Prednisolone; Tigecycline",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000890:Anti-Infective Agents; D001172:Arthritis, Rheumatoid; D002481:Cellulitis; D000068016:Clostridiales; D060085:Coinfection; D003453:Cryptococcosis; D003455:Cryptococcus neoformans; D003646:Debridement; D003937:Diagnosis, Differential; D004359:Drug Therapy, Combination; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D008532:Megacolon, Toxic; D017582:Renal Replacement Therapy",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "379-384",
"pmc": null,
"pmid": "30797689",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clostridioides difficile-related toxic megacolon after Cryptococcus neoformans cellulitis: A complex of two rare infections in an immunocompromised host.",
"title_normalized": "clostridioides difficile related toxic megacolon after cryptococcus neoformans cellulitis a complex of two rare infections in an immunocompromised host"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-207359",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"dr... |
{
"abstract": "Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy.\n\n\n\nWe did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors.\n\n\n\nBetween June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p<0·0001). After adjustment, multivariable analysis showed that the prevalence of major congenital malformations was significantly higher for all doses of carbamazepine and valproate as well as for phenobarbital at doses of more than 80 mg/day than for lamotrigine at doses of 325 mg/day or less. Valproate at doses of 650 mg/day or less was also associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250-4000 mg/day (odds ratio [OR] 2·43, 95% CI 1·30-4·55; p=0·0069). Carbamazepine at doses of more than 700 mg/day was associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250-4000 mg/day (OR 2·41, 95% CI 1·33-4·38; p=0·0055) and oxcarbazepine at doses of 75-4500 mg/day (2·37, 1·17-4·80; p=0·0169).\n\n\n\nDifferent antiepileptic drugs and dosages have different teratogenic risks. Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs. These findings facilitate rational selection of these drugs, taking into account comparative risks associated with treatment alternatives. Data for topiramate and phenytoin should be interpreted cautiously because of the small number of exposures in this study.\n\n\n\nBial, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, the Netherlands Epilepsy Foundation, and Stockholm County Council.",
"affiliations": "Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Neurology, Karolinska University Hospital, Stockholm, Sweden. Electronic address: torbjorn.tomson@sll.se.;Epilepsy Center, Department of Neurophysiology and Experimental Epileptology, IRCCS Neurological Institute Carlo Besta Foundation, Milan, Italy.;Department of Clinical Science and Community, Section of Medical Statistics, Biometry and Epidemiology, Faculty of Medicine and Surgery, University of Milan, Milan, Italy.;Department of Neurosciences, Acute and Unscheduled Care, Belfast Health and Social Care Trust, Belfast, UK.;Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands; Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, Netherlands.;Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy; Clinical Trial Center, IRCCS Mondino Foundation, Pavia, Italy.;The Epilepsy Clinic, Department of Neurology, Rigshospitalet-Blegdamsvej, University State Hospital, Copenhagen, Denmark.;Department of Neurology, Sree ChitraTirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala, India.;Department of Medicine and Department of Neurology, University of Melbourne, Royal Melbourne Hospital, Melbourne, VIC, Australia.",
"authors": "Tomson|Torbjörn|T|;Battino|Dina|D|;Bonizzoni|Erminio|E|;Craig|John|J|;Lindhout|Dick|D|;Perucca|Emilio|E|;Sabers|Anne|A|;Thomas|Sanjeev V|SV|;Vajda|Frank|F|;|||",
"chemical_list": "D000927:Anticonvulsants; D000077236:Topiramate; D002220:Carbamazepine; D000077287:Levetiracetam; D014635:Valproic Acid; D010672:Phenytoin; D000077213:Lamotrigine; D000078330:Oxcarbazepine; D010634:Phenobarbital",
"country": "England",
"delete": false,
"doi": "10.1016/S1474-4422(18)30107-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-4422",
"issue": "17(6)",
"journal": "The Lancet. Neurology",
"keywords": null,
"medline_ta": "Lancet Neurol",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D000927:Anticonvulsants; D002220:Carbamazepine; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D000077287:Levetiracetam; D016015:Logistic Models; D008297:Male; D000078330:Oxcarbazepine; D010634:Phenobarbital; D010672:Phenytoin; D011247:Pregnancy; D011248:Pregnancy Complications; D000077236:Topiramate; D014635:Valproic Acid; D055815:Young Adult",
"nlm_unique_id": "101139309",
"other_id": null,
"pages": "530-538",
"pmc": null,
"pmid": "29680205",
"pubdate": "2018-06",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry.",
"title_normalized": "comparative risk of major congenital malformations with eight different antiepileptic drugs a prospective cohort study of the eurap registry"
} | [
{
"companynumb": "SE-JNJFOC-20180614838",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "A 75-year-old Japanese woman with a 20-year history of rheumatoid arthritis presented with symptomatic bilateral pleural effusion and lung and brain tumors. She had received methotrexate for five years and tacrolimus for one year. A brain biopsy specimen showed the pathological features of lymphoproliferative disease, but a bone marrow biopsy showed proliferation of plasma cells. She was finally diagnosed with coexistent lymphomatoid granulomatosis (LYG) of the brain and lung and multiple myeloma (MM) of the bone marrow and received chemotherapy for both. This report shows that immunodeficient patients are at risk of developing the unusual coexistence of LYG and MM.",
"affiliations": "Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Japan.;Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Japan.;Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Japan.;Division of Surgical Pathology, University of Fukui Hospital, Japan.;Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Japan.",
"authors": "Lee|Shin|S|;Negoro|Eiju|E|;Oki|Hisashi|H|;Imamura|Yoshiaki|Y|;Yamauchi|Takahiro|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.2811-19",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3124321910.2169/internalmedicine.2811-19Case ReportSimultaneous Presentation of Lymphomatoid Granulomatosis and Multiple myeloma in an Immunodeficient Patient with Rheumatoid Arthritis Lee Shin 1Negoro Eiju 1Oki Hisashi 2Imamura Yoshiaki 3Yamauchi Takahiro 1\n1 Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Japan\n2 Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Japan\n3 Division of Surgical Pathology, University of Fukui Hospital, JapanCorrespondence to Dr. Shin Lee, leesin.581020@gmail.com\n\n27 6 2019 1 10 2019 58 19 2845 2849 7 2 2019 11 4 2019 Copyright © 2019 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 75-year-old Japanese woman with a 20-year history of rheumatoid arthritis presented with symptomatic bilateral pleural effusion and lung and brain tumors. She had received methotrexate for five years and tacrolimus for one year. A brain biopsy specimen showed the pathological features of lymphoproliferative disease, but a bone marrow biopsy showed proliferation of plasma cells. She was finally diagnosed with coexistent lymphomatoid granulomatosis (LYG) of the brain and lung and multiple myeloma (MM) of the bone marrow and received chemotherapy for both. This report shows that immunodeficient patients are at risk of developing the unusual coexistence of LYG and MM. \n\nlymphomatoid granulomatosismultiple myelomarheumatoid arthritismethotrexatetacrolimus\n==== Body\nIntroduction\nContinuous use of immunosuppressive agents such as methotrexate (MTX) and tacrolimus (TAC) sometimes induces hematological malignancies including lymphoproliferative disease (LPD) (1-3). Lymphomatoid granulomatosis (LYG), a rare type of LPD, can also be induced by long-term immunosuppression (4-6). Although LPD sometimes appears concurrently with other hematological disorders, few cases of the coexistence of LPD and multiple myeloma (MM) have been described (7,8). To our knowledge, the simultaneous presentation of LYG and MM has not been reported previously.\n\nIn this report, the first case of the coexistence of LYG and MM induced by MTX and TAC is presented. Physicians should keep in mind that there is a risk of developing multiple hematological malignancies in patients on long-term immunosuppressive therapy, as in the present patient.\n\nCase Report\nA 75-year-old Japanese woman with a 20-year history of rheumatoid arthritis (RA) presented with dyspnea and temporary seizures. The patient had received MTX for 5 years (4 mg per week for 6 months, 6 mg per week for 6 months, and 8 mg per week for 4 years) and 1 mg per day of TAC for 1 year for RA.\n\nHer height was 146 cm, weight 47.9 kg, temperature 37.0℃, heart rate 111 beats per minute, blood pressure 135/92 mmHg, and respiratory rate 20 breaths per minute. The patient had an oxygen saturation of 96% on 2 L/minute oxygenation through nasal cannulae on admission. Her Eastern Cooperative Oncology Group performance status (PS) was 4 due to severe arthritis and dyspnea caused by bilateral pulmonary effusion (PE). Her clinical laboratory data on admission are shown in Table.\n\nTable. Blood Chemistry Test Results on Admission.\n\nHematology\t\t\t\t\tBiochemistry\t\t\t\t\nWhite blood cell count\t\t9,400\t/μL\t\tTotal protein\t\t5.8\tg/dL\t\nLymphocyte count\t\t1,494\t/μL\t\tAlbumin\t\t3.1\tg/dL\t\nRed blood cell\t\t332\t×104/μL\t\tTotal bilirubin\t\t0.3\tmg/dL\t\nHemoglobin\t\t10.2\tg/dL\t\tAST\t\t19\tIU/L\t\nHematocrit\t\t33.4\t%\t\tALT\t\t8\tIU/L\t\nPlatelets\t\t28.7\t×104/μL\t\tLactate dehydrogenase\t\t359\tIU/L\t\n\t\t\t\t\tBlood urea nitrogen\t\t16\tmg/dL\t\nImmunology\t\t\t\t\tCreatinine\t\t0.42\tmg/dL\t\nIgA\t\t1,048\tmg/dL\t\tC-reactive protein\t\t0.74\tmg/dL\t\nIgG\t\t422\tmg/dL\t\tβ2-microglobulin\t\t3.2\tmg/dL\t\nIgM\t\t17.6\tmg/dL\t\tsIL-2R\t\t764\tIU/L\t\nALT: alanine aminotransferase, AST: aspartate aminotransferase, IgA: immunoglobulin A, IgG: immunoglobulin G, IgM: immunoglobulin M, sIL-2R: soluble interleukin-2 receptor\n\nSerum immunoelectrophoresis detected IgA-λ M-protein, urine protein electrophoresis detected Bence Jones protein, the κ/λ ratio of serum immunoglobulin-free light chain was 0.026, and Epstein-Barr virus (EBV) DNA was not detected in serum. Brain gadolinium-enhanced magnetic resonance imaging showed the enhancement of poorly marginated lesions in the right parietal lobe and left occipital lobe (Fig. 1a). Chest and abdominal contrast-enhanced computed tomography showed a poorly defined nodule in the left upper lobe and bilateral PEs (Fig. 1b). MTX and TAC were discontinued due to the possibility of immunosuppressive agent-induced LPD, but there was no improvement in the brain or lung tumors or bilateral PE. The pleural fluid showed high TP (5.8 g/dL) and high lactate dehydrogenase (LDH) (359 IU/L) concentrations, but no malignant cells were detected in the pathological cytology or flow cytometric analysis. A biopsy of the brain tumor in the right parietal lobe, performed 11 days after the discontinuation of MTX showed the pathological features of LPD (Fig. 2a and b). In contrast, plasma cells in the bone marrow aspiration specimen were increased (18.8%), and there was no evidence of LPD involvement in the bone marrow biopsy specimen. A flow cytometry analysis of the bone marrow revealed the expression of CD38 and CD138 and a discrepancy with immunoglobulin-free light chain (κ < λ), with the absence of CD19 and CD56. A fluorescence in situ hybridization analysis of a bone marrow specimen was negative for IgH-FGFR3 fusion, p53 mutation, IgH-CCND1 fusion, and IgH-MAF fusion. EBV-encoded small RNA-1 in situ hybridization (EBER-ISH) staining of these abnormal plasma cells showed negative results. Taken together, these findings led to the diagnosis of MM in the bone marrow (Fig. 2c), which was incompatible with the pathological findings of the brain biopsy.\n\nFigure 1. Brain gadolinium-enhanced magnetic resonance (Ga-MRI) and contrast-enhanced computed tomography (CECT) images at the onset. a: Brain Ga-MRI imaging at the onset. The arrow indicates enhancement of the poorly marginated lesions in the right parietal lobe. b: CECT of the chest and abdomen at the onset. The arrows indicate a poorly defined nodule in the left upper lobe and bilateral pleural effusion.\n\nFive weeks after the pathological consultation, the patient was finally diagnosed with coexistent EBV-associated LYG (grade 2) in the brain biopsy specimens and MM in the bone marrow clot and biopsy specimens. Hematoxylin and Eosin staining showed scattered perivascular infiltrates of medium-sized and large atypical lymphocytes (Fig. 2a and b). Results of Immunostaining using the CD20 antibody and EBER-ISH are shown in Fig. 2d and e. The CD20 and EBER-ISH-positive atypical B lymphocytes indicated EBV-induced B lymphocyte transformation.\n\nFigure 2. Pathological findings of a brain biopsy specimen and bone marrow aspiration specimen. a, b: Hematoxylin and Eosin staining of a brain biopsy specimen shows the scattered perivascular infiltrates of medium-sized to large atypical lymphocytes (a, ×10 magnification; b, ×60 magnification). c: May-Giemsa staining of the bone marrow aspiration specimen shows the proliferation of plasma cells (18.8%), but no EBER-positive cells are seen. d: Immunostaining using the CD20 antibody (×60 magnification) of a brain biopsy specimen. e: Immunostaining using EBV-encoded small RNA-1 in situ hybridization (×60 magnification) of a brain biopsy specimen.\n\nA brain biopsy performed after 1 month of administration of oral prednisolone (PSL; 10 mg/day) showed markedly reduced brain and lung tumor volumes (Fig. 3a) but progression of the bilateral PE (Fig. 3b). The patient developed normocytic anemia (Hb 9.0 g/dL, mean corpuscular volume 98 fL, reticulocytes 0.046×106/μL), which was thought to have been caused by MM after the exclusion of hemolytic anemia. The patient underwent treatment for symptomatic MM with Ld therapy (cycles every 4 weeks of lenalidomide 15 mg/body on days 1 to 21 and dexamethasone 40 mg/body on days 1, 8, 15, and 22). Two cycles of Ld therapy slightly reduced the bilateral PE and led to a partial response (PR) of the MM. After the final diagnosis of LYG, the patient underwent 2 cycles of reduced R-CHOP (cycles every 3 weeks of rituximab 375 mg/m2 on day 1, cyclophosphamide 375 mg/m2 on day 1, doxorubicin 25 mg/m2 on day 1, vincristine 0.7 mg/m2 on day 1, and PSL 100 mg/body on days 1 to 5), and this therapy induced a clear reduction in the bilateral PE and led to PR of the LYG.\n\nFigure 3. Repeated brain G-MRI and CECT images one month after starting oral prednisolone (PSL) followed by a brain biopsy. a: Repeated brain Ga-MRI images one month after starting oral PSL followed by a brain biopsy. The arrow indicates that oral PSL remarkably reduced the volume of brain enhancement in the right parietal lobe. b: Repeated CECT images of the chest and abdomen one month after starting oral PSL followed by a brain biopsy. The arrows indicate that oral PSL remarkably reduced the volume of the lung nodule in the left upper lobe. However, the bilateral pleural effusion had progressed despite oral PSL therapy.\n\nHowever, the treatment was discontinued because of the patient's and her family's refusal to continue due to severe febrile neutropenia, malaise, and anorexia. The patient ultimately died of LYG in the brain and lung with bilateral PE one month after recurrence and nine months after the onset.\n\nDiscussion\nTo our knowledge, this is the first reported case of the simultaneous presentation of LYG and MM induced by the long-term use of immunosuppressive agents including MTX.\n\nA previous study reported that the incidence of hematological malignancies after drug exposure in RA was 0.39%, most of which were LPD (55.9%), leukemia (28.8%), and MM (15.3%), and they were reported to be frequently associated with EBV (1). A previous study showed that latent EBV-infected B cells could escape from host cytotoxic T lymphocytes under immunodeficient conditions, which might lead to the development of hematological malignancies (9). EBV-DNA in blood is a prognostic biomarker of EBV-associated LPD and has good concordance with EBER-ISH, but it also has an association with the tumor burden (10). In the present case, the discrepancy between the EBER-ISH findings and EBV-DNA in blood might have been due to a low tumor burden. LYG cells in the brain were positive on EBER-ISH staining, but no evidence of EBV infection was detected in the abnormal plasma cells in the bone marrow, possibly indicating that the LYG and MM in the present patient arose from different origins, although the significance of this association remains unclear.\n\nThus far, few cases of LPD and MM appearing either simultaneously or sequentially have been reported (8,11,12). The treatment of LPD is sometimes prioritized over that of MM when LPD presents with a more aggressive clinical behavior than the co-existent MM (12). LYG is a rare category of LPD and has been classified as grade 1 to 3 based on the proportion of EBV-positive B lymphocytes present (13). Although several patients without symptoms and with histological low-grade (1 and 2) disease have achieved spontaneous remission (14), the majority have shown a poor prognosis with a high mortality (more than 50%) and short median survival time (14 months) (15). Patients with a high histological grade (3), any symptoms, and extensive disease, such as that with neurologic involvement, should be treated as having diffuse large B-cell lymphoma and administrated multi-agent chemotherapy, given the poor prognosis (14,15). While the spontaneous regression of LYG after discontinuation of MTX and TAC was expected, Ld therapy was started first for symptomatic MM in the present case. However, the LYG persisted despite the discontinuation of immunosuppressive agents and administration of chemotherapy for the coexistent MM. Of note, the brain involvement of LYG was an adverse prognostic factor that further justified the administration of chemotherapy. The brain involvement and poor PS probably resulted in the early relapse of LYG, which was thought to have influenced the prognosis in the present case.\n\nWe reported an unusual case of the simultaneous presentation of EBV-associated LYG and MM induced by the immunosuppressive agents, MTX and TAC. Physicians should be aware that immunodeficient patients are at a risk of developing multiple hematological malignancies. A careful examination for other hematological malignancies is needed such patients present with atypical symptoms or an atypical clinical course, even after the diagnosis of the first hematological malignancy.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\nThe authors would like to express their gratitude to Dr. Seiichi Kato and Dr. Shigeo Nakamura for pathological consultation and helpful discussions.\n==== Refs\n1. \nBernatsky S , Clarke AE , Suissa S \nHematologic malignant neoplasms after drug exposure in rheumatoid arthritis . Arch Intern Med \n168 : 378 -381 , 2008 .18299492 \n2. \nHoshida Y , Xu JX , Fujita S , et al \nLymphoproliferative disorders in rheumatoid arthritis: clinicopathological analysis of 76 cases in relation to methotrexate medication . J Rheumatol \n34 : 322 -331 , 2007 .17117491 \n3. \nSekiguchi Y , Shimada A , Imai H , et al \nEpstein-Barr virus-negative, CD5-positive diffuse large B-cell lymphoma developing after treatment with oral tacrolimus for mixed connective tissue disease: a case report and review of the literature . J Clin Exp Hematop \n52 : 211 -218 , 2012 .23269082 \n4. \nOchi N , Yamane H , Yamagishi T , Monobe Y , Takigawa N \nMethotrexate-induced lymphoproliferative disease: Epstein-Barr virus-associated lymphomatoid granulomatosis . J Clin Oncol \n31 : e348 -e350 , 2013 .23733760 \n5. \nConnors W , Griffiths C , Patel J , Belletrutti PJ \nLymphomatoid granulomatosis associated with azathioprine therapy in Crohn disease . BMC Gastroenterol \n14 : 127 , 2014 .25022612 \n6. \nYazdi AS , Metzler G , Weyrauch S , et al \nLymphomatoid granulomatosis induced by imatinib-treatment . Arch Dermatol \n143 : 1222 -1223 , 2007 .17875901 \n7. \nLee GC , Hong JS , Lee KH , et al \nA case of coincident multiple myeloma and non-Hodgkin's lymphoma . Korean J Intern Med \n9 : 113 -115 , 1994 .7865485 \n8. \nIbarrola de Andres C , Toscano R , Lahuerta JJ , Martinez-Gonzalez MA \nSimultaneous occurrence of Hodgkin's disease, nodal Langerhans' cell histiocytosis and multiple myeloma IgA(kappa) . Virchows Archiv \n434 : 259 -262 , 1999 .10190308 \n9. \nNiitsu N , Okamoto M , Nakamine H , Hirano M \nClinicopathologic correlations of diffuse large B-cell lymphoma in rheumatoid arthritis patients treated with methotrexate . Cancer Sci \n101 : 1309 -1313 , 2010 .20210795 \n10. \nLiang JH , Lu TX , Tian T , et al \nEpstein-Barr virus (EBV) DNA in whole blood as a superior prognostic and monitoring factor than EBV-encoded small RNA in situ hybridization in diffuse large B-cell lymphoma . Clin Microbiol Infect \n21 : 596 -602 , 2015 .25743579 \n11. \nMiyamura K , Osada H , Yamauchi T , et al \nSingle clonal origin of neoplastic B-cells with different immunoglobulin light chains in a patient with Richter's syndrome . Cancer \n66 : 140 -144 , 1990 .2112977 \n12. \nXu J , Tang Y , Zhao S , et al \nAngioimmunoblastic T-cell lymphoma with coexisting plasma cell myeloma: a case report and review of the literature . Tohoku J Exp Med \n235 : 283 -288 , 2015 .25816919 \n13. \nSwerdlow SH , Campo E , Harris NL , et al \nWHO Classification of Tumours of Haematopoietic and Lymphoid Tissues . 4th ed. \nIARC Press , Lyon , 2008 .\n14. \nJaffe ES , Wilson WH \nLymphomatoid granulomatosis: pathogenesis, pathology and clinical implications . Cancer Surv \n30 : 233 -248 , 1997 .9547995 \n15. \nKatzenstein AL , Carrington CB , Liebow AA \nLymphomatoid granulomatosis: a clinicopathologic study of 152 cases . Cancer \n43 : 360 -373 , 1979 .761171\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(19)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "lymphomatoid granulomatosis; methotrexate; multiple myeloma; rheumatoid arthritis; tacrolimus",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D001172:Arthritis, Rheumatoid; D001706:Biopsy; D001932:Brain Neoplasms; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes; D008175:Lung Neoplasms; D008230:Lymphomatoid Granulomatosis; D008279:Magnetic Resonance Imaging; D009101:Multiple Myeloma; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2845-2849",
"pmc": null,
"pmid": "31243219",
"pubdate": "2019-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25743579;20210795;25022612;10190308;17117491;17875901;25816919;23269082;761171;9547995;7865485;23733760;2112977;18299492",
"title": "Simultaneous Presentation of Lymphomatoid Granulomatosis and Multiple myeloma in an Immunodeficient Patient with Rheumatoid Arthritis.",
"title_normalized": "simultaneous presentation of lymphomatoid granulomatosis and multiple myeloma in an immunodeficient patient with rheumatoid arthritis"
} | [
{
"companynumb": "JP-ACCORD-137612",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drug... |
{
"abstract": "Metformin is the first-line treatment for any patient with type 2 diabetes. Metformin-associated lactic acidosis and transient blindness have only been reported in some case series and case reports. It is rare and presents especially in patients with underlying chronic kidney disease (CKD) Stage III and above and on high doses of metformin or with a normal dose of metformin and an associated renal injury. We present here a rare and interesting case of something similar. A 77-year-old woman with a past medical history of type 2 diabetes on metformin, obesity status post gastric bypass, CKD Stage III, presented with complaints of nausea, vomiting, confusion, abdominal pain, diarrhea, decreased urine output, sudden visual loss, and a hypoglycemic episode at home. She was hemodynamically stable. Lab work was suggestive of leukocytosis, hyperkalemia, severe high anion gap metabolic and lactic acidosis, acute-on-chronic kidney injury. Findings on the computed tomography (CT) brain, chest radiograph, and CT abdomen and pelvis could not explain the current scenario. She received Ringer's lactate, a bicarbonate push, and an infusion. Acidosis continued to worsen, she became hypotensive requiring pressor support, and she was immediately taken for hemodialysis. All her symptoms, including vision loss, had improved with a single session of hemodialysis, even before the acidosis had corrected. Work-up for other causes of renal dysfunction came back negative. Metformin was discontinued. She was placed on insulin for her diabetes control.",
"affiliations": "Internal Medicine, Saint Vincent Hospital, Worcester, USA.;Medicine and Surgery, Osmania Medical College, Hyderabad, IND.;Medicine and Surgery, MediCiti Institute of Medical Sciences, Hyderabad, IND.",
"authors": "Kalantri|Pooja|P|;Sahu|Abhishek|A|;Kalantri|Aarthi|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.9325",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.9325\nEndocrinology/Diabetes/Metabolism\nInternal Medicine\nNephrology\nA Case Report on Metformin-Associated Lactic Acidosis and Transient Blindness\nMuacevic Alexander Adler John R Kalantri Pooja 1 Sahu Abhishek 2 Kalantri Aarthi 3 \n1 \nInternal Medicine, Saint Vincent Hospital, Worcester, USA \n\n2 \nMedicine and Surgery, Osmania Medical College, Hyderabad, IND \n\n3 \nMedicine and Surgery, MediCiti Institute of Medical Sciences, Hyderabad, IND \n\nPooja Kalantri poojakalantri1@gmail.com\n21 7 2020 \n7 2020 \n12 7 e932526 6 2020 21 7 2020 Copyright © 2020, Kalantri et al.2020Kalantri 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/36178-a-case-report-on-metformin-associated-lactic-acidosis-and-transient-blindnessMetformin is the first-line treatment for any patient with type 2 diabetes. Metformin-associated lactic acidosis and transient blindness have only been reported in some case series and case reports. It is rare and presents especially in patients with underlying chronic kidney disease (CKD) Stage III and above and on high doses of metformin or with a normal dose of metformin and an associated renal injury. We present here a rare and interesting case of something similar. A 77-year-old woman with a past medical history of type 2 diabetes on metformin, obesity status post gastric bypass, CKD Stage III, presented with complaints of nausea, vomiting, confusion, abdominal pain, diarrhea, decreased urine output, sudden visual loss, and a hypoglycemic episode at home. She was hemodynamically stable. Lab work was suggestive of leukocytosis, hyperkalemia, severe high anion gap metabolic and lactic acidosis, acute-on-chronic kidney injury. Findings on the computed tomography (CT) brain, chest radiograph, and CT abdomen and pelvis could not explain the current scenario. She received Ringer’s lactate, a bicarbonate push, and an infusion. Acidosis continued to worsen, she became hypotensive requiring pressor support, and she was immediately taken for hemodialysis. All her symptoms, including vision loss, had improved with a single session of hemodialysis, even before the acidosis had corrected. Work-up for other causes of renal dysfunction came back negative. Metformin was discontinued. She was placed on insulin for her diabetes control.\n\nmetformin associated lactic acidosisblindnessckdtype 2 diabetesThe 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\nMetformin-associated lactic acidosis (MALA) and transient blindness are rare, life-threatening phenomena, resulting in hemodynamic instability and severe metabolic abnormalities, usually requiring renal replacement therapy (RRT) [1]. As it has a large volume of distribution, the initiation and duration of dialysis depend on clinical and laboratory targets [2] like the normalization of pH and lactate.\n\nThere are studies suggesting that the predialysis level of serum lactate is an important marker of mortality in MALA patients requiring RRT with a linear dose-response relationship [3]. The serum lactate level was significantly higher in non-survivors (median 22.5 mmol/L) than in survivors (17.0 mmol/L, p-value <0.01) and so were the median blood metformin concentrations (58.5 vs. 43.9 mg/L, p-value = 0.05). The survival advantage was not significantly different between the modalities of RRT [3].\n\nSo far, the notion was that the removal of metformin by dialysis was uncertain, and it helped correct the associated electrolyte abnormalities [4]. Hence, early recognition and treatment of this complication were very important. But there have been at least three publications suggesting otherwise. Most published reports present incomplete data: metformin clearance with high-efficiency hemodialysis (HD) surpasses 120 ml/min and has a metformin half-life that is approximately four hours. In comparison, metformin clearance with continuous renal replacement therapy is usually about one-fourth of that obtained with HD, and the half-life is at least three times as long. However, because of metformin’s large volume of distribution, the significance of these data is debatable without quantifying metformin removal. Only three publications have presented data indicating metformin removal by extracorporeal treatment. Lalau and Race reported the removal of 1105 mg, 694 mg, and 688 mg by HD in three patients [5]. Barrueto et al. reported 3.5 g removal by continuous venovenous hemodialysis in 10.5 hours [6], and Ayoub et al. reported the removal of 1039 mg in 5.5 hours during hemodialysis session one and another 463 mg in 6.2 hours during hemodialysis session two [4].\n\nCase presentation\nA 77-year-old female, with a past medical history of hypertension, obesity status post gastric bypass, chronic kidney disease (CKD) stage III, anemia of CKD, hyperlipidemia, and type 2 diabetes for 48 years, on 1250 mg twice daily metformin, presented to the hospital after she was found acutely confused at home with sudden-onset vision loss. She also complained of nausea, vomiting, poor appetite, abdominal pain, diarrhea, and decreased urine output for a few days. The blood sugar level was in the 34 mg/dL before arrival, which was treated en route.\n\nIn the emergency department, she was hemodynamically stable. She was alert and oriented to time, place, and person, with no focal neurological deficits except for the vision loss. Laboratory analysis was concerning for leukocytosis of 21,000 cells/microlitre, potassium 5.9 mEq/L, bicarbonate 3 mEq/L, blood urea nitrogen (BUN) 51 mg/dL, creatinine 4.39 mg/dL (with a baseline of 1.4 mg/dL), estimated-glomerular filtration rate (e-GFR) <30 mL/min, and lactate 23.8 mmol/L. The rest of the complete blood counts, basic metabolic panel, liver function tests, creatine kinase, troponin, urine analysis, urine toxicology, and urine alcohol levels were unremarkable. Electrocardiography (EKG) showed no changes in hyperkalemia. CT abdomen and pelvis showed a 4 mm non-obstructing calculus in the right kidney with no hydronephrosis. CT brain and chest X-ray were normal. She received a liter of Ringer’s lactate following which she was started on a bicarbonate push and drip. With worsening acidosis, due to unclear reasons at the time, with an arterial blood gas (ABG) showing pH less than 7, and bicarbonate unreadable, she was transferred to the intensive care unit (ICU) for urgent hemodialysis.\n\nIn the ICU, while undergoing HD, she was transiently hypotensive requiring two pressor supports for around eight hours. She also complained of respiratory distress. She was placed on bilevel positive airway pressure (BiPAP) intermittently, for the same. Repeat ABG after completion of hemodialysis showed a pH of 7.45, pCO2 24.8 mm/Hg, pO2 124.1 mm/Hg while the HCO3 was still 18.7 mEq/L. The patient's mental status improved and vision came back to normal after a four-hour session of hemodialysis. She was also back to room air from the transient BiPAP support. Her toxic metabolic encephalopathy was thought to be secondary to metformin toxicity in the setting of chronic kidney disease.\n\nOn the medical floor, she was slightly volume overloaded. BUN and creatinine continued to rise to reach a peak of 59 and 6.16, respectively. She also had 800 mg of proteinuria, likely related to her underlying diabetes. Serum and urine immunofixation were normal. Antinuclear antibody (ANA), cytoplasmic-antineutrophil cytoplasmic antibodies (c-ANCA), perinuclear-antineutrophil cytoplasmic antibodies (p-ANCA), anti-glomerular basement membrane (anti-GBM) antibody, and complements were all normal. While a plan was being made regarding a renal biopsy, her creatinine started to plateau and she had a good urine output. At discharge, she had a creatinine of five. Her metformin was discontinued and she was started on insulin for her diabetes. Ultimately, in a few months, she recovered her renal function to a serum creatinine of 1.8-1.9 mg/dL, a little higher than her baseline.\n\nDiscussion\nMetformin is the first-line treatment for type 2 diabetes [3]. Many patients with diabetes have underlying CKD. Based on the current recommendations, the use of this medication is acceptable, with an eGFR above 45 mL/min. Between the eGFR of 30 and 45, some recommend not initiating the medication while others prefer starting it at half the usual dose with monitoring of renal function every three months. Below the eGFR of 30, its use is contraindicated [7].\n\nBlood concentrations of metformin ranging between 0.5 and 2.0 mg/L are within the therapeutic range, whereas those higher than 4.0 mg/L are generally considered to be toxic. The lethal range of metformin concentrations is >50 mg/L [8].\n\nMetformin mostly causes gastrointestinal side effects, including diarrhea, flatulence, nausea, vomiting, and infections [8]. Other side effects include chest discomfort, flushing, palpitations, diaphoresis, cyanocobalamin deficiency, hypoglycemia, headache, and rhinitis. Lactic acidosis and blindness are rare, and their incidence is not clear, as they are reported only in some case reports and case series [9]. The most common symptoms of MALA are those related to the gastrointestinal tract (including nausea, vomiting, and diarrhea) followed by an altered mental status, shortness of breath, hypothermia, and hypotension [8].\n\nAccording to previously published reports, vision loss associated with MALA improved after the correction of metabolic acidosis [10]. Based on animal studies, the suggested mechanism involves the following: retinal cell function may be pH-dependent; retinal horizontal cell response to light is pH-sensitive; and mammalian retinal cell function becomes disrupted at pH <7.09. These effects could extend to humans and may serve as an explanation for acidosis-associated vision loss and optic nerve ischemia [11]. But, in our case, the vision improved even before the acidemia corrected. We suggest that since acute reversible blindness has been described with MALA, but not in patients with hypotension- or sepsis-induced lactic acidosis, this neurologic symptom may be a direct result of abnormal retinal horizontal cell function induced by metformin at a low pH, or the metabolic effects of metformin, rather than due to the acidemia alone.\n\nDiagnosis and therapy may be delayed due to nonspecific symptoms at presentation, with severe anion gap metabolic acidosis and elevated serum creatinine values being the most prominent laboratory findings. MALA is characterized by a blood lactate concentration greater than 5 mmol/L and arterial pH less than 7.35 in association with metformin exposure [9]. Confirmation requires measurement of serum metformin by high-performance liquid chromatography-tandem mass spectrometry, but this technique is available only at specialized institutions and cannot be relied on as a guide to immediate treatment [12]. \n\nThus, based on strong clinical suspicion, renal replacement therapy must be started promptly to achieve efficient drug clearance and correct the metabolic acidosis. However, because metformin accumulates in the intracellular compartment with prolonged treatment, a rebound in serum concentrations due to redistribution is expected at the end of dialysis [12].\n\nIn our case, the patient was a diabetic for almost 48 years, on metformin. She likely had an underlying prerenal AKI, which predisposed her to metformin toxicity. She had the classic clinical and laboratory abnormalities of the same. Though a blood level was not checked to confirm the diagnosis, her clinical picture and lab abnormalities had all corrected with the correction of her metabolic derangements. She did not require further sessions of hemodialysis. Her metformin was discontinued, and she was instead started on insulin for her diabetes, with other oral agents to be considered in an outpatient setting.\n\nConclusions\nMetformin should be discontinued in all cases of MALA and vision loss. Other hypoglycemic agents should instead be considered to prevent this life-threatening complication from occurring again. Vision improves after the correction of acidosis but, in our case, the vision improved even before the acidemia corrected. We suggest that since acute reversible blindness has been described with MALA, but not in patients with hypotension- or sepsis-induced lactic acidosis, this neurologic symptom may be a direct result of abnormal retinal horizontal cell function induced by metformin at a low pH, or the metabolic effects of metformin, rather than due to the acidemia alone. This needs to be studied further. Early treatment in the form of renal replacement therapy should be considered in any suspected case, especially with lactate levels greater than 17 mmol/L to prevent mortality and other complications like vision loss. The mainstay of renal replacement therapy is to correct metabolic derangements. Further studies regarding the metformin clearance by hemodialysis are also warranted.\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 A patient with metformin-associated lactic acidosis successfully treated with continuous renal replacement therapy: a case report Med Case Rep Kinoshita J Yanai M Ariyoshi K Ando M Tamura R 371 13 2019 \n2 Successful dialysis treatment of metformin associated lactic acidosis, report of two cases Iran J Kidney Dis Günay E Kalkan Z Ay MS Yuksel E Berekatoglu N Yaman M 160 164 14 2020 https://pubmed.ncbi.nlm.nih.gov/32165603/ 32165603 \n3 Serum lactate level and mortality in metformin-associated lactic acidosis requiring renal replacement therapy: a systematic review of case reports and case series BMC Nephrol Yeh HC Ting IW Tsai CW Wu JY Kuo CC 229 18 2017 28693440 \n4 Toxicokinetics of metformin during hemodialysis Kidney Int Rep Ayoub P Hétu PO Cormier M 759 762 2 2017 29318220 \n5 Lactic acidosis in metformin-treated patients. Prognostic value of arterial lactate levels and plasma metformin concentrations Drug Saf Lalau JD Race JM 377 384 20 1999 10230584 \n6 Clearance of metformin by hemofiltration in overdose J Toxicol Clin Toxicol Barrueto F Meggs WJ Barchman MJ 177 180 40 2002 12126190 \n7 UpToDate. Metformin, drug information 2020 https://www.uptodate.com/contents/metformin-drug-information?search=metformin&source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F50991520 \n8 Metformin accumulation: lactic acidosis and high plasmatic metformin levels in a retrospective case series of 66 patients on chronic therapy Clin Toxicol (Phila) Vecchio S Giampreti A Petrolini VM 129 135 52 2014 24283301 \n9 A patient with metformin-associated lactic acidosis successfully treated with continuous renal replacement therapy: a case report J Med Case Rep Kinoshita H Yanai M Ariyoshi K Ando M Tamura R 371 13 2019 31842973 \n10 Transient blindness in a patient with severe metformin-associated lactic acidosis (MALA) Electrolyte Blood Press Jeon JW Choi W Kim HR 16 20 17 2019 31338110 \n11 Retinal ischemia: mechanisms of damage and potential therapeutic strategies Prog Retin Eye Res Osborne NN Casson RJ Wood JP 91 147 23 2004 14766318 \n12 Treatment of metformin intoxication complicated by lactic acidosis and acute kidney injury: the role of prolonged intermittent hemodialysis Am J Kidney Dis Regolisti G Antoniotti R Fani F Greco P Fiaccadori E 290 296 70 2017 28223003\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(7)",
"journal": "Cureus",
"keywords": "blindness; ckd; metformin associated lactic acidosis; type 2 diabetes",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e9325",
"pmc": null,
"pmid": "32850203",
"pubdate": "2020-07-21",
"publication_types": "D002363:Case Reports",
"references": "24283301;28693440;14766318;31842973;31338110;32165603;10230584;29318220;12126190;28223003",
"title": "A Case Report on Metformin-Associated Lactic Acidosis and Transient Blindness.",
"title_normalized": "a case report on metformin associated lactic acidosis and transient blindness"
} | [
{
"companynumb": "US-MERCK HEALTHCARE KGAA-9184582",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugaddit... |
{
"abstract": "To know the dermatologic side effects of intravesical treatment with Mitomycin C in non muscle invasive bladder cancer.\n\n\n\nWe describe two cases of palm and plantar dermatitis after such treatment.\n\n\n\nWe describe two types of dermatitis pathogenesis during treatment with intravesical Mitomycin C: contact dermatitis and delayed hypersensitivity dermatitis.\n\n\n\nContact dermatitis of non-allergic origin is a common side effect described in many instances in the literature, on the other hand exists dermatitis secondary to delayed hypersensitivity type IV much less common, requiring treatment with corticosteroids.",
"affiliations": "Servicio de Urología. Hospital Universitari Germans Trias i Pujol. Universitat Autònoma de Barcelona. España.;Servicio de Urología. Hospital Universitari Germans Trias i Pujol. Universitat Autònoma de Barcelona. España.;Servicio de Urología. Hospital Universitari Germans Trias i Pujol. Universitat Autònoma de Barcelona. España.;Servicio de Urología. Hospital Universitari Germans Trias i Pujol. Universitat Autònoma de Barcelona. España.;Servicio de Urología. Hospital Universitari Germans Trias i Pujol. Universitat Autònoma de Barcelona. España.",
"authors": "Colomer Gallardo|A|A|;Martínez Rodríguez|R|R|;Castillo Pacheco|C|C|;González Satue|C|C|;Ibarz Servio|L|L|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D016685:Mitomycin",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-0614",
"issue": "69(2)",
"journal": "Archivos espanoles de urologia",
"keywords": null,
"medline_ta": "Arch Esp Urol",
"mesh_terms": "D000283:Administration, Intravesical; D000903:Antibiotics, Antineoplastic; D006801:Humans; D006968:Hypersensitivity, Delayed; D016685:Mitomycin; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "0064757",
"other_id": null,
"pages": "89-91",
"pmc": null,
"pmid": "26959968",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dermatological side effects of intravesical Mitomycin C: Delayed hypersensitivity.",
"title_normalized": "dermatological side effects of intravesical mitomycin c delayed hypersensitivity"
} | [
{
"companynumb": "ES-ACCORD-039056",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MITOMYCIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "This case study reports on a rare case of a woman with Behcet's disease (BD), uterine malformation and antiphospholipid syndrome, who successfully delivered a baby without any complications during the perinatal period. The woman, who was diagnosed with BD with relapsing oral, ocular, and genital involvement 8 years ago, registered in our clinic with a history of two inevitable miscarriages. Laboratory findings were positive for anti-β2 -glycoprotein I antibodies (anti-β2 -GP-I). Three-dimensional ultrasound showed that her uterus was unicornuate, with only a normal left side. After treatment, the woman had a cesarean section for breech presentation of a healthy male infant weighing 2700 g. The postpartum period was uneventful. The possible effects of BD on pregnancy outcomes and how to manage BD patients are discussed with a review of the literature.",
"affiliations": "Department of Obstetrics, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.;Department of Reproductive Immunology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.",
"authors": "Xu|Chuanlu|C|;Bao|Shihua|S|",
"chemical_list": "D001323:Autoantibodies",
"country": "Denmark",
"delete": false,
"doi": "10.1111/aji.12530",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1046-7408",
"issue": "77(1)",
"journal": "American journal of reproductive immunology (New York, N.Y. : 1989)",
"keywords": "Behcet's disease; antiphospholipid syndrome; autoimmune disease; pregnancy; uterine malformation",
"medline_ta": "Am J Reprod Immunol",
"mesh_terms": "D000022:Abortion, Spontaneous; D000328:Adult; D000818:Animals; D016736:Antiphospholipid Syndrome; D001323:Autoantibodies; D001528:Behcet Syndrome; D002585:Cesarean Section; D005260:Female; D006801:Humans; D008297:Male; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D014463:Ultrasonography; D014599:Uterus",
"nlm_unique_id": "8912860",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27296674",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Behcet's disease and pregnancy-a case report and literature review.",
"title_normalized": "behcet s disease and pregnancy a case report and literature review"
} | [
{
"companynumb": "CN-BAYER-2017-067540",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nOlmesartan, which is an angiotensin II receptor blocker, reportedly causes spruelike enteropathy, with intestinal villous atrophy as its typical histopathological finding. Interestingly, collagenous and/or lymphocytic gastritis and colitis occur in some patients. We report the case of a 73-year-old Japanese man with a 2-month clinical history of severe diarrhea and weight loss. There were few reports in which spruelike enteropathy and collagenous colitis were both observed and could be followed up.\n\n\nMETHODS\nWe report a case of a 73-year-old man with a 2-month clinical history of severe diarrhea and weight loss. He had taken olmesartan for hypertension treatment for 5 years. Endoscopic examination with biopsies revealed intestinal villous atrophy and collagenous colitis. Suspecting enteropathy caused by olmesartan, which was discontinued on admission because of hypotension, we continued to stop the drug. Within 3 weeks after olmesartan discontinuation, his clinical symptoms improved. After 3 months, follow-up endoscopy showed improvement of villous atrophy but not of the thickened collagen band of the colon. However, the mucosa normalized after 6 months, histologically confirming that the preexistent pathology was finally resolved.\n\n\nCONCLUSIONS\nThis report presents a case in which spruelike enteropathy and collagenous colitis were both observed and could be followed up. In unexplained cases of diarrhea, medication history should be reconfirmed and this disease should be considered a differential diagnosis.",
"affiliations": "Depertment of Gastroenterology, Kitami Red Cross Hospital, Higashi-2, Kita-6, Kitami, 090-0026, Japan.;Depertment of Gastroenterology, Kitami Red Cross Hospital, Higashi-2, Kita-6, Kitami, 090-0026, Japan. kana.matsuda@true.ocn.ne.jp.;Depertment of Gastroenterology, Kitami Red Cross Hospital, Higashi-2, Kita-6, Kitami, 090-0026, Japan.;Depertment of Gastroenterology, Kitami Red Cross Hospital, Higashi-2, Kita-6, Kitami, 090-0026, Japan.;Depertment of Gastroenterology, Kitami Red Cross Hospital, Higashi-2, Kita-6, Kitami, 090-0026, Japan.;Depertment of Gastroenterology, Kitami Red Cross Hospital, Higashi-2, Kita-6, Kitami, 090-0026, Japan.;Depertment of Gastroenterology, Kitami Red Cross Hospital, Higashi-2, Kita-6, Kitami, 090-0026, Japan.;Depertment of Gastroenterology, Kitami Red Cross Hospital, Higashi-2, Kita-6, Kitami, 090-0026, Japan.;Depertment of Gastroenterology, Kitami Red Cross Hospital, Higashi-2, Kita-6, Kitami, 090-0026, Japan.;Department of Pathology, Asahikawa Medical University, 1-1 Midorigaoka Higashi-2 Hokkaido, Asahikawa, Japan.",
"authors": "Kaneko|Shiho|S|;Matsuda|Kana|K|http://orcid.org/0000-0003-2570-4517;Mizuta|Yasuko|Y|;Shiratori|Shoya|S|;Kishi|Kazuma|K|;Nakamura|Akihisa|A|;Yagisawa|Masataka|M|;Ehira|Nobuyuki|N|;Uebayashi|Minoru|M|;Kobayashi|Hiroya|H|",
"chemical_list": "D007093:Imidazoles; D013777:Tetrazoles; C437965:olmesartan",
"country": "England",
"delete": false,
"doi": "10.1186/s12876-021-01926-y",
"fulltext": "\n==== Front\nBMC Gastroenterol\nBMC Gastroenterol\nBMC Gastroenterology\n1471-230X\nBioMed Central London\n\n1926\n10.1186/s12876-021-01926-y\nCase Report\nSevere spruelike enteropathy and collagenous colitis caused by olmesartan\nKaneko Shiho 1\nhttp://orcid.org/0000-0003-2570-4517\nMatsuda Kana kana.matsuda@true.ocn.ne.jp\n\n1\nMizuta Yasuko 1\nShiratori Shoya 1\nKishi Kazuma 1\nNakamura Akihisa 1\nYagisawa Masataka 1\nEhira Nobuyuki 1\nUebayashi Minoru 1\nKobayashi Hiroya 2\n1 Depertment of Gastroenterology, Kitami Red Cross Hospital, Higashi-2, Kita-6, Kitami, 090-0026 Japan\n2 grid.252427.4 0000 0000 8638 2724 Department of Pathology, Asahikawa Medical University, 1-1 Midorigaoka Higashi-2 Hokkaido, Asahikawa, Japan\n23 9 2021\n23 9 2021\n2021\n21 35022 5 2021\n14 9 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nOlmesartan, which is an angiotensin II receptor blocker, reportedly causes spruelike enteropathy, with intestinal villous atrophy as its typical histopathological finding. Interestingly, collagenous and/or lymphocytic gastritis and colitis occur in some patients. We report the case of a 73-year-old Japanese man with a 2-month clinical history of severe diarrhea and weight loss. There were few reports in which spruelike enteropathy and collagenous colitis were both observed and could be followed up.\n\nCase presentation\n\nWe report a case of a 73-year-old man with a 2-month clinical history of severe diarrhea and weight loss. He had taken olmesartan for hypertension treatment for 5 years. Endoscopic examination with biopsies revealed intestinal villous atrophy and collagenous colitis. Suspecting enteropathy caused by olmesartan, which was discontinued on admission because of hypotension, we continued to stop the drug. Within 3 weeks after olmesartan discontinuation, his clinical symptoms improved. After 3 months, follow-up endoscopy showed improvement of villous atrophy but not of the thickened collagen band of the colon. However, the mucosa normalized after 6 months, histologically confirming that the preexistent pathology was finally resolved.\n\nConclusions\n\nThis report presents a case in which spruelike enteropathy and collagenous colitis were both observed and could be followed up. In unexplained cases of diarrhea, medication history should be reconfirmed and this disease should be considered a differential diagnosis.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1186/s12876-021-01926-y.\n\nKeywords\n\nVillous atrophy\nCollagenous colitis\nSpruelike enteropathy\nIntestinal diseases\nCase report\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\n,1,1,1,2]. Pathological evidence of the stomach and colon suggests that olmesartan may affect the entire gastrointestinal tract. There were few reports in which spruelike enteropathy and collagenous colitis were both observed and could be followed up.\n\nHerein, we report a case of severe enteropathy and collagenous colitis associated with olmesartan use.\n\nCase presentation\n\nA 73-year-old Japanese man with a history of olmesartan intake (20 mg daily for 5 years) for hypertension treatment was admitted to a local hospital complaining of watery, nonbloody diarrhea approximately 10 times daily since 2 months. In 2 months, he lost 10 kg of his weight. Blood tests, CT, and endoscopy were performed, but the cause of his diarrhea remained unknown. Hence, he was referred to our hospital for further examination. His physical examination results were unremarkable. However, laboratory results (Additional file 1) indicated anemia (hemoglobin, 10.5 g/dL) and hypoalbuminemia (3.4 g/dL). We searched DQA1 and DQB1. HLA DQ4 and DQ6 were positive. Meanwhile, stool culture, Clostridium difficile toxin, HLA-DQ2/DQ8, and IgA antibodies to tissue transglutaminase and endomysial, were all negative. Abdominal computer tomography was unremarkable. Esophagogastroduodenoscopy (EGD) revealed villous atrophy and a mosaic pattern of the duodenal mucosa (Fig. 1), while colonoscopy (CS) detected villous atrophy of the terminal ileum and diffuse slight edema of the colon (Additional file 2). The stomach, duodenum, terminal ileum, and colon were randomly biopsied. Pathological findings of the duodenum and ileum showed villous atrophy, intraepithelial lymphocyte infiltration, and collagen band, and those of the colon showed a 14 μm collagen band (Fig. 2). Moreover, capsule endoscopy displayed villous atrophy of the entire small intestine. Taken together, we suspected that the patient had olmesartan-associated spruelike enteropathy. Hence, olmesartan, which was stopped on admission because of hypotension, remained withdrawn, and was switched to amlodipine.Fig. 1 Esophagogastroduodenoscopy at the initial visit. a White-light imaging shows villous atrophy and a mosaic pattern of the duodenal mucosa. b Magnification endoscopy with narrow-band imaging shows villous atrophy of the duodenal mucosa\n\nFig. 2 a Duodenal biopsy (hematoxylin–eosin, 0924; top: –743; width: 5205; height: 3719; visibility: visible; mso-wrap-style: square); b Duodenal biopsy (Masson trichrome, ichromeichrome eosin, 0924; top: Colonic biopsy (hematoxylin–eosin, 0924; top: − 743; width: 5205; height: 3719; visibility: visible)\n\nWithin 3 weeks after olmesartan discontinuation, his clinical symptoms improved. Three months later, diarrhea resolved, and the duodenum, terminal ileum, and colon showed a normal appearance on EGD/CS (Fig. 3). As shown in the biopsies of the duodenum and terminal ileum, the villous architecture of the duodenal and ileal mucosa almost completely recovered (Fig. 4), but in colonic biopsies, the collagen band only slightly improved (Additional file 3). Six months after discontinuing olmesartan, follow-up endoscopy showed a histologically normal colonic mucosa.Fig. 3 Esophagogastroduodenoscopy showed a normal appearance of the duodenum 3 months after olmesartan discontinuation\n\nFig. 4 Biopsy showed an almost complete recovery of the villi on the duodenal mucosa 3 months after olmesartan discontinuation (hematoxylin–eosin, redof)\n\nDiscussion and conclusion\n\nOlmesartan-associated spruelike enteropathy is a type of enteropathy induced by olmesartan administration. It is characterized by severe diarrhea and weight loss. The duration of olmesartan exposure before the onset of diarrhea varies from months to years [1,3,1,1,1,4]. HLA-DQ2 or DQ8 haplotypes were present in 71% of patients with olmesartan-associated spruelike enteropathy [3,1,5,6,2,\n\n,2]. CS or capsule endoscopy may reveal villous atrophy and ulceration in the jejunum and ileum [2,\n\n,7,8,9,\n\n,1,10,11,12,\n\n,13,14,1,15,16,17,15]. Some patients with collagenous colitis showed a typical histology but had no symptoms [18,\n\nHence, this report presents a rare case in which spruelike enteropathy and collagenous colitis were both observed and could be followed up. Villous atrophy of the small intestine may have a greater effect on diarrhea caused by olmesartan even in cases with collagenous colitis.\n\nIn conclusion, both the large and small intestines should be assessed for villous atrophy and other abnormalities.\n\nSupplementary Information\n\nAdditional file 1. Initial Laboratory Studies.\n\nAdditional file 2. Colonoscopy showed a diffuse slight edema of the colon.\n\nAdditional file 3. Biopsy showed slight improvement of the collagen band in the colon 3 months after olmesartan discontinuation (Masson trichrome).\n\nAbbreviations\n\nARBs Angiotensin II receptor blockers\n\nCS Colonoscopy\n\nEGD Esophagogastroduodenoscopy\n\nAcknowledgements\n\nThe authors acknowledge the technical and clerical assistance of Dr. Fujita of the Department of Endoscopy of Aiiku Hospital in Sapporo, in the preparation of the manuscript. The authors also would like to thank Enago (www.enago.jp) for the English language review.\n\nAuthors' contributions\n\nSK contributed to conceptualization, data curation, resource collection, and writing of the original manuscript. KM contributed to conceptualization, data curation, resources, original draft writing, and review and editing. YM, SS, KK, AN, MY, NE, and MU contributed to conceptualization, data curation, and resource collection. HK contributed to data curation and resources. All authors have read and approved the manuscript.\n\nFunding\n\nNo funding was received to accomplish this work.\n\nAvailability of data and materials\n\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nEthics approval by committee was not required for this case report. It was conducted in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent for study participation was obtained from the patient.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\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. Rubio-Tapia A Herman ML Ludvigsson JF Kelly DG Mangan TF Wu TT Murray JA Severe spruelike enteropathy associated with olmesartan Mayo Clin Proc 2012 87 732 738 10.1016/j.mayocp.2012.06.003,PMID22728033 22728033\n2. Marthey L Cadiot G Seksik P Pouderoux P Lacroute J Skinazi F Olmesartan-associated enteropathy: results of a national survey Aliment Pharmacol Ther 2014 40 1103 1109 10.1111/apt.12937,PMID25199794 25199794\n3. Ianiro G Bibbò S Montalto M Ricci R Gasbarrini A Cammarota G Systematic review: sprue-like enteropathy associated with olmesartan Aliment Pharmacol Ther 2014 40 16 23 10.1111/apt.12780,PMID24805127 24805127\n4. Matt P Schoenhoff F Habashi J Holm T Van Erp C Loch D Circulating transforming growth factor-beta in Marfan syndrome Circulation 2009 120 526 532 10.1161/CIRCULATIONAHA.108.841981,PMID19635970 19635970\n5. Shahzad MA Harding D Ruszkiewicz A Tran E England G Philpott H Gastrointestinal: olmesartan-induced enteropathy J Gastroenterol Hepatol 2018 33 1691 10.1111/jgh.14317,PMID29968297 29968297\n6. Choi EY McKenna BJ Olmesartan-associated enteropathy: a review of clinical and histologic findings Arch Pathol Lab Med 2015 139 1242 1247 10.5858/arpa.2015-0204-RA,PMID26414468 26414468\n7. Badreldin R Barrett P Wooff DA Mansfield J Yiannakou Y How good is zoom endoscopy for assessment of villous atrophy in coeliac disease? Endoscopy 2005 37 994 998 10.1055/s-2005-870245,PMID16189773 16189773\n8. Eusébio M Caldeira P Antunes AG Ramos A Velasco F Cadillá J Olmesartan-induced enteropathy: an unusual cause of villous atrophy GE Port J Gastroenterol 2016 23 91 95 10.1016/j.jpge.2015.09.005,PMID28868439 28868439\n9. Rondonotti E Spada C Cave D Pennazio M Riccioni ME De Vitis I Video capsule enteroscopy in the diagnosis of celiac disease: a multicenter study Am J Gastroenterol 2007 102 1624 1631 10.1111/j.1572-0241.2007.01238.x,PMID17459022 17459022\n10. Fujisawa M Matsushima M Ueda T Kaneko M Fujimoto R Sano M Celiac disease complicated by rhabdomyolysis Intern Med 2021 60 217 222 10.2169/internalmedicine.5358-20,PMID32921688 32921688\n11. Yamamoto Y Yamada T Akutsu D Sugaya A Murashita T Matsuda K Collagenous sprue diagnosed by double balloon endoscopy Case Reports Dig Endosc 2014 26 108 112 10.1111/den.12007,PMID23368698 23368698\n12. Jansson-Knodell CL Hujoel IA Rubio-Tapia A Murray JA Not all that flattens villi is celiac disease: a review of enteropathies Mayo Clin Proc 2018 93 509 517 10.1016/j.mayocp.2017.10.025,PMID29622097 29622097\n13. Uehara T Ikusaka M Ohira Y Noda K Suzuki S Shikino K Olmesartan-induced enteropathy manifesting as Wernicke-Korsakoff syndrome Intern Med 2016 55 3675 3678 10.2169/internalmedicine.55.7388,PMID27980272 27980272\n14. Fukushima M Kitamoto H Inokuma T Imai Y Severe spruelike enteropathy associated with olmesartan observed by double-balloon enteroscopy Gastrointest Endosc 2016 83 269 270 10.1016/j.gie.2015.06.004,PMID26149710 26149710\n15. Bashari DR Severe sprue-like enteropathy and colitis due to olmesartan: lessons learned from a rare entity Gastroenterology Res 2020 13 150 154 10.14740/gr1301,PMID32864026 32864026\n16. Ebrahim VS Martin J Murthy S Odstrcil E Huang H Polter D Olmesartan-associated enteropathy Proc (Bayl Univ Med Cent) 2017 30 348 350 10.1080/08998280.2017.11929644,PMID28670083 28670083\n17. Costetti M Schiepatti A Fraticelli S Costa S Maimaris S Lenti MV Dig Liver Dis 2021 S1590–8658 371 376 10.1016/j.dld.2021.07.002,PMID34330666\n18. Thörn M Sjöberg D Holmström T Rönnblom A Collagenous colitis without diarrhoea at diagnosis – a follow up study Scand J Gastroenterol 2019 54 194 197 10.1080/00365521.2019.1570325,PMID30782025 30782025\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-230X",
"issue": "21(1)",
"journal": "BMC gastroenterology",
"keywords": "Case report; Collagenous colitis; Intestinal diseases; Spruelike enteropathy; Villous atrophy",
"medline_ta": "BMC Gastroenterol",
"mesh_terms": "D000368:Aged; D003092:Colitis; D046729:Colitis, Collagenous; D003967:Diarrhea; D006801:Humans; D007093:Imidazoles; D008297:Male; D013777:Tetrazoles",
"nlm_unique_id": "100968547",
"other_id": null,
"pages": "350",
"pmc": null,
"pmid": "34556042",
"pubdate": "2021-09-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26149710;28868439;32864026;24805127;29968297;26414468;17459022;19635970;25199794;27980272;29622097;22728033;28670083;30782025;16189773;32921688;23368698",
"title": "Severe spruelike enteropathy and collagenous colitis caused by olmesartan.",
"title_normalized": "severe spruelike enteropathy and collagenous colitis caused by olmesartan"
} | [
{
"companynumb": "JP-DSJP-DSJ-2021-131421AA",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLMESARTAN MEDOXOMIL"
},
"drugadditional": "1... |
{
"abstract": "We assessed in a French regional healthcare network the distribution of treatments, prognostic factors, and outcome of 334 newly diagnosed acute myeloid leukemia patients aged 60 years or older over a 4-year period of time (2007-2010). Patients were selected in daily practice for intensive chemotherapy (n = 115), azacitidine (n = 95), or best supportive care (n = 124). In these three groups, median overall survival was 18.9, 11.3, and 1.8 months, respectively. In the azacitidine group, multivariate analysis showed that overall survival was negatively impacted by higher age (P = 0.010 for one unit increase), unfavorable cytogenetics (P = 0.001), lymphocyte count <0.5 G/L (P = 0.015), and higher lactate dehydrogenase level (P = 0.005 for one unit increase). We compared the survival of patients treated by azacitidine versus intensive chemotherapy and best supportive care using time-dependent analysis and propensity score matching. Patients treated by intensive chemotherapy had a better overall survival compared with those treated by azacitidine from 6 months after diagnosis, whereas patients treated by azacitidine had a better overall survival compared with those treated by best supportive care from 1 day after diagnosis. This study of \"real life\" practice shows that there is a room for low intensive therapies such as azacitidine in selected elderly acute myeloid leukemia patients.",
"affiliations": "Département d'Hématologie-Médecine Interne, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France; Service d'Hématologie, Hôpitaux Universitaires de Strasbourg, F-67098, Strasbourg, France.",
"authors": "Bories|Pierre|P|;Bertoli|Sarah|S|;Bérard|Emilie|E|;Laurent|Julie|J|;Duchayne|Eliane|E|;Sarry|Audrey|A|;Delabesse|Eric|E|;Beyne-Rauzy|Odile|O|;Huguet|Françoise|F|;Récher|Christian|C|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D007770:L-Lactate Dehydrogenase; D001374:Azacitidine",
"country": "United States",
"delete": false,
"doi": "10.1002/ajh.23848",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0361-8609",
"issue": "89(12)",
"journal": "American journal of hematology",
"keywords": null,
"medline_ta": "Am J Hematol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine; D005260:Female; D005602:France; D006801:Humans; D007770:L-Lactate Dehydrogenase; D015470:Leukemia, Myeloid, Acute; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010166:Palliative Care; D011379:Prognosis; D011446:Prospective Studies; D012041:Regional Medical Programs; D016019:Survival Analysis",
"nlm_unique_id": "7610369",
"other_id": null,
"pages": "E244-52",
"pmc": null,
"pmid": "25195872",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Intensive chemotherapy, azacitidine, or supportive care in older acute myeloid leukemia patients: an analysis from a regional healthcare network.",
"title_normalized": "intensive chemotherapy azacitidine or supportive care in older acute myeloid leukemia patients an analysis from a regional healthcare network"
} | [
{
"companynumb": "FR-CELGENE-056-50794-14081086",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": null,
... |
{
"abstract": "Recent evidence suggests the involvement of Toxoplasma gondii infection in the emergence of psychotic and affective disorders. In this report, we describe the case of a young Brazilian woman affected by recurrent ocular toxoplasmosis and presenting with a manic episode with psychotic features in the context of a diagnosis of Bipolar Disorder (BD), type I. We observed a relationship between ocular manifestations and the clinical course of bipolar illness, confirmed by molecular analyses (nested-PCR), as well as by the high level of T. gondii specific IgG. This case report is the first showing the presence of circulating parasite DNA at the time of occurrence of psychiatric symptoms, thus providing further support for a possible role of the parasite in the pathogenesis of some cases of BD.",
"affiliations": "*Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Pisa; †Department of Medical Sciences, Section of Infectious Diseases, University of Ferrara, Ferrara; ‡Institute for Maternal and Child Health-IRCCS \"Burlo Garofolo\", Trieste; and §Department of Translational Research, N.T.M.S., School of Medicine, University of Pisa, Pisa, Italy.",
"authors": "Del Grande|Claudia|C|;Contini|Carlo|C|;Schiavi|Elisa|E|;Rutigliano|Grazia|G|;Maritati|Martina|M|;Seraceni|Silva|S|;Pinto|Barbara|B|;Dell'Osso|Liliana|L|;Bruschi|Fabrizio|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/NMD.0000000000000496",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3018",
"issue": "205(3)",
"journal": "The Journal of nervous and mental disease",
"keywords": null,
"medline_ta": "J Nerv Ment Dis",
"mesh_terms": "D000328:Adult; D001714:Bipolar Disorder; D001938:Brazil; D005260:Female; D006801:Humans; D014126:Toxoplasmosis, Ocular; D055815:Young Adult",
"nlm_unique_id": "0375402",
"other_id": null,
"pages": "192-195",
"pmc": null,
"pmid": "27741079",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bipolar Disorder With Psychotic Features and Ocular Toxoplasmosis: A Possible Pathogenetic Role of the Parasite?",
"title_normalized": "bipolar disorder with psychotic features and ocular toxoplasmosis a possible pathogenetic role of the parasite"
} | [
{
"companynumb": "IT-MYLANLABS-2017M1019886",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": "3",
... |
{
"abstract": "Acute erythroleukemia (AEL) is a rare disease typically associated with a poor prognosis. The median survival ranges between 3-9 months from initial diagnosis. Hypomethylating agents (HMAs) have been shown to prolong survival in patients with myelodysplastic syndromes (MDS) and AML, but there is limited data of their efficacy in AEL. We collected data from 210 AEL patients treated at 28 international sites. Overall survival (OS) and PFS were estimated using the Kaplan-Meier method and the log-rank test was used for subgroup comparisons. Survival between treatment groups was compared using the Cox proportional hazards regression model. Eighty-eight patients were treated with HMAs, 44 front line, and 122 with intensive chemotherapy (ICT). ICT led to a higher overall response rate (complete or partial) compared to first-line HMA (72% vs. 46.2%, respectively; p ≤ 0.001), but similar progression-free survival (8.0 vs. 9.4 months; p = 0.342). Overall survival was similar for ICT vs. HMAs (10.5 vs. 13.7 months; p = 0.564), but patients with high-risk cytogenetics treated with HMA first-line lived longer (7.5 for ICT vs. 13.3 months; p = 0.039). Our results support the therapeutic value of HMA in AEL.",
"affiliations": "Instituto Português de Oncologia de Lisboa (IPOL), 1200-795 Lisbon, Portugal. amalmeida@ipolisboa.min-saude.pt.;Institut Paoli Calmettes, Marseille, France and Yale New Haven Hospital, New Haven, CT 06512, USA. thomas.prebet@yale.edu.;Hopital Saint-Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris Diderot University, 75010 Paris, France. itzykson@gmail.com.;Hospital Universitario de Leon, 24071 Leon, Spain. mail@fernandoramosmd.es.;University Hospital of Halle, 06120 Halle, Germany. alah@medizin.uni-leipzig.de.;Rush University Medical Center, Chicago, IN 60612, USA. Jamile_Shammo@rush.edu.;Hospital Sao Joao, 4200-319 Porto, Portugal. rjsmpinto@gmail.com.;University Tor Vergata, 00173 Rome, Italy. luca.maurillo@uniroma2.it.;Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 44195, USA. FENSTEJ@ccf.org.;RCCS-CROB, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture (Pz), Italy. p.musto@tin.it.;Department of Hematology VU University Medical Center, 1081 HV Amsterdam, The Netherlands. a.vandeloosdrecht@vumc.nl.;Centro Hospitalar Lisboa Norte Hospital Santa Maria, 1649-035 Lisbon, Portugal. mjoaocosta@gmail.com.;Instituto Português de Oncologia de Lisboa (IPOL), 1200-795 Lisbon, Portugal. sesteves@ipolisboa.min-saude.pt.;Department of Internal Medicine IV, Hospital Wels-Grieskirchen, 4600 Wels, Austria. sonja.burgstaller@klinikum-wegr.at.;Department of Internal Medicine V (Haematology and Oncology), Innsbruck Medical University, 6020 Innsbruck, Austria. reinhard.stauder@i-med.ac.at.;1st Department of Internal Medicine, Center for Oncology and Hematology, Wilhelminenspital, 1160 Vienna, Austria. eva-maria.autzinger@wienkav.at.;Internal Medicine, Hospital Feldkirch,6800 Feldkirch, Austria. alois.lang@lkhf.at.;Department of Internal Medicine, Hospital Fürstenfeld, 8280 Fürstenfeld, Austria. peter.krippl@lkh-fuerstenfeld.at.;Department for Internal Medicine, Klinikum Klagenfurt am Wörthersee, 9020 Pörtschach am Wörthersee, Austria. dietmar.geissler@kabeg.at.;Hospital Universitario Virgen del Rocio, 41013 Sevilla, Spain. jfalantes@gmail.com.;Hospital del Mar, 08003 Barcelona, Spain. MPedro@parcdesalutmar.cat.;Hospital Son Llatzer, 07198 Palma de Mallorca, Spain. jbargay@hsll.es.;Hospital Universitario, 15006 A Coruña, Spain. gdebari@canalejo.org.;Hospital de la Santa Creu i Sant Pau, 08026 Barcelona, Spain. AGarridoD@santpau.cat.;Hospital Universitario de la Ribera, 46600 Alzira, Spain. sbonanad@gmail.com.;Hospital Universitario de Salamanca, 37007 Salamanca, Spain. mdiezcampelo@usal.es.;Centre Hospitalier Universitaire, 49100 Angers, France. Sylvain.Thepot@chu-angers.fr.;Hopital Saint-Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris Diderot University, 75010 Paris, France. lionel.ades@sls.aphp.fr.;Department of Internal Medicine I, Division of Hematology & Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, 1090 Vienna, Austria. wolfgang.r.sperr@meduniwien.ac.at.;Department of Internal Medicine I, Division of Hematology & Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, 1090 Vienna, Austria. peter.valent@meduniwien.ac.at.;Hopital Saint-Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris Diderot University, 75010 Paris, France. pierre.fenaux@sls.aphp.fr.;Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 44195, USA. SEKEREM@ccf.org.;3rd Med. Department, Paracelsus Medical University, 5020 Salzburg, Austria. r.greil@salk.at.;3rd Med. Department, Paracelsus Medical University, 5020 Salzburg, Austria. l.pleyer@salk.at.",
"authors": "Almeida|Antonio M|AM|;Prebet|Thomas|T|;Itzykson|Raphael|R|;Ramos|Fernando|F|;Al-Ali|Haifa|H|;Shammo|Jamile|J|;Pinto|Ricardo|R|;Maurillo|Luca|L|;Wetzel|Jaime|J|;Musto|Pellegrino|P|;Van De Loosdrecht|Arjan A|AA|;Costa|Maria Joao|MJ|;Esteves|Susana|S|;Burgstaller|Sonja|S|;Stauder|Reinhard|R|;Autzinger|Eva M|EM|;Lang|Alois|A|;Krippl|Peter|P|;Geissler|Dietmar|D|;Falantes|Jose Francisco|JF|;Pedro|Carmen|C|;Bargay|Joan|J|;Deben|Guillermo|G|;Garrido|Ana|A|;Bonanad|Santiago|S|;Diez-Campelo|Maria|M|;Thepot|Sylvain|S|;Ades|Lionel|L|;Sperr|Wolfgang R|WR|;Valent|Peter|P|;Fenaux|Pierre|P|;Sekeres|Mikkael A|MA|;Greil|Richard|R|;Pleyer|Lisa|L|",
"chemical_list": "D015415:Biomarkers; D000077209:Decitabine; D001374:Azacitidine",
"country": "Switzerland",
"delete": false,
"doi": "10.3390/ijms18040837",
"fulltext": "\n==== Front\nInt J Mol SciInt J Mol SciijmsInternational Journal of Molecular Sciences1422-0067MDPI 10.3390/ijms18040837ijms-18-00837ArticleClinical Outcomes of 217 Patients with Acute Erythroleukemia According to Treatment Type and Line: A Retrospective Multinational Study Almeida Antonio M. 1*Prebet Thomas 2Itzykson Raphael 3Ramos Fernando 4Al-Ali Haifa 5Shammo Jamile 6Pinto Ricardo 7Maurillo Luca 8Wetzel Jaime 9Musto Pellegrino 10Van De Loosdrecht Arjan A. 11Costa Maria Joao 12Esteves Susana 1Burgstaller Sonja 13Stauder Reinhard 14Autzinger Eva M. 15Lang Alois 16Krippl Peter 17Geissler Dietmar 18Falantes Jose Francisco 19Pedro Carmen 20Bargay Joan 21Deben Guillermo 22Garrido Ana 23Bonanad Santiago 24Diez-Campelo Maria 25Thepot Sylvain 26Ades Lionel 3Sperr Wolfgang R. 27Valent Peter 27Fenaux Pierre 3Sekeres Mikkael A. 9Greil Richard 28293031Pleyer Lisa 28293031*Brown Geoffrey Academic EditorMarcinkowska Ewa Academic Editor1 Instituto Português de Oncologia de Lisboa (IPOL), 1200-795 Lisbon, Portugal; sesteves@ipolisboa.min-saude.pt2 Institut Paoli Calmettes, Marseille, France and Yale New Haven Hospital, New Haven, CT 06512, USA; thomas.prebet@yale.edu3 Hopital Saint-Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris Diderot University, 75010 Paris, France; itzykson@gmail.com (R.I.); lionel.ades@sls.aphp.fr (L.A.); pierre.fenaux@sls.aphp.fr (P.F.)4 Hospital Universitario de Leon, 24071 Leon, Spain; mail@fernandoramosmd.es5 University Hospital of Halle, 06120 Halle, Germany; alah@medizin.uni-leipzig.de6 Rush University Medical Center, Chicago, IN 60612, USA; Jamile_Shammo@rush.edu7 Hospital Sao Joao, 4200-319 Porto, Portugal; rjsmpinto@gmail.com8 University Tor Vergata, 00173 Rome, Italy; luca.maurillo@uniroma2.it9 Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 44195, USA; FENSTEJ@ccf.org (J.W.); SEKEREM@ccf.org (M.A.S.)10 RCCS-CROB, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture (Pz), Italy; p.musto@tin.it11 Department of Hematology VU University Medical Center, 1081 HV Amsterdam, The Netherlands; a.vandeloosdrecht@vumc.nl12 Centro Hospitalar Lisboa Norte Hospital Santa Maria, 1649-035 Lisbon, Portugal; mjoaocosta@gmail.com13 Department of Internal Medicine IV, Hospital Wels-Grieskirchen, 4600 Wels, Austria; sonja.burgstaller@klinikum-wegr.at14 Department of Internal Medicine V (Haematology and Oncology), Innsbruck Medical University, 6020 Innsbruck, Austria; reinhard.stauder@i-med.ac.at15 1st Department of Internal Medicine, Center for Oncology and Hematology, Wilhelminenspital, 1160 Vienna, Austria; eva-maria.autzinger@wienkav.at16 Internal Medicine, Hospital Feldkirch,6800 Feldkirch, Austria; alois.lang@lkhf.at17 Department of Internal Medicine, Hospital Fürstenfeld, 8280 Fürstenfeld, Austria; peter.krippl@lkh-fuerstenfeld.at18 Department for Internal Medicine, Klinikum Klagenfurt am Wörthersee, 9020 Pörtschach am Wörthersee, Austria; dietmar.geissler@kabeg.at19 Hospital Universitario Virgen del Rocio, 41013 Sevilla, Spain; jfalantes@gmail.com20 Hospital del Mar, 08003 Barcelona, Spain; MPedro@parcdesalutmar.cat21 Hospital Son Llatzer, 07198 Palma de Mallorca, Spain; jbargay@hsll.es22 Hospital Universitario, 15006 A Coruña, Spain; gdebari@canalejo.org23 Hospital de la Santa Creu i Sant Pau, 08026 Barcelona, Spain; AGarridoD@santpau.cat24 Hospital Universitario de la Ribera, 46600 Alzira, Spain; sbonanad@gmail.com25 Hospital Universitario de Salamanca, 37007 Salamanca, Spain; mdiezcampelo@usal.es26 Centre Hospitalier Universitaire, 49100 Angers, France; Sylvain.Thepot@chu-angers.fr27 Department of Internal Medicine I, Division of Hematology & Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, 1090 Vienna, Austria; wolfgang.r.sperr@meduniwien.ac.at (W.R.S.); peter.valent@meduniwien.ac.at (P.V.)28 3rd Med. Department, Paracelsus Medical University, 5020 Salzburg, Austria; r.greil@salk.at29 Salzburg Cancer Research Institute, 5020 Salzburg, Austria30 Cancer Cluster Salzburg, 5020 Salzburg, Austria31 Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT), 5020 Salzburg, Austria* Correspondence: amalmeida@ipolisboa.min-saude.pt (A.M.A.); l.pleyer@salk.at (L.P.); Tel.: +351-21-724-9036 (A.M.A.); +43-(0)5-7255-58271 (L.P.)14 4 2017 4 2017 18 4 83710 2 2017 06 4 2017 © 2017 by the authors.2017Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Acute erythroleukemia (AEL) is a rare disease typically associated with a poor prognosis. The median survival ranges between 3–9 months from initial diagnosis. Hypomethylating agents (HMAs) have been shown to prolong survival in patients with myelodysplastic syndromes (MDS) and AML, but there is limited data of their efficacy in AEL. We collected data from 210 AEL patients treated at 28 international sites. Overall survival (OS) and PFS were estimated using the Kaplan-Meier method and the log-rank test was used for subgroup comparisons. Survival between treatment groups was compared using the Cox proportional hazards regression model. Eighty-eight patients were treated with HMAs, 44 front line, and 122 with intensive chemotherapy (ICT). ICT led to a higher overall response rate (complete or partial) compared to first-line HMA (72% vs. 46.2%, respectively; p ≤ 0.001), but similar progression-free survival (8.0 vs. 9.4 months; p = 0.342). Overall survival was similar for ICT vs. HMAs (10.5 vs. 13.7 months; p = 0.564), but patients with high-risk cytogenetics treated with HMA first-line lived longer (7.5 for ICT vs. 13.3 months; p = 0.039). Our results support the therapeutic value of HMA in AEL.\n\nacute erythroleukemiaazacitidinedecitabine\n==== Body\n1. Introduction\nAcute erythroleukemia (AEL) is a rare subtype of acute myeloid leukemia (AML), accounting for 3–5% of all AML cases [1]. It is characterized by an expanded erythroid component with a variable, but increased, percentage of blasts [1]. Although recognized as a distinct entity by most classification systems, the diagnostic criteria have changed from system to system, which has been subject to discussion [2,3,4,5]. The recently-published WHO 2016 classification [6] advocates the use of blast percentage on the total cell population rather than that of the non-erythroid component. This reclassifies almost all cases of AEL into myelodysplasia (MDS) or AML subtypes [7,8].\n\nTypical laboratory features include pancytopenia, few peripheral blood blasts, the presence of dysplasia in BM and peripheral blood, especially with dysplastic PAS-positive erythroblasts overexpression of the multidrug resistance (MDR) gene product P-glycoprotein, frequent occurrence of high-risk karyotypes, and a high frequency of mutations, especially of TP53 [2,9,10,11,12,13,14]. In addition, AEL is frequently secondary to previous myelodysplastic syndrome (MDS) [15]. Consequently, it is associated with a poor prognosis, with a median overall survival (OS) of 3–14 months from diagnosis [1,2,10,14]. The only recurring molecular alteration reported has been translocation t(1;16) generating the fusion gene NFIA/CBFA2T3 [16]. Furthermore, a high proerythroblast/myeloblast ratio correlates with significant increases in cytogenetic aberrations, proliferation markers, and worse outcomes [1,17,18,19], although this is not consensual [10,14]. In fact, several authors believe that the association of AEL with adverse prognostic factors imparts the adverse prognosis, rather than the diagnosis of AEL itself [14,20].\n\nDue to the rarity of the disease (2–5% of all leukemias), few publications focus on this entity alone, with single cases or case series predominating [9,10,15,21] and patients with AEL are usually treated similarly to patients with other types of AML [1,3]. When treated with intensive chemotherapy (ICT), the median OS of AEL patients range between 7.6 and nine months [14,22]. The poor results achieved with ICT in AEL are likely due to the adverse prognostic factors described above.\n\nHypomethylating agents (HMAs; azacitidine and decitabine) have become the first-line therapy of choice for patients with MDS [23,24], CMML [25,26,27], and AML [28,29,30,31,32,33,34,35,36] who are not candidates for, or decline, intensive chemotherapy (ICT) and/or allo-SCT. HMAs have demonstrated improved outcomes for patients with AML when compared to conventional care regimens, including ICT, low-dose cytarabine, or best supportive care (BSC) [28,29,30,37,38]. Despite some limitations, several studies indicate that the OS of older AML patients treated with HMAs may not be inferior to those treated with ICT [28,29,39,40,41,42,43,44].\n\nThe few existing studies of HMA in AEL report favourable response rates and survival times [21,45,46,47,48]. Larger patient series or randomized clinical trials are lacking. In this international effort, we report on the largest cohort of AEL patients in whom we describe baseline characteristics, overall response rates (ORR), and OS in those treated with HMAs or ICT. In an exploratory analysis, we also compare the treatment outcomes of patients receiving first-line HMA line with those treated with ICT.\n\n2. Results\n2.1. Total Acute Erythroleukemia (AEL) Cohort (n = 217)\nThe overall sample comprised 210 patients with AEL. Of these, 88 (41%) received treatment with HMA in the first or subsequent lines of therapy (82 were treated with azacitidine, six with decitabine) and 122 (56%) received ICT alone. Median age at diagnosis was 69 years (range: 28–88) for the HMA group, and 60 years (range: 20–86) for the ICT group. Poor cytogenetic risk was found in 51% of the HMA and 43% of the ICT groups. Baseline patient characteristics according to treatment group and line of therapy are detailed in Table 1. In the whole AEL cohort, 135 deaths were documented, 79 (59%) due to disease progression, 21 (15%) due to infection, 12 (9%) due to other causes, and in 23 cases (17%) the cause of death was unknown. The median follow-up of all patients was 7.7 (range, 0.2–148.5) months. One patient from the ICT group and four patients from the HMA group were not evaluable for PFS or OS (data regarding time to treatment start and/or death were missing) and, thus, were excluded from the survival analysis. For the total treated cohort (first-line HMA, second-line or later HMA, ICT), the median PFS was 7.1 (range: 6.3–9.4) months, the median OS was 11.1 (range: 9.8–14.3) months and the one-year survival rate was 49% (range: 42–57%) (Tables S1 and S2).\n\n2.2. AEL Treated with HMA (n = 88)\nIn the cohort treated with HMAs, 41 patients (47%) received HMA as a front-line treatment, 45 as a second-line or later treatment, and two patients were excluded from the analysis as no data were provided regarding the treatment line of HMA. Prior disease-modifying treatments in patients receiving HMA as a second-line or later therapy included allo-SCT (5/45), ICT (40/45), low-dose cytarabine (5/45), and/or IMiDs (immunomodulatory agents, e.g., Lenalidomide) (4/45); four patients received concomitant growth factors, one patient received growth factors without prior disease-modifying treatment. The median time from initial diagnosis to treatment was 0.72 (range, 0.03–18.43) months in patients treated with first-line HMA, and 7.6 (range, 0.07–85.27) months in the group receiving HMA as a second-line or later treatment (n = 45). In patients treated with HMA, the median number of cycles in patients for whom data were available (n = 72) was five (range, 1–37); those treated with first-line HMA received a median of seven cycles (range, 1–37), and those treated in the second-line received a median of three cycles (range, 1–22). Those treated with azacitidine (n = 82) were treated with 28 day cycles: 35% received the schedule 5-2-2 (75 mg/m2 days 1–5, rest days 6–7, administer days 8–9), 32% received the schedule 1–7 (75 mg/m2 days 1–7), 26% received the schedule 1–5 (100 mg/m2 days 1–5), and 7% received other schedules. Those treated with decitabine (n = 6) received 15 mg/m2 for three days every six weeks. At the time of data assessment, 66 patients (76%) had died, of which seven died of subsequent allo-SCT complications. Twenty-two patients (24%) were alive; of these, nine had stopped treatment with HMA, nine were still on treatment with HMA (eight with azacitidine and one with decitabine), and four patients were alive at follow-up, but it was unknown whether they were still receiving HMA or not. The main reason for treatment discontinuation was disease progression (n = 39, 62%). Other reasons included infection/toxicity (n = 8, 12%), death (n = 8, 12%), allo-SCT (n = 5, 8%), and others (n = 4, 6%). Causes for death were similarly distributed between HMA and ICT treatment groups (Table S3).\n\nResponse data for patients treated with HMA were available for 75 patients. Among these, best overall response rate (ORR) according to the ELN criteria (complete, CR, or partial, PR) of patients treated with HMA was 40%; when including hematological improvement (HI), ORR rose to 59%; 27% had CR, 13% had PR, and 19% had HI; 35% of patients who were initially dependent on red blood cell transfusion achieved transfusion independence, and 29% of patients who were initially platelet transfusion dependent achieved transfusion independence (Table 2). Of those with an abnormal karyotype at the start of treatment, 11 (21%) of 51 HMA patients reached cytogenetic remission and 40 (53%) of 75 ICT-treated patients achieved cytogenetic remission. The median time to first response was 2.6 months (range, 0.6–27.4) and the median time to best response was 3.9 months (range, 0.66–38.3), respectively.\n\nAfter a median follow-up of 12.3 (range, 0.03–35.2) and 4.8 (range, 0.0–68.8) months for patients treated with first-line HMA and second line or later HMA treatment, respectively, the median (range) PFS was longer for those treated with HMA in first-line treatment compared to second-line or later (9.4 (range 4.2–14.5) vs. 3.4 (2.0–6.3) months, respectively; Table 1). The median OS (range) was also longer for those treated with first-line HMA compared to second-line or later (13.7 (12.3–20.5) vs. 9.8 (4.6–13.5), respectively; Table S2).\n\nThe median OS for AEL patients treated with HMA (all treatment lines) was superior for patients with intermediate- compared to high-risk cytogenetics (13.5 vs. 12.3 months; p = 0.0376) (Figure 1A). AEL patients treated with first-line HMA with intermediate-risk cytogenetics had a median OS of 29.3, whereas those with high-risk cytogenetics had a median OS of 13.3 months (Table 3).\n\nTen (11.3%) patients had an allogeneic bone marrow transplant following treatment with HMA. The median OS in this subgroup was 9.66 months (range, 2.8–25).\n\nIn univariate analysis, response to HMA had a significant impact on OS (Figure 1B). The median survival in patients with CR was 18.2 months, 12.7 months in patients with PR or HI, and 4.5 months in patients with no response (stable disease, SD, or primary progressive disease, PD; p < 0.001).\n\n2.3. AEL Treated with ICT (n = 122)\nIn the group of 122 patients receiving front-line ICT treatment, response data were available for 119 patients. The most frequently used (n = 81; 66%) induction regimen was Daunorubicin (45 or 60 mg/m2 × 3 days) with Cytarabine (100 mg/m2 bid × 7 days). Similar 3 + 7 regimens using Idarubicin 12 mg/m2 or Mitoxantrone 12 mg/m2 for three days, instead of Daunorubicin, were used in 25 (20%) and eight (7%) patients, respectively. Information regarding induction regimen was not available in eight (7%) patients.\n\nORR according to the ELN criteria was 72%; CR in 79 patients was 66%; PR in seven patients was 6%; SD in 16 patients was 13%; PPD in 17 patients was 14% (see Table 2). Data on HI was not assessed in this subgroup of patients, as this response form is considered irrelevant for AML-patients treated with ICT.\n\nAt the time of data assessment, 84 patients (69%) had died, and 37 (31%) were alive. The main cause of death was disease progression (65%) (Table S3).\n\nMedian follow-up was 7.8 (range, 0.03–148.5) months for patients treated with ICT. Median PFS was 8.0 months (range, 6.8–14.5) for AEL-patients treated with ICT (Table S1). Median OS for patients treated with ICT was 10.5 (range, 9.1–20.0) months (Table S2). Median OS for AEL-patients treated with ICT was not significantly superior for patients with intermediate- vs. high-risk cytogenetics (16.9 vs. 7.5 months; p = 0.277) (Table 3). For AEL-patients treated with ICT, the median OS of intermediate- vs. high-risk cytogenetics was 29.3 vs. 13.3 months, p = 0.0.039 (Table 3). In univariate analysis, the response to ICT had a significant impact on overall survival. The median OS in patients with CR was 23.17 months, as compared to 4.07 months in patients with PR, and 5.63 months in patients with no response (SD or primary PD; p < 0.001).\n\nTwenty-three (18.8%) patients had an allogeneic bone marrow transplant following treatment with ICT. Median OS in this subgroup was 5.9 months (range, 2.0–17.9).\n\n2.4. Comparison of AEL Treated with ICT vs. HMA\nThere were no significant differences in baseline characteristics (Table 1) or causes of death in the HMA vs. ICT group (Table 3).\n\nAEL-patients treated with ICT had a higher rate of CR (66% vs. 30.8%; p < 0.001), and ORR according to the ELN criteria (CR + PR) (72% vs. 46.2%, p = 0.016) compared to patients treated with first-line HMA, respectively. Notably, there were significantly more progressions in the ICT group compared to the HMA group (14.3% vs. 7.7%, p = 0.004) and more disease stability in the HMA group (28.2% vs. 13.4%, p = 0.001).\n\nDespite this higher response rate, there was no significant difference in median PFS (8.0 vs. 9.4 months; p = 0.342) or 1-year PFS rates (42% vs. 41%; p = 0.896) (Table S2). In multivariate analyses controlling for cytogenetic risk group and age, treatment with ICT was not superior to treatment with first-line HMA in prolonging PFS (p = 0.6907) (Table 4).\n\nA likelihood ratio test was used to compare models with and without interaction between first line treatment and cytogenetic risk group: p-value = 0.0994.\n\nComparing AEL-patients treated with ICT vs. first-line HMA, no significant differences in 1-year survival rates (47% vs. 66%; p = 0.072) or median OS times could be detected (10.5 vs. 13.7 months; p = 0.564), respectively, though absolute numbers favored HMAs (Figure 2A). When stratified by the cytogenetic risk group, there was no significant difference in the median survival of AEL-patients with intermediate cytogenetic risk treated with ICT vs. first-line HMA (16.9 vs. 29.3 months; p = 0.277; Figure 2B). However, a shorter survival was detected for AEL-patients with high risk cytogenetics treated with ICT, as compared to those treated with first-line HMA (7.5 vs. 13.3 months; p = 0.039; Figure 2C). In multivariate analysis, controlling for age and cytogenetic risk, treatment with ICT was not superior to treatment with first-line HMA in prolonging OS (p = 0.2489), whereas both the MRC cytogenetic risk group (p < 0.0001) and age per additional year (p = 0.0032) did (Table 4).\n\n3. Discussion\nNo prospective clinical trial has been conducted exclusively in patients with AEL. Little is known about the responses to specific drugs in AEL. Case reports and small series indicate possible efficacy of azacitidine [21,45,49], interferon-α [50], and even high dose erythropoietin combined with granulocyte colony-stimulating factor [51].\n\nIt was demonstrated several decades ago that HMA can induce erythroid differentiation and increase the synthesis of hemoglobin in both murine and human erythroleukemia cell lines in vitro [52,53,54]. In addition, the HMA decitabine was shown to induce down-regulation of the multidrug resistance (MDR) gene phospho-glycoprotein in a human erythroleukemia cell line, which coincided with modulation of response to cytostatic drugs [55,56].\n\nWe report here the largest series to date of patients with AEL treated with HMA. The overall response rate of 46% in the front-line setting, with a CR rate of 30% and an additional HI rate of 18%, in our cohort are encouraging and similar to those reported in other smaller studies [21,46,49]. Our study reinforces that, when treating AEL with HMA, any type of response, including hematological improvement, is beneficial. The observation that, despite a significantly lower ORR rate than ICT, PFS similarly suggests that the significantly higher SD rate also has an impact on survival. This highlights the importance of maintaining treatment in all patients who do not progress, even in the absence of marrow responses.\n\nIt is also noteworthy that initial responses were seen after a median of 79 days, but the best responses were documented after a median of 120 days, confirming that responses improve with continued treatment and reinforcing the importance of not interrupting treatment too early due to a lack of response.\n\nWhen compared to AEL patients who were treated with ICT alone, those treated with HMA in as a first-line had similar progression-free and overall survival. This is significant considering the more advanced age of the HMA group. Older patients tolerate intensive chemotherapy poorly. In addition, aggressive treatment options are associated with long hospital admissions and poor quality of life, which may not be justified in an elderly patient group with a disease that is unlikely to be cured. HMA are administered in an outpatient setting and associated with reduced hospital admissions. Given the lack of a curative option for most patients and similar survival, the toxicity profile of HMA makes this option more attractive [57]. In addition, our data shows that adverse karyotype patients have better outcomes when treated with HMA compared to ICT. This suggests that HMA may be the preferred treatment option for older individuals with a poor prognosis karyotype, as is often seen in AEL.\n\nNevertheless, it is important to note that HMAs do not preclude the option of a bone marrow transplant. The therapeutic goal in younger patients with a donor should be to cure the disease and allo-SCT is the only option. Reduced intensity conditioning regimens have opened the option of allo-SCT to more elderly and frail patients but the toxicities associated with conventional intensive AML induction chemotherapy can increase the risk of death or compromise allo-SCT. It has been shown that Azacitidine before SCT does not significantly affect rates of remission, relapse, acute and chronic GVHD, and survival after transplant, and may actually be an alternative for inducing remission in patients with higher risk MDS [58], and eventually AEL [10]. Despite only 10 patients treated with HMA in our cohort having a subsequent SCT, their median survival is encouraging.\n\nOur series analyses patients with AEL but we now know that there is great genetic heterogeneity in myeloid disorders, with a large variety of mutations having been described which have differing impacts on the natural history of the disease. Very recent analyses of the mutational profiles have significantly increased our understanding and prognostication of acute leukemias [59,60]. Future studies in this regard are needed in order to identify those patients with AEL who are most likely to respond to HMA.\n\n4. Methods\n4.1. Patient Population\nPatient data were collected retrospectively and pooled from registries or patient files from 28 different Institutions representing eight different countries (Austria, France, Germany, Italy, Netherlands, Portugal, Spain, and USA). All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Medical Ethics Committee of each individual centre. AEL diagnosis by WHO 2008 criteria was the only entry criterion and this was confirmed by local diagnostic laboratories. MRC cytogenetic risk stratification was applied to all patients.\n\nPatients were included in the HMA group if they had received HMA at any stage of their treatment, whether first, or subsequent, lines. Patients in the ICT group must have been treated with ICT in first-line and never received HMA. Patients diagnosed between March 1998 and November 2014 were included. Treatment choice was made by the treating physician according to personal practice and local protocols. Seven AEL patients treated only with supportive care were proposed for the study, but their outcomes were not included in the analysis.\n\n4.2. Definition of Endpoints\nResponse was defined according to European Leukemia Network (ELN) criteria for AML, and included complete remission (CR) and partial remission (PR) [61]. In addition, hematologic improvement (HI) was assessed according to the modified International Working Group (IWG) criteria 2006 [62]. OS was defined as time from start of treatment with HMA (either first- or second-line or later) or ICT to death from any cause, or last follow-up. Patients who underwent allogeneic stem cell transplantation (allo-SCT) after treatment with HMA or after ICT were censored at the date of allo-SCT. Progression-free survival (PFS) was defined as the time from the start of treatment until disease relapse/progression, or death from any cause.\n\n4.3. Statistics\nDescriptive statistics were used to describe the baseline patient characteristics. OS and PFS were estimated using the Kaplan-Meier method and the log-rank test was used for subgroup comparisons. The comparison of baseline features between the subgroups HMA and ICT was performed using the Pearson’s χ-squared test for categorical baseline variables and the Wilcoxon rank sum test for quantitative variables. In the exploratory analysis to evaluate the impact of treatment (HMA first-line vs. ICT) on OS and PFS we used the Cox proportional hazards regression model. Adjusted hazard ratios were calculated controlling for the potential confounding factors age and cytogenetic risk group. The likelihood ratio test was used to test the interaction between treatment and cytogenetic risk groups. All tests were two-tailed and p-values less than 0.05 were considered to be statistically significant. No adjustment was made for multiple comparisons. All analyses were performed using R [63].\n\n5. Conclusions\nOur data reinforces the utility of HMA in patients with acute erythroleukamia, especially those with poorest prognosis. Future studies in this regard are needed in order to identify those patients with AEL who are most likely to respond to HMA.\n\nAcknowledgments\nPublication costs were supported by the University of Salzburg.\n\nSupplementary Materials\nClick here for additional data file.\n\n Supplementary materials can be found at www.mdpi.com/1422-0067/18/4/837/s1.\n\nAuthor Contributions\nAntonio M. Almeida and Lisa Pleyer conceived and designed the database; Susana Esteves performed the statistical analysis; Antonio M. Almeida wrote the paper; all authors contributed with patient data and critical analysis of the manuscript.\n\nConflicts of Interest\nAntonio M. Almeida: speaker and advisory board for Celgene; Arjan A. Van De Loosdrecht: speaker and advisory board Celgene, advisory board Novartis; Jamile Shammo: Received research funding and honoraria for speaking engagements and consultancy from Celgene; Peter Valent received a research grant and speaker´s honoraria from Celgene and served as an advisory board member for Celgene. Fernando Ramos: Honoraria/Consultation fees for Celgene, Janssen, Amgen, Novatis, Pfizer, Glaxo-Smith-Kline, Merck-Sharp & Dohme. Maria Diez Campelo: speaker, research founding and advisory boards for Celgene.\n\nFigure 1 (A) Overall survival of HMA-treated patients stratified by cytogenetic risk group (total HMA cohort): the median OS for patients treated with HMA was superior for patients with intermediate-compared to high-risk cytogenetics (13.5 months vs. 12.3 months; p = 0.0376); and (B) the overall survival by response to HMA: the median survival in patients with CR was 18.2 months, 12.7 months in patients with PR or HI, and 4.5 months in patients with no response (SD or primary PD; p < 0.001).\n\nFigure 2 Overall survival of AEL patients stratified by type of first line treatment. (A) Total cohorts: median OS for patients treated with first-line HMA was similar to that of those treated with first-line ICT (13.7 months vs. 10.5 months; p = 0.564); (B) stratified by MRC intermediate cytogenetic risk: AEL-patients with intermediate-risk cytogenetics treated with first-line HMA did not have a significantly different median survival as compared to AEL-patients treated with first-line ICT (16.9 months vs. 29.3 months; p = 0.277); and (C) stratified by MRC high cytogenetic risk: AEL-patients with high-risk cytogenetics treated with first-line HMA had a significantly longer median survival as compared to AEL-patients treated with first-line ICT (13.3 months vs. 7.5 months; p = 0.0391).\n\nijms-18-00837-t001_Table 1Table 1 Baseline clinical and demographic characteristics according to treatment group and line.\n\nParameter\tHMA All Lines (n = 88)\tFirst-Line HMA (n = 41)\tFirst-Line ICT (n = 122)\tp-Value First-Line HMA vs. ICT\t\nMedian age at diagnosis, years\t69\t73\t60\t0.1698\t\n (min–max)\t(28–88)\t(44–88)\t(20–86)\t\n\t\nMale gender, n (%)\t54 (61)\t26 (63)\t88 (72)\t0.3919\t\nBM blasts at start of treatment\t\n\t\n\t\n\t\n\t\n Median\t22\t22\t24\t0.8576\t\n Mean (Standard Deviation)\t25.8 (17.2)\t25.8 (15.9)\t27.1 (15.8)\t\n\t\n Unknown, n (%)\t12 (14)\t2 (5)\t6 (5)\t\n\t\nHemoglobin at start of treatment, n (%)\t\n\t\n\t\n\t\n\t\n ≤10 g/dL\t55 (63)\t32 (78)\t32/64 (50)\t1.00\t\n Pts. with unknown hemoglobin\t3 (3)\t0 (0)\t71 (58)\t\n\t\nMedian WBC count at start of treatment, ×109/L (min–max)\t2.35\t2.42\t1.81\t0.7294\t\n(0.1–32.3)\t(0.6–24.0)\t(0.2–23.9)\t\n\t\nNeutrophil count at start of treatment, n (%)\t\n\t\n\t\n\t\n\t\n ≤ 0.5 × 109/L\t34 (39)\t18 (44)\t18/57 (31)\t0.7326\t\n Pts. with unknown neutrophil count\t5 (6)\t1 (2)\t79 (65)\t\n\t\nPlatelet count at start of treatment, n (%)\t\n\t\n\t\n\t\n\t\n ≤50 × 109/L\t54 (61)\t24 (69)\t62 (51)\t0.8673\t\n Unknown\t3 (3)\t0 (0)\t10 (8)\t\n\t\nAML subtype, n (%)\t\n\t\n\t\n\t\n\t\n Primary\t66 (75)\t35 (85)\t81 (66)\t0.4373\t\n Secondary\t11 (13)\t4 (10)\t17 (14)\t\n\t\n Unknown\t11 (13)\t2 (5)\t24 (20)\t\n\t\nMRC cytogenetic risk group, n (%)\t\n\t\n\t\n\t\n\t\n Good risk\t1 (1)\t0 (0)\t0 (0)\t0.6943\t\n Intermediate risk\t39 (44)\t17 (42)\t51 (42)\t\n\t\n Poor risk\t45 (51)\t22 (54)\t53 (43)\t\n\t\n Unknown\t3 (3)\t2 (5)\t18 (15)\t\n\t\nMRC = Medical research council.\n\nijms-18-00837-t002_Table 2Table 2 Responses of AEL patients treated with HMA or ICT.\n\n\n\tHMA All Lines (n = 75) 1\tHMA 1st Line (n = 39) 2\tHMA ≥ 2nd Line (n = 34) 3\tICT 1st Line (n = 119) 4\t\nOverall response acc. to ELN, n (%)\t30 (40.0)\t18 (46.2)\t10 (29.4)\t86 (72.3)\t\n Complete\t20 (26.7)\t12 (30.8)\t7 (20.6)\t79 (66.4)\t\n Partial\t10 (13.3)\t6 (15.4)\t3 (8.8)\t7 (5.9)\t\nOverall response including HI, n (%)\t44 (58.7)\t25 (64.1)\t17 (50.0)\tND\t\nHI without marrow response\t14 (18.7)\t7 (17.9)\t7 (20.6)\tND\t\n ANC\t9 (12.0)\t6 (15.4)\t3 (8.8)\t\n\t\n RBC\t7 (9.3)\t5 (12.8)\t2 (5.9)\t\n\t\n PLT\t9 (12.0)\t5 (12.8)\t4 (11.8)\t\n\t\nTransfusion independence, n/n (%) 5\t\n\t\n\t\n\t\n\t\n RBC-TI\t19/55 (35)\t13/32 (40.6)\t6/21 (28.6)\tND\t\n PLT-TI\t8/28 (29)\t3/14 (21.4)\t4/12 (33.3)\t\n\t\nStable disease\t26 (34.7)\t11 (28.2)\t15 (44.1)\t16 (13.4)\t\nPrimary disease progression\t5 (6.7)\t3 (7.7)\t2 (5.9)\t17 (14.3)\t\nTime to first response, days 6\t\n\t\n\t\n\tND\t\n Median (min–max)\t79 (18–822) 7\t66 (18–233)\t85 (30–822)\t\n\t\nTime to best response, days 8\t\n\t\n\t\n\t\n\t\n Median (min–max)\t120 (20–1150) 7\t143 (20–353)\t89.5 (30–1150)\tND\t\n1 Data available for 75 patients; 2 Data available for 39 patients; 3 Data available for 34 patients; 4 Data on HI was not assessed in this subgroup of patients, as this response form is considered irrelevant for AML-patients treated with ICT; 5 Evaluated in the subset of patients who were transfusion dependent at the start of HMA therapy; 6 Data available for 51 patients; 7 The longest time (822 days to fist response and 1150 days to best response) is a single patient. Other late responders are all ~200 days (6.6 months); and 8 Data available for 52 patients; and ND: not detected.\n\nijms-18-00837-t003_Table 3Table 3 Comparison of AEL patient characteristics and outcomes according to front-line treatment with ICT or HMA in univariate analysis.\n\nOutcomes\tFirst-Line ICT\tFirst-Line HMA\tp-Value\t\nOverall response acc. to ELN, %\t72.3\t46.2\t0.016\t\n Complete response\t64.4\t30.8\t<0.001\t\n Partial response\t5.9\t15.4\t0.101\t\nStable disease, %\t13.4\t28.2\t0.001\t\nPrimary disease progression, %\t14.3\t7.7\t0.004\t\nMedian time to best response, months\tNA 1\t89.5\tNA 1\t\nMedian PFS, months\t8.0\t9.4\t0.107\t\nMRC intermediate cytogenetic risk\t22.7\t5.9\t0.004\t\nMRC high cytogenetic risk\t6.5\t11.3\t0.279\t\n1-year PFS, %\t41.8\t40.6\t0.896\t\nMedian OS total cohort, months\t10.5\t13.7\t0.564\t\nMRC intermediate cytogenetic risk\t16.9\t29.3\t0.277\t\nMRC high cytogenetic risk\t7.5\t13.3\t0.039\t\n1-year OS total cohort, %\t46.7\t65.8\t0.072\t\n1 NA = not available.\n\nijms-18-00837-t004_Table 4Table 4 PFS and OS comparison for first-line treatment with HMA vs. ICT, controlling for cytogenetic risk group and age.\n\nPFS Comparison\tHazard Ratio\t95% CI\tp-Value\t\nFirst line AZA vs. ICT\t0.90\t0.54–1.51\t0.6907\t\nCytogenetic risk group:\t\n\t\n\t\n\t\nHigh vs. Intermediate\t1.86\t1.19–2.90\t0.0064\t\nAge\t\n\t\n\t\n\t\nPer additional year\t1.03\t1.01–1.05\t0.0118\t\nOS Comparison\tHazard Ratio\t95% CI\tp-Value\t\nFirst line AZA vs. ICT\t0.75\t0.45–1.23\t0.2489\t\nCytogenetic risk group\t\n\t\n\t\n\t\nHigh vs. Intermediate\t2.40\t1.54–3.69\t<0.0001\t\nAge\t\n\t\n\t\n\t\nPer additional year\t1.03\t1.01–1.05\t0.0032\n==== Refs\nReferences\n1. Santos F.P. Bueso-Ramos C.E. Ravandi F. Acute erythroleukemia: Diagnosis and management Expert Rev. Hematol. 2010 3 705 718 10.1586/ehm.10.62 21091147 \n2. Liu W. Hasserjian R.P. Hu Y. Zhang L. Miranda R.N. Medeiros L.J. Wang S.A. Pure erythroid leukemia: A reassessment of the entity using the 2008 World Health Organization classification Mod. Pathol. 2011 24 375 383 10.1038/modpathol.2010.194 21102413 \n3. Zuo Z. Polski J.M. Kasyan A. Medeiros L.J. Acute erythroid leukemia Arch. Pathol. Lab. Med. 2010 134 1261 1270 20807044 \n4. Kasyan A. Medeiros L.J. Zuo Z. Santos F.P. Ravandi-Kashani F. Miranda R. Vadhan-Raj S. Koeppen H. Bueso-Ramos C.E. Acute erythroid leukemia as defined in the World Health Organization classification is a rare and pathogenetically heterogeneous disease Mod. Pathol. 2010 23 1113 1126 10.1038/modpathol.2010.96 20473273 \n5. Selby D.M. Valdez R. Schnitzer B. Ross C.W. Finn W.G. Diagnostic criteria for acute erythroleukemia Blood 2003 101 2895 2896 10.1182/blood-2002-11-3459 12642345 \n6. Arber D.A. Orazi A. Hasserjian R. Thiele J. Borowitz M.J. Le Beau M.M. Bloomfield C.D. Cazzola M. Vardiman J.W. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia Blood 2016 127 2391 2405 10.1182/blood-2016-03-643544 27069254 \n7. Arenillas L. Calvo X. Luno E. Senent L. Alonso E. Ramos F. Ardanaz M.T. Pedro C. Tormo M. Marco V. Considering Bone Marrow Blasts From Nonerythroid Cellularity Improves the Prognostic Evaluation of Myelodysplastic Syndromes J. Clin. Oncol. 2016 34 3284 3292 10.1200/JCO.2016.66.9705 27382099 \n8. Calvo X. Arenillas L. Luno E. Senent L. Arnan M. Ramos F. Ardanaz M.T. Pedro C. Tormo M. Montoro J. Erythroleukemia shares biological features and outcome with myelodysplastic syndromes with excess blasts: A rationale for its inclusion into future classifications of myelodysplastic syndromes Mod. Pathol. 2016 29 1541 1551 10.1038/modpathol.2016.146 27562492 \n9. Jogai S. Varma N. Garewal G. Das R. Varma S. Acute erythroleukemia (AML-M6)—A study of clinicohematological, morphological and dysplastic features in 10 cases Indian J. Cancer 2001 38 143 148 12593454 \n10. Olopade O.I. Thangavelu M. Larson R.A. Mick R. Kowal-Vern A. Schumacher H.R. Le Beau M.M. Vardiman J.W. Rowley J.D. Clinical, morphologic, and cytogenetic characteristics of 26 patients with acute erythroblastic leukemia Blood 1992 80 2873 2882 1450412 \n11. Domingo-Claros A. Larriba I. Rozman M. Irriguible D. Vallespi T. Aventin A. Ayats R. Milla F. Sole F. Florensa L. Acute erythroid neoplastic proliferations. A biological study based on 62 patients Haematologica 2002 87 148 153 11836165 \n12. Lessard M. Struski S. Leymarie V. Flandrin G. Lafage-Pochitaloff M. Mozziconacci M.J. Talmant P. Bastard C. Charrin C. Baranger L. Cytogenetic study of 75 erythroleukemias Cancer Genet. Cytogenet. 2005 163 113 122 10.1016/j.cancergencyto.2005.05.006 16337853 \n13. Mazzella F.M. Kowal-Vern A. Shrit M.A. Rector J.T. Cotelingam J.D. Schumacher H.R. Effects of multidrug resistance gene expression in acute erythroleukemia Mod. Pathol. 2000 13 407 413 10.1038/modpathol.3880070 10786807 \n14. Grossmann V. Bacher U. Haferlach C. Schnittger S. Potzinger F. Weissmann S. Roller A. Eder C. Fasan A. Zenger M. Acute erythroid leukemia (AEL) can be separated into distinct prognostic subsets based on cytogenetic and molecular genetic characteristics Leukemia 2013 27 1940 1943 10.1038/leu.2013.144 23648669 \n15. Atkinson J. Hrisinko M.A. Weil S.C. Erythroleukemia: A review of 15 cases meeting 1985 FAB criteria and survey of the literature Blood Rev. 1992 6 204 214 10.1016/0268-960X(92)90016-J 1486289 \n16. Micci F. Thorsen J. Panagopoulos I. Nyquist K.B. Zeller B. Tierens A. Heim S. High-throughput sequencing identifies an NFIA/CBFA2T3 fusion gene in acute erythroid leukemia with t(1;16)(p31;q24) Leukemia 2013 27 980 982 10.1038/leu.2012.266 23032695 \n17. Srinivas U. Kumar R. Pati H.P. Saxena R. Tyagi S. Sub classification and clinico-hematological correlation of 40 cases of acute erythroleukemia—Can proerythroblast/myeloblast and proerythroblast/total erythroid cell ratios help subclassify? Hematology 2007 12 381 385 10.1080/10245330701393816 17852448 \n18. Mazzella F.M. Kowal-Vern A. Shrit M.A. Wibowo A.L. Rector J.T. Cotelingam J.D. Collier J. Mikhael A. Cualing H. Schumacher H.R. Acute erythroleukemia: Evaluation of 48 cases with reference to classification, cell proliferation, cytogenetics, and prognosis Am. J. Clin. Pathol. 1998 110 590 598 10.1093/ajcp/110.5.590 9802343 \n19. Kowal-Vern A. Mazzella F.M. Cotelingam J.D. Shrit M.A. Rector J.T. Schumacher H.R. Diagnosis and characterization of acute erythroleukemia subsets by determining the percentages of myeloblasts and proerythroblasts in 69 cases Am. J. Hematol. 2000 65 5 13 10.1002/1096-8652(200009)65:1<5::AID-AJH2>3.0.CO;2-U 10936857 \n20. Santos F.P. Faderl S. Garcia-Manero G. Koller C. Beran M. O‘Brien S. Pierce S. Freireich E.J. Huang X. Borthakur G. Adult acute erythroleukemia: An analysis of 91 patients treated at a single institution Leukemia 2009 23 2275 2280 10.1038/leu.2009.181 19741728 \n21. Pierdomenico F. Almeida A. Treatment of acute erythroleukemia with Azacitidine: A case series Leuk. Res. Rep. 2013 2 41 43 10.1016/j.lrr.2013.04.001 24371777 \n22. Colita A. Belhabri A. Chelghoum Y. Charrin C. Fiere D. Thomas X. Prognostic factors and treatment effects on survival in acute myeloid leukemia of M6 subtype: A retrospective study of 54 cases Ann. Oncol. 2001 12 451 455 10.1023/A:1011133115435 11398875 \n23. Fenaux P. Mufti G.J. Hellstrom-Lindberg E. Santini V. Finelli C. Giagounidis A. Schoch R. Gattermann N. Sanz G. List A. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: A randomised, open-label, phase III study Lancet Oncol. 2009 10 223 232 10.1016/S1470-2045(09)70003-8 19230772 \n24. Garcia-Manero G. Jabbour E. Borthakur G. Faderl S. Estrov Z. Yang H. Maddipoti S. Godley L.A. Gabrail N. Berdeja J.G. Randomized open-label phase II study of decitabine in patients with low- or intermediate-risk myelodysplastic syndromes J. Clin. Oncol. 2013 31 2548 2553 10.1200/JCO.2012.44.6823 23733767 \n25. Pleyer L. Germing U. Sperr W.R. Linkesch W. Burgstaller S. Stauder R. Girschikofsky M. Schreder M. Pfeilstocker M. Lang A. Azacitidine in CMML: Matched-pair analyses of daily-life patients reveal modest effects on clinical course and survival Leuk. Res. 2014 38 475 483 10.1016/j.leukres.2014.01.006 24522248 \n26. Thorpe M. Montalvao A. Pierdomenico F. Moita F. Almeida A. Treatment of chronic myelomonocytic leukemia with 5-Azacitidine: A case series and literature review Leuk. Res. 2012 36 1071 1073 10.1016/j.leukres.2012.04.024 22607959 \n27. Fianchi L. Criscuolo M. Breccia M. Maurillo L. Salvi F. Musto P. Mansueto G. Gaidano G. Finelli C. Aloe-Spiriti A. High rate of remissions in chronic myelomonocytic leukemia treated with 5-azacytidine: Results of an Italian retrospective study Leuk. Lymphoma 2013 54 658 661 10.3109/10428194.2012.719617 22873829 \n28. Fenaux P. Mufti G.J. Hellstrom-Lindberg E. Santini V. Gattermann N. Germing U. Sanz G. List A.F. Gore S. Seymour J.F. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia J. Clin. Oncol. 2010 28 562 569 10.1200/JCO.2009.23.8329 20026804 \n29. Dombret H. Seymour J.F. Butrym A. Wierzbowska A. Selleslag D. Jang J.H. Kumar R. Cavenagh J. Schuh A.C. Candoni A. International phase 3 study of azacitidine vs. conventional care regimens in older patients with newly diagnosed AML with >30% blasts Blood 2015 126 291 299 10.1182/blood-2015-01-621664 25987659 \n30. Kantarjian H.M. Thomas X.G. Dmoszynska A. Wierzbowska A. Mazur G. Mayer J. Gau J.P. Chou W.C. Buckstein R. Cermak J. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia J. Clin. Oncol. 2012 30 2670 2677 10.1200/JCO.2011.38.9429 22689805 \n31. Thepot S. Itzykson R. Seegers V. Recher C. Raffoux E. Quesnel B. Delaunay J. Cluzeau T. Marfaing Koka A. Stamatoullas A. Azacitidine in untreated acute myeloid leukemia: A report on 149 patients Am. J. Hematol. 2014 89 410 416 10.1002/ajh.23654 24375487 \n32. Pleyer L. Burgstaller S. Girschikofsky M. Linkesch W. Stauder R. Pfeilstocker M. Schreder M. Tinchon C. Sliwa T. Lang A. Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: Results from the Austrian Azacitidine Registry of the AGMT-Study Group Ann. Hematol. 2014 93 1825 1838 10.1007/s00277-014-2126-9 24951123 \n33. Falantes J. Thepot S. Pleyer L. Maurillo L. Martínez-Robles V. Itzykson R. Bargay J. Stauder R. Venditti A. Martínez M.P. Seegers V. Azacitidine in older patients with acute myeloid leukemia (AML). Results from the expanded international E-ALMA series (E-ALMA+) according to the MRC risk index score Blood 2015 126 2554 \n34. Pleyer L. Stauder R. Burgstaller S. Schreder M. Tinchon C. Pfeilstocker M. Steinkirchner S. Melchardt T. Mitrovic M. Girschikofsky M. Azacitidine in patients with WHO-defined AML—Results of 155 patients from the Austrian Azacitidine Registry of the AGMT-Study Group J. Hematol. Oncol. 2013 6 32 10.1186/1756-8722-6-32 23627920 \n35. Maurillo L. Venditti A. Spagnoli A. Gaidano G. Ferrero D. Oliva E. Lunghi M. D’Arco A.M. Levis A. Pastore D. Azacitidine for the treatment of patients with acute myeloid leukemia: Report of 82 patients enrolled in an Italian Compassionate Program Cancer 2012 118 1014 1022 10.1002/cncr.26354 21761399 \n36. Pleyer L. Burgstaller S. Stauder R. Girschikofsky M. Sill H. Schlick K. Thaler J. Halter B. Machherndl-Spandl S. Zebisch A. Azacitidine front-line in 339 patients with myelodysplastic syndromes and acute myeloid leukaemia: Comparison of French-American-British and World Health Organization classifications J. Hematol. Oncol. 2016 9 39 10.1186/s13045-016-0263-4 27084507 \n37. Kadia T.M. Thomas X.G. Dmoszynska A. Wierzbowska A. Minden M. Arthur C. Delaunay J. Ravandi F. Kantarjian H. Decitabine improves outcomes in older patients with acute myeloid leukemia and higher blast counts Am. J. Hematol. 2015 90 E139 E141 10.1002/ajh.24036 25858582 \n38. Mayer J. Arthur C. Delaunay J. Mazur G. Thomas X.G. Wierzbowska A. Ravandi F. Berrak E. Jones M. Li Y. Multivariate and subgroup analyses of a randomized, multinational, phase 3 trial of decitabine vs. treatment choice of supportive care or cytarabine in older patients with newly diagnosed acute myeloid leukemia and poor- or intermediate-risk cytogenetics BMC Cancer 2014 14 69 10.1186/1471-2407-14-69 24498872 \n39. Gupta N. Miller A. Gandhi S. Ford L.A. Vigil C.E. Griffiths E.A. Thompson J.E. Wetzler M. Wang E.S. Comparison of epigenetic versus standard induction chemotherapy for newly diagnosed acute myeloid leukemia patients ≥60 years old Am. J. Hematol. 2015 90 639 646 10.1002/ajh.24016 25808347 \n40. Lao Z. Yiu R. Wong G.C. Ho A. Treatment of elderly patients with acute myeloid leukemia with azacitidine results in fewer hospitalization days and infective complications but similar survival compared with intensive chemotherapy Asia Pac. J. Clin. Oncol. 2015 11 54 61 10.1111/ajco.12331 25545192 \n41. Van der Helm L.H. Scheepers E.R. Veeger N.J. Daenen S.M. Mulder A.B. van den Berg E. Vellenga E. Huls G. Azacitidine might be beneficial in a subgroup of older AML patients compared to intensive chemotherapy: A single centre retrospective study of 227 consecutive patients J. Hematol. Oncol. 2013 6 29 10.1186/1756-8722-6-29 23587459 \n42. Jabbour E. Mathisen M.S. Garcia-Manero G. Champlin R. Popat U. Khouri I. Giralt S. Kadia T. Chen J. Pierce S. Allogeneic hematopoietic stem cell transplantation versus hypomethylating agents in patients with myelodysplastic syndrome: A retrospective case-control study Am. J. Hematol. 2013 88 198 200 10.1002/ajh.23371 23345254 \n43. Ravandi F. Issa J.P. Garcia-Manero G. O’Brien S. Pierce S. Shan J. Borthakur G. Verstovsek S. Faderl S. Cortes J. Superior outcome with hypomethylating therapy in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome and chromosome 5 and 7 abnormalities Cancer 2009 115 5746 5751 10.1002/cncr.24661 19795507 \n44. Almeida A. Ferreira A.R. Costa M.J. Silva S. Alnajjar K. Bogalho I. Pierdomenico F. Esteves S. Alpoim M. Braz G. Clinical outcomes of AML patients treated with Azacitidine in Portugal: A retrospective multicenter study Leuk. Res. Rep. 2017 7 6 10 10.1016/j.lrr.2016.12.002 28066705 \n45. Hansen S.B. Dufva I.H. Kjeldsen L. Durable complete remission after azacitidine treatment in a patient with erythroleukaemia Eur. J. Haematol. 2012 89 369 370 10.1111/j.1600-0609.2012.01816.x 22681642 \n46. Hangai S. Nakamura F. Kamikubo Y. Honda A. Arai S. Nakagawa M. Ichikawa M. Kurokawa M. Erythroleukemia showing early erythroid and cytogenetic responses to azacitidine therapy Ann. Hematol. 2013 92 707 709 10.1007/s00277-012-1603-2 23070126 \n47. Vigil C.E. Cortes J. Kantarjian H. Garcia-Manero G. Lancet J. List A. Hypomethylating Therapy for the Treatment of Acute Erythroleukemia Patients Blood 2009 114 2069 \n48. King R.J. Crouch A. Radojcic V. Marini B.L. Perissinotti A.J. Bixby D. Therapeutic Outcomes of Patients with Acute Erythroid Leukemia Treated with Hypomethylating Agents Blood 2016 128 5203 \n49. Uchida T. Hagihara M. Hua J. Inoue M. The effects of azacitidine on the response and prognosis of myelodysplastic syndrome and acute myeloid leukemia involving a bone marrow erythroblast frequency of >50 Leuk. Res. 2016 53 35 38 10.1016/j.leukres.2016.11.012 28013105 \n50. Steger G.G. Dittrich C. Chott A. Derfler K. Schwarzmeier J.D. Long-term remission in a patient with erythroleukemia following interferon-α treatment J. Biol. Response Modif. 1989 8 351 354 \n51. Camera A. Volpicelli M. Villa M.R. Risitano A.M. Rossi M. Rotoli B. Complete remission induced by high dose erythropoietin and granulocyte colony stimulating factor in acute erythroleukemia (AML-M6 with maturation) Haematologica 2002 87 1225 1227 12414355 \n52. Creusot F. Acs G. Christman J.K. Inhibition of DNA methyltransferase and induction of Friend erythroleukemia cell differentiation by 5-azacytidine and 5-aza-2’-deoxycytidine J. Biol. Chem. 1982 257 2041 2048 6173384 \n53. Gambari R. del Senno L. Barbieri R. Viola L. Tripodi M. Raschella G. Fantoni A. Human leukemia K-562 cells: Induction of erythroid differentiation by 5-azacytidine Cell Differ. 1984 14 87 97 10.1016/0045-6039(84)90033-2 6205767 \n54. Zucker R.M. Decal D.L. Whittington K.B. 5-Azacytidine increases the synthesis of embryonic hemoglobin (E2) in murine erythroleukemic cells FEBS Lett. 1983 162 436 441 10.1016/0014-5793(83)80803-5 6195020 \n55. Ando T. Nishimura M. Oka Y. Decitabine (5-Aza-2′-deoxycytidine) decreased DNA methylation and expression of MDR-1 gene in K562/ADM cells Leukemia 2000 14 1915 1920 10.1038/sj.leu.2401914 11069027 \n56. Efferth T. Futscher B.W. Osieka R. 5-Azacytidine modulates the response of sensitive and multidrug-resistant K562 leukemic cells to cytostatic drugs Blood Cells Mol. Dis. 2001 27 637 648 10.1006/bcmd.2001.0427 11482878 \n57. Pleyer L. Greil R. Digging deep into “dirty” drugs—Modulation of the methylation machinery Drug Metab. Rev. 2015 47 252 279 10.3109/03602532.2014.995379 25566693 \n58. Damaj G. Duhamel A. Robin M. Beguin Y. Michallet M. Mohty M. Vigouroux S. Bories P. Garnier A. El Cheikh J. Impact of azacitidine before allogeneic stem-cell transplantation for myelodysplastic syndromes: A study by the Societe Francaise de Greffe de Moelle et de Therapie-Cellulaire and the Groupe-Francophone des Myelodysplasies J. Clin. Oncol. 2012 30 4533 4540 10.1200/JCO.2012.44.3499 23109707 \n59. Figueroa M.E. Skrabanek L. Li Y. Jiemjit A. Fandy T.E. Paietta E. Fernandez H. Tallman M.S. Greally J.M. Carraway H. MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation Blood 2009 114 3448 3458 10.1182/blood-2009-01-200519 19652201 \n60. Papaemmanuil E. Gerstung M. Bullinger L. Gaidzik V.I. Paschka P. Roberts N.D. Potter N.E. Heuser M. Thol F. Bolli N. Genomic Classification and Prognosis in Acute Myeloid Leukemia N. Engl. J. Med. 2016 374 2209 2221 10.1056/NEJMoa1516192 27276561 \n61. Dohner H. Estey E.H. Amadori S. Appelbaum F.R. Buchner T. Burnett A.K. Dombret H. Fenaux P. Grimwade D. Larson R.A. Diagnosis and management of acute myeloid leukemia in adults: Recommendations from an international expert panel, on behalf of the European LeukemiaNet Blood 2010 115 453 474 10.1182/blood-2009-07-235358 19880497 \n62. Cheson B.D. Greenberg P.L. Bennett J.M. Lowenberg B. Wijermans P.W. Nimer S.D. Pinto A. Beran M. de Witte T.M. Stone R.M. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia Blood 2006 108 419 425 10.1182/blood-2005-10-4149 16609072 \n63. R: The R Project for Statistical Computing Available online: https://www.r-project.org/ (accessed on 12 April 2017)\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1422-0067",
"issue": "18(4)",
"journal": "International journal of molecular sciences",
"keywords": "acute erythroleukemia; azacitidine; decitabine",
"medline_ta": "Int J Mol Sci",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine; D015415:Biomarkers; D001853:Bone Marrow; D020732:Cytogenetic Analysis; D000077209:Decitabine; D005260:Female; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "101092791",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28420120",
"pubdate": "2017-04-14",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "10786807;10936857;11069027;11398875;11482878;11836165;12414355;12593454;12642345;1450412;1486289;16337853;16609072;17852448;19230772;19652201;19741728;19795507;19880497;20026804;20473273;20807044;21091147;21102413;21761399;22607959;22681642;22689805;22873829;23032695;23070126;23109707;23345254;23587459;23627920;23648669;23733767;24371777;24375487;24498872;24522248;24951123;25545192;25566693;25808347;25858582;25987659;27069254;27084507;27276561;27382099;2754435;27562492;28013105;28066705;28838276;6173384;6195020;6205767;9802343",
"title": "Clinical Outcomes of 217 Patients with Acute Erythroleukemia According to Treatment Type and Line: A Retrospective Multinational Study.",
"title_normalized": "clinical outcomes of 217 patients with acute erythroleukemia according to treatment type and line a retrospective multinational study"
} | [
{
"companynumb": "PT-CELGENEUS-PRT-2015061345",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe effects of thiopurines on white cell count are well documented.\n\n\nOBJECTIVE\nWe compared the effects of infliximab 5 mg/kg monotherapy and combination of infliximab with thiopurines on the total and differential white cell count (WBC).\n\n\nMETHODS\n13 IBD patients treated with infliximab monotherapy and 18 IBD patients treated with a combination of infliximab and thiopurines were included in the study. Using retrospective data, cell counts were examined prior to induction of infliximab, and at 6 weeks and 1 year post-induction.\n\n\nRESULTS\nThe patients on combination therapy had an absolute WBC at 52 weeks of 5.7 whereas that of patients on Infliximab monotherapy at the same time point was 8.3 with comparable neutrophil count of 3.4 and 5.4. The results showed a significant reduction in white cell count and neutrophils at 6 weeks which persisted at 52 weeks in both groups (p < 0.05) with a greater drop in patients on combination infliximab and thiopurine (p < 0.05) as compared to Infliximab monotherapy. There was no significant change in the lymphocyte count.\n\n\nCONCLUSIONS\nFull blood counts should be closely monitored in all patients starting infliximab therapy, in particular patients receiving concomitant thiopurines.",
"affiliations": "Department of Gastroenterology, Connolly Hospital, Blanchardstown, Dublin-15, Ireland. vikpar37@ahoo.com.;Department of Gastroenterology, Connolly Hospital, Blanchardstown, Dublin-15, Ireland.;Department of Gastroenterology, Connolly Hospital, Blanchardstown, Dublin-15, Ireland.;Department of Gastroenterology, Connolly Hospital, Blanchardstown, Dublin-15, Ireland.;Department of Gastroenterology, Connolly Hospital, Blanchardstown, Dublin-15, Ireland.;Department of Gastroenterology, Connolly Hospital, Blanchardstown, Dublin-15, Ireland.;Department of Gastroenterology, Connolly Hospital, Blanchardstown, Dublin-15, Ireland.;Department of Gastroenterology, Connolly Hospital, Blanchardstown, Dublin-15, Ireland.;Department of Gastroenterology, Connolly Hospital, Blanchardstown, Dublin-15, Ireland.",
"authors": "Parihar|V|V|;Maceneaney|O|O|;Maguire|S|S|;Garry|C|C|;O'Sullivan|M|M|;Kennedy|M|M|;Safaya|K|K|;Smyth|C|C|;Farrell|R|R|",
"chemical_list": "D000069285:Infliximab; D015122:Mercaptopurine; D001379:Azathioprine",
"country": "Ireland",
"delete": false,
"doi": "10.1007/s11845-016-1469-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-1265",
"issue": "186(2)",
"journal": "Irish journal of medical science",
"keywords": "Inflammatory bowel disease; Infliximab; Neutrophils; Thiopurines; White cell count",
"medline_ta": "Ir J Med Sci",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001379:Azathioprine; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases; D000069285:Infliximab; D008297:Male; D015122:Mercaptopurine; D008875:Middle Aged; D009504:Neutrophils; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "7806864",
"other_id": null,
"pages": "329-332",
"pmc": null,
"pmid": "27241033",
"pubdate": "2017-05",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "12899609;15561677;12047962;15895899;21108590;22943199;25266439;20393175;20951835;19756557;11096165;16618399;22725726;15505264",
"title": "Combination of infliximab with thiopurines significantly reduces white cell and neutrophil counts in inflammatory bowel disease patients.",
"title_normalized": "combination of infliximab with thiopurines significantly reduces white cell and neutrophil counts in inflammatory bowel disease patients"
} | [
{
"companynumb": "IE-JNJFOC-20170611094",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Despite high response rates, there has been reluctance to use radiation therapy for patients with relapsed/refractory (r/r) Hodgkin (HL) or aggressive non-Hodgkin lymphoma (NHL) given concerns for subacute and late toxicities. Symptomatic pneumonitis, a subacute toxicity, has an incidence of 17% to 24% (≥grade 2) even with intensity modulated radiation therapy. Proton therapy (PT), which has no exit radiation dose, is associated with a lower dose to lung compared with other radiation techniques. As risk of radiation pneumonitis is associated with lung dose, we evaluated whether pneumonitis rates are lower with PT.\n\n\n\nWithin an international, multi-institutional cohort, we retrospectively evaluated the incidence and grade of radiation pneumonitis (National Cancer Institute Common Terminology Criteria for Adverse Events v4) among patients with r/r HL or NHL treated with PT.\n\n\n\nA total of 85 patients with r/r lymphoma (66% HL, 34% NHL; 46% primary chemorefractory) received thoracic PT from 2009 to 2017 in the consolidation (45%) or salvage (54%) setting. Median dose was 36 Gy(RBE). Before PT, patients underwent a median of 1 salvage systemic therapy (range, 0-4); 40% received PT within 4 months of transplant. With a median follow-up of 26.3 months among living patients, 11 patients developed symptomatic (grade 2) pneumonitis (12.8%). No grade 3 or higher pneumonitis was observed. Dose to lung, including mean lung dose, lung V5, and V20, significantly predicted risk of symptomatic pneumonitis, but not receipt of brentuximab, history of bleomycin toxicity, sex, or peritransplant radiation.\n\n\n\nPT for relapsed/refractory lymphoma was associated with favorable rates of pneumonitis compared with historical controls. We confirm that among patients treated with PT, pneumonitis risk is associated with mean lung and lung V20 dose. These findings highlight how advancements in radiation delivery may improve the therapeutic ratio for patients with relapsed/refractory lymphoma. PT may be considered as a treatment modality for patients with relapsed/refractory lymphoma in the consolidation or salvage setting.",
"affiliations": "Department of Radiation Oncology, University of Washington, Seattle, Washington; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Proton Collaborative Group Registry Membership Site, Warrenville, Illinois. Electronic address: ydt2@uw.edu.;Department of Radiation Oncology, Mayo Clinic Florida, Jacksonville, Florida.;Proton Therapy Center Czech, Prague.;Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA.;Department of Radiation Oncology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Radiation Oncology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Radiation Oncology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, Florida.;Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, Florida.;Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA.;Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio.;Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia.;Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, North Carolina.;Proton Collaborative Group Registry Membership Site, Warrenville, Illinois; Department of Radiation Oncology, University of Maryland School of Medicine and Maryland Proton Treatment Center, Baltimore, Maryland.;Department of Radiation Oncology, Willis-Knighton Cancer Center, Shreveport, Lousiana.;Proton Collaborative Group Registry Membership Site, Warrenville, Illinois; Procure Proton Therapy Center, Somerset, New Jersey.;Proton Collaborative Group Registry Membership Site, Warrenville, Illinois; Oklahoma Proton Center, Oklahoma City, Oklahoma.;Proton Collaborative Group Registry Membership Site, Warrenville, Illinois; Northwestern Medicine Proton Center, Warrenville, Illinois.;Department of Radiation Oncology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania.",
"authors": "Tseng|Yolanda D|YD|;Hoppe|Bradford S|BS|;Dedeckova|Katerina|K|;Patel|Chirayu G|CG|;Hill-Kayser|Christine E|CE|;Miller|David M|DM|;Maity|Amit|A|;Mendenhall|Nancy P|NP|;Mailhot Vega|Raymond B|RB|;Yock|Torunn I|TI|;Baliga|Sujith|S|;Hess|Clayton B|CB|;Winkfield|Karen M|KM|;Mohindra|Pranshu|P|;Rosen|Lane R|LR|;Tsai|Henry|H|;Chang|John|J|;Hartsell|William F|WF|;Plastaras|John P|JP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ijrobp.2020.08.055",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0360-3016",
"issue": "109(1)",
"journal": "International journal of radiation oncology, biology, physics",
"keywords": null,
"medline_ta": "Int J Radiat Oncol Biol Phys",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D005260:Female; D006801:Humans; D008223:Lymphoma; D008297:Male; D008482:Mediastinum; D008875:Middle Aged; D061766:Proton Therapy; D017564:Radiation Pneumonitis; D012008:Recurrence; D012307:Risk Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7603616",
"other_id": null,
"pages": "220-230",
"pmc": null,
"pmid": "32866566",
"pubdate": "2021-01-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Risk of Pneumonitis and Outcomes After Mediastinal Proton Therapy for Relapsed/Refractory Lymphoma: A PTCOG and PCG Collaboration.",
"title_normalized": "risk of pneumonitis and outcomes after mediastinal proton therapy for relapsed refractory lymphoma a ptcog and pcg collaboration"
} | [
{
"companynumb": "US-MYLANLABS-2021M1003474",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "Phlegmasia cerulea dolens (PCD) is a rare, fulminant, potentially lethal and often debilitating presentation of deep venous thrombosis (DVT). Mortality and amputations rates are high. We present a rare case of bilateral PCD in the lower extremities. A 67-year-old woman presented with newly diagnosed squamous cell cancer of unknown primary origin with lymph node metastases to the neck. The patient started curatively intended treatment, consisting of removal of one lymph node on the neck, radiotherapy with concomitant carboplatin and nimorazol. The patient developed bilateral DVT in the legs. Despite treatment with low-molecular-weight heparins, the patient developed thrombosis in the inferior vena cava and lungs. Due to developing painful discolouration and necrosis on the legs, the patient underwent acute and extensive surgery. PCD is a severe and potentially lethal form of DVT. There are several known risk factors for developing DVT, including active cancer and the use of chemotherapy.",
"affiliations": "Department of Plastic and Breast Surgery, Aarhus University Hospital, Aarhus, Denmark soderman.martin@gmail.com.;Department of Oncology, Odense University Hospital, Odense, Denmark.",
"authors": "Söderman|Martin|M|;Grimm|Peter|P|",
"chemical_list": "D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D009554:Nimorazole; D016190:Carboplatin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-233760",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(4)",
"journal": "BMJ case reports",
"keywords": "cancer intervention; surgery; venous thromboembolism",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D016190:Carboplatin; D059248:Chemoradiotherapy; D005260:Female; D005343:Fibrinolytic Agents; D006258:Head and Neck Neoplasms; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D007866:Leg; D018307:Neoplasms, Squamous Cell; D009382:Neoplasms, Unknown Primary; D009554:Nimorazole; D013514:Surgical Procedures, Operative; D013924:Thrombophlebitis; D020246:Venous Thrombosis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32295798",
"pubdate": "2020-04-14",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Phlegmasia cerulea dolens in a patient treated with carboplatin.",
"title_normalized": "phlegmasia cerulea dolens in a patient treated with carboplatin"
} | [
{
"companynumb": "DK-MYLANLABS-2020M1046811",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIMORAZOLE"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nAminobisphosphonates may cause orbital/ocular inflammation. Awareness of the clinical presentation and disease course is crucial. The purpose of this study was to analyse demographics, clinical presentation, disease course and treatment of aminobisphosphonate-associated orbital/ocular inflammation in a large series of patients.\n\n\nMETHODS\nA retrospective study of patients with aminobisphosphonate-associated orbital/ocular inflammation and a literature review to differentiate disease presentation and course between various aminobisphosphonates.\n\n\nRESULTS\nEight patients from our institution (6 women and 2 men, median age 62 years) were included. The used drugs were zoledronate, alendronate and risedronate. The most common clinical presentation was conjunctival hyperaemia/chemosis. Scleritis was the most common manifestation, followed by diffuse orbital inflammation and anterior uveitis. Ultrasound aided in diagnosis in all our patients. The aminobisphosphonate was halted in all patients, and some patients had anti-inflammatory treatment. Literature review included 68 patients (83 eyes), of them the most abundant drugs causing orbital/ocular inflammation were pamidronate (38 eyes) and zoledronate (35 eyes). Overall, among 76 patients, all drugs induced orbital disease, while uveitis was induced mostly by zoledronate and pamidronate, less by alendronate and not found among risedronate users. Time interval from drug administration to symptoms was hours to 28 days. Resolution was achieved in all patients, after 1-60 days from disease presentation, and the longer resolution period was found among alendronate users.\n\n\nCONCLUSIONS\nOrbital/ocular inflammation was mostly caused by intravenous aminobisphosphonates. Uveitis was not induced by risedronate. The putative aminobisphosphonate should be halted at the onset of orbital/ocular involvement and prognosis is favourable.",
"affiliations": "Division of Ophthalmology, Tel-Aviv Sourasky Medical Center, Affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.;Division of Ophthalmology, Tel-Aviv Sourasky Medical Center, Affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.;Division of Ophthalmology, Tel-Aviv Sourasky Medical Center, Affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.;Division of Ophthalmology, Tel-Aviv Sourasky Medical Center, Affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.;Division of Ophthalmology, Tel-Aviv Sourasky Medical Center, Affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.;Institute of Endocrinology, Metabolism and Hypertension, Tel-Aviv Sourasky Medical Center, Affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.;Division of Ophthalmology, Tel-Aviv Sourasky Medical Center, Affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.;Division of Ophthalmology, Tel-Aviv Sourasky Medical Center, Affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.;Division of Ophthalmology, Tel-Aviv Sourasky Medical Center, Affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.",
"authors": "Keren|Shay|S|https://orcid.org/0000-0002-7891-2478;Leibovitch|Igal|I|;Ben Cnaan|Ran|R|;Neudorfer|Meira|M|;Fogel|Ortal|O|;Greenman|Yona|Y|;Shulman|Shiri|S|;Zur|Dinah|D|https://orcid.org/0000-0003-1147-444X;Habot-Wilner|Zohar|Z|https://orcid.org/0000-0002-1058-0286",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005938:Glucocorticoids",
"country": "England",
"delete": false,
"doi": "10.1111/aos.14063",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1755-375X",
"issue": "97(5)",
"journal": "Acta ophthalmologica",
"keywords": "aminobisphosphonates; bisphosphonates; ocular inflammation; orbital inflammation; osteoporosis; uveitis",
"medline_ta": "Acta Ophthalmol",
"mesh_terms": "D000328:Adult; D000368:Aged; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005260:Female; D005500:Follow-Up Studies; D005938:Glucocorticoids; D006801:Humans; D007249:Inflammation; D007275:Injections, Intravenous; D008279:Magnetic Resonance Imaging; D008297:Male; D033401:Microscopy, Acoustic; D008875:Middle Aged; D009916:Orbital Diseases; D011379:Prognosis; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed; D014605:Uveitis; D055815:Young Adult",
"nlm_unique_id": "101468102",
"other_id": null,
"pages": "e792-e799",
"pmc": null,
"pmid": "30816018",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Aminobisphosphonate-associated orbital and ocular inflammatory disease.",
"title_normalized": "aminobisphosphonate associated orbital and ocular inflammatory disease"
} | [
{
"companynumb": "CA-ALLERGAN-1649985",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RISEDRONATE SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "Lacosamide (LCM) is a novel anticonvulsant that modulates voltage-dependent sodium channels. Although it is known to cause a slight, dose-dependent prolongation of the PR interval on the ECG, third-degree atrioventricular (AV) block has been described as an adverse event in only a few patients participating in diabetic neuropathic pain studies and in no patient with epilepsy. We describe an 89-year old patient with decreased renal function and taking two other negative dromotropic agents who accidentally received two intravenous boli of 400 mg LCM within 6 hours. She had a normal PQ interval before and after the first dose of LCM and developed a reversible complete AV block approximately 30 minutes after the second bolus. We conclude that particular caution must be exercised when using very high doses of LCM in patients with significant cardial and renal risk factors.",
"affiliations": "Department of Neurology, Klinikum Osnabrück, Osnabrück, Germany.",
"authors": "Krause|Lars U|LU|;Brodowski|Kai O|KO|;Kellinghaus|Christoph|C|",
"chemical_list": "D000081:Acetamides; D000906:Antibodies; D000927:Anticonvulsants; D016194:Receptors, N-Methyl-D-Aspartate; D000078334:Lacosamide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.yebeh.2011.02.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-5050",
"issue": "20(4)",
"journal": "Epilepsy & behavior : E&B",
"keywords": null,
"medline_ta": "Epilepsy Behav",
"mesh_terms": "D000081:Acetamides; D000369:Aged, 80 and over; D000906:Antibodies; D000927:Anticonvulsants; D054537:Atrioventricular Block; D004562:Electrocardiography; D004569:Electroencephalography; D004827:Epilepsy; D005260:Female; D006801:Humans; D000078334:Lacosamide; D016194:Receptors, N-Methyl-D-Aspartate",
"nlm_unique_id": "100892858",
"other_id": null,
"pages": "725-7",
"pmc": null,
"pmid": "21411374",
"pubdate": "2011-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Atrioventricular block following lacosamide intoxication.",
"title_normalized": "atrioventricular block following lacosamide intoxication"
} | [
{
"companynumb": "DE-MYLANLABS-2020M1015769",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METOPROLOL"
},
"drugadditional": "1",
... |
{
"abstract": "Dose and schedule optimization of treatment with tyrosine kinase inhibitors is of utmost importance. On the basis of preclinical data, a phase I clinical trial of once weekly or once every 2 weeks administration of high-dose sunitinib in patients with refractory solid malignancies was conducted.\n\n\n\nPatients with advanced cancer refractory to standard treatment were eligible. With use of a standard 3 + 3 phase I design, patients received escalating doses of sunitinib, in 100 mg increments, starting at 200 mg once weekly. In both the once weekly and once every 2 weeks cohorts, 10 more patients were included at the maximum tolerated dose level. Primary end points were safety and tolerability.\n\n\n\nSixty-nine patients with advanced cancer, predominantly colorectal cancer (42%), were treated with this alternative dosing regimen. Maximum tolerated dose was established at 300 mg once weekly and 700 mg once every 2 weeks, resulting in nine- and 18-fold higher maximum plasma concentrations compared with standard dose, respectively. Treatment was well tolerated, with fatigue (81%), nausea (48%), and anorexia (33%) being the most frequent adverse events. The only grade 3 or 4 treatment-related adverse event in 5% or more of patients was fatigue (6%). Sixty-three percent of patients had significant clinical benefit, with a 30% progression-free survival of 5 months or more.\n\n\n\nSunitinib administered once weekly at 300 mg or once every 2 weeks at 700 mg is feasible, with comparable tolerability as daily administration. Administration of 700 mg once every 2 weeks can be considered as the most optimal schedule because of the highest maximum plasma concentration being reached. The promising preliminary antitumor activity of this alternative schedule in heavily pretreated patients warrants further clinical evaluation and might ultimately indicate a class characteristic of tyrosine kinase inhibitors.",
"affiliations": "Vrije Universiteit Medical Center, Amsterdam, the Netherlands.;Vrije Universiteit Medical Center, Amsterdam, the Netherlands.;Vrije Universiteit Medical Center, Amsterdam, the Netherlands.;Vrije Universiteit Medical Center, Amsterdam, the Netherlands.;Vrije Universiteit Medical Center, Amsterdam, the Netherlands.;Vrije Universiteit Medical Center, Amsterdam, the Netherlands.;Vrije Universiteit Medical Center, Amsterdam, the Netherlands.;Vrije Universiteit Medical Center, Amsterdam, the Netherlands.;Vrije Universiteit Medical Center, Amsterdam, the Netherlands.",
"authors": "Rovithi|Maria|M|;Gerritse|Sophie L|SL|;Honeywell|Richard J|RJ|;Ten Tije|Albert J|AJ|;Ruijter|Rita|R|;Peters|Godefridus J|GJ|;Voortman|Jens|J|;Labots|Mariette|M|;Verheul|Henk M W|HMW|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000077210:Sunitinib",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.18.00725",
"fulltext": "\n==== Front\nJ Clin OncolJ. Clin. OncoljcojcoJCOJournal of Clinical Oncology0732-183X1527-7755American Society of Clinical Oncology 30586316180072510.1200/JCO.18.00725FAZEPhase I and Clinical PharmacologyORIGINAL REPORTSClinical TrialsPhase I Dose-Escalation Study of Once Weekly or Once Every Two Weeks Administration of High-Dose Sunitinib in Patients With Refractory Solid Tumors Weekly or Once Every Two Weeks High-Dose Sunitinib TreatmentRovithi Maria MD1Gerritse Sophie L. MD1Honeywell Richard J. PhD1ten Tije Albert J. MD, PhD1Ruijter Rita RN1Peters Godefridus J. PhD1Voortman Jens MD, PhD1Labots Mariette MD1Verheul Henk M.W. MD, PhD11Vrije Universiteit Medical Center, Amsterdam, the Netherlands.Henk M.W. Verheul, MD, PhD, Amsterdam University Medical Center, Cancer Center Amsterdam, Vrije Universiteit Medical Center, De Boelelaan 1117, Room 3A46, Amsterdam, North Holland 1081 HV, the Netherlands; e-mail: h.verheul@vumc.nl.10 2 2019 26 12 2018 10 11 2019 37 5 411 418 © 2018 by American Society of Clinical Oncology2018American Society of Clinical OncologyCreative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by/4.0/PURPOSE\nDose and schedule optimization of treatment with tyrosine kinase inhibitors is of utmost importance. On the basis of preclinical data, a phase I clinical trial of once weekly or once every 2 weeks administration of high-dose sunitinib in patients with refractory solid malignancies was conducted.\n\nPATIENTS AND METHODS\nPatients with advanced cancer refractory to standard treatment were eligible. With use of a standard 3 + 3 phase I design, patients received escalating doses of sunitinib, in 100 mg increments, starting at 200 mg once weekly. In both the once weekly and once every 2 weeks cohorts, 10 more patients were included at the maximum tolerated dose level. Primary end points were safety and tolerability.\n\nRESULTS\nSixty-nine patients with advanced cancer, predominantly colorectal cancer (42%), were treated with this alternative dosing regimen. Maximum tolerated dose was established at 300 mg once weekly and 700 mg once every 2 weeks, resulting in nine- and 18-fold higher maximum plasma concentrations compared with standard dose, respectively. Treatment was well tolerated, with fatigue (81%), nausea (48%), and anorexia (33%) being the most frequent adverse events. The only grade 3 or 4 treatment-related adverse event in 5% or more of patients was fatigue (6%). Sixty-three percent of patients had significant clinical benefit, with a 30% progression-free survival of 5 months or more.\n\nCONCLUSION\nSunitinib administered once weekly at 300 mg or once every 2 weeks at 700 mg is feasible, with comparable tolerability as daily administration. Administration of 700 mg once every 2 weeks can be considered as the most optimal schedule because of the highest maximum plasma concentration being reached. The promising preliminary antitumor activity of this alternative schedule in heavily pretreated patients warrants further clinical evaluation and might ultimately indicate a class characteristic of tyrosine kinase inhibitors.\n\n261-566-3525Targeted therapy13613-225-2577-2545Maximum tolerable dose13283-237-255Colorectal cancer12613-225-2782Pharmacokinetics11613-225-325Drug safety10261-492-2769Treatment efficacy10613-225-0-382Anticancer drugs9613-225-0-9542-427-2615-2418Tyrosine kinase inhibitors2298-145-222-184-1022-9122Phase I trials2281-318-9082Advanced disease2613-225-2577-2545Maximum tolerable dose2613-302-309Fatigue2137sunitinib malate54106lapatinib4137sunitinib malate3213imatinib3137sunitinib malate2303mechlorethamine2129erlotinib hydrochloride1250regorafenib12442trifluridine154fluorouracil1239oxaliplatin116irinotecan1 SJS Export v1\n==== Body\nINTRODUCTION\nTreatment with tyrosine kinase inhibitors (TKIs) often results in durable clinical responses and survival benefit with an acceptable safety profile for patients with advanced malignancies.1 Nonetheless, resistance to TKIs eventually develops in all patients. The current use of TKIs is based on the principle that prolonged drug exposure is necessary for optimal antitumor activity because of continuous inhibition of angiogenesis and specific intracellular signaling.2 However, the occurrence of toxicity leads to a narrow therapeutic window, which impedes additional dose escalation and drug exposure.3 It is hypothesized that the clinical efficacy of these agents might be further improved by optimization of treatment schedules and dosing.4 Disease progression has been attributed to subtherapeutic levels, whereas dose escalation might overcome the initial development of resistance,5 and increased exposure correlates with improvement in clinical benefit.6\n\nSunitinib malate (SUTENT; Pfizer, New York, NY) is an orally administered TKI that targets multiple kinase receptors, including the vascular endothelial growth factor (VEGF) receptor and platelet-derived growth factor receptor. It is approved for patients with renal cell cancer, GI stromal cell tumors (GISTs), or pancreatic neuroendocrine tumors in a dose of 50 mg per day for 4 weeks followed by a 2-week off period or a continuous regimen of 37.5 mg doses per day.7\n\nClinical feasibility and safety of higher sunitinib doses were previously reported when a single dose of sunitinib up to 300 mg was safely administered to patients.8 We hypothesized that intermittent, high-dose administration of sunitinib might ultimately result in higher plasma and subsequent intratumoral concentrations, leading to enhanced efficacy. We have previously demonstrated that short exposure to high concentrations of sunitinib leads to complete inhibition of tumor cell proliferation in vitro and significantly impairs tumor growth in vivo compared with continuous lower exposure.9 Other scientific support for the role of TKI dose escalation comes from a meta-analysis that indicated the proportional relationship between drug exposure and the probability of response.6 Recently, intrapatient dose escalation at the time of progression in patients who were receiving sunitinib was shown to overcome resistance, although transiently, and resulted in an increase in progression-free survival of greater than or equal to 5 months.5\n\nIdentification of optimal treatment strategies is actively pursued for other TKIs. Comparable to our study with sunitinib, weekly 10-fold–higher doses of erlotinib have been reported as salvage therapy in patients with non–small-cell lung cancer and leptomeningeal metastases with an acceptable toxicity profile.10 Imatinib dose escalation has been suggested as an effective therapy for advanced GIST after progression on standard dose in patients who harbor exon 9 mutations, which underscores the need for dose individualization.11 Almost all patients with imatinib-resistant metastatic GIST eventually develop resistance to treatment with sunitinib, generally within 1 year, which results in disease progression.12 Mechanisms of GIST resistance to sunitinib treatment are largely unknown.13 Because sunitinib targets a broader spectrum of kinases compared with imatinib, additional mechanisms possibly play a role in the acquisition of resistance. The promising antitumor activity of this high-dose sunitinib strategy potentially could overcome therapy resistance to sunitinib in these patients similar to those observed with imatinib.14 On the basis of these preclinical and clinical findings, the current phase I clinical trial was conducted to investigate the maximum tolerated dose (MTD) of once weekly or once every 2 weeks administration of sunitinib, the safety and clinical feasibility, the pharmacokinetic parameters, and the preliminary efficacy in patients with advanced solid malignancies refractory to standard treatment.\n\nPATIENTS AND METHODS\nPatient Eligibility\nEligible patients included adults with histologically confirmed advanced solid tumors that were progressive after standard treatment. Major inclusion and exclusion criteria are listed in the Data Supplement. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Before inclusion, patients provided informed consent on the study protocol approved by the local institutional review board.\n\nStudy Design and Treatment Plan\nThis dose escalation, phase I, single-institution clinical trial was conducted at the Vrije Universiteit Medical Center, Amsterdam, the Netherlands. A standard 3 + 3 design was used with a starting dose cohort of 200 mg sunitinib administered orally once weekly and escalating in increments of 100 mg. Patients continued sunitinib until progression, intolerance, or consent withdrawal. The primary objective was to determine the MTD and evaluate the safety and tolerability, whereas secondary objectives were to assess the pharmacokinetic parameters of this scheduling and preliminary assessment of the efficacy of sunitinib intermittent treatment. Once weekly MTD level was subsequently set as the starting dose level for the once every 2 weeks schedule, which followed the same design principles. Patients were considered evaluable (for toxicity, pharmacokinetics, and response) who completed a minimum of 2 weeks of sunitinib treatment, which means two administrations of sunitinib on the once weekly schedule and one administration of sunitinib in the once every 2 weeks schedule, including 2 weeks of follow-up. After determination of the MTD, both schedules expanded to include 10 additional patients at the MTD level to evaluate preliminary efficacy.\n\nSafety Assessment\nPhysical condition assessments, including ECG and blood hematology and chemistry, were performed weekly during the first 8 weeks and once every 4 weeks thereafter. Adverse events (AEs) were monitored throughout the study and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). MTD was defined as the highest dose level at which less than or equal to 33% of patients experienced dose-limiting toxicities (DLTs). DLT was defined as any grade 3 or higher toxicity attributable to sunitinib that occurred during the first 6 weeks of therapy.\n\nPharmacokinetics\nBlood samples for pharmacokinetic assessments were collected pretreatment and subsequently at multiple time points (0, 2, 4, 6, 8, 10, and 24 hours postdose on day 1 for both time schedules and thereafter at days 3, 8, 10, 15, 17, and 22 for the once weekly schedule and at days 3, 15, 17, and 29 for the once every 2 weeks schedule). Sunitinib plasma concentrations were determined by liquid chromatography-mass spectrometry.15 To evaluate sunitinib exposure, peak concentration, half-life, area under the concentration-time curve, and time to half-life were calculated with the validated PKSolver add-in for Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA).\n\nTreatment Efficacy\nAll patients underwent computed tomography scanning at baseline and subsequently every 8 weeks for evaluation of efficacy. Antitumor response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. PFS was defined as the time from the date of the first dose of study medication to the date of first disease progression or the date of death.\n\nStatistical Analysis\nDescriptive statistics were used for baseline characteristics, safety assessment, and pharmacokinetic data. Data are expressed as mean ± standard deviation when appropriate.\n\nRESULTS\nPatients\nA total of 73 patients had been included in the study of whom 71 started study medication and 69 received sunitinib for 2 weeks or more. The baseline patient characteristics are listed in Table 1. Median age was 62 years (range, 29 to 85 years), and 64 patients (88%) had a WHO performance status of 1. Colorectal cancer (CRC) was the most frequent tumor type (42%). All patients were pretreated extensively, with 67% having received two or more previous treatment lines. The reason for not starting study medication for two patients after enrollment was rapid deterioration in clinical status. In the escalation cohorts, 12 patients at the MTD (six in the 300 mg once weekly cohort and six in the 700 mg once every 2 weeks cohort) received (at least) every dose that was scheduled in the first 6 weeks of therapy (DLT window). In the expansion cohort, another 20 patients (10 in each cohort) received at least 6 weeks of sunitinib treatment.\n\nTABLE 1. Patient Demographics and Clinical Characteristics\n\nSafety\nHigh-dose, intermittent sunitinib demonstrated a toxicity profile comparable to the standard flat dose. Table 2 lists all clinically significant toxicities that occurred in 10% or more of the 69 patients evaluable for toxicity (grade 1 or 2) and all grade 3 or 4 treatment-related AEs. The most commonly observed AEs of any grade were fatigue (n = 56; 81%), nausea (n = 33; 81%), and anorexia (n = 23; 33%). With regard to grade 3 or higher AEs, four patients (6%) experienced grade 3 fatigue. The majority of adverse effects were constitutional and manageable with standard supportive care interventions. Severe bowel toxicity (presacral abscess) was observed in one patient who received the first dose level (200 mg) in the once weekly cohort (outside the DLT period), whereas one patient who received the third dose level (400 mg once weekly) presented with a fatal bowel perforation (during the DLT period). Both patients had been irradiated previously in the affected area. These serious AEs led to an amendment of the study protocol to exclude patients with a history of pelvic, thoracic, and extended vertebral irradiation. After the amendment, at the dose level of 400 mg once weekly, DLTs occurred in two patients: One developed grade 3 bile stasis, and one developed grade 3 fatigue. One patient on the 400 mg once weekly schedule and with CRC and extensive peritoneal carcinomatosis with a substantial clinical benefit lasting longer than 7 months developed a bowel perforation at the time of disease progression as a result of a growing peritoneal tumor lesion. He underwent a successful operation. The dose level of 300 mg weekly was expanded to six patients and no additional DLTs were observed. Therefore, the MTD was determined at 300 mg once weekly.\n\nTABLE 2. Related Adverse Events\n\nSubsequently, enrollment in the once every 2 weeks schedule was initiated at the MTD level of the once weekly schedule, that is, 300 mg once every 2 weeks, and escalated in steps of 100 mg. Because patients experienced no DLTs, doses were escalated up to 800 mg once every 2 weeks in subsequent cohorts. In the 800-mg cohort, two patients experienced a DLT: One developed a combination of a grade 3 increase in ALT and AST, and one developed a grade 3 hepatobiliary disorder (bile duct obstruction). The MTD of the administration of sunitinib once every 2 weeks was set at 700 mg. Dose escalation steps and DLTs are listed in Appendix Table A1 (online only).\n\nPharmacokinetics\nPharmacokinetic parameters of sunitinib16 are listed and compared with standard scheduling in Table 3. Exposure to sunitinib, as designated by an increase in the maximum plasma concentration (Cmax), increased across dose levels (0.167 ± 0.06, 0.261 ± 0.12, and 0.219 ± 0.07 μg/mL for the 200-, 300-, and 400-mg dose levels once weekly, respectively, and 0.215 ± 0.12, 0.400 ± 0.12, 0.301 ± 0.16, 0.357 ± 0.12, 0.505 ± 0.15, and 0.551 ± 0.28 μg/mL for the 300, 400, 500, 600, 700, and 800 mg dose levels once every 2 weeks, respectively). Cmax was achieved in approximately 2 to 8 hours and provided nine to 18 times higher peak concentrations than standard dosing.16 Although significant interpatient variability was noted, intrapatient variability was minimal, and almost no plasma drug accumulation of sunitinib occurred in time. The mean terminal half-life of sunitinib was approximately 44 hours. The majority of patients (97%) reached a Cmax higher than 0.1 μg/mL (250 nM). Dose escalation led to a proportionate increase in drug exposure (Fig 1). Pharmacokinetics of the metabolite of sunitinib (SU12662) followed the same pattern of sunitinib itself and are both listed in Appendix Table A2 (online only).\n\nTABLE 3. Pharmacokinetic Parameters of Intermittent High-Dose Sunitinib\n\nFIG 1. Mean sunitinib plasma concentrations of all evaluable patients after intake of the drug once per week and once every 2 weeks. Mean sunitinib plasma concentrations of all evaluable patients after intake of the drug once per week (O1W) and once every 2 weeks (O2W).\n\nTreatment Efficacy\nClinical benefit from treatment was characterized by prolonged disease stabilization, tumor marker response, and improvement of disease-related symptoms. Of 69 patients, 59 were evaluable for response. Of the other 10 patients, five presented with a DLT, two withdrew consent at week 3 for nonmedical reasons, two stopped because of a non–treatment-related serious AE, and treatment of one patient was discontinued by the investigator when the study was put on hold to await for the amendment. Thirty-seven patients (63%) had clinical benefit defined as progression free at 2 months of treatment, whereas 30% (18 of 59) had stable disease for 5 months or longer (Fig 2). Mean PFS in the MTD group was 3.5 months (range, 0.5 to 9.2 months). The range for the duration of treatment (all patients) was 0.5 to 47 weeks. The median duration of therapy was 8 weeks, and the mean was 14 weeks.\n\nFIG 2. Progression-free survival (PFS) for all evaluable patients after once per week and once every 2 weeks administration of sunitinib.\n\nDespite RECIST version 1.1 stable disease on computed tomography evaluation, on-treatment scans were indicative of tumor necrosis in most patients with clinical benefit characterized by homogenous hypo-attenuation and sharp tumor-liver interface17 (Fig 3). When response evaluation was based on modified Choi criteria,18 a 32% response rate was reached for the 59 patients at the time of first evaluation.\n\nFIG 3. Stable disease in a patient with metastatic colorectal cancer during treatment. Computed tomography scans (A) before treatment and (B) at first evaluation (8 weeks). The on-treatment scan indicates tumor necrosis characterized by homogeneous hypo-attenuation and sharp tumor-liver interface (Data Supplement).\n\nTwenty-seven of all participating patients had detectable blood tumor markers (eg, carcinoembryonic antigen, CA15.3, CA19.9 [greater than the upper limit of normal]). Compared with baseline, the eight patients with the longest time on treatment (5 months or more PFS) had a significant tumor marker decrease at first evaluation compared with baseline (−35% ± 22%; P = .02). No tumor marker response was seen in the 10 patients who progressed (an increase of 94 ± 124%; P = .2). Almost all patients (96%) presented with a significant tumor marker increase 24 to 72 hours after first dose ingestion.\n\nDISCUSSION\nTreatment strategies with multitargeted TKIs have been focused on continuous drug exposure at their MTD for optimal target inhibition.3 This continuous inhibition of targeted signaling pathways has been proposed as key for their mechanism of action leading to clinical antitumor activity.19\n\nProof of concept for this dogma is lacking mainly because of the difficulty to measure adequately true inhibition of specific drug targets in patient tumor samples. Dissimilarly, conventional cytotoxic approaches include the administration of intense, intermittent doses.20 In this study, we aimed to reach the highest tolerable peak plasma concentrations with the subsequent highest intratumoral peak concentrations for the drug to exert direct cytocidal effects and suffice to block targets with a lower drug-binding affinity at the tumor level on the basis of preclinical experiments.9 On the basis of this hypothesis, we conclude that administration of 700 mg of sunitinib once every 2 weeks, the dose at which the highest Cmax is received, is the optimal alternative high-dose treatment schedule.\n\nThe sunitinib daily dosing strategy was established in the original first-in-human, phase I study where responses were reported in five patients.16 Phase III studies of sunitinib standard dosing, with 4 weeks 50 mg per day administration followed by 2 weeks treatment interruption, resulted in the approval of sunitinib to treat patients with metastatic renal cell cancer, imatinib-resistant GIST, and advanced neuroendocrine pancreatic cancers with significant clinical and overall survival benefit.\n\nIn the current phase I clinical trial, sunitinib administration at a dose of 300 mg once weekly or 700 mg once every 2 weeks was shown to be safe and tolerable with a comparable toxicity profile as the standard sunitinib schedule of 50 mg given for 28 days with a 14-day break recently reported in the Alliance 031203 CABOSUN trial.21 In our phase I trial, grade 3/4 and 5 AEs related to intermittent high-dose sunitinib (once weekly or once every 2 weeks) occurred in 46% and 2% of patients compared with 68% and 7% of patients treated with the standard sunitinib schedule in the CABOSUN trial. The most frequently reported grade 3/4 toxicity was fatigue, which occurred in four (6%) of 69 patients in our phase I trial compared with 11 (15.3%) of 72 patients in the CABOSUN trial. The AEs of nausea and anorexia were predominantly seen on days 1 and 2 of the new schedule and well manageable with standard use of antiemetics.\n\nPharmacokinetic evaluation in our trial clearly indicated that intermittent high peak concentrations could be reached without detrimental toxicity because the majority of the patients reached a Cmax greater than 0.1 μg/mL (250 nM). Patients in the standard scheduling with trough concentrations of more than 0.1 μg/mL exhibited DLTs.22 We consider these peak concentrations as most likely responsible for the direct antitumor activity in accordance with preclinical findings.9\n\nAdministration of this alternative scheduling was complicated by the development of serious bowel toxicity in two patients who both received prior radiotherapy. Radiotherapy has previously been reported as a contributing factor to serious bowel toxicity seen with concomitant anti-angiogenic treatment, including sunitinib specifically.23,24 The underlying mechanisms are still to be elucidated. The working hypothesis assumes inadequate capability of tissue repair after radiation-induced bowel injury because of an impaired VEGF response.25 After exclusion of patients who were previously irradiated at the bowel region, no additional serious bowel toxicity was observed.\n\nRecently, Chien et al26 translated data from mouse models in which intermittent high- dose lapatinib resulted in improved efficacy compared with the standard continuous low- dose therapy. These investigators reported a phase I trial that investigated this schedule in patients with advanced solid tumors. High-dose, intermittent lapatinib was well tolerated and resulted in significantly increased plasma concentrations. In addition, a relationship between lapatinib exposure and biologic activity was established; patients with plasma concentrations approximating 10 μg/mL presented with marked responses, whereas all patients with low lapatinib plasma concentrations had progressive disease.26\n\nIn this trial, 20% of the evaluable patients with CRC reached a PFS of more than 5 months (range, 5.5 to 12.5 months), which is notable because in the original phase I study, none of the three patients with CRC showed a long-lasting response or tumor stabilization.16 In a subsequent phase II clinical trial, sunitinib was evaluated in the metastatic CRC setting where 16% of patients with CRC reached a PFS of 5 months or more27 and concluded that daily sunitinib monotherapy provides no significant clinical benefit; therefore, further development of sunitinib for CRC was terminated. Although the only approved TKI for CRC, regorafenib shows a small, but significant overall survival benefit with a challenging toxicity profile.28 Our results indicate that alternative dosing of sunitinib may provide a promising strategy for the treatment of patients with advanced CRC with an acceptable toxicity profile.\n\nTo determine the efficacy of pulsatile, high-dose sunitinib in patients with metastatic CRC, we will start shortly a prospective, randomized, open-label, phase II/III clinical trial to compare 700 mg sunitinib once every 2 weeks with standard treatment with Trifluridine plus tipiracil (TAS-102) in patients with metastatic adenocarcinoma of the colon or rectum who are refractory or intolerant to therapy with fluorouracil, oxaliplatin, and irinotecan anti-VEGF therapy (and anti–epidermal growth factor receptor therapy in KRAS wild type).\n\nIn conclusion, pulsatile, high-dose sunitinib was well tolerated and exhibited preliminary clinical significant benefit in patients with refractory solid malignancies, which warrants its development. The once every 2 weeks administration of 700 mg sunitinib is feasible and the most optimal schedule because of the highest Cmax being reached. Our study highlights the importance to improve further the efficacy of this new class of agents by optimization of dose and scheduling strategies.\n\nPresented at the 104th Annual Meeting of the American Association of Cancer Research, Washington, DC, April 6-10, 2013; 105th Annual Meeting of the American Association of Cancer Research, San Diego, CA, April 5-9, 2014; 2015 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 29 to June 2, 2015; and 2017 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 2-6, 2017.\n\nClinical trial information: NCT02058901.\n\nACKNOWLEDGMENT\nPfizer provided the study drug but had no involvement in the design or conduct of the study or in the analysis or interpretation of the results.\n\nAUTHOR CONTRIBUTIONS\nConception and design: Maria Rovithi, Sophie L. Gerritse, Albert J. ten Tije, Godefridus J. Peters, Jens Voortman, Mariette Labots, Henk M.W. Verheul\n\nFinancial support: Henk M.W. Verheul\n\nAdministrative support: Albert J. ten Tije, Henk M.W. Verheul\n\nProvision of study material or patients: Maria Rovithi, Albert J. ten Tije, Mariette Labots, Henk M.W. Verheul\n\nCollection and assembly of data: Maria Rovithi, Sophie L. Gerritse, Richard J. Honeywell, Rita Ruijter, Jens Voortman, Henk M.W. Verheul\n\nData analysis and interpretation: Maria Rovithi, Sophie L. Gerritse, Richard J. Honeywell, Albert J. ten Tije, Godefridus J. Peters, Jens Voortman, Henk M.W. Verheul\n\nManuscript writing: All authors\n\nFinal approval of manuscript: All authors\n\nAccountable for all aspects of the work: All authors\n\nAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST\nPhase I Dose-Escalation Study of Once Weekly or Once Every Two Weeks Administration of High-Dose Sunitinib in Patients With Refractory Solid Tumors\nThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.\n\nRichard J. Honeywell\nEmployment: Lundbeck (I)\n\nStock and Other Ownership Interests: Merck Sharp & Dohme (I)\n\nTravel, Accommodations, Expenses: Lundbeck (I)\n\nAlbert J. ten Tije\nConsulting or Advisory Role: Bristol-Myers Squibb\n\nGodefridus J. Peters\nConsulting or Advisory Role: Taiho Pharmaceutical, Clear Creek Bio, Ellipses Pharma\n\nResearch Funding: Rexahn Pharmaceuticals (Inst)\n\nTravel, Accommodations, Expenses: Rexahn Pharmaceuticals, Taiho Pharmaceutical\n\nJens Voortman\nTravel, Accommodations, Expenses: Sanofi, Pfizer, Merck, TEVA Pharmaceuticals Industries, Astellas Pharma, Ipsen\n\nMariette Labots\nConsulting or Advisory Role: Bristol-Myers Squibb (Inst)\n\nResearch Funding: VitrOmics Healthcare Services (Inst)\n\nHenk M.W. Verheul\nConsulting or Advisory Role: Glycostem (Inst)\n\nNo other potential conflicts of interest were reported.\n\nAPPENDIX\nTABLE A1. Dose Levels and Dose-Limiting Toxicities (escalating cohorts)\n\nTABLE A2. Summary of Measured Pharmacokinetic Parameters of SU12662\n==== Refs\nREFERENCES\n1. Zhang J Yang PL Gray NS : Targeting cancer with small molecule kinase inhibitors . Nat Rev Cancer \n9 :28 -39 , 2009 19104514 \n2. Gotink KJ Verheul HM : Anti-angiogenic tyrosine kinase inhibitors: What is their mechanism of action? \nAngiogenesis \n13 :1 -14 , 2010 20012482 \n3. Mathijssen RH Sparreboom A Verweij J : Determining the optimal dose in the development of anticancer agents . Nat Rev Clin Oncol \n11 :272 -281 , 2014 24663127 \n4. Rovithi M Verheul HMW : Pulsatile high-dose treatment with antiangiogenic tyrosine kinase inhibitors improves clinical antitumor activity . Angiogenesis \n20 :287 -289 , 2017 28421290 \n5. Adelaiye R Ciamporcero E Miles KM et al : Sunitinib dose escalation overcomes transient resistance in clear cell renal cell carcinoma and is associated with epigenetic modifications . Mol Cancer Ther \n14 :513 -522 , 2015 25519701 \n6. Houk BE Bello CL Kang D et al : A population pharmacokinetic meta-analysis of sunitinib malate (SU11248) and its primary metabolite (SU12662) in healthy volunteers and oncology patients . Clin Cancer Res \n15 :2497 -2506 , 2009 19258444 \n7. Faivre S Demetri G Sargent W et al : Molecular basis for sunitinib efficacy and future clinical development . Nat Rev Drug Discov \n6 :734 -745 , 2007 17690708 \n8. O’Farrell AM Foran JM Fiedler W et al : An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients . Clin Cancer Res \n9 :5465 -5476 , 2003 14654525 \n9. Rovithi M de Haas RR Honeywell RJ et al : Alternative scheduling of pulsatile, high dose sunitinib efficiently suppresses tumor growth . J Exp Clin Cancer Res \n35 :138 , 2016 27604186 \n10. Kuiper JL Smit EF : High-dose, pulsatile erlotinib in two NSCLC patients with leptomeningeal metastases--one with a remarkable thoracic response as well . Lung Cancer \n80 :102 -105 , 2013 23375403 \n11. Maki RG Blay JY Demetri GD et al : Key issues in the clinical management of gastrointestinal stromal tumors: An expert discussion . Oncologist \n20 :823 -830 , 2015 26070915 \n12. Demetri GD van Oosterom AT Garrett CR et al : Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: A randomised controlled trial . Lancet \n368 :1329 -1338 , 2006 17046465 \n13. Gajiwala KS Wu JC Christensen J et al : KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients . Proc Natl Acad Sci U S A \n106 :1542 -1547 , 2009 19164557 \n14. Blanke CD Rankin C Demetri GD et al : Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033 . J Clin Oncol \n26 :626 -632 , 2008 18235122 \n15. Honeywell R Yarzadah K Giovannetti E et al : Simple and selective method for the determination of various tyrosine kinase inhibitors used in the clinical setting by liquid chromatography tandem mass spectrometry . J Chromatogr B Analyt Technol Biomed Life Sci \n878 :1059 -1068 , 2010 \n16. Faivre S Delbaldo C Vera K et al : Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer . J Clin Oncol \n24 :25 -35 , 2006 16314617 \n17. Chun YS Vauthey JN Boonsirikamchai P et al : Association of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases . JAMA \n302 :2338 -2344 , 2009 19952320 \n18. van der Veldt AA Meijerink MR van den Eertwegh AJ et al : Choi response criteria for early prediction of clinical outcome in patients with metastatic renal cell cancer treated with sunitinib . Br J Cancer \n102 :803 -809 , 2010 20145618 \n19. Ebos JM : Prodding the beast: Assessing the impact of treatment-induced metastasis . Cancer Res \n75 :3427 -3435 , 2015 26229121 \n20. Kummar S Chen HX Wright J et al : Utilizing targeted cancer therapeutic agents in combination: Novel approaches and urgent requirements . Nat Rev Drug Discov \n9 :843 -856 , 2010 21031001 \n21. Choueiri TK Halabi S Sanford BL et al : Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: The Alliance A031203 CABOSUN trial . J Clin Oncol \n35 :591 -597 , 2017 28199818 \n22. Kalra S Rini BI Jonasch E : Alternate sunitinib schedules in patients with metastatic renal cell carcinoma . Ann Oncol \n26 :1300 -1304 , 2015 25628443 \n23. Pollom EL Deng L Pai RK et al : Gastrointestinal toxicities with combined antiangiogenic and stereotactic body radiation therapy . Int J Radiat Oncol Biol Phys \n92 :568 -576 , 2015 26068491 \n24. Walraven M Witteveen PO Lolkema MP et al : Antiangiogenic tyrosine kinase inhibition related gastrointestinal perforations: A case report and literature review . Angiogenesis \n14 :135 -141 , 2011 21188500 \n25. Lee MO Song SH Jung S et al : Effect of ionizing radiation induced damage of endothelial progenitor cells in vascular regeneration . Arterioscler Thromb Vasc Biol \n32 :343 -352 , 2012 22075244 \n26. Chien AJ Munster PN Melisko ME et al : Phase I dose-escalation study of 5-day intermittent oral lapatinib therapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer . J Clin Oncol \n32 :1472 -1479 , 2014 24711549 \n27. Saltz LB Rosen LS Marshall JL et al : Phase II trial of sunitinib in patients with metastatic colorectal cancer after failure of standard therapy . J Clin Oncol \n25 :4793 -4799 , 2007 17947727 \n28. Grothey A Van Cutsem E Sobrero A et al : Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicentre, randomised, placebo-controlled, phase 3 trial . Lancet \n381 :303 -312 , 2013 23177514\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0732-183X",
"issue": "37(5)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D015179:Colorectal Neoplasms; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D047428:Protein Kinase Inhibitors; D000077210:Sunitinib",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "411-418",
"pmc": null,
"pmid": "30586316",
"pubdate": "2019-02-10",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": "21188500;26068491;17690708;20382575;28199818;17046465;24711549;23177514;22075244;14654525;19952320;24663127;19104514;20145618;25519701;19164557;23375403;26229121;25628443;26070915;18235122;19258444;27604186;21031001;28421290;17947727;20012482;16314617",
"title": "Phase I Dose-Escalation Study of Once Weekly or Once Every Two Weeks Administration of High-Dose Sunitinib in Patients With Refractory Solid Tumors.",
"title_normalized": "phase i dose escalation study of once weekly or once every two weeks administration of high dose sunitinib in patients with refractory solid tumors"
} | [
{
"companynumb": "NL-PFIZER INC-2019473547",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SUNITINIB MALATE"
},
"drugadditional": null,
... |
{
"abstract": "Human leukocyte antigens (HLA) have been linked to adverse drug reactions. Generally, HLA association is phenotype specific and is related to either liver or skin injury. HLA-A*13:01 has been linked to dapsone-induced severe cutaneous drug reactions and its role in drug-induced liver injury (DILI) is unclear. In our series, all of the four patients with immunoallergic dapsone DILI were carrying HLA-B*13:01 compared to its prevalence of 1-12% among Indians. HLA-B*13:01 plays a role not only in dapsone-induced severe cutaneous adverse reaction (SCAR) but also in dapsone-induced liver injury with immunoallergic features and highlights the role of adaptive immune response in the pathogenesis of both liver and skin injury and associated other organ involvement.",
"affiliations": "Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, India.;Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, India.;Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, India.",
"authors": "Devarbhavi|Harshad|H|https://orcid.org/0000-0002-3593-3746;Patil|Mallikarjun|M|;Menon|Mahesh|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bcp.15054",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": null,
"journal": "British journal of clinical pharmacology",
"keywords": "MHC; cytotoxic T lymphocytes; hepatotoxicity; jaundice; pathogenesis",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": null,
"nlm_unique_id": "7503323",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34427944",
"pubdate": "2021-08-24",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Association of human leukocyte antigen-B*13:01 with dapsone-induced liver injury.",
"title_normalized": "association of human leukocyte antigen b 13 01 with dapsone induced liver injury"
} | [
{
"companynumb": "IN-ALVOGEN-2021-ALVOGEN-117465",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DAPSONE"
},
"drugadditional": "3",
... |
{
"abstract": "Folic acid is B-9 vitamin. Folic acid is prescribed commonly for pregnant women to prevent neural tube defects in the fetus, patients under chemotherapy, pernicious anemia and to reduce the risk of stroke and cardiovascular disease. Acute or chronic ingestion of a large dose of folic acid generally manifests as neurological complications, which are reversible. In this present case, a 23-year-old pregnant woman committed suicide by consuming folic acid tablets and succumbed to death within 36 h. Postmortem toxicological analysis detected folic acid in viscera. Death following acute consumption of folic acid is rare and has been not reported in the literature, to the best of our knowledge.",
"affiliations": "Department of Forensic Medicine and Toxicology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006, India.;Department of Forensic Medicine and Toxicology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006, India.;Scientific Officer, Regional Forensic Science Laboratory (Villupuram), 605602, Tamil Nadu, India.;Department of Forensic Medicine and Toxicology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006, India.;Department of Forensic Medicine and Toxicology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006, India.",
"authors": "Devnath|Gerard Pradeep|GP|;Kumaran|Senthil|S|;Rajiv|R|R|;Shaha|Kusa Kumar|KK|;Nagaraj|Ashok|A|",
"chemical_list": "D014803:Vitamin B Complex; D005492:Folic Acid",
"country": "United States",
"delete": false,
"doi": "10.1111/1556-4029.13489",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1198",
"issue": "62(6)",
"journal": "Journal of forensic sciences",
"keywords": "folic acid; forensic science; histopathology; pregnant woman; suicide; toxicological analysis",
"medline_ta": "J Forensic Sci",
"mesh_terms": "D005260:Female; D005492:Folic Acid; D006801:Humans; D007422:Intestines; D007668:Kidney; D008099:Liver; D011247:Pregnancy; D013270:Stomach; D013405:Suicide; D014803:Vitamin B Complex; D055815:Young Adult",
"nlm_unique_id": "0375370",
"other_id": null,
"pages": "1668-1670",
"pmc": null,
"pmid": "28261784",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Fatal Folic Acid Toxicity in Humans.",
"title_normalized": "fatal folic acid toxicity in humans"
} | [
{
"companynumb": "IN-SUNRISE PHARMACEUTICAL, INC.-2079041",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FOLIC ACID"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nDrug reaction with eosinophilia and systemic symptoms (DRESS) is a severe and rare adverse drug reaction. Several drugs are known to induce DRESS. Furosemide, a sulfonamide loop diuretic drug, is known to induce hypersensitive reactions such as bullous eruptions, acute generalized exanthematous pustulosis and lichenoid eruptions, but rarely DRESS. We describe herein a case of furosemide-induced DRESS that recurred after bumetanide administration.\n\n\nMETHODS\nA 67-year-old man was admitted to the nephrology department for hypertension, gout and chronic renal failure. He received a multidrug therapy including captopril, nifedipine, allopurinol and furosemide. Six weeks after starting this treatment, he developed a maculopapular itchy and edematous skin reaction, facial edemaand fever. The laboratory findings showed 2200/mm3 of eosinophils (20%). Creatinine clearance decreased from 18.9 to 14.4 mL/min. Lactate dehydrogenase was at 600 IU/L (normal range 190-390 IU/L). Chest X-ray showed an interstitial lung injury. Skin biopsy findings were in accordance with a hypersensitive reaction. Furosemide was withdrawn and symptoms resolved completely three weeks later. A patch test with furosemide performed six weeks later was negative. The patient was given bumetanide, another sulfonamide loop diuretic, with recurrence of symptoms two months later. Bumetanide was withdrawn with a complete resolution of both clinical and biological symptoms within three weeks.\n\n\nCONCLUSIONS\nWe add to the literature another case of furosemide-induced DRESS with the particularity of cross reactivity with bumetanide.",
"affiliations": "Department of clinical pharmacology, University Hospital of Fattouma Bourguiba Monastir, University of Monastir, rue Avicenne, 5019 Monastir, Tunisia. Electronic address: benfadhelnaj@hotmail.com.;Department of clinical pharmacology, University Hospital of Fattouma Bourguiba Monastir, University of Monastir, rue Avicenne, 5019 Monastir, Tunisia; Department of dermatology in Monastir, Monastir, Tunisia.;Department of clinical pharmacology, University Hospital of Fattouma Bourguiba Monastir, University of Monastir, rue Avicenne, 5019 Monastir, Tunisia.;Department of dermatology in Monastir, Monastir, Tunisia.;Department of clinical pharmacology, University Hospital of Fattouma Bourguiba Monastir, University of Monastir, rue Avicenne, 5019 Monastir, Tunisia.;Department of clinical pharmacology, University Hospital of Fattouma Bourguiba Monastir, University of Monastir, rue Avicenne, 5019 Monastir, Tunisia.;Department of clinical pharmacology, University Hospital of Fattouma Bourguiba Monastir, University of Monastir, rue Avicenne, 5019 Monastir, Tunisia.",
"authors": "Ben Fadhel|N|N|;Ben Romdhane|H|H|;Chaabane|A|A|;Belhadj Ali|H|H|;Boughattas|N A|NA|;Aouam|K|K|;Ben Fredj|N|N|",
"chemical_list": "D004232:Diuretics; D002034:Bumetanide; D005665:Furosemide",
"country": "France",
"delete": false,
"doi": "10.1016/j.nephro.2020.08.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1769-7255",
"issue": "16(7)",
"journal": "Nephrologie & therapeutique",
"keywords": "Cross reactivity; DRESS syndrome; Furosemide; Loop diuretic",
"medline_ta": "Nephrol Ther",
"mesh_terms": "D000368:Aged; D002034:Bumetanide; D003429:Cross Reactions; D004232:Diuretics; D063926:Drug Hypersensitivity Syndrome; D005665:Furosemide; D006801:Humans; D008297:Male",
"nlm_unique_id": "101248950",
"other_id": null,
"pages": "437-438",
"pmc": null,
"pmid": "33203615",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "DRESS syndrome following furosemide administration: An unusual association.",
"title_normalized": "dress syndrome following furosemide administration an unusual association"
} | [
{
"companynumb": "TN-FRESENIUS KABI-FK202013128",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional": "1",
... |
{
"abstract": "Primary plasma cell leukemia (PCL) is a rare and aggressive variant of multiple myeloma (MM). PCL is characterized by peripheral blood involvement by malignant plasma cells and an aggressive clinical course leading to poor survival. There is considerable overlap between MM and PCL with respect to clinical, immunophenotypic, and cytogenetic features, but circulating plasma cell count exceeding 20% of peripheral blood leukocytes or an absolute plasma cell count of >2000/mm3 distinguishes it from MM. After initial stabilization and diagnosis confirmation, treatment of PCL in a fit patient typically includes induction combination chemotherapy containing novel agents typically, with proteasome inhibitors (such as bortezomib) and immunomodulatory drugs (eg, lenalidomide), followed by autologous hematopoietic stem cell transplant (HSCT) and multidrug maintenance therapy using novel agents post-HSCT. Long-term outcomes have improved employing this strategy but the prognosis for non-HSCT candidates remains poor and new approaches are needed for such PCL patients not eligible for HSCT. Here, we report a case of primary PCL, and a comprehensive and up to date review of the literature for diagnosis and management of PCL. We also present the findings of Positron Emission Tomography (PET) scan. Since PCL is often associated with extra-medulary disease, including PET scan at the time of staging and restaging may be a novel approach particularly to evaluate the extra-medullary disease sites.",
"affiliations": "Department of Hematology and Oncology, Maroone Cancer Center, Myeloma and Amyloidosis Program, Cleveland Clinic Florida, Weston, FL, USA.;Department of Pathology, Cleveland Clinic Florida, Weston, FL, USA.;Department of Internal Medicine, Cleveland Clinic Florida, Weston FL, USA.;Department of Radiology, Cleveland Clinic Florida, Weston, FL, USA.;Department of Hematology and Oncology, Maroone Cancer Center, Myeloma and Amyloidosis Program, Cleveland Clinic Florida, Weston, FL, USA.;Division of Stem Cell Transplant & Cell Therapy, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA.;Department of Hematology and Oncology, Maroone Cancer Center, Myeloma and Amyloidosis Program, Cleveland Clinic Florida, Weston, FL, USA.;Multiple Myeloma Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.",
"authors": "Chaulagain|Chakra P|CP|https://orcid.org/0000-0002-4641-2217;Diacovo|Maria-Julia|MJ|;Van|Amy|A|;Martinez|Felipe|F|;Fu|Chieh-Lin|CL|;Jimenez Jimenez|Antonio Martin|AM|;Ahmed|Wesam|W|;Anwer|Faiz|F|https://orcid.org/0000-0001-6914-7439",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2634853521999389",
"fulltext": "\n==== Front\nClin Med Insights Blood Disord\nClin Med Insights Blood Disord\nBDX\nspbdx\nClinical Medicine Insights: Blood Disorders\n1179-545X\nSAGE Publications Sage UK: London, England\n\n10.1177/2634853521999389\n10.1177_2634853521999389\nReview\nManagement of Primary Plasma Cell Leukemia Remains Challenging Even in the Era of Novel Agents\nhttps://orcid.org/0000-0002-4641-2217\nChaulagain Chakra P 1\nDiacovo Maria-Julia 2\nVan Amy 3\nMartinez Felipe 4\nFu Chieh-Lin 1\nJimenez Jimenez Antonio Martin 5\nAhmed Wesam 1\nhttps://orcid.org/0000-0001-6914-7439\nAnwer Faiz 6\n1 Department of Hematology and Oncology, Maroone Cancer Center, Myeloma and Amyloidosis Program, Cleveland Clinic Florida, Weston, FL, USA\n2 Department of Pathology, Cleveland Clinic Florida, Weston, FL, USA\n3 Department of Internal Medicine, Cleveland Clinic Florida, Weston FL, USA\n4 Department of Radiology, Cleveland Clinic Florida, Weston, FL, USA\n5 Division of Stem Cell Transplant & Cell Therapy, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA\n6 Multiple Myeloma Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA\nChakra P Chaulagain, Department of Hematology-Oncology, Maroone Cancer Center, Myeloma and Amyloidosis Program, Cleveland Clinic Florida, 2950 Cleveland Clinic Blvd, Weston, FL 33331, USA. Email: CHAULAC@ccf.org\n26 2 2021\n2021\n14 263485352199938914 1 2021\n2 2 2021\n© The Author(s) 2021\n2021\nSAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses\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).\nPrimary plasma cell leukemia (PCL) is a rare and aggressive variant of multiple myeloma (MM). PCL is characterized by peripheral blood involvement by malignant plasma cells and an aggressive clinical course leading to poor survival. There is considerable overlap between MM and PCL with respect to clinical, immunophenotypic, and cytogenetic features, but circulating plasma cell count exceeding 20% of peripheral blood leukocytes or an absolute plasma cell count of >2000/mm3 distinguishes it from MM. After initial stabilization and diagnosis confirmation, treatment of PCL in a fit patient typically includes induction combination chemotherapy containing novel agents typically, with proteasome inhibitors (such as bortezomib) and immunomodulatory drugs (eg, lenalidomide), followed by autologous hematopoietic stem cell transplant (HSCT) and multidrug maintenance therapy using novel agents post-HSCT. Long-term outcomes have improved employing this strategy but the prognosis for non-HSCT candidates remains poor and new approaches are needed for such PCL patients not eligible for HSCT. Here, we report a case of primary PCL, and a comprehensive and up to date review of the literature for diagnosis and management of PCL. We also present the findings of Positron Emission Tomography (PET) scan. Since PCL is often associated with extra-medulary disease, including PET scan at the time of staging and restaging may be a novel approach particularly to evaluate the extra-medullary disease sites.\n\nPlasma cell leukemia\nnovel agents\nmultiple myeloma\nautologous hematopoietic stem cell transplantation\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nPrimary plasma cell leukemia (PCL) is a rare and aggressive form of multiple myeloma (MM). The PCL accounts for 0.5% to 2% of MM cases with annual incidence ranging between 0.4 and 1.2 cases per million individuals per year.1,2 Although the definition of PCL is still evolving, a circulating plasma cell count that exceeds 20% of peripheral blood leukocytes, or an absolute plasma cell count >2000/mm3, has been the arbitrary but traditional definition of PCL.3 Multiple myeloma (MM) patients exhibiting circulating plasma cell levels as low as 2%, counted morphologically at the time of diagnosis, demonstrated poor survival, similar to that seen in PCL patients.4 Granell et al5 in another analysis of 482 newly diagnosed MM patients, demonstrated that the presence of ⩾5% circulating plasma cells counted in the peripheral blood has a similar adverse prognostic impact as that of PCL. As also reported, extremely low levels (~0.26%) of circulating clonal plasma cells (CPC) in MM patients, as detected by immunophenotyping (flow cytometry) at the time of diagnosis and treated with novel agents, was also associated with inferior overall survival (OS).6 For example, the 3-year OS for the MM patients with presence of CPC was 67% compared with 87% for those with no CPC.6 Currently, the optimal diagnostic threshold of CPC levels necessary to define PCL is being debated by multiple myeloma experts worldwide.\n\nPrimary PCL is rare and arises de novo, but secondary PCL occurs via clonal evolution from a pre-existing MM. This is typically observed following several lines of therapy and often as a terminal event as part of aggressive relapsed of multiple myeloma. Therefore, for the purpose of this report, “PCL” will refer to primary PCL only.\n\nA brief comparison of the clinical features of PCL and MM is presented in Table 1. Compared to MM, PCL is more aggressive at presentation, patients more often than not present with bone marrow insufficiency (in the form of anemia, or thrombocytopenia,) and end organ damage (in the form of hypercalcemia or renal dysfunction) and multi-organ dysfunction. The clinical course is much more aggressive and outcome is associated with poorer prognosis despite treatment in PCL when compared to MM.5 Additionally, higher LDH and B2-microglobulin levels are often observed in PCL, indicating significantly higher disease burden and proliferation rate at the time of presentation. The higher propensity for extra-medullary involvement at diagnosis, in addition to a larger incidence of high-risk cytogenetics (eg, 17p deletion/TP53 mutation and t[14;16]) also reflects the biologically much more aggressive nature of PCL compared to MM.7,8\n\nTable 1. Clinical features of primary plasma cell leukemia (PCL) compared to multiple myeloma.\n\nClinical features\tMultiple myeloma\tPlasma cell leukemia\t\nIncidence\t52 to 75 cases per million individuals per year1,2\t0.4 to 1.2 cases per million individuals per year or 0.5% to 2% of all MM cases1,2\t\nAge of onset (years)\tOlder (median age, 65-74)23\tRelatively younger (median age 55)1-3\t\nMost common subtype\tIgG (46%) followed by IgA\tIgG (58%) followed by light chain only\t\nBone marrow failure (anemia, thrombocytopenia)\tLess common\tMore common\t\nHypercalcemia\tLess common\tMore common\t\nB2-microglobulin\t+\t+++\t\nLDH\t+\t+++\t\nRenal dysfunction\t+\t+++\t\nTumor lysis syndrome\tLess common\tMore common\t\nExtra-medullary involvement (liver, spleen, other organs) at diagnosis\tLess common\tMore common\t\nDeletion 17p/TP53 mutation\tLess common (~10%)\tMore common (~50%)12\t\nt (11;14)\tLess common (10%-31%)24\tMore common 30%12 to 50%14\t\nPrognosis (median overall survival)\tBetter (median OS = 5.2 years with median follow up 5.9 years)25\tWorse [median OS 28% at 4 years (range 22%-35%)]10\t\nAbbreviations: LDH, lactate dehydrogenase; MM, multiple myeloma; OS, overall survival; PFS, progression free survival.\n\nIn this review, we present a patient with primary PCL who exhibited complete response to induction therapy with lenalidomide, bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide and etoposide (RVD-PACE), but relapsed quickly after autologous peripheral blood hematopoietic stem cell transplantation (HSCT). A second remission was not inducible with salvage therapy containing carfilzomib, pomalidomide, and dexamethasone, and the patient subsequently died from progression of PCL.\n\nCase Presentation\n\nA 62-year-old male with a history of bladder cancer status post transurethral resection of the bladder tumor 5 years prior, was seen in the emergency room for progressively worsening low back pain for 6 weeks prior to his presentation. His past medical history was complicated and included: anxiety/depression, Type II diabetes, hypertension, coronary artery disease, hypercholesterolemia, morbid obesity, obstructive sleep apnea, and cigaratte smoking(active smoker with 20-pack year history). In the emergency room, patient’s vital signs were normal and laboratory studies showed WBC 10 500/mm3, hemoglobin 13.7 gm/dL, platelets 66 000/mm3, absolute neutrophil count 4400/mm3, absolute lymphocyte count, 4200/mm3, and 13% blasts. The patient’s creatinine, uric acid, bilirubin, calcium, total protein, and serum albumin levels were normal. The LDH was elevated to 958 IU/L (normal range 135-225). A peripheral blood smear showed frequent (53%) atypical plasmacytoid cells (Figure 1A) and the flow cytometry of peripheral blood confirmed 50% monotypic lambda restricted clonal plasma cells consistent with PCL. The Serum protein electrophoresis with immunofixation revealed IgG lambda monoclonal gammopathy, with M spike 0.52 gm/dL, serum free kappa light chain level 4.3 mg/L (range 3.3-19.4), serum free lambda light chain level was 2695 mg/L (range 5.7-26.3), with lambda to kappa ratio of ~627. The Beta-2-microglobulin level was 4.5 mg/L (range 0.3-1.9), and levels of IgG, IgA, and IgM levels were 775, 31, and 13 mg/dL respectively. A lumbar spine magnetic resonance imaging (MRI) showed no vertebral fractures, cord compression, or cauda equina lesions but did report widespread T1 hypointensity, and heterogeneous areas of T2/inversion recovery hyperintensity, consistent with possible leukemic infiltration of the bone marrow. A bone marrow aspiration/biopsy demonstrated plasma cell neoplasm with plasmablastic features replacing the bone marrow cellularity. The MM fluorescent in situ hybridization (FISH) was positive for 17p (TP53) deletion, along with presence of additional copies of chromosomes 5, 9, and 15. Final clinical diagnosis of primary PCL, with 17P deletion, was made. The Positron Emission Tomography (PET) scan (Figure 2A) revealed numerous, intensely fluorodeoxyglucose (FDG) avid, bone marrow lesions throughout the skeleton. A core needle biopsy of right 8th rib lesion (Figure 2A arrow) confirmed the presence of plasmablastic malignancy.\n\nFigure 1. Peripheral blood smear at the time of diagnosis (A) and at the time of relapse (B). Peripheral blood smear, Wright-Giemsa stain, 10× shows circulating large neoplastic plasma cells and thrombocytopenia (A). Peripheral blood smear, Wright-Giemsa stain, 40× shows that the neoplastic plasma cells have blastoid features (B).\n\nFigure 2. Attenuation corrected 3-D maximum intensity projections (MIP) positron emission tomography (PET) images of fluorine 18 FDG PET-CT scan: (A) baseline study, demonstrating numerous bone marrow tracer avid lesions involving cervical, thoracic and lumbar spine as well as bilateral ribs, scapula, humeri, pelvis, sacrum, and bilateral femurs. Maximum standard uptake value (SUVmax) in the sacrum = 27 and (B) follow up post-treatment study demonstrating resolution of previously noted tracer avid lesions. Moderate intensity heterogeneous tracer uptake throughout the bone marrow felt to be related to granulocyte colony stimulation factor therapy effect.\n\nImmediate initialization of induction chemotherapy using a combination regimen with bortezomib, dexamethasone, lenalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide (RVD-PACE) achieved stringent complete response (sCR) as defined by previously published criteria9 after 3 cycles. The patient received additional 2 cycles of bortezomib, dexamethasone, and lenalidomide (RVD) while waiting for HSCT. To prevent skeletal-related events, he also received zoledronic acid. He underwent HSCT conditioning, with melphalan (200 mg/m2 (MEL 200)), with engraftment on day +11.\n\nThe post-HSCT course was complicated with profound physical deconditioning and prolonged hospitalization. The patient developed generalized bone pain and a repeat bone marrow biopsy was performed on day +90 post-HSCT, which reveled 40% blastoid monoclonal plasma cells with plasmablastic features consistent with relapsed PCL.\n\nThe patient started salvage chemotherapy using carfilzomib, pomalidomide, and dexamethasone (KPD) to treat relapsed PCL with palliative intention as the patient was not felt to be a candidate for second HSCT or allogeneic HSCT. Cycle 1 of KPD therapy was complicated by acute hypoxemic respiratory failure due to bilateral pneumonia, and severe thrombocytopenia. A Flow cytometry of peripheral blood detected a small plasma cell clone and the peripheral blood smear showed blastoid neoplastic plasma cells confirming the relapsed of the PCL. Later, pomalidomide was discontinued due to intolerance (profound fatigue and cytopenia). He resumed carfilzomib at an increased dose 56 mg/m2, weekly, with dexamethasone. Progressive PCL was noted in the next several weeks and the patient became transfusion-dependent for red blood cells and platelets. Subsequently, the patient performance status deteriorated. Anti-CD 38 monoclonal antibody immunotherapy with daratumumab was offered but the patient elected for hospice, at-home, and died peacefully 14 months after the initial diagnosis.\n\nDiscussion\n\nEven with employing the novel agents available for treatment of clonal plasma cell neoplasms in combination regimen, the treatment of PCL remains challenging. A prompt diagnosis and early stabilization of metabolic challenges, tumor lysis syndrome (TLS), hypercalcemia, acute renal failure and immediate use of multi-agent induction therapy containing novel agents can reduce the risk of early morbidity and may help prolong survival. There is a high response rate with induction therapies containing bortezomib, lenalidomide or thalidomide. Cytotoxic chemotherapies can also be combined with novel agents, which may not be routinely available on the formulary of many USA hospitals as most myeloma care is delivered on the outpatient basis. Rapid and complete responses are often observed after multi-agent induction therapy containing novel agents, but early relapse is common in PCL. For a durable remission, the induction therapy containing proteasome inhibitor (PI) should follow immediately with consolidation therapy, often with HSCT for eligible candidates. In HSCT-ineligible patients, the optimal strategy is unknown but a several cycles of remission induction therapy, followed by long term multi-agent maintenance therapy containing PI and an immunomodulatory agent (IMiD) may provide durable remission. A recently published multicenter retrospective analysis of 348 patients with PCL by Dhakal et al10 concluded that despite incorporation of modern induction therapy containing novel agents and despite increased utilization of both autologous and allogeneic HSCT in the last several years, the survival of PCL patients has not improved in comparison to the historical cohort of PCL patients prior to the widespread use of novel agents. The study underscored that the main reason for the lack of improvement in the survival despite utilization of modern therapies is due to the high relapse rate after HSCT (~76% relapsed at 4 years post-HSCT).10 Allogeneic HSCT is only suitable for a minority of PCL patients as shown in a few small studies10 demonstrating initial good response, a small PFS benefit of 19% at 4 years and overall survival (OS) of only 31% at 4 years. Small studies of tandem double autologous or tandem autologous/allogeneic HSCT showed limited benefit as well.11,12 For autologous or allogeneic HSCT, relapse was the main cause of death in approximately 80% of patients after HSCT. Allogeneic HSCT may have a role for treatment of younger and fit patients, ideally in the context of a clinical trial. For example , Currently an ongoing clinical trial in Europe (EudraCT Number: 2016-003105-33) incorporates a potent second generation irreversible PI, carfilzomib and lenalidomide during remission induction, consolidation, and maintenance phase of therapy and offers allogeneic HSCT to younger, fit, and responding patients.13\n\nThe median overall survival of PCL patients, before the use of novel agents, was historically measured in only a few months.14 However, with the incorporation of novel agents (bortezomib, lenalidomide or thalidomide) and autologous HSCT, survival has been reported to improve to 12 months.15 While this represents favorable progress for this patient group, more improvement is necessary to improve outcomes in the treatment of PCL. There is signal showing that further improvement can be achieved with post-HSCT maintenance therapy with novel agents. This was demonstrated by Mina et al16 in their retrospective analysis of 38 patients with PCL treated with bortezomib plus either thalidomide or lenalidomide as induction therapy followed by HSCT and maintenance therapy with bortezomib and lenalidomide for 3 years in majority of the cohort. The median PFS was 20 months, and the median OS was 33 months with PFS better for those who received HSCT (25 vs 6 months). Most important finding was that the patients who received maintenance therapy after HSCT had prolonged median PFS (27 vs 11 months) and a trend toward prolonged OS (median, 38 vs 22 months) compared with those who did not receive maintenance therapy.16\n\nOver half of patients with PCL harbor highly adverse prognostic factor of 17p deletion.17 Bortezomib and other proteasome inhibitors (carfilzomib, ixazomib) are postulated to help overcome the adverse prognostic impact of poor cytogenetics in MM, especially in 17p deletion/TP53 mutation and cytogenetic aberrations involving chromosome 14 in high risk MM.18 Due to this observation and the retrospective data in high risk MM, PI appears to be an important therapeutic tool to be used in the treatment of PCL. To conduct a well-funded randomized phase III study is challenging due to multiple logistic factors and relatively rare nature of PCL. Therefore, randomized phase III studies in PCL are lacking. A phase II study evaluated the effectiveness of bortezomib and chemotherapy (doxorubicin or cyclosphosphamide), followed by HSCT, and 1 year of maintenance therapy with RVD. The results thereof indicated a good response rate (the overall response rate to induction therapy was 69%) and improved median survival to 3 years.19 In another report Nooka et al20 reported encouraging results of RVD maintenance with 51% of patients achieving stringent complete response (sCR) and 96% achieving VGPR or better and median PFS of 32 months and a 3-year OS of 93%. These studies support induction therapy with regimen containing novel agents followed by early HSCT for consolidation and post-HSCT maintenance therapy with RVD for the best results. Only 27% of post-autologous HSCT and only 12% of post allo-HCT PCL patients had received maintenance therapy in the study by Dhakal et al10 which may have contributed to the high relapse rate in the HSCT survivors in their cohort.\n\nIn summary, patients who are fit enough to undergo HSCT, and who receive PI containing multi-agent maintenance therapy after HSCT, tend to exhibit improved survival compared to patients who did not undergo HSCT and did not receive maintenance therapy. The standard low dose lenalidomide maintenance monotherapy (10-15 mg daily), prescribed after HSCT in MM, appears to be inadequate in PCL due to reported 50% relapse rate within first year.21 The maintenance strategy with combination therapy of RVD appears to be more effective and is tolerated by majority of patients after HSCT in PCL.21,22 Three factors affecting survival outcomes in PCL appear to be (1) incorporating novel agents with PI and IMiD in the induction therapy, (2) consolidation with HSCT in fit stronger and younger patients, and (3) maintenance therapy containing multiple novel agents (bortezomib and lenalidomide). Patients who are able to tolerate these therapies tend to have the best possible outcomes but relapses still do occur including at unusual sites for example, meningeal relapses after both allogeneic and autologous HSCT.19\n\nThe timing and sequencing of newer generation proteasome inhibitors, carfilzomib and ixazomib, is still evolving in PCL and there are no published studies as of the writing of this review. Ixazomib, as an oral agent, may be suitable as a combination therapy with an IMiD, such as lenalidomide or pomalidomide, particularly for maintenance therapy. Both ixazomib and pomalidomide are effective agents against relapsed myeloma, but no study has been conducted to prospectively examine the efficacy of either in PCL. However, a phase II study of pomalidomide, ixazomib, and dexamethasone, in treating patients with previously treated MM or secondary PCL, is currently ongoing and will help answer questions surrounding the effectiveness of these biologic agents for patients with relapsed myeloma and secondary PCL (ClinicalTrials.gov Identifier: NCT02547662). Additionally, a phase I study of filanesib and carfilzomib in treating patients with relapsed or refractory MM, or secondary PCL, was completed and the final results of which are pending (ClinicalTrials.gov Identifier: NCT01372540). The results of a clinical study of carfilzomib, pomalidomide, and dexamethasone (KPD) for relapsed or refractory myeloma indicate that the regimen is a well-tolerated and highly active combination for patients with relapsed/refractory multiple myeloma22 and there is evolving preliminary safety and efficacy data from an ongoing phase II non-randomized clinical trial that examined carfilzomib, lenalidomide and dexamethasone (KRD) for first line treatment of PCL.23 In this study patients eligible for HSCT underwent 4 cycles of KRd induction followed by HSCT, KRd consolidation, and then maintenance with KD until progression. Patients not eligible for HSCT received KRd followed by KD maintenance. The final results are not published yet but preliminary results are encouraging with high response rate and acceptable safety (⩾VGPR in 80% and ⩾CR in 33%).23 The patient in this report received KPD therapy at the time of relapse, with less than partial response (Figure 3) attesting to the much more aggressive biology of relapsed PCL.\n\nFigure 3. The levels of serum free lambda light chain (LLC), lactate dehydrogenase (LDH) and beta 2 microglobulin at the time of diagnosis, relapse, and disease progression.\n\nRVD-PACE = lenalidomide, bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide; HSCT = hematopoietic stem cell transplantation; KPD = carfilzomib, pomalidomide, and dexamethasone; LDH = lactate dehydrogenase.\n\nDaratumumab and isatuximab are highly effective anti-CD38 monoclonal antibodies approved for MM in combination with novel agents.24-27 Studies are needed to understand how and when to incorporate this highly active novel immunotherapy for treatment of PCL. Unfortunately, a phase I study of daratumumab, in combination with bortezomib, dexamethasone, pegylated liposomal doxorubicin hydrochloride, and lenalidomide in treating patients with PCL has been withdrawn citing budgetary constraints (ClinicalTrials.gov Identifier: NCT03591744). Similarly, antibody drug conjugates, bi-specific antibodies and CAR-T therapy may have a future for the treatment of PCL, but initial trials usually exclude PCL from the inclusion criteria (ClinicalTrials.gov Identifier: NCT03815383).\n\nVenetoclax is an attractive molecule for patients with PCL given its good tolerability as an oral inhibitor of BCL-2 and the high prevalence (30-50%) of the t(11;14) in PCL population.17,18 When venetoclax was evaluated in a phase 1 study in relapsed/refractory MM, 86% of responders had the t(11;14) with overall response rate of 40%, with 27% of patients achieving very good partial response (VGPR) or better in this heavily pretreated population.28 Future studies of PCL should examine venetocalx either as single agent or in combination with novel agents, cellular therapies or immunotherapies.\n\nFinally, due to the high frequency of extra-medullary involvement, international myeloma working group (IMWG) has recommended that PET scan be included in the diagnosis and monitoring of PCL.29\n\nConclusion\n\nPrimary plasma cell leukemia (PCL) is a rare and aggressive hematologic malignancy. Response to induction therapy, with a combination of novel agents (PI and IMiD) with or without cytotoxic chemotherapy, is common but durability of such response is brief unless consolidated with HSCT followed by maintenance therapy. A single agent lenalidomide, as maintenance therapy after HSCT, is inadequate due to high relapse rate. Therefore, it is recommended to incorporate both lenalidomide and bortezomib, in combination with dexamethasone (RVD), for maintenance in PCL when tolerated. For HSCT-ineligible patients, efficacious treatment remains a challenge and we recommend treating with multiple cycles of therapies containing lenalidomide and bortezomib or participation in a clinical trial when available. Employing immunotherapy with monoclonal antibodies, antibody drug conjugates, bi-specific antibodies and engineered cellular therapy such as CAR-T cell therapy, are all attractive concepts that require investigations in future in treatment of PCL. Incorporating newer generation proteasome inhibitors (carfilzomib, ixazomib) and immunomodulatory agent such as pomalidomide may further improve the outcomes. Venetoclax may also play an important role in future for the treatment of PCL harboring t(11;14) mutation. Prospective multicenter studies are required to further understand the definitions, pathogenesis, treatment and prognosis of PCL. Employing novel imaging technique such as PET scan when done at diagnosis and follow up may provide valuable insight in to the status of the disease outside of the bone marrow.\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\nInformed Consent: Informed patient consent was not possible due to the death of the patient. Patient’s surviving spouse provided the verbal informed consent to publish the case report on 7/15/2020. This was documented in patient’s chart in the electronic medical record system of Cleveland Clinic per Cleveland Clinic IRB guidance.\n\nEthics Approval: Ethics approval is not required for case report because such report does not constitute a research per Cleveland Clinic Institutional Review Board (IRB).\n\nORCID iDs: Chakra P Chaulagain https://orcid.org/0000-0002-4641-2217\n\nFaiz Anwer https://orcid.org/0000-0001-6914-7439\n==== Refs\nReferences\n\n1 Gimsing P Holmström MO Klausen TW , et al . The Danish national multiple myeloma registry. Clin Epidemiol. 2016;25 :583-587.\n2 Sant M Allemani C Tereanu C , et al . Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood. 2010;116 :3724-3734.20664057\n3 Kyle RA Maldonado JE Bayrd ED . Plasma cell leukemia. Report on 17 cases. Arch Intern Med. 1974;133 :813-818.4821776\n4 An G Qin X Acharya C , et al . Multiple myeloma patients with low proportion of circulating plasma cells had similar survival with primary plasma cell leukemia patients. Ann Hematol. 2015;94 :257-264.25231928\n5 Granell M Calvo X Garcia-Guinon A , et al . Prognostic impact of circulating plasma cells in patients with multiple myeloma: implications for plasma cell leukemia definition. Haematologica. 2017;102 :1099-1104.28255016\n6 Gonsalves WI Rajkumar SV Gupta V , et al . Quantification of clonal circulating plasma cells in newly diagnosed multiple myeloma: implications for redefining high-risk myeloma. Leukemia. 2014;28 :2060-2065.24618735\n7 Gundesen MT Lund T Moeller HEH Abildgaard N. Plasma cell leukemia: definition, presentation, and treatment. Curr Oncol Rep. 2019;21 :8.30689121\n8 Cifola I Lionetti M Pinatel E , et al . Whole-exome sequencing of primary plasma cell leukemia discloses heterogeneous mutational patterns. Oncotarget. 2015;6 :17543-17558.26046463\n9 Kumar S Paiva B Anderson KC , et al . International myeloma working group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17 :e328-e346.27511158\n10 Dhakal B Patel S Girnius S , et al . Hematopoietic cell transplantation utilization and outcomes for primary plasma cell leukemia in the current era. Leukemia. Published online ahead of print, April 20, 2020.\n11 Pagano L Valentini CG De Stefano V , et al . Primary plasma cell leukemia: a retrospective multicenter study of 73 patients. Ann Oncol. 2011;22 :1628-1635.21252060\n12 Royer B Minvielle S Diouf M , et al . Cyclophosphamide, dexamethasone induction followed by stem cell transplantation for primary plasma cell leukemia: a prospective phase II study of the intergroupe francophone du myélome. J Clin Oncol. 2016;34 :2125-2132.27114594\n13 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2016-003105-33\n14 Lal A Rauf A Warraich Z , et al . A systematic review of conventional therapy and role of stem cell transplantation for primary plasma cell leukemia. Biol Blood Marrow Transplant. 2018;24 :S253-S254.\n15 Gonsalves WI Rajkumar SV Go RS , et al . Trends in survival of patients with primary plasma cell leukemia: a population-based analysis. Blood. 2014;124 :907-912.24957143\n16 Mina R Joseph NS Kaufman JL , et al . Survival outcomes of patients with primary plasma cell leukemia (pPCL) treated with novel agents. Cancer. 2019;125 :416-423.30332496\n17 Tiedemann RE Gonzalez-Paz N Kyle RA , et al . Genetic aberrations and survival in plasma cell leukemia. Leukemia. 2008;22 :1044-1052.18216867\n18 Neben K Lokhorst HM Jauch A , et al . Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119 :940-948.22160383\n19 Royer B Minvielle S Diouf M , et al . Bortezomib, doxorubicin, cyclophosphamide, dexamethasone induction followed by stem cell transplantation for primary plasma cell leukemia: a prospective phase II study of the Intergroupe Francophone du Myélome. J Clin Oncol. 2016;34 :2125-2132.27114594\n20 Nooka AK Kaufman JL Muppidi S , et al . Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia. 2014;28 :690-693.24220275\n21 Musto P Simieon V Martorelli MC , et al . Lenalidomide and low-dose dexamethasone for newly diagnosed primary plasma cell leukemia. Leukemia. 2014;28 :222-225.23958922\n22 Shah JJ Stadtmauer EA Abonour R , et al . Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood. 2015;126 :2284-2290.26384354\n23 Van De Donk M van der Holt B Schjeavold FH , et al . Treatment of primary plasma cell leukemia with carfilzomib and lenalidomide-based therapy: results of the first interim analysis of the phase 2 EMN12/HOVON129 study. Blood. 2019;134 : 693.\n24 Usmani SZ Weiss BM Plesner T , et al . Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated elapsed or refractory multiple myeloma. Blood. 2016;128 :37-44.27216216\n25 Chari A Suvannasankha A Fay JW , et al . Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130 :974-981.28637662\n26 Palumbo A Chanan-Khan A Weisel K , et al . Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375 :754-766.27557302\n27 Klyuchnikov E von Pein UM Ayuk F , et al . Daratumumab is an effective and safe salvage therapy in relapsed/refractory patients with multiple myeloma after allogeneic stem cell transplantation. Blood. 2016;128 :3437.\n28 Kumar S Kaufman JL Gasparetto C , et al . Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017;130 :2401-2409.29018077\n29 De Larrea CF Kyle RA Durie BGM , et al . Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria, and treatment recommendations by the International Myeloma Working Group (IMWG). Leukemia. 2013;27 :780-791.23288300\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-545X",
"issue": "14()",
"journal": "Clinical medicine insights. Blood disorders",
"keywords": "Plasma cell leukemia; autologous hematopoietic stem cell transplantation; multiple myeloma; novel agents",
"medline_ta": "Clin Med Insights Blood Disord",
"mesh_terms": null,
"nlm_unique_id": "101640243",
"other_id": null,
"pages": "2634853521999389",
"pmc": null,
"pmid": "33716516",
"pubdate": "2021",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "23288300;26046463;4821776;30332496;28255016;20664057;30689121;27511158;21252060;24220275;28637662;24957143;32313109;27114594;23958922;18216867;25231928;29018077;22160383;27822103;26384354;24618735;27216216;27557302",
"title": "Management of Primary Plasma Cell Leukemia Remains Challenging Even in the Era of Novel Agents.",
"title_normalized": "management of primary plasma cell leukemia remains challenging even in the era of novel agents"
} | [
{
"companynumb": "US-DRREDDYS-LIT/USA/21/0142622",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARFILZOMIB"
},
"drugadditional": "3",
... |
{
"abstract": "A 31-year-old term primigravid woman had an intrathecal catheter placed following a dural puncture during attempted epidural analgesia during labour. After 23 hours she developed sudden loss of consciousness and an urgent brain computed tomography scan demonstrated a large left hyper-acute subdural haematoma. Craniotomy revealed active bleeding from a ruptured left temporal bridging vein. She was extubated 12 hours after surgery and was discharged home 11 days later without neurological deficit. Although subdural haematoma is a recognised complication of dural puncture, it has not been reported in the presence of an intrathecal catheter. An intrathecal catheter may not always prevent cerebrospinal fluid efflux, so subdural haematoma remains a potential complication of inadvertent dural puncture.",
"affiliations": "Department of Anaesthesia, Westmead Hospital, Sydney, New South Wales, Australia. dr_sanjaysharma@hotmail.com",
"authors": "Sharma|S|S|;Halliwell|R|R|;Dexter|M|M|;Mudaliar|Y|Y|;Yee|K|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0310057X1003800521",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0310-057X",
"issue": "38(5)",
"journal": "Anaesthesia and intensive care",
"keywords": null,
"medline_ta": "Anaesth Intensive Care",
"mesh_terms": "D000328:Adult; D015360:Analgesia, Epidural; D016362:Analgesia, Obstetrical; D002404:Catheterization; D005260:Female; D020199:Hematoma, Subdural, Acute; D006801:Humans; D051299:Post-Dural Puncture Headache; D011247:Pregnancy; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0342017",
"other_id": null,
"pages": "939-41",
"pmc": null,
"pmid": "20865883",
"pubdate": "2010-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute subdural haematoma in the presence of an intrathecal catheter placed for the prevention of post-dural puncture headache.",
"title_normalized": "acute subdural haematoma in the presence of an intrathecal catheter placed for the prevention of post dural puncture headache"
} | [
{
"companynumb": "AU-FRESENIUS KABI-FK202010408",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUPIVACAINE"
},
"drugadditional": null,
... |
{
"abstract": "Phenytoin induces lymphoid proliferation, resulting in complications that can range from tissue hyperplasia to lymphoma. Some of the complications resolve spontaneously after drug discontinuation. This report describes for the first time a case of dysphagia with lack of velopharyngeal coordination and nasopharyngeal reflux combined with massive palatine tonsillar hypertrophy. The condition did not develop before phenytoin administration, was induced by phenytoin, and spontaneously resolved upon drug discontinuation. The patient was referred for a video-fluoroscopic swallowing study owing to a recurring nasal reflux of foods that had developed since phenytoin administration. The video-fluoroscopic swallowing study revealed incidentally that the large bilateral elongated masses extended downward into the larynx and disturbed velar elevation. This finding was confirmed by computed tomography of the neck, which showed that palatine tonsillar hypertrophy disturbed the laryngopharynx on both sides. The symptoms (sleep apnea and nasal reflux) and the abnormal imaging findings disappeared without surgery approximately 1 month after drug discontinuation. This case suggests that dysphagia related to phenytoin-induced lymphoid hypertrophy may be treated by phenytoin discontinuation followed by a sufficient amount of time to allow symptom resolution rather than by prompt surgery.",
"affiliations": "From the Department of Physical Medicine and Rehabilitation, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.",
"authors": "Hwang|Chang Ho|CH|",
"chemical_list": "D000927:Anticonvulsants; D010672:Phenytoin",
"country": "United States",
"delete": false,
"doi": "10.1097/PHM.0000000000000558",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0894-9115",
"issue": "96(2)",
"journal": "American journal of physical medicine & rehabilitation",
"keywords": null,
"medline_ta": "Am J Phys Med Rehabil",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D001259:Ataxia; D003680:Deglutition Disorders; D005764:Gastroesophageal Reflux; D006801:Humans; D006984:Hypertrophy; D008297:Male; D014066:Palatine Tonsil; D010609:Pharyngeal Muscles; D010672:Phenytoin; D012640:Seizures",
"nlm_unique_id": "8803677",
"other_id": null,
"pages": "e24-e27",
"pmc": null,
"pmid": "27386809",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Velopharyngeal Incoordination Caused by Phenytoin-Induced Toxicity.",
"title_normalized": "velopharyngeal incoordination caused by phenytoin induced toxicity"
} | [
{
"companynumb": "KP-AMNEAL PHARMACEUTICALS-2017AMN00830",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PHENYTOIN SODIUM"
},
"drugadditi... |
{
"abstract": "Beta-adrenergic blocking agents or beta-blockers are a class of medications used to treat cardiac arrhythmias and systemic hypertension. In therapeutic dosages, they have known adverse outcomes that can include muscular fatigue and cramping, dizziness, and dyspnea. In patients with mitochondrial disease, these effects can be amplified. Previous case reports have been published in the adult population; however, their impact in pediatric patients has not been reported. We describe a pediatric patient with a mitochondrial disorder who developed respiratory distress after metoprolol was prescribed for hypertension. As the patient improved with discontinuation of medication and no alternative etiology was found for symptoms, we surmise that administration of metoprolol aggravated his mitochondrial dysfunction, thus worsening underlying chest wall weakness.",
"affiliations": "Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX, USA.;Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX, USA.;Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX, USA.;Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX, USA.;Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX, USA.",
"authors": "Samuels|Cheryl|C|0000-0002-3107-0875;Koenig|Mary Kay|MK|;Hernandez|Mariana|M|;Yadav|Aravind|A|;Mosquera|Ricardo A|RA|0000-0002-5350-331X",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2016/7869174",
"fulltext": "\n==== Front\nCase Rep PediatrCase Rep PediatrCRIPECase Reports in Pediatrics2090-68032090-6811Hindawi Publishing Corporation 10.1155/2016/7869174Case ReportMitochondrial Disorder Aggravated by Metoprolol http://orcid.org/0000-0002-3107-0875Samuels Cheryl Koenig Mary Kay Hernandez Mariana Yadav Aravind http://orcid.org/0000-0002-5350-331XMosquera Ricardo A. \n*\nDepartment of Pediatrics, University of Texas Medical School at Houston, Houston, TX, USA*Ricardo A. Mosquera: ricardo.a.mosquera@uth.tmc.eduAcademic Editor: Alberto Spalice\n\n2016 20 10 2016 2016 78691743 6 2016 12 9 2016 3 10 2016 Copyright © 2016 Cheryl Samuels et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Beta-adrenergic blocking agents or beta-blockers are a class of medications used to treat cardiac arrhythmias and systemic hypertension. In therapeutic dosages, they have known adverse outcomes that can include muscular fatigue and cramping, dizziness, and dyspnea. In patients with mitochondrial disease, these effects can be amplified. Previous case reports have been published in the adult population; however, their impact in pediatric patients has not been reported. We describe a pediatric patient with a mitochondrial disorder who developed respiratory distress after metoprolol was prescribed for hypertension. As the patient improved with discontinuation of medication and no alternative etiology was found for symptoms, we surmise that administration of metoprolol aggravated his mitochondrial dysfunction, thus worsening underlying chest wall weakness.\n==== Body\n1. Introduction\nMitochondrial disorders are a group of diseases characterized by dysfunction of the mitochondria, the organelles responsible for generating the energy required to sustain life and support growth [1]. Mitochondria are present throughout our body and their dysfunction can affect any organ, including the brain, heart, skeletal muscle, or respiratory system; symptoms may include loss of motor control, muscle weakness, failure to thrive, cardiac disease, gastrointestinal disorders, and seizures, among others. Diagnosis of a mitochondrial disease is made via a combination of clinical, laboratory, and molecular analysis and often involves the use of standardized diagnostic criteria [2, 3]. There is no specific therapy for mitochondrial disease. Treatment focuses on nutritional supplements that theoretically improve mitochondrial function along with optimization of care during times of stress and avoidance of substances that are known to be toxic to the mitochondria themselves [4]. A recent guideline released by the Mitochondria Medical Society helps to standardize evaluation, diagnosis, and care of these patients [5].\n\nBeta-adrenergic blocking agents or beta-blockers are a class of medications used to treat cardiac arrhythmias and systemic hypertension. Beta-blockers' pharmaceutical action lies with their ability to block the effects of epinephrine. This blockage causes the heart to beat slower and less forcefully, thereby decreasing blood pressure. Known adverse outcomes include fatigue, dizziness, dyspnea, and bradycardia. Beta-blockers have a strong potential to damage mitochondrial biogenesis. The damage is assumed to be due to direct effect on the respiratory electron transport chain with decreased levels of arginine impairing aerobic exercise capacity [6, 7]. These medications can also inhibit the biological pathway of coenzyme Q10 (CoQ10). CoQ10 is a mitochondrial coenzyme essential for the production of adenosine triphosphate (ATP), the basis of cellular energy processes. CoQ10 also scavenges free radicals and blockage of its action interferes with protection against free radicals, contributing to further mitochondrial dysfunction [8].\n\nSkeletal muscle predominantly expresses β\n2-receptors and the use of a β-blocker limits aerobic muscle pathways by decreasing oxygen availability to the muscle. Clinically, these drugs have been associated with muscle cramps, muscular weakness, generalized fatigue, myopathy, lactic acidosis, and elevation of creatinine kinase levels [9]. Included in the potentially affected muscles are the diaphragm and chest wall muscles where weakness can negatively impact respiratory status.\n\n2. Case Presentation\nWe present the case of a 7-year-old Caucasian boy diagnosed clinically with a mitochondrial disorder. The patient presented with multisystem disease including autonomic dysfunction, gastroesophageal reflux, gastroparesis, nocturnal hypoventilation, and metabolic derangements including elevations in lactate and pyruvate. Muscle biopsy found a global reduction (<25%) in all enzyme complexes of the electron transport chain and the patient was placed in a category of definite mitochondrial disease using the modified Walker criteria [2, 3].\n\nAt his baseline, the patient had a sleep related breathing disorder with hypoventilation, characterized by hypercapnia with end tidal carbon dioxide levels (EtCO2) of more than 50 torr for greater than 25% of the measured sleep time. A nocturnal polysomnography study performed immediately prior to the acute decompensation period revealed continued hypoventilation with hypoxemia (average oxygen levels were 88% with a nadir of 73% without breathing support) and hypercapnia (EtCO2: 49–65) with an average of 3 central apneas per hour. In order to treat the sleep disturbances noninvasive ventilation was initiated with Bilevel Positive Airway Pressure (BiPap) at settings of 12/6 cmH2O.\n\nPrior to his acute respiratory decompensation he was doing well, at his medical baseline, was active, and was attending school. His mother reported headaches associated with elevated blood pressure (averaging 135/88: stage 2 hypertension) a reason why metoprolol was prescribed at a dose of 25 mg (1 mg/kg) by his pediatric cardiologist for treatment of both hypertension and dysautonomia.\n\nAfter the treatment with metoprolol was initiated, blood pressure returned to normal levels. Within weeks the child's mother reported intermittent, mild episodes of dyspnea exacerbated by activity and associated with periodic grunting and generalized weakness. These symptoms persisted and worsened and, two months following the initiation of metoprolol, he was admitted to the pediatric intensive care unit with acute respiratory insufficiency.\n\nThe child's mother reported that on the day of admission his breathing became rapid and shallow and the presence of a thoracoabdominal asynchronous breathing pattern was noted. At the time of admission, he was alert, active, and cooperative, with his baseline activity and oral intake. He was not experiencing any evidence of infection: no fever, cough, rhinorrhea, or sputum production. Later his breathing becomes more labored and erratic with a respiratory rate of 7-8 breaths per minute. On physical examination no wheezing or crackles were auscultated. His oxygen saturations remained above 90%, and his EtCO2 levels were 34 mmHg. Difficulty breathing and thoracoabdominal asynchrony were evident. Oxygen therapy was initiated and BiPap settings were increased and expanded to 24-hour coverage.\n\nStudies performed were normal. Specifically, a CBC gave no evidence of infection. Blood gases at time of PICU admission revealed a pH of 7.44, pCO2 34.8. A chest X-ray and a CT scan of the lung revealed normal lung parenchyma. EEG showed no abnormalities and CT of the brain was normal. He was placed on an arterial line for continuous monitoring of his arterial blood gases, which remained within normal limits and his lactic acid level was at 1.7 mmol/L.\n\nHe was discharged after 4 days and sent home with BiPap with settings of 14/5 cm H2O for use while asleep and when needed while awake with supplemental oxygen therapy. He continued to experience mild episodes of hypoventilation and asynchronous breathing a week following discharge and was evaluated by his pediatric pulmonologist.\n\nAt this point, no clear origin for his respiratory symptoms had been found. Specifically, he continued with the thoracoabdominal asynchrony accompanied by the absence of abnormal chest sounds with normal chest CT, chest X-ray, and normal carbon dioxide and oxygen levels. Negative findings suggested a chest wall weakness disorder rather than lung parenchymal disease. In order to exclude a possible relationship between the beta-blockers and the chest wall weakness, metoprolol was discontinued. As an alternative diagnosis to the chest wall weakness was central dysventilation was considered less likely based on the recent sleep study without evidence of central sleep apnea.\n\nAfter discontinuation of the metoprolol, dyspnea and abdominal breathing pattern gradually improved. He returned to his medical baseline within four weeks after discontinuation of the medication.\n\n3. Discussion\nIn the present case, our pediatric mitochondrial patient developed respiratory insufficiency in the presence of reassuring lab values. In children with respiratory failure associated with neuromuscular disease, the initial arterial carbon dioxide tension can drop to levels at or below the normal range. This phenomenon reflects alveolar hyperventilation which is most likely produced by a combination of fear, small airway collapse, and reflex tachypnea. It is only later in the development of severe respiratory weakness that alveolar ventilation fails and carbon dioxide tension rises to first normal and then elevated levels. In our patient noninvasive mechanical ventilation was started in the early stages of respiratory failure while his pCO2 was still within the normal range (34 mmHg).\n\nReview of the medical literature found a previous case report of an adult mitochondrial patient who developed muscular weakness, generalized fatigue, and muscle cramps after starting a beta-blocker [10]. An additional report identified beta-blockers as mitochondrial-toxic agents, causing a significant impact in patients with mitochondrial disorders [11]. With no other cause apparent to explain our patient's respiratory decompensation, the decision was made to discontinue the medication and symptoms resolved.\n\nBased on these previous reports and our clinical scenario, we speculate that beta-blockers can aggravate or trigger muscle weakness in patients with a mitochondrial disease. Given the absence of studies and case reports regarding the use of beta-blockers in pediatric mitochondrial patients, the main objective of this report is to alert providers that beta-blockers should be used with caution in patients with mitochondrial disease as these agents may trigger or further aggravate muscle manifestations.\n\nAbbreviations \nCoQ10:Coenzyme Q10\n\nATP:Adenosine triphosphate\n\nΒ:Beta\n\nBiPap:Bilevel Positive Airway Pressure\n\nEtCO2:End tidal carbon dioxide.\n\nCompeting Interests\nThe authors have no conflict of interests to disclose.\n\nAuthors' Contributions\nAll authors were involved in the conception and design of the paper and in the drafting and revising of the article. They were also involved in the final approval of the completed article.\n==== Refs\n1 Schmidt C. W. Unraveling environmental effects on mitochondria Environmental Health Perspectives 2010 118 7 A292 A297 10.1289/ehp.118-a292 \n2 Koenig M. K. Presentation and Diagnosis of Mitochondrial disorders in children Pediatric Neurology 2008 38 5 305 313 10.1016/j.pediatrneurol.2007.12.001 2-s2.0-41849123439 18410845 \n3 Bernier F. P. Boneh A. Dennett X. Chow C. W. Cleary M. A. Thorburn D. R. Diagnostic criteria for respiratory chain disorders in adults and children Neurology 2002 59 9 1406 1411 10.1212/01.wnl.0000033795.17156.00 2-s2.0-0037069229 12427892 \n4 Arveladze G. Geladze N. Khachapuridze N. Mitochondrial dysfunction: modern aspects of therapy Georgian Medical News 2015 244-245 78 84 \n5 Parikh S. Goldstein A. Koenig M. K. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society Genetics in Medicine 2015 17 9 689 701 10.1038/gim.2014.177 2-s2.0-84940939416 25503498 \n6 Finsterer J. Segall L. Drugs interfering with mitochondrial disorders Drug and Chemical Toxicology 2010 33 2 138 151 10.3109/01480540903207076 2-s2.0-77949878549 19839725 \n7 Scatena R. Bottoni P. Botta G. Martorana G. E. Giardina B. The role of mitochondria in pharmacotoxicology: a reevaluation of an old, newly emerging topic American Journal of Physiology 2007 293 1 12 21 10.1152/ajpcell.00314.2006 2-s2.0-34547104596 \n8 Kishi T. Watanabe T. Folkers K. Bioenergetics in clinical medicine. XV. Inhibition of coenzyme q10 enzyme by clinically adrenergic blockade of beta-receptors Research Communications in Chemical Pathology and Pharmacology 1977 17 1 157 164 17892 \n9 Imai Y. Watanabe N. Hashimoto J. Muscle cramps and elevated serum creatine phosphokinase levels induced by β -adrenoceptor blockers European Journal of Clinical Pharmacology 1995 48 1 29 34 10.1007/bf00202168 2-s2.0-0028900641 7621844 \n10 Finsterer J. Gelpi E. Mitochondrial disorder aggravated by propranolol Southern Medical Journal 2006 99 7 768 771 10.1097/01.smj.0000223360.66759.90 2-s2.0-33745934695 16866064 \n11 Blessing W. Walsh J. C. Myotonia precipitated by propranolol therapy The Lancet 1977 1 8002 73 74 2-s2.0-0017364369\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2016()",
"journal": "Case reports in pediatrics",
"keywords": null,
"medline_ta": "Case Rep Pediatr",
"mesh_terms": null,
"nlm_unique_id": "101581030",
"other_id": null,
"pages": "7869174",
"pmc": null,
"pmid": "27840760",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "17892;16866064;19839725;17475665;63714;12427892;26177139;18410845;25503498;7621844",
"title": "Mitochondrial Disorder Aggravated by Metoprolol.",
"title_normalized": "mitochondrial disorder aggravated by metoprolol"
} | [
{
"companynumb": "US-CLARIS PHARMASERVICES-1060501",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METOPROLOL"
},
"drugadditional": "1",
... |
{
"abstract": "The polymerase chain reaction (PCR) assay for varicella zoster virus (VZV), herpes simplex virus (HSV)-1 and HSV-2 is available for use. Sometimes the differential diagnosis of the generalized herpes zoster (HZ), HSV1/2, and drug eruption is difficult. We report a case of HZ followed by the vesicular erythema multiforme (EM)-like lesion. In this case the use of PCR was of great assistance. A 78-year-old Japanese man without any significant previous history of disease was admitted to our hospital complaining of zosteriform vesicle on an erythematous base from his right shoulder to the upper arm. We diagnosed him with HZ at the level of right Th2. In spite of the prompt start of antiviral therapy, a secondary new vesiculous erythema developed on his trunk. Clinically, it was quite difficult to differentiate the lesion from the generalized HZ. Rapid PCR assay of effusion and crust for VZV was performed. A PCR assay of VZV was positive for the crust taken from the primary lesion, while it was negative for the effusion and crust of the secondary widespread lesion. We diagnosed the secondary widespread lesion as an EM-type drug eruption induced by acyclovir, or an EM associated with herpes zoster. We then stopped the use of acyclovir and applied steroid ointment of a very strong class for the secondary lesions, which improved after a few days. A PCR assay for VZV was useful for ruling out the generalized HZ in our case with secondary developed vesiculous lesions.",
"affiliations": "Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.",
"authors": "Kasuya|Akira|A|;Sakabe|Jun-ichi|J|;Kageyama|Reiko|R|;Ikeya|Shigeki|S|;Fujiyama|Toshiharu|T|;Tokura|Yoshiki|Y|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/1346-8138.12479",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-2407",
"issue": "41(6)",
"journal": "The Journal of dermatology",
"keywords": "Erythema multiforme; generalized herpes zoster; herpes simplex virus-1; polymerase chain reaction; varicella zoster virus",
"medline_ta": "J Dermatol",
"mesh_terms": "D000368:Aged; D003937:Diagnosis, Differential; D004892:Erythema Multiforme; D006562:Herpes Zoster; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction",
"nlm_unique_id": "7600545",
"other_id": null,
"pages": "542-4",
"pmc": null,
"pmid": "24909215",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful differentiation of herpes zoster-associated erythema multiforme from generalized extension of herpes by rapid polymerase chain reaction analysis.",
"title_normalized": "successful differentiation of herpes zoster associated erythema multiforme from generalized extension of herpes by rapid polymerase chain reaction analysis"
} | [
{
"companynumb": "JP-GLAXOSMITHKLINE-B1010818A",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACYCLOVIR"
},
"drugadditional": null,
... |
{
"abstract": "Oculogyric crisis (OGC), frequently caused by medications such as antiemetics, antidepressants, and anti-epileptics, is an acute dystonic reaction of the ocular muscles. It consists of wide-staring gaze (lasting variably from seconds to minutes), seizures, and a widely-opened mouth. To date, there have been no reports of anti-tuberculosis medications such as rifampicin, isoniazid, pyrazinamide or ethambutol inducing OGC. It is of utmost importance to recognize this adverse reaction, which could be incorrectly diagnosed as an anaphylactic-like reaction. In this paper, we highlight a case of a 66-year-old Indian man who presented with OGC induced by anti-tuberculosis medications which was initially suspected to be an anaphylactic reaction and was subsequently halted with the administration of diphenhydramine.",
"affiliations": "University College Cork, Cork, Ireland.;Tan Tock Seng Hospital, Singapore.",
"authors": "Wong|Lin Ho|LH|;Tan|Endean|E|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/IMCRJ.S147779",
"fulltext": "\n==== Front\nInt Med Case Rep JInt Med Case Rep JInternational Medical Case Reports JournalInternational Medical Case Reports Journal1179-142XDove Medical Press 10.2147/IMCRJ.S147779imcrj-10-341Case ReportAnti-tuberculosis medication-induced oculogyric crisis and the importance of proper history taking Wong Lin Ho 1Tan Endean 2\n1 University College Cork, Cork, Ireland\n2 Tan Tock Seng Hospital, SingaporeCorrespondence: Lin Ho Wong, 1 Jalan Senang, S418511, Singapore, Tel +353 83 446 3304, Fax +65 6357 7588, Email 113103563@umail.ucc.ie2017 13 10 2017 10 341 344 © 2017 Wong and Tan. This work is published and licensed by Dove Medical Press Limited2017The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Oculogyric crisis (OGC), frequently caused by medications such as antiemetics, antidepressants, and anti-epileptics, is an acute dystonic reaction of the ocular muscles. It consists of wide-staring gaze (lasting variably from seconds to minutes), seizures, and a widely-opened mouth. To date, there have been no reports of anti-tuberculosis medications such as rifampicin, isoniazid, pyrazinamide or ethambutol inducing OGC. It is of utmost importance to recognize this adverse reaction, which could be incorrectly diagnosed as an anaphylactic-like reaction. In this paper, we highlight a case of a 66-year-old Indian man who presented with OGC induced by anti-tuberculosis medications which was initially suspected to be an anaphylactic reaction and was subsequently halted with the administration of diphenhydramine.\n\nKeywords\noculogyric crisistuberculosisrifampicinisoniazidethambutoladverse drug reaction\n==== Body\nIntroduction\nDystonia consists of intermittent contractions of muscles resulting in irregular and repetitive movements. It is frequently triggered or aggravated by any voluntary action.1 Oculogyric crisis (OGC), is a form of ocular dystonia frequently caused by medications such as antipsychotics which usually lasts from seconds to minutes.2 It usually presents with contraction of extraocular muscles resulting in a deviation of the eyes.3 The adverse side effects of anti-tuberculosis (anti-TB) medications are well-documented, including arthralgia, neurological disorders, hepatotoxicity, allergic reactions, and gastrointestinal disorders.4,5 To date, there have been no reports of rifampicin, isoniazid, ethambutol, and pyrazinamide (RHEZ) causing OGC. We report a case of a 66-year-old Indian man, admitted to the Department of General Medicine, Tan Tock Seng Hospital, Singapore, who developed acute OGC 30 minutes after ingesting RHEZ.\n\nCase report\nWritten consent was obtained from the patient for the publication of his case and images. A 66-year-old Indian male patient presented to the Tuberculosis Control Unit after sudden onset of near syncope, nausea, diaphoresis, light-headedness, and a wide-staring gaze with upward and lateral deviation of eyes 30 minutes after consuming newly-prescribed RHEZ. These symptoms resolved on the administration of diphenhydramine 25 mg intravenously at the Emergency Department. The patient was referred, initially, to the Department of Rheumatology, Allergy and Immunology based on the suspicion of a reaction to RHEZ. A diagnosis of anaphylaxis-like and possibly idiosyncratic reaction to rifampicin was made.\n\nOn further questioning by the primary team, the patient reported that while he was aware of his surroundings and was able to hear conversations around him, he felt “physical blocked” in that he was unable to respond with purposeful voluntary movements or speech; he additionally described abdominal discomfort and generalized weakness.\n\nThe patient had just been prescribed daily rifampicin 600 mg, isoniazid 300 mg, ethambutol 1.6 g, pyrazinamide 1.75 g (i.e., standard RHEZ combination therapy for TB of uncertain origin and resistance, according to his weight of 98.3 kg) and pyridoxine 10 mg after increased nodular opacities in the left upper zone were observed on sequential chest X-rays (Figures 1 and 2), suggestive of granulomata. A small calcified pleural plaque was also noted. Blood cultures, sputum cultures, and Mycobacterium tuberculosis polymerase chain reaction were negative.\n\nOn his initial presentation after the near syncope, the patient’s vitals were stable and physical examination, including neurological examination, did not reveal any conclusive findings. A full blood count, liver function test, thyroid function test, drug screen, troponin I, electrocardiogram (Figure 3), and a two-dimensional echocardiography were performed.\n\nHowever, the diagnosis was subsequently changed to OGC based on the more complete history recorded. Another possible cause of OGC would include trauma. However, the patient did not suffer from any trauma recently.\n\nDiscussion\nAcute dystonia is intermittent or sustained involuntary muscle contractions involving the face, neck, and other parts of the body.6 OGC is a subset of acute dystonia which frequently affects the extraocular muscles resulting in spasmodic-like action. The most common cause includes medications such as metoclopramide, olanzapine, haloperidol, and carbam-azepine.7,8 Certain recreational drugs such as cocaine have also been reported to cause OGC.9 Interestingly, until now there have been no reports of anti-TB medications causing OGC. In addition, OGC can occur in Wilson’s disease, cystic glioma, and post-encephalitic parkinsonism.10-13\n\nThe pathophysiology of OGC is still uncertain, but it is believed to be caused by blockage of dopaminergic pathways centrally, which results in an upregulation of striatal acetylcholine.14 This in turn causes involuntary, irregular muscular contractions. A study done by Mendhekar et al. showed that, at low doses, amisulpride (100–300 mg/day) preferentially binds to D2/D3 presynaptic receptors which subsequently increases dopaminergic transmission in the prefrontal cortex. However, OGC occurred at a dose of 400-800 mg/day where there is antagonism of the postsynaptic dopaminergic receptors.15 Shumy et al. reported a case of pyrazinamide-induced parkinsonism which could be linked to the dopaminergic antagonist effects of it.16 Similarly, the dopaminergic antagonist effects of pyrazinamide could have resulted in the OGC.\n\nReversal of OGC may be effected with the use of anti- cholinergic medications like promethazine or diphenhydramine. Diphenhydramine served both as a diagnostic test and therapeutic intervention in this 66-year-old gentleman.\n\nIn this case, the diagnosis was based on history and the resolution of symptoms with diphenhydramine.\n\nConclusion\nOGC is often a diagnosis that is overlooked because of an incomplete history, poor appreciation of the presentation of OGC, and a low index of suspicion in cases where the medication implicated is not often associated with such a reaction. In such cases, rather than assigning a label such as an “allergic” reaction, the history should be confirmed and if possible, a monitored drug challenge undertaken to ascertain the reaction provoked. Physicians should also be alert toward medications which are not known to cause OGC, but may also cause it.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Nodular opacities in left upper zone periphery on chest X-ray (posteroanterior view).\n\nFigure 2 Nodular opacities in left upper zone periphery on chest X-ray (apical lordotic view).\n\nFigure 3 Electrocardiogram showing normal sinus rhythm.\n==== Refs\nReferences\n1 Albanese A Bhatia K Bressman SB Phenomenology and classification of dystonia: a consensus update Mov Disord 2013 28 7 863 873 23649720 \n2 Gardner DM Abidi S Ursuliak Z Morrison J Teehan MD Tibbo PG Incidence of oculogyric crisis and long-term outcomes with second-generation antipsychotics in a first-episode psychosis program J Clin Psychopharmacol 2015 35 6 715 718 26485339 \n3 Robottom BJ Factor SA Weiner WJ Movement disorders emergencies part 2: hyperkinetic disorders Arch Neurol 2011 68 6 719 724 21670395 \n4 Singla R Sharma SK Mohan A Evaluation of risk factors for antituberculosis treatment induced hepatotoxicity Indian J Med Res 2010 132 7 81 86 20693595 \n5 Volmink J Garner P Directly observed therapy for treating tuberculosis Cochrane Database Syst Rev 2007 4 CD003343 17943789 \n6 Munhoz RP Moscovich M Araujo PD Teive HA Movement disorders emergencies: a review Arq Neuropsiquiatr 2012 70 6 453 461 22699544 \n7 Bateman DN Rawlins MD Simpson JM Extrapyramidal reactions with metoclopramide Br Med J (Clin Res Ed) 1985 291 6500 930 932 \n8 Bhachech JT Aripiprazole-induced oculogyric crisis (acute dystonia) J Pharmacol Pharmacother 2012 3 3 279 281 23129969 \n9 van Harten PN Hoek HW Kahn RS Fortnightly review: acute dystonia induced by drug treatment BMJ 1999 319 7210 623 626 10473482 \n10 Onuaguluchi G Crises in post-encephalitic parkinsonism Brain 1961 84 395 414 14482072 \n11 Matsumura K Sakuta M Oculogyric crisis in acute herpetic brainstem encephalitis J Neurol Neurosurg Psychiatry 1987 50 3 365 366 3559623 \n12 Lee MS Kim YD Lyoo CH Oculogyric crisis as an initial manifestation of Wilson’s disease Neurology 1999 52 8 1714 1715 10331711 \n13 Stechison MT Cystic glioma with positional oculogyric crisis J Neurosurg 1989 71 6 955 957 \n14 Blanchet PJ Antipsychotic drug-induced movement disorders Can J Neurol Sci 2003 30 Suppl 1 S101 S107 12691483 \n15 Mendhekar DN Lohia D Kateria P Tardive oculogyric crisis associated with amisulpride monotherapy J Postgrad Med 2010 56 4 305 306 20935407 \n16 Shumy F Anam A Chowdhury M Shazzad M Pyrazinamide Induced Parkinsonism Journal Of Medicine 2017 18 1 44 46\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-142X",
"issue": "10()",
"journal": "International medical case reports journal",
"keywords": "adverse drug reaction; ethambutol; isoniazid; oculogyric crisis; rifampicin; tuberculosis",
"medline_ta": "Int Med Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101566269",
"other_id": null,
"pages": "341-344",
"pmc": null,
"pmid": "29075142",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "2627222;21670395;20935407;20693595;3559623;23129969;3929968;14482072;10473482;12691483;17943789;22699544;23649720;10331711;26485339",
"title": "Anti-tuberculosis medication-induced oculogyric crisis and the importance of proper history taking.",
"title_normalized": "anti tuberculosis medication induced oculogyric crisis and the importance of proper history taking"
} | [
{
"companynumb": "SG-AKORN PHARMACEUTICALS-2017AKN01409",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ETHAMBUTOL HYDROCHLORIDE"
},
"dr... |
{
"abstract": "OBJECTIVE\nTo determine if changes in Day 1 to Day 4 serum human chorionic gonadotropin (hCG) levels can predict treatment failure of single-dose methotrexate (MTX) in medical management of tubal ectopic pregnancies (EP).\n\n\nMETHODS\nThis retrospective cohort study was conducted at a tertiary level hospital. Files were reviewed for all women who received at least one dose of 50 mg/m2 intramuscular MTX for treatment of ultrasound-confirmed tubal EPs between 2013 and 2018. \"Treatment failure\" is defined as needing additional MTX or surgery to manage the EP. The primary purpose is to establish a threshold percentage change in Day 1 to Day 4 (Day 1/4) hCG that best predicts treatment failure, with clinically and statistically significant sensitivity and specificity, based on receiver-operator characteristic (ROC) analysis.\n\n\nRESULTS\n252 files were reviewed, with 108 included for final analysis. 17% of cases required a second dose of MTX and 12% required surgery to manage the EP. Women in the treatment failure group had significantly higher median hCG levels on Day 1, 4 and 7, but were otherwise similar to women who were successful in age, parity, history of previous EP, and EP size. ROC curve analysis of Day 1/4 hCG demonstrates that ≥5% rise best predicts treatment failure with sensitivity 68% (95% confidence interval [CI] 49-83%), specificity 69% (95%CI 56-78%), and AUC 0.77 (95%CI 0.68-0.86, p < 0.001). The positive predictive value is 46% (95%CI 36-56%) and negative predictive value is 84% (95%CI 75-90%). In comparison, ROC analysis of Day 4 to Day 7 hCG demonstrates that a drop of ≤17% best predicted failure, with sensitivity 83% (95%CI 64-94%), specificity 82% (95%CI 71-90%), and AUC 0.90 (95%CI 0.84-0.96), p < 0.001.\n\n\nCONCLUSIONS\nThis study suggests that ≥5% rise in Day 1/4 serum hCG levels could potentially predict treatment failure of single-dose MTX for tubal EPs, and that conversely, <5% rise or any drop in Day 1/4 hCG levels can reliably predict treatment success. Clinicians could consider factoring-in Day 1/4 hCG changes during the course of medically managing patients. They must bear in mind, however, that acting on the Day 1/4 hCG change would lead to increased interventions.",
"affiliations": "Department of Obstetrics and Gynaecology, Westmead Hospital, Hawkesbury Rd, Westmead, New South Wales, 2145, Australia; Sydney West Advanced Pelvic Surgery Unit, 6 Kempsey St, Blacktown, New South Wales, 2148, Australia. Electronic address: amy.goh@health.nsw.gov.au.;Department of Obstetrics and Gynaecology, Westmead Hospital, Hawkesbury Rd, Westmead, New South Wales, 2145, Australia. Electronic address: Priyanka.Karine@health.nsw.gov.au.;NHMRC Clinical Trials Centre at The University of Sydney, The University of Sydney, Sydney, New South Wales, 2006, Australia. Electronic address: Adrienne.Kirby@ctc.usyd.edu.au.;Department of Obstetrics and Gynaecology, Westmead Hospital, Hawkesbury Rd, Westmead, New South Wales, 2145, Australia. Electronic address: CoreyAtendra.Williams@health.nsw.gov.au.;Department of Obstetrics and Gynaecology, Westmead Hospital, Hawkesbury Rd, Westmead, New South Wales, 2145, Australia; Sydney West Advanced Pelvic Surgery Unit, 6 Kempsey St, Blacktown, New South Wales, 2148, Australia; The University of Sydney School of Medicine, Sydney, New South Wales, 2006, Australia. Electronic address: supuni.kapurubandara@health.nsw.gov.au.",
"authors": "Goh|Amy|A|;Karine|Priyanka|P|;Kirby|Adrienne|A|;Williams|Corey|C|;Kapurubandara|Supuni|S|",
"chemical_list": "D000020:Abortifacient Agents, Nonsteroidal; D018997:Chorionic Gonadotropin, beta Subunit, Human; D008727:Methotrexate",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.ejogrb.2020.10.036",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-2115",
"issue": "255()",
"journal": "European journal of obstetrics, gynecology, and reproductive biology",
"keywords": "Ectopic pregnancy; Methotrexate; Prognostic accuracy; Resource allocation; Tubal pregnancy",
"medline_ta": "Eur J Obstet Gynecol Reprod Biol",
"mesh_terms": "D000020:Abortifacient Agents, Nonsteroidal; D018997:Chorionic Gonadotropin, beta Subunit, Human; D005260:Female; D006801:Humans; D008727:Methotrexate; D011247:Pregnancy; D011271:Pregnancy, Ectopic; D011274:Pregnancy, Tubal; D012189:Retrospective Studies; D017211:Treatment Failure",
"nlm_unique_id": "0375672",
"other_id": null,
"pages": "105-110",
"pmc": null,
"pmid": "33113399",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Day 1 to day 4 serum hCG change in predicting single-dose methotrexate treatment failure for tubal ectopic pregnancies.",
"title_normalized": "day 1 to day 4 serum hcg change in predicting single dose methotrexate treatment failure for tubal ectopic pregnancies"
} | [
{
"companynumb": "AU-MYLANLABS-2021M1040445",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "Tremor is a frequent patient complaint in the neurologist's office. Nevertheless, despite the routine nature of this office presentation, misdiagnosis of common tremors is not an infrequent practice. In addition, there are less common causes of tremor that can be missed if the clinician is not aware of key features. An organized and methodical history and neurologic examination are essential in developing the differential diagnosis in tremor patients and ultimately in achieving the correct diagnosis. Awareness of key historical features associated with tremor and knowledge of the movement disorders examination will improve tremor assessment.",
"affiliations": "Neurology, Icahn School of Medicine at Mount Sinai, 10 Union Square East, Suite 5H, New York, NY 10003, USA. Electronic address: vshanker@chpnet.org.",
"authors": "Shanker|Vicki L|VL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0733-8619",
"issue": "34(3)",
"journal": "Neurologic clinics",
"keywords": "Dystonia; Essential tremor; FXTAS; Functional tremor; Parkinson’s disease; Tremor",
"medline_ta": "Neurol Clin",
"mesh_terms": "D000328:Adult; D000368:Aged; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009460:Neurologic Examination; D014202:Tremor",
"nlm_unique_id": "8219232",
"other_id": null,
"pages": "651-65",
"pmc": null,
"pmid": "27445246",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Case Studies in Tremor.",
"title_normalized": "case studies in tremor"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0086017",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo describe a case of aripiprazole-induced problem gambling and impulse-control deficit in a gambling-naïve patient following commencement of low-dose aripiprazole.\n\n\nMETHODS\nCase report.\n\n\nRESULTS\nThis case adds to the literature on the dopamine partial agonist aripiprazole causing or exacerbating problem gambling, and extends that literature to low-dose use of aripiprazole in the gambling naïve.\n\n\nCONCLUSIONS\nWhen commencing a patient on aripiprazole the possibility of emergence of problem gambling and other impulse-control deficits should be monitored, even in those with no history of similar behaviours and even on a low dose.",
"affiliations": "Psychiatry Resident, Alfred Health, Prahran, VIC, Australia.;Consultant Psychiatrist, Alfred Health, Prahran, VIC, Australia.",
"authors": "Peterson|Evan|E|;Forlano|Rosaria|R|",
"chemical_list": "D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D000068180:Aripiprazole",
"country": "England",
"delete": false,
"doi": "10.1177/1039856217715996",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1039-8562",
"issue": "25(6)",
"journal": "Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists",
"keywords": "antipsychotic; aripiprazole; dopamine partial agonist; pathological gambling",
"medline_ta": "Australas Psychiatry",
"mesh_terms": "D014150:Antipsychotic Agents; D000068180:Aripiprazole; D007174:Disruptive, Impulse Control, and Conduct Disorders; D018491:Dopamine Agonists; D005715:Gambling; D006801:Humans",
"nlm_unique_id": "9613603",
"other_id": null,
"pages": "614-616",
"pmc": null,
"pmid": "28696131",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Partial dopamine agonist-induced pathological gambling and impulse-control deficit on low-dose aripiprazole.",
"title_normalized": "partial dopamine agonist induced pathological gambling and impulse control deficit on low dose aripiprazole"
} | [
{
"companynumb": "AU-APOTEX-2017AP023780",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": "1",
... |
{
"abstract": "Cardiac perforation by pacemaker is a rare but potentially fatal complication. Acute perforations occurring within twenty-four hours of insertion of pacemaker can lead to hemopericardium, cardiac tamponade, and death. Hemothorax occurring as an acute complication of pacemaker insertion is reported but extremely rare. Previously, hemothorax and shock as a subacute complication following pacemaker insertion have not been reported. We report the case of an 85-year-old patient who presented with shock from hemothorax caused by pacemaker perforation, two weeks after insertion. Device interrogation showed normal function. Chest X-ray and echocardiogram missed lead dislocation and the diagnosis was made on computed tomogram (CT) of the chest. Following surgical repair, a new ventricular pacemaker was placed transvenously in the right ventricular septum. This case illustrates that CT scan of the chest should be performed in all patients in whom cardiac perforation by pacemaker is suspected but not diagnosed on chest X-ray and echocardiogram. Normal functioning of pacemaker on device interrogation does not exclude perforation.",
"affiliations": "Department of Medicine, University of CT Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA.;Department of Medicine, University of CT Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA.;Department of Medicine, University of CT Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA.;Division of Pulmonary and Critical Care Medicine, University of CT Health Center, Farmington, CT 06030, USA.",
"authors": "Nichols|Julianne|J|;Berger|Natalie|N|;Joseph|Praveen|P|;Datta|Debapriya|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2015/983930",
"fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi Publishing Corporation 10.1155/2015/983930Case ReportSubacute Right Ventricle Perforation by Pacemaker Lead Presenting with Left Hemothorax and Shock Nichols Julianne \n1\nBerger Natalie \n1\nJoseph Praveen \n1\nDatta Debapriya \n2\n\n*\n1Department of Medicine, University of CT Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA2Division of Pulmonary and Critical Care Medicine, University of CT Health Center, Farmington, CT 06030, USA*Debapriya Datta: ddatta@uchc.eduAcademic Editor: Tayfun Sahin\n\n2015 18 2 2015 2015 9839306 12 2014 27 1 2015 Copyright © 2015 Julianne Nichols et al.2015This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Cardiac perforation by pacemaker is a rare but potentially fatal complication. Acute perforations occurring within twenty-four hours of insertion of pacemaker can lead to hemopericardium, cardiac tamponade, and death. Hemothorax occurring as an acute complication of pacemaker insertion is reported but extremely rare. Previously, hemothorax and shock as a subacute complication following pacemaker insertion have not been reported. We report the case of an 85-year-old patient who presented with shock from hemothorax caused by pacemaker perforation, two weeks after insertion. Device interrogation showed normal function. Chest X-ray and echocardiogram missed lead dislocation and the diagnosis was made on computed tomogram (CT) of the chest. Following surgical repair, a new ventricular pacemaker was placed transvenously in the right ventricular septum. This case illustrates that CT scan of the chest should be performed in all patients in whom cardiac perforation by pacemaker is suspected but not diagnosed on chest X-ray and echocardiogram. Normal functioning of pacemaker on device interrogation does not exclude perforation.\n==== Body\n1. Introduction\nCardiac perforation by pacemaker is a rare but potentially fatal complication. Acute perforations occurring within twenty-four hours of insertion of pacemaker can lead to hemopericardium, cardiac tamponade, and death. Hemothorax as an acute complication of pacemaker is extremely rare and has not been reported as a subacute complication. We report the case of an 85-year-old patient with shock from hemothorax caused by pacemaker perforation, two weeks after insertion, which was missed on chest X-ray and echocardiogram but diagnosed on computed tomogram (CT) of chest.\n\n2. Case Description\nAn eighty-five-year-old female presented to the emergency room with complaints of sudden onset substernal chest pain and dizziness. Her past medical history was significant for atrial fibrillation. She had a pacemaker inserted at another facility 2 weeks before. No perioperative complications were reported and patient had been doing well without any complaints till the day of presentation. Medications included dabigatran for her atrial fibrillation. On examination, the patient was diaphoretic but in no respiratory distress. Temperature was 97°F, pulse 96/minute, irregular; systolic blood pressure was 70 mm Hg; respiratory rate was 22/minute; and oxygen saturation was 95% on room air. No jugular venous distension was noted. Cardiac examination revealed irregular rhythm, no murmur or rub. Lung auscultation revealed slightly diminished breath sounds at left base. Chest X-ray showed a mild-to-moderate left-sided pleural effusion; pacemaker leads appeared to be in the right ventricle (Figure 1). Electrocardiogram (EKG) showed trioventricular (AV) sequential pacing (Figure 2). Echocardiogram (ECHO) revealed no wall motion abnormality with normal ejection fraction. Pacemaker leads were visualized in the right ventricle (RV) on ECHO. Her hemoglobin was 8 gm%; prothrombin time (PT) was 19 seconds; and INR was 2.9.\n\nNo pacing or sensing failure was noted on device interrogation. The patient's hypotension persisted despite vigorous intravenous fluid resuscitation including transfusion of 2 units of blood cell and 6 units of fresh frozen plasma and improvement in her hemoglobin to 11 gm%. A computed tomogram (CT) of the chest was performed which showed a moderate left pleural effusion, with the pacemaker wire extending to the left pleural cavity and a small localized pericardial effusion adjoining the pleural effusion (Figure 3). The patient's hemodynamic instability was not due to tamponade effect as the pericardial effusion was small but due to continued hemorrhage into the pleural cavity due to her coagulopathic state from being on dabigatran for her atrial fibrillation, which was not fully corrected by fresh frozen plasma infusion.\n\nThe patient was taken to the operating room where she underwent a median sternotomy. The pacemaker lead was found to be protruding out of the right ventricle (Figure 4). The external portion was cut with the remaining intracardiac portion of the pacemaker lead left in place. The perforation of the RV wall was repaired. The hemothorax and hemopericardium were evacuated. Subsequently, the patient's hemodynamic status improved. Two days later, the remaining portion of the pacemaker lead was removed transvenously. A new pacemaker was inserted transvenously and placed on the right ventricular septum. The patient did not have further complications and was discharged home subsequently. On follow-up 6 weeks later, she was doing well.\n\n3. Discussion\nThough rare, cardiac perforation in patients after pacemaker implantation is potentially life-threatening. Reported rate of occurrence of pacemaker perforation is 0.1–3% [1–4]. Perforations occurring within 24 h after implantation are labeled as acute; those occurring within one month after implantation are subacute while perforations which occur after one month are labeled as chronic [5, 6]. Pacemaker perforations may occur through the walls of the large veins, atria, or ventricles. Perforations involve the RV apex, which is thinner, more commonly than the intraventricular septum or the outflow tract [6].\n\nThe pathophysiology behind the occurrence of pacemaker perforation is not clearly understood but is believed to be multifactorial and related to the pacemaker lead dimension and overtorquing of the leads [2]. It is hypothesized that increased pressure force exerted by the thin pacemaker leads per unit of the ventricular wall, as well as the imbalance between the pacemaker lead tip forces and the ventricle, result in perforation [5, 7].\n\nSymptoms and signs of pacemaker perforation depend on the location of the displaced lead [3, 5]. The pacemaker may perforate the vascular chamber and migrate to the pericardial cavity, pleural cavity, mediastinum, lung, diaphragm, chest muscles, and the peritoneal cavity [6]. The common symptoms are chest pain, dyspnea, abdominal pain, and dizziness [8]. Hiccups due to diaphragm contraction or visible chest muscle contraction may occur from displaced pacemaker stimulation [3, 9]. Hemodynamic instability may occur if hemopericardium develops and leads to cardiac tamponade which can result in shock, heart failure, and cardiac arrest [6]. Occurrence of left hemothorax with pacemaker perforation is very rare and can also result in hemodynamic instability which may be life-threatening, as in this patient. Perforated pacemaker leads can result in pacing and sensing failures [8, 10]. Changes of pacing parameters such as capture threshold and sensing threshold depend on the location of the displaced lead tip. Loss of consciousness, heart failure, and cardiac arrest may occur because of pacing failure [2, 8].\n\nChest X-ray is an easy and commonly used diagnostic method for detecting pacemaker perforation. On chest X-ray, a diagnosis of pacemaker perforation can be made if the lead is located beyond the confines of the cardiac silhouette. A lateral view of the chest should always be performed as it can localize the position of the pacemaker lead more accurately. Chest X-ray can also detect extracardiac complications such as pleural or pericardial effusion and pneumothorax. Echocardiography (ECHO), a simple and noninvasive test that can be performed easily at the bedside, can also help to assess electrode location and detect presence of the pacemaker lead tip in the pericardium and presence of pericardial effusion. However both of these diagnostic tests have their limitations and the location of the pacemaker lead tip may not be correctly located, as is evident in this case. CT scan of the chest is currently regarded as the gold standard in the diagnosis of pacemaker lead perforations [11, 12]. Performing CT scans is standard care in most departments dealing with cardiac implantable electronic devices implants. Chest CT accurately reveals pacemaker lead displacement which can sometimes be missed by chest X-ray or ECHO as in this patient. In addition, it can confirm the presence of an associated pericardial effusion/hemopericardium or pleural effusion/hemothorax [13]. However, it should be borne in mind that the position of pacemaker wires may be misinterpreted on CT due to artifacts. An atypical position of the pacemaker lead with a left-sided pleural effusion, decreased hemoglobin, and hemodynamic instability should lead to the diagnosis without the need for a CT scan.\n\nPacemaker interrogation should be performed as part of the evaluation in patients with suspected pacemaker perforation. However, normal function and absence of sensing and pacing failure do not rule out pacemaker perforation [2]. Several studies have reported various factors that serve as predictors of lead perforation. These include temporary leads, steroid use, active fixation leads, low body mass index (<20 kg/m2), older age, female gender, and concomitant anticoagulation [14, 15]. In this case, three of these predictor factors were present: older age, female gender, and ongoing anticoagulation. The only known protective factor for cardiac perforation is right ventricular systolic pressure >35 mm Hg, which is attributed to coexisting right ventricular hypertrophy [15].\n\nManagement depends on patients' hemodynamic status, patients' symptoms, and the presence of associated pericardial or pleural effusion [16]. Emergent surgical management is required if the patient is hemodynamically unstable or if the patient has a large pericardial effusion where tamponade may be imminent or a large pleural effusion with respiratory impairment is present or imminent [16, 17]. In such cases, sternotomy with surgical removal of the perforating leads, evacuation of effusions, and repair of tear should be performed. In cases of lead perforation outside the pericardium, as in this patient, cardiac surgery or video-assisted thoracoscopic surgery is recommended for cutting the extracardiac portion of the tip, repairing the tear and then removing the remaining intracardiac portion of the lead removed transvenously [6, 8]. In hemodynamically stable patients, the pacemaker can be extracted by direct traction or percutaneous lead extraction in the operating room, under close echocardiographic or fluoroscopic monitoring, with surgical backup being available [5, 18]. Lead extraction should be followed by new lead placement in a different location, preferably in the right ventricular outflow tract or the intraventricular septum.\n\nNo consensus exists regarding the appropriate management of lead perforation in stable patients without symptoms or the management of chronic lead perforation without pacemaker malfunction. Some experts recommend lead removal in all such cases [12] while others [2] recommend against the removal of a chronically perforated lead without pacemaker malfunction.\n\n4. Conclusion\nAt the present time, pacemaker insertion is a commonly performed therapeutic intervention for the management of specific arrhythmias. Though the complications arising from pacemaker insertion are uncommon, they can be life-threatening and hence should be considered in all patients with cardiac pacemakers in the appropriate clinical setting. Normal function on device interrogation does not rule out perforation. Chest X-rays and echocardiogram, though easy to perform, may miss displaced pacemaker leads. CT chest is the gold standard for the diagnosis of pacemaker lead perforation. Hence, CT scan of the chest should be performed in all patients in whom pacemaker perforation is suspected but not diagnosed on chest X-ray and ECHO.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Chest X-ray AP view: opacity at left base consistent with a moderate left-sided pleural effusion; pacemaker leads appear to be present in the right ventricle.\n\nFigure 2 EKG showing AV sequential pacing.\n\nFigure 3 CT scan of chest showing the pacemaker wire extending to the left pleural cavity with a moderate pleural effusion and a small localized adjoining pericardial effusion.\n\nFigure 4 The tip of pacemaker lead is seen protruding out of the right ventricle.\n==== Refs\n1 Burney K. Burchard F. Papouchado M. Wilde P. Cardiac pacing systems and implantable cardiac defibrillators: a radiological perspective of equipment, anatomy and complications Clinical Radiology 2004 59 8 699 708 2-s2.0-3543129491 10.1016/j.crad.2004.01.009 15262543 \n2 Hirschl D. A. Jain V. R. Spindola-Franco H. Gross J. N. Haramati L. B. Prevalence and characterization of asymptomatic pacemaker and ICD lead perforation on CT Pacing and Clinical Electrophysiology 2007 30 1 28 32 10.1111/j.1540-8159.2007.00575.x 2-s2.0-33846271454 17241311 \n3 Piekarz J. Lelakowski J. Rydlewska A. Majewski J. Heart perforation in patients with permanent cardiac pacing—pilot personal observations Archives of Medical Science 2012 8 1 70 74 10.5114/aoms.2012.27284 2-s2.0-84858117988 22457678 \n4 Akyol A. Aydin A. Erdinler I. Oguz E. Late perforation of the heart, pericardium, and diaphragm by an active-fixation ventricular lead Pacing and Clinical Electrophysiology 2005 28 4 350 351 10.1111/j.1540-8159.2005.09374.x 2-s2.0-18044386589 15826277 \n5 Laborderie J. Barandon L. Ploux S. Management of subacute and delayed right ventricular perforation with a pacing or an implantable cardioverter-defibrillator lead American Journal of Cardiology 2008 102 10 1352 1355 10.1016/j.amjcard.2008.07.025 2-s2.0-55249112099 18993154 \n6 Banaszweski M. Stepinska J. Right heart perforation by pacemaker leads Archives of Medical Science 2012 8 11 13 22457667 \n7 Singhal S. Cooper J. M. Cheung A. T. Acker M. A. Rib perforation from a right ventricular pacemaker lead Circulation 2007 115 14 e391 e392 10.1161/CIRCULATIONAHA.106.669630 2-s2.0-34247103969 17420357 \n8 Welch A. R. Yadav P. Lingle K. Subacute right ventricular perforation Journal of Innovations in Cardiac Rhythm Management 2011 2 442 445 \n9 Haq S. A. Heitner J. F. Lee L. Kassotis J. T. Late presentation of a lead perforation as a complication of permanent pacemaker insertion Angiology 2008 59 5 619 621 10.1177/0003319707306438 2-s2.0-53949107157 18388077 \n10 Selcuk H. Selcuk M. T. Maden O. Uncomplicated heart and lung perforation by a displaced ventricular pacemaker lead Pacing and Clinical Electrophysiology 2006 29 4 429 430 10.1111/j.1540-8159.2006.00366.x 2-s2.0-33645725071 16650275 \n11 Henrikson C. A. Leng C. T. Yuh D. D. Brinker J. A. Computed tomography to assess possible cardiac lead perforation Pacing and Clinical Electrophysiology 2006 29 5 509 511 10.1111/j.1540-8159.2006.00385.x 2-s2.0-33646505037 16689847 \n12 Khan M. N. Joseph G. Khaykin Y. Ziada K. M. Wilkoff B. L. Delayed lead perforation: a disturbing trend Pacing and Clinical Electrophysiology 2005 28 3 251 253 2-s2.0-15344339217 10.1111/j.1540-8159.2005.40003.x 15733190 \n13 Greenberg S. Lawton J. Chen J. Images in cardiovascular medicine. Right ventricular lead perforation presenting as left chest wall muscle stimulation Circulation 2005 111 25 e451 e452 10.1161/circulationaha.104.494732 2-s2.0-33644828166 15983254 \n14 Sterliński M. Przybylski A. Macia̧g A. Subacute cardiac perforations associated with active fixation leads Europace 2009 11 2 206 212 10.1093/europace/eun363 2-s2.0-59449096055 19109359 \n15 Mahapatra S. Bybee K. A. Bunch T. J. Incidence and predictors of cardiac perforation after permanent pacemaker placement Heart Rhythm 2005 2 9 907 911 10.1016/j.hrthm.2005.06.011 2-s2.0-25444441460 16171740 \n16 Sanoussi A. El Nakadi B. Lardinois I. De Bruyne Y. Joris M. Late right ventricular perforation after permanent pacemaker implantation: how far can the lead go? Pacing and Clinical Electrophysiology 2005 28 7 723 725 10.1111/j.1540-8159.2005.00156.x 2-s2.0-22244477456 16008811 \n17 Wilkoff B. L. Love C. J. Byrd C. L. Transvenous lead extraction Heart Rhythm 2009 6 1085 1184 19560098 \n18 Bigdeli A. K. Beiras-Fernandez A. Kaczmarek I. Kowalski C. Schmoeckel M. Reichart B. Successful management of late right ventricular perforation after pacemaker implantation Vascular Health and Risk Management 2010 6 1 27 30 2-s2.0-77950833137 20191080\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6404",
"issue": "2015()",
"journal": "Case reports in cardiology",
"keywords": null,
"medline_ta": "Case Rep Cardiol",
"mesh_terms": null,
"nlm_unique_id": "101576452",
"other_id": null,
"pages": "983930",
"pmc": null,
"pmid": "25785204",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "19109359;18388077;15733190;19560098;17241311;18993154;17420357;22457667;16008811;15262543;16171740;15826277;16650275;16689847;22457678;20191080;15983254",
"title": "Subacute right ventricle perforation by pacemaker lead presenting with left hemothorax and shock.",
"title_normalized": "subacute right ventricle perforation by pacemaker lead presenting with left hemothorax and shock"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-01349GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "Rat-bite fever (RBF) is a challenging diagnosis transmitted by the bite of the rats. We present the first reported case of RBF complicated by vertebral osteomyelitis. It is important to consider performing the MRI to differentiate vertebral osteomyelitis from simple back pain to determine the appropriate duration of antibiotic therapy.",
"affiliations": "Department of Emergency and Critical Care Medicine, Urasoe General Hospital, Okinawa, Japan. Electronic address: st051035@gmail.com.;Department of General Medicine, Kurashiki Central Hospital, Okayama, Japan.;Department of Emergency and Critical Care Medicine, Urasoe General Hospital, Okinawa, Japan.",
"authors": "Sato|Ryota|R|;Kuriyama|Akira|A|;Nasu|Michitaka|M|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "22(8)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Rat-bite fever; Spirillum minus; Streptobacillus moniliformis; Vertebral osteomyelitis",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000818:Animals; D001733:Bites and Stings; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010019:Osteomyelitis; D011906:Rat-Bite Fever; D051381:Rats",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "574-6",
"pmc": null,
"pmid": "26948832",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rat-bite fever complicated by vertebral osteomyelitis: A case report.",
"title_normalized": "rat bite fever complicated by vertebral osteomyelitis a case report"
} | [
{
"companynumb": "PHHY2017JP086497",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe use of cisplatin in patients with chronic kidney disease (CKD) is risky and depends on a number of factors. The optimal procedure in stage I of a non seminomatous germ cell tumor without proven lymphangioinvasion after orchiectomy is controversial and is the subject of a number of discussions due to the lack of randomized studies assessing individual treatment options. The adjuvant method of choice is surveillance or application of cisplatin-based chemotherapy with the risk of treatment related nephrotoxicity. Information about cisplatin safety in renal transplant patients is particularly limited. The aim of this paper is to share the experience with the application of adjuvant chemotherapy Bleomycin, Etoposide, Cisplatin (BEP) in high-risk patient with nonseminoma after kidney transplantation.\nWe report a case report of rare group of high-risk patient with non-seminomatous germ cell testicular tumor (NSGCT) after kidney transplantation before application of adjuvant chemotherapy BEP. Patient presented with month-long discomfort in the scrotal area. Previously, he was treated with chronic kidney disease based on chronic glomerulonephritis, which was treated with repeated kidney transplantation.\n\n\nMETHODS\nThe ultrasound examination for a month-long discomfort in the scrotal area found a solid mass of the left testis. Radical inguinal orchiectomy confirmed NSGCT with the presence of lymphovascular invasion (LVI). Postoperative staging with computed tomography of the chest and abdomen did not show obvious dissemination of the disease.\n\n\nMETHODS\nReducing original dose of chemotherapeutics according to the recommendations of the summary of product characteristics led to only a transient increase in creatinine levels.\n\n\nRESULTS\nThe 5-year risk of relapse in surveillance was reduced to around 3% by applying cisplatin-based chemotherapy.\n\n\nCONCLUSIONS\nApplication of cisplatin-based chemotherapy is safe and effective in patients with CKD and in patients with a kidney transplant.",
"affiliations": "Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute.;Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute.;Department of Radiation Oncology, Masaryk Memorial Cancer Institute.;Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute.;Department of Comprehensive Cancer Care, Faculty of Medicine, Masaryk University, Kamenice 5.;Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute.",
"authors": "Pokrivcak|Tomas|T|0000-0002-5910-9209;Lakomy|Radek|R|;Kazda|Tomas|T|;Poprach|Alexandr|A|;Fabian|Pavel|P|;Kiss|Igor|I|",
"chemical_list": "D001761:Bleomycin; D005047:Etoposide; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000026381",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\n34128899\nMD-D-21-01686\n10.1097/MD.0000000000026381\n26381\n5700\nResearch Article\nClinical Case Report\nThe use of cisplatin in patients after kidney transplantation with chronic renal insufficiency\nIs the benefit higher than potential risks in therapy of non-seminomatous germ cell tumors?\nPokrivcak Tomas MD ab\nLakomy Radek MD, PhD ab\nKazda Tomas PhD c\nPoprach Alexandr PhD ab\nFabian Pavel MD, PhD bd\nKiss Igor PhD ab∗\nSaranathan. Maya\na Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute\nb Department of Comprehensive Cancer Care, Faculty of Medicine, Masaryk University, Kamenice 5\nc Department of Radiation Oncology, Masaryk Memorial Cancer Institute\nd Department of Pathology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.\n∗ Correspondence: Igor Kiss, Zluty kopec 7, 656 53 Brno, Czech Republic (e-mail: kiss@mou.cz).\n18 6 2021\n18 6 2021\n100 24 e263818 3 2021\n25 5 2021\n2 6 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nRationale:\n\nThe use of cisplatin in patients with chronic kidney disease (CKD) is risky and depends on a number of factors. The optimal procedure in stage I of a non seminomatous germ cell tumor without proven lymphangioinvasion after orchiectomy is controversial and is the subject of a number of discussions due to the lack of randomized studies assessing individual treatment options. The adjuvant method of choice is surveillance or application of cisplatin-based chemotherapy with the risk of treatment related nephrotoxicity. Information about cisplatin safety in renal transplant patients is particularly limited. The aim of this paper is to share the experience with the application of adjuvant chemotherapy Bleomycin, Etoposide, Cisplatin (BEP) in high-risk patient with nonseminoma after kidney transplantation.\n\nPatient concerns:\n\nWe report a case report of rare group of high-risk patient with non-seminomatous germ cell testicular tumor (NSGCT) after kidney transplantation before application of adjuvant chemotherapy BEP. Patient presented with month-long discomfort in the scrotal area. Previously, he was treated with chronic kidney disease based on chronic glomerulonephritis, which was treated with repeated kidney transplantation.\n\nDiagnosis:\n\nThe ultrasound examination for a month-long discomfort in the scrotal area found a solid mass of the left testis. Radical inguinal orchiectomy confirmed NSGCT with the presence of lymphovascular invasion (LVI). Postoperative staging with computed tomography of the chest and abdomen did not show obvious dissemination of the disease.\n\nInterventions:\n\nReducing original dose of chemotherapeutics according to the recommendations of the summary of product characteristics led to only a transient increase in creatinine levels.\n\nOutcomes:\n\nThe 5-year risk of relapse in surveillance was reduced to around 3% by applying cisplatin-based chemotherapy.\n\nLessons:\n\nApplication of cisplatin-based chemotherapy is safe and effective in patients with CKD and in patients with a kidney transplant.\n\nKeywords\n\ncisplatin\ngerm-cell tumor\nnephrotoxicity\ntreatment\nMinisterstvo Zdravotnictví Ceské RepublikyMMCI, 00209805 Igor KissOPEN-ACCESSTRUE\n==== Body\n1 Introduction\n\nThe optimal procedure in stage I of a non seminomatous germ cell tumor without proven lymphangioinvasion after orchiectomy is controversial and is the subject of a number of discussions due to the lack of randomized studies assessing individual treatment options. The risk of tumor relapse in 5 years after orchiectomy is in the absence of lymphangioinvasion in “low risk” tumors around 15%.[1] The adjuvant method of choice is surveillance or application of cisplatin-based chemotherapy. In the presence of lymphangioinvasion is tumor defined as a “high risk” and the probability of tumor relapse in 5 years after surgery is about 50%. The 5-year risk of relapse in surveillance can be reduced to around 3% by applying cisplatin-based chemotherapy (BEP—Bleomycin, Etoposide, Cisplatin).[2] One of the limiting side effects of cisplatin is nephrotoxicity. The use of cisplatin in patients with chronic renal failure is risky and depends on a number of factors. Information about cisplatin safety in renal transplant patients is particularly limited. The aim of this paper is to share the experience with the application of adjuvant chemotherapy BEP in high-risk patient with nonseminoma after kidney transplantation.\n\n2 Case report\n\nA 58-year-old patient was referred to the urologist in January 2017 for a month-long discomfort in the scrotal area. The ultrasound examination found a solid mass of the left testis, which led to a radical inguinal orchiectomy on February 1, 2017. The examination by a pathologist showed a 20 mm tumor with histological findings of non-seminomatous germ cell testicular tumors (NSGCT). The dominant component was embryonal carcinoma with admixture of yolk sac tumor. The presence of lymphovascular invasion (LVI) was confirmed in the tumor (Fig. 1). Postoperative staging with computed tomography of the chest and abdomen did not show obvious dissemination of the disease. The level of tumor blood markers before and after surgery was without elevation. The definitive staging was closed according to the 8th TNM classification as pT2 N0 M0 S0—clinical stage IB. Due to the presence of LVI, the finding met the definition of “high risk” tumor. In March 2017, the patient was referred to the Masaryk Memorial Cancer Institute to consult further therapy. In addition to the tumor, the patient was also treated with chronic kidney disease (CKD) based on chronic glomerulonephritis, which was treated with repeated kidney transplantation. The first kidney transplantation was performed in December 2003. The second kidney transplantation—based on graft rejection—was performed in October 2008. Actual creatinine values ranged from 1.58 to 1.7 mg/dL and the graft function met the definition of CKD 3a-b.\n\nFigure 1 The presence of tumor cells within a lymphatic vessel lumen at 400× magnification.\n\nThe guidelines of the National Comprehensive Cancer Network and European Association of Urology recommend cisplatin-based adjuvant chemotherapy (BEP) in patients with stage I NSGCT with confirmed LVI.[3,4] By applying of 1 series of BEP chemotherapy it is possible to reduce the risk of relapse in 5 years from 50% to 3.2%.[2] Due to the CKD in the transplanted kidney, benefits and risks of chemotherapy were discussed with the patient, including the possibility of graft failure and the dialysis. In the second variant, the patient was also acquainted with the possibility of active surveillance. However, due to the presence of a high risk tumor, there was a risk of relapse of up to 50% during the first 5 years after orchiectomy. In case of dissemination, curative chemotherapy with ≥3 series of chemotherapy would be then indicated with uncertain results and higher toxicity than in adjuvant administration. The functionality of the transplanted kidney and the time from transplantation to the time of diagnosis (9 years) also played an important role in the shared decision-making process. In this context, there was a risk of dialysis for 2 to 3 years, followed by a very limited possibility of using chemotherapy at that time. These options have been repeatedly discussed with the patient. Based on the information provided, patient agreed to the application of 1 series of adjuvant chemotherapy BEP. According to the recommendations of the Summary of product characteristics, the dose of individual chemotherapeutics was reduced to 75% of the original dose.[5] Due to the risk of nephrotoxicity, chemotherapy was administered through the intensive care unit from March 22, 2017 to March 26, 2017 with careful monitoring of fluid balance and creatinine levels. On day 9, the patient developed fever above 38°. The control laboratory showed grade 4 neutropenia and an elevated level of CRP. Due to the presence of febrile neutropenia, therapy with broad-spectrum antibiotics was initiated. Following administration of 5 granulocyte colony stimulating factor, neutrophil levels normalized. Other forms of hematological toxicity included grade 4 asymptomatic thrombocytopenia. Diuresis was sufficient, with creatinine fluctuations from 1.58 to 2.51 mg/dL, Fig. 2. The further course then proceeded without complications and the patient was subsequently discharged in a stable state and with satisfactory laboratory parameters for home treatment. Relapse of the disease has not been proven so far in the dispensary. The last computed tomography examination of the abdomen in September 2020 was without evidence of metastases. At regular nephrology examinations, the transplanted kidney has a stable function, without the need to include the patient in a dialysis program. Informed consent was obtained from the patient for the purpose of research and presentation of data in anonymous form.\n\nFigure 2 Time course of creatinine concentrations. Dates are in MM.DD.YYYY format.\n\n3 Discussion\n\nAccording to the Surveillance, Epidemiology, and End Results database, >67% of testicular tumors are diagnosed in stage I and >60% have >1 histological component.[6] The optimal procedure for stage I NSGCT is inconsistent and depends on the presence of risk factors, most importantly by presence of LVI.[7] The management after orchiectomy includes surveillance, cisplatin-based chemotherapy (BEP), and retroperitoneal lymph node dissection. Among chemotherapeutics with potentially lower nephrotoxicity, the inferiority of the carboplatin-Carboplatin, Etoposide, Bleomycin (CEB) versus BEP regimen has been previously demonstrated in randomized trials.[8,9] In the Horwich study, patients received either 4 series of BEP or 4 series of CEB. Failure after BEP chemotherapy occurred in 30 patients compared with 79 cases after CEB (log-rank X2 = 6.9; P < .001). The most important risk factor is the presence of LVI, which is detected in about 1/3 of patients.[10] In the presence of LVI, the tumor is defined as a “high risk” and the risk of relapse in 5 years after surgery is about 50%. In the absence of LVI, it is a “low risk” tumor and the risk of relapse decreases to 15% to 20%.[1] The current recommendation of the NCCCN based on data from the prospective study SWENOTECA in low-risk tumors (LVI-) leaves the choice between surveillance and 1 series of BEP. The 5-year risk of relapse in surveillance can be reduced from 15% to 1.6% by applying 1× BEP. For high risk tumors (LVI +), the application of 1 series of BEP is recommend which can reduce the risk of relapse to 3.2%.[2] Original data from Cullen et al[11] from 1996 without stratification of patients according to risk factors show a relapse risk of 2.7% after administration of 2 series of adjuvant BEP chemotherapy. A number of studies have confirmed a direct link between the total dose of chemotherapy administered and the increased incidence of late adverse events.[12–14] However, in most studies, the incidence of adverse reactions was reported following the curative chemotherapy—≥3 cisplatin-based series. Typical adverse reactions associated with cisplatin include kidney damage, high emetogenic potential, peripheral neuropathy, ototoxicity, and hematological toxicity potentiated by other chemotherapeutic agents. Due to the predominant renal excretion of cisplatin, the concentration in tubular epithelial cells is 5 times higher than in blood. An early clinical use of cisplatin has demonstrated the occurrence of acute renal failure in direct response to cumulative dose.[15] The current use of cisplatin in regimens involving pre and posthydration with careful monitoring of diuresis in the treatment of testicular tumors is associated with renal impairment in about 20% to 30% of patients. The renal function generally recovers 2 to 4 weeks after treatment.[16] In our patient, despite the limited lifespan of the transplanted kidney, dialysis has not been indicated for 11 years. The efficacy and safety of cisplatin-based chemotherapy have been demonstrated in the past in a number of case reports in renal transplant patients.[17–21] It, however, included cases of patients with disseminated NSGCT where the absence of chemotherapy led to disease progression.\n\nIn summary, based on our experience and presented case reports, it can be assumed that the application of cisplatin-based chemotherapy is safe and effective in CKD and in patients with a kidney transplant. An important part of the therapy is careful fluid balance and control of the internal environment. The key part is sharing the decision-making process with the patient.\n\nAuthor contributions\n\nConceptualization: Tomas Pokrivcak, Radek Lakomy, Pavel Fabian, Igor Kiss.\n\nData curation: Tomas Pokrivcak.\n\nFunding acquisition: Igor Kiss.\n\nInvestigation: Radek Lakomy, Pavel Fabian.\n\nMethodology: Tomas Pokrivcak, Pavel Fabian.\n\nResources: Tomas Kazda.\n\nSupervision: Alexandr Poprach.\n\nWriting – original draft: Tomas Pokrivcak, Radek Lakomy, Tomas Kazda.\n\nWriting – review & editing: Tomas Pokrivcak, Radek Lakomy, Tomas Kazda, Alexandr Poprach, Igor Kiss.\n\nAbbreviations: BEP = Bleomycin, Etoposide, Cisplatin, CEB = Carboplatin, Etoposide, Bleomycin, CKD = chronic kidney disease, LVI = lymphovascular invasion, NSGCT = non-seminomatous germ cell testicular tumor.\n\nHow to cite this article: Pokrivcak T, Lakomy R, Kazda T, Poprach A, Fabian P, Kiss I. The use of cisplatin in patients after kidney transplantation with chronic renal insufficiency - is the benefit higher than potential risks in therapy of non-seminomatous germ cell tumors? Medicine. 2021;100:24(e26381).\n\nSupported by MH CZ – DRO (MMCI, 00209805).\n\nThe authors have no conflicts of interest to disclose.\n\nThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\n==== Refs\nReferences\n\n[1] Tandstad T Ståhl O Håkansson U . One course of adjuvant BEP in clinical stage I nonseminoma mature and expanded results from the SWENOTECA group. Ann Oncol 2014;25 :2167–72.25114021\n[2] Divrik RT Akdoğan B Ozen H Zorlu F . Outcomes of surveillance protocol of clinical stage I nonseminomatous germ cell tumors-is shift to risk adapted policy justified? J Urol 2006;176 ((4 pt 1)) :1424–9.16952649\n[3] National Comprehensive Cancer Network. Testicular Cancer (Version 1.2021). Available at: https://www.nccn.org/professionals/physician_gls/pdf/testicular.pdf. Accessed December 16, 2020.\n[4] EAU Guidelines. Edn. presented at the EAU Annual Congress Amsterdam; 2020. ISBN 978–94-92671-07-3.\n[5] Ebewe Pharma Ges.m.b.H. Nfg. KG(2019) Cisplatin Ebewe 1 mg/ml Concentrate for Solution for Infusion SmPC. Available at: http://www.sukl.cz/modules/medication/detail.php?code=0189992&tab=texts (Accessed: March 20, 2017).[Article in Czech].\n[6] Albers P Siener R Kliesch S . Risk factors for relapse in clinical stage I nonseminomatous testicular germ cell tumors: results of the German Testicular Cancer Study Group Trial. J Clin Oncol 2003;21 :1505–12.12697874\n[7] Bokemeyer C Köhrmann O Tischler J . A randomized trial of cisplatin, etoposide and bleomycin (PEB) versus carboplatin, etoposide and bleomycin (CEB) for patients with ’good-risk’ metastatic non-seminomatous germ cell tumors. Ann Oncol 1996;7 :1015–21.9037359\n[8] Horwich A Sleijfer DT Fosså SD . Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide, and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer: a Multiinstitutional Medical Research Council/European Organization for Research and Treatment of Cancer Trial. J Clin Oncol 1997;15 :1844–52.9164194\n[9] Ghazarian AA Trabert B Devesa SS McGlynn KA . Recent trends in the incidence of testicular germ cell tumors in the United States. Andrology 2015;3 :13–8.25331158\n[10] Pont J Albrecht W Postner G . Adjuvant chemotherapy for high-risk clinical stage I nonseminomatous testicular germ cell cancer: long-term results of a prospective trial. J Clin Oncol 1996;14 :441–8.8636755\n[11] Cullen MH Stenning SP Parkinson MC . Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: a Medical Research Council report. J Clin Oncol 1996;14 :1106–13.8648364\n[12] Travis LB Fosså SD Schonfeld SJ . Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst 2005;97 :1354–65.16174857\n[13] Van den Belt-Dusebout AW de Wit R Gietema JA . Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 2007;25 :4370–8.17906202\n[14] Haugnes HS Bosl GJ Boer H . Long-term and late effects of germ cell testicular cancer treatment and implications for follow-up. J Clin Oncol 2012;30 :3752–63.23008318\n[15] Goldstein RS Mayor GH . Minireview. The nephrotoxicity of cisplatin. Life Sci 1983;32 :685–90.6338333\n[16] Hartmann JT Kollmannsberger C Kanz L Bokemeyer C . Platinum organ toxicity and possible prevention in patients with testicular cancer. Int J Cancer 1999;83 :866–9.10597214\n[17] Osiason AW Polackwich RJ . Curative, platinum-based cytoxic drug therapy in a renal transplant recipient with metastatic testicular cancer. Cancer 1986;58 :850–1.2424586\n[18] Vogelzang NJ . Cisplatin and etoposide for metastatic testis cancer in a renal transplant recipient. J Urol 1990;143 :1235–6.2160550\n[19] Wood DP Jr Novick AC Johnson DE . Treatment of metastatic transitional cell carcinoma following renal transplantation. Cleve Clin J Med 1989;56 :61–3.2659198\n[20] Droz JP Chailley J Kreis H . Germinal cell tumors of the testis (GCTT) in renal transplanted patients (RTP): report of two cases. Prog Clin Biol Res 1985;203 :685–6.3008190\n[21] Juric I Basic-Jukic N . Testicular seminoma occurring after kidney transplantation in a patient previously treated for teratoma: de novo malignancy or recurrence in a different histologic form? Transplant Proc 2016;48 :3128–9.27932163\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "100(24)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin; D005047:Etoposide; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal; D009919:Orchiectomy; D051436:Renal Insufficiency, Chronic; D018570:Risk Assessment; D013736:Testicular Neoplasms",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e26381",
"pmc": null,
"pmid": "34128899",
"pubdate": "2021-06-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The use of cisplatin in patients after kidney transplantation with chronic renal insufficiency: Is the benefit higher than potential risks in therapy of non-seminomatous germ cell tumors?",
"title_normalized": "the use of cisplatin in patients after kidney transplantation with chronic renal insufficiency is the benefit higher than potential risks in therapy of non seminomatous germ cell tumors"
} | [
{
"companynumb": "CZ-TEVA-2021-CZ-1935732",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BLEOMYCIN SULFATE"
},
"drugadditional": null,
... |
{
"abstract": "A 23-year-old white man experienced burning pain up his right forearm while receiving phenytoin intravenously in the dorsal wrist. Swelling occurred, followed a few days later by an erythematous eruption that eventuated in superficial skin sloughing. The histopathology of two right forearm biopsies, taken a few days apart 3 to 4 weeks after the infusion, was characterized by partial epidermal necrosis and frequent multinucleate keratinocytes. Localized cutaneous reactions to phenytoin and the occurrence of multinucleate epidermal cells in inflammatory skin disease are reviewed.",
"affiliations": "Division of Dermatology, UCSD Medical Center, San Diego, California 92103, USA.",
"authors": "Hunt|S J|SJ|",
"chemical_list": "D010672:Phenytoin",
"country": "United States",
"delete": false,
"doi": "10.1097/00000372-199508000-00017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-1091",
"issue": "17(4)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D000328:Adult; D002467:Cell Nucleus; D003875:Drug Eruptions; D004817:Epidermis; D004890:Erythema; D005542:Forearm; D006801:Humans; D007275:Injections, Intravenous; D015603:Keratinocytes; D008297:Male; D009336:Necrosis; D010672:Phenytoin; D012867:Skin",
"nlm_unique_id": "7911005",
"other_id": null,
"pages": "399-402",
"pmc": null,
"pmid": "8600807",
"pubdate": "1995-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cutaneous necrosis and multinucleate epidermal cells associated with intravenous phenytoin.",
"title_normalized": "cutaneous necrosis and multinucleate epidermal cells associated with intravenous phenytoin"
} | [
{
"companynumb": "US-PFIZER INC-2015227270",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PHENYTOIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "We present the case of ceftazidime-induced immune-mediated haemolysis with associated acute kidney injury in a 43-year-old woman. The patient initially presented to the regional cystic fibrosis centre for treatment of an infective exacerbation of cystic fibrosis. After initiation of ceftazidime (a third-generation cephalosporin), renal function rapidly deteriorated and a fall in haemoglobin was noted. On transfer to our care, a haemolysis screen identified immune-mediated haemolysis, and renal biopsy confirmed the finding of acute tubular necrosis secondary to haem pigment. The patient's renal function deteriorated such that she required haemodialysis, although she subsequently recovered and is now dialysis-independent. Although acute haemolytic reactions are recognised with third-generation cephalosporins, this is the first reported case of ceftazidime-induced immune-mediated haemolysis with acute kidney injury. Given the increased frequency of cephalosporin usage, it is important for both nephrologists and general physicians to be aware of this rare but very serious complication.",
"affiliations": "Department of Nephrology, Addenbrooke's Hospital, Cambridge, UK ashley.ferro@addenbrookes.nhs.uk.;Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK.;Department of Nephrology, Addenbrooke's Hospital, Cambridge, UK.;Department of Nephrology, Addenbrooke's Hospital, Cambridge, UK.",
"authors": "Ferro|Ashley|A|;Griffiths|Meryl|M|;Smith|Rona|R|;Fry|Andrew|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002442:Ceftazidime",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-232884",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(11)",
"journal": "BMJ case reports",
"keywords": "acute renal failure; contraindications and precautions; haematology (drugs and medicines); renal system; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D002442:Ceftazidime; D003550:Cystic Fibrosis; D003937:Diagnosis, Differential; D005260:Female; D006461:Hemolysis; D006801:Humans; D007683:Kidney Tubular Necrosis, Acute",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31732539",
"pubdate": "2019-11-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26794659;1996549;24887228;29770214;28369704;20008184;24868179;20783577",
"title": "Acute kidney injury as the presenting complaint of ceftazidime-induced immune-mediated haemolysis.",
"title_normalized": "acute kidney injury as the presenting complaint of ceftazidime induced immune mediated haemolysis"
} | [
{
"companynumb": "GB-PFIZER INC-2019508106",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Dexmedetomidine-related polyuria has been observed in animal experimental studies, while only limited cases have been reported in humans. Thus, this rare effect is not well recognized. Herein, we report the case of a 26-year-old man who underwent total thyroidectomy and experienced intraoperative dexmedetomidine-related polyuria, which was subsequently resolved using pituitrin. Moreover, we review the current literature on dexmedetomidine-related polyuria and analyze the potential mechanisms of this rare effect.",
"affiliations": null,
"authors": "Zhu|Jiao|J|;Lu|Dan|D|;Liu|Ji Feng|JF|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.5414/CP204129",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": null,
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": null,
"nlm_unique_id": "9423309",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34889734",
"pubdate": "2021-12-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Intraoperative dexmedetomidine-related polyuria: A case report and review of the literature.",
"title_normalized": "intraoperative dexmedetomidine related polyuria a case report and review of the literature"
} | [
{
"companynumb": "CN-Accord-248140",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXMEDETOMIDINE HYDROCHLORIDE"
},
"drugadditional": "3... |
{
"abstract": "Treatment of pediatric multiple sclerosis (MS) has been increasingly debated in the last few years due to limited knowledge of treatment strategies and therapeutic options. When MS develops at a young age, it usually has a very inflammatory disease course, with many relapses and disease activity as seen in magnetic resonance imaging (MRI). Therefore, treatment with immunomodulatory drugs may be beneficial in these patients. However, limited data are available to date on the treatment of pediatric MS. Although observational, prospective, and retrospective studies provide some information on its treatment course, only one clinical trial in pediatric patients has been published, the PARADIGMS trial, which showed an 82% reduction in relapse rate with fingolimod (0.5 mg/day) versus interferon β-1a (30 μg once weekly intramuscularly). Here, we present the case of a pediatric patient with MS (age of onset, 13 years), who was initially treated with interferon β-1a for 2 years and subsequently switched to fingolimod, owing to clinical and radiological activity despite treatment with interferon β-1a.",
"affiliations": "Neurology Unit, Guglielmo da Saliceto Civil Hospital, Via Giuseppe Taverna 49, 29121, Piacenza, Italy. Paolo.immovilli.md@gmail.com.;Neurology Unit, San Giacomo Hospital, ASL AL, Novi Ligure, Italy.;Neurology Unit, Guglielmo da Saliceto Civil Hospital, Via Giuseppe Taverna 49, 29121, Piacenza, Italy.;Neurology Unit, Guglielmo da Saliceto Civil Hospital, Via Giuseppe Taverna 49, 29121, Piacenza, Italy.",
"authors": "Immovilli|Paolo|P|http://orcid.org/0000-0001-9417-3903;Rota|Eugenia|E|;Morelli|Nicola|N|;Guidetti|Donata|D|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride; D000068556:Interferon beta-1a",
"country": "Italy",
"delete": false,
"doi": "10.1007/s10072-021-05058-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-1874",
"issue": "42(Suppl 1)",
"journal": "Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology",
"keywords": "Fingolimod; Interferon β-1a; Pediatric multiple sclerosis; Treatment strategies",
"medline_ta": "Neurol Sci",
"mesh_terms": "D000293:Adolescent; D002648:Child; D000068876:Fingolimod Hydrochloride; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D000068556:Interferon beta-1a; D009103:Multiple Sclerosis; D020529:Multiple Sclerosis, Relapsing-Remitting; D011446:Prospective Studies; D012189:Retrospective Studies",
"nlm_unique_id": "100959175",
"other_id": null,
"pages": "15-18",
"pmc": null,
"pmid": "33469816",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Two-year follow-up during fingolimod treatment in a pediatric multiple sclerosis patient still active on first-line treatment.",
"title_normalized": "two year follow up during fingolimod treatment in a pediatric multiple sclerosis patient still active on first line treatment"
} | [
{
"companynumb": "IT-EMD SERONO-9216446",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Recently, an association between granulomatous mastitis and local infection with Corynebacterium (C.) kroppenstedtii has been suggested. We herein report two cases of granulomatous mastitis resulting from C. kroppenstedtii infection in nulliparous young women with hyperprolactinemia. Both cases involved nulliparous patients with drug-induced hyperprolactinemia, and both individuals received incision and drainage, after which the pus was sent to our laboratory. Corynebacterium spp. grew on blood agar, and 16S rRNA gene sequencing identified the pathogen as C. kroppenstedtii. In conclusion, lactational changes caused by drug-induced hyperprolactinemia may increase the risk of granulomatous mastitis after C. kroppenstedtii infection.",
"affiliations": "Disease Control and Prevention Center, National Center for Global Health and Medicine, Japan.",
"authors": "Kutsuna|Satoshi|S|;Mezaki|Kazuhisa|K|;Nagamatsu|Maki|M|;Kunimatsu|Junwa|J|;Yamamoto|Kei|K|;Fujiya|Yoshihiro|Y|;Mawatari|Momoko|M|;Takeshita|Nozomi|N|;Hayakawa|Kayoko|K|;Kato|Yasuyuki|Y|;Kanagawa|Shuzo|S|;Ohmagari|Norio|N|",
"chemical_list": "D000900:Anti-Bacterial Agents; D012336:RNA, Ribosomal, 16S; D064704:Levofloxacin; D013469:Sulpiride; D011388:Prolactin",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.54.4254",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "54(14)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D003352:Corynebacterium; D003354:Corynebacterium Infections; D004322:Drainage; D005260:Female; D058890:Granulomatous Mastitis; D006801:Humans; D006966:Hyperprolactinemia; D064704:Levofloxacin; D011388:Prolactin; D012336:RNA, Ribosomal, 16S; D013469:Sulpiride; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1815-8",
"pmc": null,
"pmid": "26179543",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Two Cases of Granulomatous Mastitis Caused by Corynebacterium kroppenstedtii Infection in Nulliparous Young Women with Hyperprolactinemia.",
"title_normalized": "two cases of granulomatous mastitis caused by corynebacterium kroppenstedtii infection in nulliparous young women with hyperprolactinemia"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-102153",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"dr... |
{
"abstract": "BACKGROUND\nUse of second generation antipsychotics in England and Wales has increased in recent years whilst prescription of first generation antipsychotics has decreased.\n\n\nMETHODS\nTo evaluate the impact of this change and of the withdrawal of thioridazine in 2000 on antipsychotic-related fatal poisoning, we reviewed all such deaths in England and Wales 1993-2013 recorded on the Office for National Statistics drug poisoning deaths database. We also reviewed antipsychotic prescribing in the community, England and Wales, 2001-2013. Use of routine mortality data: When an antipsychotic was recorded with other drug(s), the death certificate does not normally say if the antipsychotic caused the death rather than the other substance(s). A second consideration concerns intent. A record of \"undetermined intent\" is likely to have been intentional self-poisoning, the evidence being insufficient to be certain that the individual intended to kill. A record of drug abuse/dependence, on the other hand, is likely to have been associated with an unintentional death. Accuracy of the diagnosis of poisoning: When investigating a death in someone prescribed antipsychotics, toxicological analysis of biological samples collected post-mortem is usually performed. However, prolonged attempts at resuscitation, or diffusion from tissues into blood as autolysis proceeds, may serve to alter the composition of blood sampled after death from that circulating at death. With chlorpromazine and with olanzapine a further factor is that these compounds are notoriously unstable in post-mortem blood. Deaths from antipsychotics: There were 1544 antipsychotic-related poisoning deaths. Deaths in males (N = 948) were almost twice those in females. For most antipsychotics, the proportion of deaths in which a specific antipsychotic featured either alone, or only with alcohol was 30-40%, but for clozapine (193 deaths) such mentions totalled 66%. For clozapine, the proportion of deaths attributed to either intentional self-harm, or undetermined intent was 44%, but for all other drugs except haloperidol (20 deaths) the proportion was 56% or more. The annual number of antipsychotic-related deaths increased from some 55 per year (1.0 per million population) between 1993 and 1998 to 74 (1.5 per million population) in 2000, and then after falling slightly in 2002 increased steadily to reach 109 (1.9 per million population) in 2013. Intent: The annual number of intentional and unascertained intent poisoning deaths remained relatively constant throughout the study period (1993: 35 deaths, 2013: 38 deaths) hence the increase in antipsychotic-related deaths since 2002 was almost entirely in unintentional poisoning involving second generation antipsychotics. Clozapine, olanzapine, and quetiapine were the second generation antipsychotics mentioned most frequently in unintentional poisonings (99, 136, and 99 deaths, respectively). Mentions of diamorphine/morphine and methadone (67 and 99 deaths, respectively) together with an antipsychotic were mainly (84 and 90%, respectively) in either unintentional or drug abuse-related deaths. Deaths and community prescriptions: Deaths involving antipsychotics (10 or more deaths) were in the range 11.3-17.1 deaths per million community prescriptions in England and Wales, 2001-2013. Almost all (96%) such deaths now involve second generation antipsychotics. This is keeping with the increase in annual numbers of prescriptions of these drugs overall (<1 million in 2000, 7 million in 2013), largely driven by increases in prescriptions for olanzapine and quetiapine. In contrast, deaths involving thioridazine declined markedly (from 40 in 2000 to 10 in 2003-2013) in line with the fall in prescriptions for thioridazine from 2001.\n\n\nCONCLUSIONS\nThe removal of thioridazine has had no apparent effect on the incidence of antipsychotic-related fatal poisoning in England and Wales. That such deaths have increased steadily since 2001 is in large part attributable to an increase in unintentional deaths related to (i) clozapine, and (ii) co-exposure to opioids, principally diamorphine and methadone.",
"affiliations": "a Toxicology Unit, Department of Clinical Biochemistry , King's College Hospital NHS Foundation Trust , London , UK ;;b Department of Psychosis Studies , Institute of Psychiatry, Psychology and Neuroscience, King's College London , London , UK.;a Toxicology Unit, Department of Clinical Biochemistry , King's College Hospital NHS Foundation Trust , London , UK ;",
"authors": "Handley|S|S|;Patel|M X|MX|;Flanagan|R J|RJ|",
"chemical_list": "D014150:Antipsychotic Agents; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D003932:Heroin; D009020:Morphine; D003024:Clozapine; D013881:Thioridazine; D000077152:Olanzapine; D002746:Chlorpromazine; D008691:Methadone",
"country": "England",
"delete": false,
"doi": "10.3109/15563650.2016.1164861",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "54(6)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Antipsychotics; clozapine; death; poisoning; suicide; thioridazine; toxicity",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D014150:Antipsychotic Agents; D001569:Benzodiazepines; D002746:Chlorpromazine; D003024:Clozapine; D056736:Drug Recalls; D004739:England; D003932:Heroin; D006801:Humans; D008691:Methadone; D009020:Morphine; D000077152:Olanzapine; D011041:Poisoning; D000069348:Quetiapine Fumarate; D013881:Thioridazine; D014852:Wales",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "471-80",
"pmc": null,
"pmid": "27023487",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Antipsychotic-related fatal poisoning, England and Wales, 1993-2013: impact of the withdrawal of thioridazine.",
"title_normalized": "antipsychotic related fatal poisoning england and wales 1993 2013 impact of the withdrawal of thioridazine"
} | [
{
"companynumb": "GB-JNJFOC-20160608576",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIACETYLMORPHINE"
},
"drugadditional": null,
... |
{
"abstract": "Anemia in hemodialysis patients is effectively treated by intravenous (IV) injections of recombinant human erythropoietin (rHuEPO) at each dialysis session. Because the hormone is effective by subcutaneous (SC) administration, it was decided that this study would evaluate low-dose weekly SC rHuEPO therapy. To determine the safety and efficacy of weekly SC rHuEPO administration to hemodialysis patients, only one third the weekly IV dose was given and the effects were compared with those from an age-, gender-, and nephrologic disease-matched control group treated in the standard fashion. Forty-four patients entered the trial and 27 completed the protocol along with 27 control subjects. During Phase 1, experimental and control subjects received standard IV rHuEPO at dialysis for 6 months. During Phase 2, experimental patients received weekly SC rHuEPO at one third the weekly IV dose for 10 months; control subjects continued to receive IV therapy. In Phase 3, both groups were treated for 6 more months with IV rHuEPO. In Phase 2, there was no significant reduction in hematocrit value, reticulocyte count, transferrin saturation, or ferritin level in the experimental group, even with only one third the weekly rHuEPO IV dose over the 10-month period. There were no significant differences between IV and SC rHuEPO administration or between experimental and control subjects in blood pressure, serum chemistries, or parameters of \"dialysis adequacy.\" It was concluded that low-dose weekly SC rHuEPO administration is a safe and effective method for maintaining the hematocrit level of stable hemodialysis patients. This therapy could enhance the efficacy of rHuEPO and substantially reduce costs while preserving patient care outcomes.",
"affiliations": "Nell Hodgson Woodruff School of Nursing, Emory University School of Medicine, Atlanta, Georgia, USA.",
"authors": "Parker|K P|KP|;Mitch|W E|WE|;Stivelman|J C|JC|;Macon|E J|EJ|;Bailey|J L|JL|;Sands|J M|JM|",
"chemical_list": "D011994:Recombinant Proteins; D014168:Transferrin; D004921:Erythropoietin; D005293:Ferritins",
"country": "United States",
"delete": false,
"doi": "10.1681/ASN.V82288",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1046-6673",
"issue": "8(2)",
"journal": "Journal of the American Society of Nephrology : JASN",
"keywords": null,
"medline_ta": "J Am Soc Nephrol",
"mesh_terms": "D000740:Anemia; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004921:Erythropoietin; D005260:Female; D005293:Ferritins; D006400:Hematocrit; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D006435:Renal Dialysis; D017701:Reticulocyte Count; D012449:Safety; D013997:Time Factors; D014168:Transferrin",
"nlm_unique_id": "9013836",
"other_id": null,
"pages": "288-93",
"pmc": null,
"pmid": "9048348",
"pubdate": "1997-02",
"publication_types": "D016430:Clinical Trial; D018848:Controlled Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Safety and efficacy of low-dose subcutaneous erythropoietin in hemodialysis patients.",
"title_normalized": "safety and efficacy of low dose subcutaneous erythropoietin in hemodialysis patients"
} | [
{
"companynumb": "US-AMGEN-USASP2021082499",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ERYTHROPOIETIN"
},
"drugadditional": null,
... |
{
"abstract": "Sodium picosulfate/magnesium citrate (Picolight Powder), which is used as a bowel preparation for the colon and the rectum, can cause a severe electrolyte imbalance like hyponatremia. When hyponatremia gets severe or occurs rapidly, it can lead to death due to associated complications. We have experienced a case of hyponatremia associated with seizure and loss of consciousness in a 76-year-old woman, who took sodium picosulfate/magnesium citrate as a bowel preparation for colonoscopy. She was taking thiazide and synthroid for the treatment of hypertension and hypothyroidism, respectively, and she had other underlying medical conditions such as a history of seizure and dementia. Following the diagnosis of hyponatremia, we used an intravenous injection of 3% NaCl to normalize the sodium level in her serum, and her associated symptoms soon disappeared.",
"affiliations": "Department of Internal Medicine, Wallace Memorial Baptist Hospital, Busan, Korea.;Department of Internal Medicine, Wallace Memorial Baptist Hospital, Busan, Korea.;Department of Internal Medicine, Wallace Memorial Baptist Hospital, Busan, Korea.;Department of Internal Medicine, Wallace Memorial Baptist Hospital, Busan, Korea.;Department of Internal Medicine, Wallace Memorial Baptist Hospital, Busan, Korea.;Department of Internal Medicine, Wallace Memorial Baptist Hospital, Busan, Korea.",
"authors": "Cho|Young Sun|YS|;Nam|Kyung Min|KM|;Park|Jang Ho|JH|;Byun|Sang Hwan|SH|;Ryu|Jin Suck|JS|;Kim|Hyun Ju|HJ|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.3393/ac.2014.30.6.290",
"fulltext": "\n==== Front\nAnn ColoproctolAnn ColoproctolACAnnals of Coloproctology2287-97142287-9722The Korean Society of Coloproctology 10.3393/ac.2014.30.6.290Case ReportAcute Hyponatremia With Seizure and Mental Change After Oral Sodium Picosulfate/Magnesium Citrate Bowel Preparation Cho Young Sun Nam Kyung Min Park Jang Ho Byun Sang Hwan Ryu Jin Suck Kim Hyun Ju Department of Internal Medicine, Wallace Memorial Baptist Hospital, Busan, Korea.Correspondence to: Hyun Ju Kim, M.D. Department of Internal Medicine, Wallace Memorial Baptist Hospital, 200 Geumdan-ro, Geumjeong-gu, Busan 609-728, Korea. Tel: +82-51-580-1388, Fax: +82-51-580-7114, lotlot98@naver.com12 2014 31 12 2014 30 6 290 293 22 7 2014 12 9 2014 © 2014 The Korean Society of Coloproctology2014This 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.Sodium picosulfate/magnesium citrate (Picolight Powder), which is used as a bowel preparation for the colon and the rectum, can cause a severe electrolyte imbalance like hyponatremia. When hyponatremia gets severe or occurs rapidly, it can lead to death due to associated complications. We have experienced a case of hyponatremia associated with seizure and loss of consciousness in a 76-year-old woman, who took sodium picosulfate/magnesium citrate as a bowel preparation for colonoscopy. She was taking thiazide and synthroid for the treatment of hypertension and hypothyroidism, respectively, and she had other underlying medical conditions such as a history of seizure and dementia. Following the diagnosis of hyponatremia, we used an intravenous injection of 3% NaCl to normalize the sodium level in her serum, and her associated symptoms soon disappeared.\n\nPicosulfate sodiumBowel preparationHyponatremiaSeizuresColonoscopy\n==== Body\nINTRODUCTION\nAs colonoscopy is becoming more common, a pretreatment solution compatible with the patient's compliance represents an unmet medical need. Four liters of polyethylene glycol (PEG) and sodium phosphate (NaP) have been widely used for pretreatment. In addition, sodium picosulfate and magnesium citrate complex (MC-SP) has been registered as a patent in Korea since 2012. Sodium picosulfate increases bowel peristalsis whereas magnesium citrate acts as an osmosis laxative [1]. In 2005, hyponatremia that caused encephalopathy as a result of taking MC-SP complex was reported in New Zealand [2]. In 2013, one poster presentation reported hyponatremia caused by taking MC-SP complex in Korea. However, no seizures, loss of consciousness or neurologic symptoms have been reported in Korea. We report a case of hyponatremia accompanied by seizure and loss of consciousness in a patient who has normal renal function after taking MC-SP for bowel preparation prior to colonoscopy.\n\nCASE REPORT\nA 76-year-old woman came into our Emergency Department due to the loss of consciousness and a seizure. The patient was given an oral prescription of MC-SP complex (Picolight powder, Pharmbio Korea Co., Seoul, Korea) for the colonoscopy. She orally took one pack (10-mg sodium picosulfate, 3.5-g magnesium citrate) with 150 mL of water. Within 3 hours of her first dose of MC-SP, she suffered diarrhea, and about 11 hours after taking the first medicine, she suffered nausea, vomiting, and then symptoms of decreased energy and seizure accompanied by ocular deviation. Seizures lasted for 2-3 minutes. When she arrived at the Emergency Department, loss of consciousness was evident, but there were no signs of seizure. She had no history of seizures. About 5 years earlier, she had been taking levothyroxine sodium, 0.05 mg, (Synthroid, Bukwang Pharm, Seoul, Korea), atorvastatin calcium, 10 mg, (Lipinon, Dong-A Pharm, Seoul, Korea), hydrochlorothiazide, 12.5 mg (Dichlozid, Yuhan Pharm, Seoul, Korea), propranolol, 10 mg twice a day (Indenol, Dongkwang Pharm, Seoul, Korea), and diazepam, 2 mg (Myungin Diazepam, Myung In Pharm, Seoul, Korea) for hypothyroidism, hyperlipidemia, hypertension and depression, respectively. She had no family history of specific medical diseases. She had no history of alcohol consumption or smoking.\n\nUpon arrival, her blood pressure was 150/90 mmHg, her pulse rate was 83 times per minute, her respiratory rate was 20 times per minute, her body temperature was 36℃, her blood glucose was 205 mg/dL, and her oxygen saturation level was 92%. The patient looked very sick and vomited continuously. On both sides, the pupil reflex was normal, and no signs of nystagmus manifested. The consciousness of the patient was vague. She couldn't respond to questions and could not even follow verbal instructions. According the Glasgow Coma Scale, her rating was 8 points, which is referred to as semicoma state. Auscultation of the abdomen produced no specific finding. During chest auscultation of both sides of the lower lung, rales were auscultated. Chest radiography showed a shadow increasing on both lower lung field, but there were no specific findings on the electrocardiogram.\n\nArterial blood gas analysis showed pH, 7.532, pCO2, 27.4 mmHg, pO2, 56.5 mmHg, HCO3, 22.5 mmol/L, base excess, 1.1 mmol/L, and oxygen saturation, 88.5%, indicating that she had acute respiratory alkalosis. In serum biochemical tests, the total calcium level was 8.2 mg/dL (reference value, 8.8-10.8 mg/dL), the ionized calcium level was 0.80 mmol/L (reference value, 1.0-1.2 mmol/L) and phosphate was 2.4 mg/dL (reference value, 2.4-5.1 mg/dL), indicating hypocalcemia and hypophosphatemia. Blood urea nitrogen was 9.6 mg/dL (reference value, 9-23 mg/dL), and the creatinine level was 0.6 mg/dL (reference value, 0.7-1.3 mg/dL), indicating no abnormality. The serum sodium level was 112 mEq/L (reference value, 132-146 mEq/L), and the potassium level was 2.4 mEq/L (reference value, 3.5-5.0 mEq/L), indicating hypokalemia and hyponatremia. The serum osmolality had decreased to 240 mOsmol/kg (reference value, 289-308 mOsmol/kg), and the urine osmolality was 370 mOsmol/kg (reference value, 300-900 mOsmol/kg). The fasting blood glucose level was 205 mg/dL, Hg A1C was 7.1% (reference value, 4.4%-6.4%), thyroid-stimulating hormone was 0.99 µIU/mL (reference value, 0.55-4.78 µIU/mL), free thyroxine (fT4) was 1.78 ng/dL (reference value, 0.89-1.8 ng/dL) at 8 AM. Cortisol was 46.88 µg/dL (reference value, 4.3-22.4 µg/dL), and at 8 AM. Aadrenocorticotropic hormone (ACTH) was 134.7 pg/dL (reference value, 5-50 pg/mL). The cortisol and ACTH levels had increased.\n\nThe brain computed tomography showed no acute brain lesions, such as bleeding (Fig. 1), and the brain magnetic resonance imaging showed no specific lesions. Magnetic resonance angiography showed no specific lesions associated with her current symptoms. She was diagnosed as having hyponatremia accompanied by vomiting and neurological symptoms, such as unconsciousness and seizures, and accompanied by aspiration pneumonia with respiratory alkalosis. To the treat pneumonia, we gave her antibiotics, and to treat the hyponatremia, we gave her an intravenous injection of 3% saline. We aimed to increase her sodium level to 124 mEq/L, so we injected 3% saline at a rate of 20 mL/hr for 24 hours, which corresponded to a corrected rate of 0.4 mEq/L. After 24 hours, she got had recovered to a 124-mEq/L level of serum sodium, and she was in a lethargy state. However, she was not completely oriented and could not questions. Symptoms, including vomiting and nausea, remained. After 48 hours, she had fully recovered to a 132-mEq/L level of serum sodium, her consciousness was normal, and even her symptoms of vomiting and nausea had disappeared. After that, she showed no neurological symptoms, such as seizures or unconsciousness.\n\nDISCUSSION\nColonoscopy is a common and widespread test for adults over the age of 50 to screen for colorectal cancer, and its usage is increasing. Doing a proper colonoscopy requires a proper bowel preparation. If the bowel preparation is poorly done, another colonoscopy or another test has to be done, giving an extra burden to the patient and even the physician [3, 4, 5]. The most ideal bowel preparation should not only achieve excellent colon cleansing but also minimize the adverse impact on the mucosa and changes in the water and the electrolyte level. The bowel preparation should be drinkable so that patients experience less discomfort [6]. Thus, the patient's compliance has to be acceptable. As a matter of fact, some patients fear a colonoscopy because of the inconvenience of taking the bowel preparation.\n\nCurrently the most widely used solutions for bowel preparation are PEG and NaP. In addition, because the MC-SP complex has been approved for clinical use, its benefits and side effects must be evaluated. Sodium picosulfate is commonly used as a bowel preparation solution in Europe and is available in a powder form that can be dissolved in water before use. In 2012, a MC-SP was patented in Korea. Compared with NaP and PEG, its cleansing ability is similar and it is easy to use [7, 8], so interest in its use in Korea is growing. The patient compliance when using the MC-SP complex has been reported to be better than those of PEG and NaP, and its the bowel cleaning effect has been reported to be comparable [8]. One flaw is that the MC-SP complex causes inflammation in the mucous membrane, although the patient's preference for this complex is higher than it is for either PEG or NaP [9, 10, 11]. According to studies that investigated hyponatremia that occurred when elderly patients over the age of 65 took PEG and sodium picosulfate, the incidence of hyponatremia was higher when the patients took sodium picosulfate, but no significant differences in the neurological symptoms and the lengths of hospital stay were observed [12]. Because taking picosulfate can cause side effects like severe dehydration or electrolyte disturbances, patients should be instructed to take it with enough water. In addition, care should be exercised when using picosulfate in patients with impaired renal function, heart failure, and with inflammatory bowel disease [13].\n\nLooking at the cases reported in other countries, hyponatremia after taking MC-SP complex was associated with taking medicine for hypothyroidism, receiving treatment for hypertension, and being elderly. Underlying diseases and advanced age represent risk factors [3]. A poster presentation at the 2013 Korean Association of Internal Medicine Meeting reported one case of hyponatremia associated with MC-SP. The patient was old and had taken medicines for hyperlipidemia and hypertension.\n\nHyponatremia is defined as a serum sodium level less than 135 mEq/L. Symptoms do not normally occur unless the serum sodium level is below 120 mEq/L. However, symptoms might occur at a level above that level when the rate of decrease of the serum sodium level is higher than usual. The symptoms range from milder ones, such as loss of appetite, nausea, and vomiting, to more severe ones, such as seizure, lethargy, coma, and even death. If the patient has neurological symptoms or a serum sodium concentration less than 110 mEq/L, that patient requires emergency treatment. If the plasma volume is normal, the cause of hyponatremia could be attributed to hypothyroidism, adrenal insufficiency, inappropriate secretion of antidiuretic hormone syndrome, and drugs, and if the plasma volume is high, chronic kidney disease, heart failure, liver failure, and nephrotic syndrome may be the cause. When the patient has a small plasma volume, a lack of water due to dehydration, diarrhea, and vomiting, or a deficiency in renal sodium reabsorption may be the problem. Hyponatremia symptoms are treated with a hypersaline solution when the plasma volume is large or when it is normal with concentrated urine. In the case of a patient having diluted urine, water intake needs to be restricted. If the symptoms become severe, a hypersaline injection is needed.\n\nThe case we report here is an elderly patient, who first suffered nausea and vomiting, after taking MC-SP complex for bowel preparation. Eventually, her symptoms manifested a severe hyponatremia accompanied by the loss of consciousness and seizures. She had been taking the drug thiazide. We reasoned that the hyponatremia was attributable to excess dehydration caused by vomiting and diarrhea and that the thiazide diuretics, which decrease urine dilution, made hyponatremia even more severe, to the extent that it was accompanied by loss of consciousness. For patients having risk factors such as aging and underlying medical conditions such as taking diuretics medicine, we highly recommend that they be informed of the enhanced likeliness of having an electrolyte imbalance, which could be accompanied by other complication. In addition, serum electrolytes should be checked if behavioral abnormalities, such as altered consciousness, are apparent at the time of colonoscopy.\n\nNo potential conflict of interest relevant to this article was reported.\n\nFig. 1 Brain computed tomography. (A) No evidence of any abnormal density is seen on the pre-enhanced image. (B) No abnormal lesion is noted.\n==== Refs\n1 Jauch R Hankwitz R Beschke K Pelzer H Bis-(p-hydroxyphenyl)-pyridyl-2-methane: the common laxative principle of Bisacodyl and sodium picosulfate Arzneimittelforschung 1975 25 1796 1800 1243088 \n2 Frizelle FA Colls BM Hyponatremia and seizures after bowel preparation: report of three cases Dis Colon Rectum 2005 48 393 396 15812590 \n3 Forde H O'Shea T Davenport C Smith D Acute symptomatic hyponatremia following sodium picosulfate/magnesium citrate as bowel preparation for colonoscopy: a case series Case Rep Clin Med 2014 3 101 104 \n4 Harewood GC Sharma VK de Garmo P Impact of colonoscopy preparation quality on detection of suspected colonic neoplasia Gastrointest Endosc 2003 58 76 79 12838225 \n5 Froehlich F Wietlisbach V Gonvers JJ Burnand B Vader JP Impact of colonic cleansing on quality and diagnostic yield of colonoscopy: the European Panel of Appropriateness of Gastrointestinal Endoscopy European multicenter study Gastrointest Endosc 2005 61 378 384 15758907 \n6 Rex DK Imperiale TF Latinovich DR Bratcher LL Impact of bowel preparation on efficiency and cost of colonoscopy Am J Gastroenterol 2002 97 1696 1700 12135020 \n7 Wexner SD Beck DE Baron TH Fanelli RD Hyman N Shen B A consensus document on bowel preparation before colonoscopy: prepared by a task force from the American Society of Colon and Rectal Surgeons (ASCRS), the American Society for Gastrointestinal Endoscopy (ASGE), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Gastrointest Endosc 2006 63 894 909 16733101 \n8 Barkun A Chiba N Enns R Marcon M Natsheh S Pham C Commonly used preparations for colonoscopy: efficacy, tolerability, and safety: a Canadian Association of Gastroenterology position paper Can J Gastroenterol 2006 20 699 710 17111052 \n9 Katz PO Rex DK Epstein M Grandhi NK Vanner S Hookey LC A dual-action, low-volume bowel cleanser administered the day before colonoscopy: results from the SEE CLEAR II study Am J Gastroenterol 2013 108 401 409 23318484 \n10 Tan JJ Tjandra JJ Which is the optimal bowel preparation for colonoscopy: a meta-analysis Colorectal Dis 2006 8 247 258 16630226 \n11 Worthington J Thyssen M Chapman G Chapman R Geraint M A randomised controlled trial of a new 2 litre polyethylene glycol solution versus sodium picosulphate + magnesium citrate solution for bowel cleansing prior to colonoscopy Curr Med Res Opin 2008 24 481 488 18179734 \n12 Lawrance IC Willert RP Murray K Bowel cleansing for colonoscopy: prospective randomized assessment of efficacy and of induced mucosal abnormality with three preparation agents Endoscopy 2011 43 412 418 21547879 \n13 Weir MA Fleet JL Vinden C Shariff SZ Liu K Song H Hyponatremia and sodium picosulfate bowel preparations in older adults Am J Gastroenterol 2014 109 686 694 24589671\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2287-9714",
"issue": "30(6)",
"journal": "Annals of coloproctology",
"keywords": "Bowel preparation; Colonoscopy; Hyponatremia; Picosulfate sodium; Seizures",
"medline_ta": "Ann Coloproctol",
"mesh_terms": null,
"nlm_unique_id": "101605121",
"other_id": null,
"pages": "290-3",
"pmc": null,
"pmid": "25580417",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article",
"references": "18179734;15758907;12135020;21547879;24589671;1243088;23318484;16630226;15812590;16733101;17111052;12838225",
"title": "Acute hyponatremia with seizure and mental change after oral sodium picosulfate/magnesium citrate bowel preparation.",
"title_normalized": "acute hyponatremia with seizure and mental change after oral sodium picosulfate magnesium citrate bowel preparation"
} | [
{
"companynumb": "KR-ALEMBIC PHARMACUETICALS LIMITED-2015SCAL000927",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE"
},
... |
{
"abstract": "To assess the benefits of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as neoadjuvant/adjuvant therapies in locally advanced EGFR mutation-positive non-small-cell lung cancer.\n\n\n\nThis was a multicenter (17 centers in China), open-label, phase II, randomized controlled trial of erlotinib versus gemcitabine plus cisplatin (GC chemotherapy) as neoadjuvant/adjuvant therapy in patients with stage IIIA-N2 non-small-cell lung cancer with EGFR mutations in exon 19 or 21 (EMERGING). Patients received erlotinib 150 mg/d (neoadjuvant therapy, 42 days; adjuvant therapy, up to 12 months) or gemcitabine 1,250 mg/m2 plus cisplatin 75 mg/m2 (neoadjuvant therapy, two cycles; adjuvant therapy, up to two cycles). Assessments were performed at 6 weeks and every 3 months postsurgery. The primary end point was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; secondary end points were pathologic complete response, progression-free survival (PFS), overall survival, safety, and tolerability.\n\n\n\nOf 386 patients screened, 72 were randomly assigned to treatment (intention-to-treat population), and 71 were included in the safety analysis (one patient withdrew before treatment). The ORR for neoadjuvant erlotinib versus GC chemotherapy was 54.1% versus 34.3% (odds ratio, 2.26; 95% CI, 0.87 to 5.84; P = .092). No pathologic complete response was identified in either arm. Three (9.7%) of 31 patients and zero of 23 patients in the erlotinib and GC chemotherapy arms, respectively, had a major pathologic response. Median PFS was significantly longer with erlotinib (21.5 months) versus GC chemotherapy (11.4 months; hazard ratio, 0.39; 95% CI, 0.23 to 0.67; P < .001). Observed adverse events reflected those most commonly seen with the two treatments.\n\n\n\nThe primary end point of ORR with 42 days of neoadjuvant erlotinib was not met, but the secondary end point PFS was significantly improved.",
"affiliations": "Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.;Peking University Cancer Hospital and Institute, Beijing, People's Republic of China.;Fujian Medical University Union Hospital, Fuzhou, People's Republic of China.;First Affiliated Hospital of Dalian Medical University, Dalian, People's Republic of China.;Peking University People's Hospital, Beijing, People's Republic of China.;Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.;Zhejiang Cancer Hospital, Hangzhou, People's Republic of China.;Zhongshan Hospital, Shanghai, People's Republic of China.;Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.;Jilin Provincial Tumor Hospital, Changchun, People's Republic of China.;Jiangsu Cancer Institute and Hospital, Nanjing, People's Republic of China.;Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China.;First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China.;Peking University Cancer Hospital and Institute, Beijing, People's Republic of China.;Peking University Cancer Hospital and Institute, Beijing, People's Republic of China.;Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.;Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.;Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.;Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.;Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.;Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.",
"authors": "Zhong|Wen-Zhao|WZ|;Chen|Ke-Neng|KN|;Chen|Chun|C|;Gu|Chun-Dong|CD|;Wang|Jun|J|;Yang|Xue-Ning|XN|;Mao|Wei-Min|WM|;Wang|Qun|Q|;Qiao|Gui-Bin|GB|;Cheng|Ying|Y|;Xu|Lin|L|;Wang|Chang-Li|CL|;Chen|Ming-Wei|MW|;Kang|Xiaozheng|X|;Yan|Wanpu|W|;Yan|Hong-Hong|HH|;Liao|Ri-Qiang|RQ|;Yang|Jin-Ji|JJ|;Zhang|Xu-Chao|XC|;Zhou|Qing|Q|;Wu|Yi-Long|YL|",
"chemical_list": "D047428:Protein Kinase Inhibitors; D003841:Deoxycytidine; C056507:gemcitabine; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.19.00075",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "37(25)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin; D003841:Deoxycytidine; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "2235-2245",
"pmc": null,
"pmid": "31194613",
"pubdate": "2019-09-01",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment of Stage IIIA-N2 EGFR-Mutant Non-Small-Cell Lung Cancer (EMERGING-CTONG 1103): A Randomized Phase II Study.",
"title_normalized": "erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage iiia n2 egfr mutant non small cell lung cancer emerging ctong 1103 a randomized phase ii study"
} | [
{
"companynumb": "CN-HQ SPECIALTY-CN-2019INT000279",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Radium-223 has demonstrated efficacy in improving overall survival (OS) and in delaying symptomatic skeletal-related events (SREs). Bone Health Agents (BHA), i.e. RANK ligand inhibitor (Denosumab) and bisphosphonate such as zoledronic acid, are indicated to prevent SREs without a clear survival benefit. SREs on patient health have a high impact and it is, therefore, important to consider the role of new therapies with BHA to better understand the involvement of combination therapy. The primary aim of this multicentric study is to assess OS in mCRPC patients treated with Radium-223 in combination with BHA.\n\n\n\n430 consecutive patients treated with Radium-223 alone or in combination with BHA, affected by mCRPC, from January 2015 to July 2019 in six Italian Nuclear Medicine Units, were included. Furthermore, data were collected at baseline, after every Radium-223 administration, and during follow-up, at 3 and 6 months and 1 year after the 6th cycle. Clinical data have been evaluated before starting treatment with Radium-223 and at the end of treatment and/or at progression. Patients who received target bone therapy with BHA before Radium-223 treatment together with patients who did not receive this therapy at all (NO BHA GROUP), were compared to patients treated with concomitant Radium-223 and BHA (BHA GROUP).\n\n\n\nIn univariate models (p < .05) several clinical aspects have an impact on OS: concomitant BHA (p = .018), BMI (p .001), ECOG PS (p = .000), Baseline Hb (p = .000), Baseline PSA (p = .000), Baseline tALP (p = .000), Baseline LDH (p = .000), and Baseline neutrophils (p = .009). Baseline Hb, Baseline tALP, and Baseline LDH have been confirmed as statistically significant parameters in multivariate models. Indeed, concomitant BHA has not a significant impact on OS (p = .244) in multivariate models.\n\n\n\nAt univariate analysis, our data showed that NO BHA GROUP and BHA GROUP differ in OS by 7 months (95%CI: (1-16.4), p = .02). This is not confirmed at multivariate analysis where after adjusting for other baseline factors, BHA is not significant anymore. This is clearly explained as bias by indication: patients with the same levels of tALP, Hb, and LDH receiving or not receiving BHA are expected to have a similar survival. Our results support and confirm the role of Radium-223 therapy on OS and, furthermore, appear to confirm that BHA treatment has not a survival benefit.",
"affiliations": "Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.;Radiation Oncology Center, S.Orsola-Malpighi Hospital, Bologna, Italy.;Unit of Nuclear Medicine, Spirito Santo Hospital, Pescara, Italy.;Unit of Nuclear Medicine, Biomedical Department of Internal and Specialist Medicine, University of Palermo, Palermo, Italy.;Nuclear Medicine Department, University of Bari \"Aldo Moro\", Bari, Italy.;Unit of Nuclear Medicine, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy.;Department of Economics & Finance, University of Rome \"Tor Vergata\", Rome, Italy.;Nuclear Medicine Unit, S.Orsola-Malpighi Hospital, Bologna, Italy.;Department of Urology, \"Villa Stuart\" Private Hospital, Rome, Italy.;Unit of Nuclear Medicine, Biomedical Department of Internal and Specialist Medicine, University of Palermo, Palermo, Italy.;Nuclear Medicine Department, University of Bari \"Aldo Moro\", Bari, Italy.;Unit of Nuclear Medicine, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy.;Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza University of Rome, Rome, Italy.;Radiation Oncology Center, S.Orsola-Malpighi Hospital, Bologna, Italy.;Nuclear Medicine Department, University of Bari \"Aldo Moro\", Bari, Italy.;Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza University of Rome, Rome, Italy.",
"authors": "Frantellizzi|Viviana|V|0000-0003-3497-4236;Monari|Fabio|F|0000-0002-0242-3301;Mascia|Manlio|M|0000-0002-5009-9112;Costa|Renato|R|0000-0001-5181-2242;Rubini|Giuseppe|G|0000-0003-1972-3308;Spanu|Angela|A|0000-0001-5753-399X;Farcomeni|Alessio|A|0000-0002-7104-5826;Lodi Rizzini|Elisa|E|;Cindolo|Luca|L|0000-0002-2102-7507;Licari|Maria|M|0000-0002-1674-814X;Lavelli|Valentina|V|0000-0002-7603-1706;Nuvoli|Susanna|S|0000-0002-7194-985X;Ricci|Maria|M|0000-0002-9277-6337;Dionisi|Valeria|V|;Nappi|Anna Giulia|AG|0000-0002-9046-6378;De Vincentis|Giuseppe|G|0000-0003-4690-1528",
"chemical_list": "C000615150:Radium-223; D007770:L-Lactate Dehydrogenase; D000469:Alkaline Phosphatase; D011883:Radium",
"country": "England",
"delete": false,
"doi": "10.1080/09553002.2020.1838655",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0955-3002",
"issue": "96(12)",
"journal": "International journal of radiation biology",
"keywords": "Radium-223 dichloride; bone health agents; mCRPC; overall survival; prostate cancer",
"medline_ta": "Int J Radiat Biol",
"mesh_terms": "D000368:Aged; D000469:Alkaline Phosphatase; D001853:Bone Marrow; D001842:Bone and Bones; D006801:Humans; D007770:L-Lactate Dehydrogenase; D008297:Male; D009362:Neoplasm Metastasis; D064129:Prostatic Neoplasms, Castration-Resistant; D011883:Radium; D016019:Survival Analysis",
"nlm_unique_id": "8809243",
"other_id": null,
"pages": "1608-1613",
"pmc": null,
"pmid": "33074066",
"pubdate": "2020-12",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Overall survival in mCPRC patients treated with Radium-223 in association with bone health agents: a national multicenter study.",
"title_normalized": "overall survival in mcprc patients treated with radium 223 in association with bone health agents a national multicenter study"
} | [
{
"companynumb": "IT-AMGEN-ITASP2021062173",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Acetaminophen (APAP)-induced liver injury is initiated by metabolism of APAP by the cytochrome P-450 (CYP) system, primarily CYP2E1. We previously demonstrated CYP inhibition following administration of a liquid APAP formulation containing propylene glycol, a CYP2E1 inhibitor, and other excipients. This study was undertaken to determine if propylene glycol specifically inhibits production of CYP-derived metabolites and if propylene glycol reduces the rise in alanine aminotransferase (ALT) seen following prolonged APAP dosing. Human subjects were randomized to receive 4 g of APAP daily in one arm of the study or 4 g of APAP with 5 mL of 99% propylene glycol in the other arm, both for 14 days. After a washout period of at least 14 days, subjects were crossed over between arms. Outcomes were rise of ALT greater than 2 times baseline (responders) and proportion of randomly sampled CYP-derived metabolites relative to total metabolites produced. There was no difference in percentage of responders between treatment groups: 6 of 21 in the APAP group (29%) compared with 8 of 20 in the APAP + propylene glycol group (40%); chi-square, P = .59. For all subjects, the mean percentage of CYP-derived metabolites produced was 5.8% (APAP) versus 4.3% (APAP + propylene glycol); P = .018. This effect was solely attributable to the responders: the mean percentage of CYP metabolites of responders was 7.7% (APAP) versus 4.6% (APAP + propylene glycol), P = .050, whereas there was no difference for the nonresponders. Five subjects were responders in both arms (2% probability of random occurrence). Our data indicates that propylene glycol inhibits CYP2E1 metabolism of APAP in some subjects but does not effect hepatocellular indury at the dose given.",
"affiliations": "Department of Emergency Medicine, Division of Medical Toxicology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.;Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.;Department of Integrated Medical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA.;Staff Toxicologist, Children's Hospital, Boston, MA, USA.",
"authors": "Ganetsky|Michael|M|;Berg|Anders H|AH|;Solano|Joshua J|JJ|;Salhanick|Steven|S|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D000082:Acetaminophen; D019946:Propylene Glycol; D019392:Cytochrome P-450 CYP2E1; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase",
"country": "England",
"delete": false,
"doi": "10.1002/jcph.1299",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-2700",
"issue": "59(1)",
"journal": "Journal of clinical pharmacology",
"keywords": "CYP2E1; acetaminophen; propylene glycol",
"medline_ta": "J Clin Pharmacol",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D000410:Alanine Transaminase; D018712:Analgesics, Non-Narcotic; D001219:Aspartate Aminotransferases; D056486:Chemical and Drug Induced Liver Injury; D018592:Cross-Over Studies; D019392:Cytochrome P-450 CYP2E1; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D019946:Propylene Glycol; D055815:Young Adult",
"nlm_unique_id": "0366372",
"other_id": null,
"pages": "131-138",
"pmc": null,
"pmid": "30151903",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Inhibition of CYP2E1 With Propylene Glycol Does Not Protect Against Hepatocellular Injury in Human Acetaminophen Daily-Dosing Model.",
"title_normalized": "inhibition of cyp2e1 with propylene glycol does not protect against hepatocellular injury in human acetaminophen daily dosing model"
} | [
{
"companynumb": "US-JNJFOC-20190125001",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROPYLENE GLYCOL"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nWe evaluated the clinical efficacy of intravenous (i.v.) and intraperitoneal (i.p.) paclitaxel (PTX) combined with S-1 in patients with chemotherapy-naïve pancreatic ductal adenocarcinoma (PDAC) with peritoneal metastasis.\n\n\nMETHODS\nForty-nine patients were diagnosed with peritoneal metastasis during 2007-2014; 29 received gemcitabine or S-1-based chemo(radio)therapy from 2007 to 2011 (control group), and the remaining 20 received i.v. (50 mg/m2 ) and i.p. (20 mg/m2 ) PTX on days 1 and 8, and S-1 at 80 mg/m2 per day for 14 consecutive days, followed by 7 days of rest from 2012 to 2014 (study group).\n\n\nRESULTS\nThe median survival time in the study group was significantly longer than that in the control group (20 vs. 10 months, respectively; P = 0.004). At 1 year after initial treatment, a significant difference in ascites development on CT was found between the study (5/20 patients) and the control group (18/29 patients, P = 0.009). The frequency of objective response (9/20 patients) and conversion surgery (6/20 patients) in the study group was higher than those in the control group (8/29 and 2/29, respectively). Patients who underwent conversion surgery had improved survival in both groups.\n\n\nCONCLUSIONS\nImplementation of the S-1+i.v./i.p. PTX regimen was closely associated with improved overall survival in PDAC patients with peritoneal metastasis.",
"affiliations": "Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010, Japan.;Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010, Japan.;Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010, Japan.;Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010, Japan.;Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010, Japan.;Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010, Japan.;Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010, Japan.;Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010, Japan.;Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010, Japan.;Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010, Japan.",
"authors": "Satoi|Sohei|S|;Yanagimoto|Hiroaki|H|;Yamamoto|Tomohisa|T|;Hirooka|Satoshi|S|;Yamaki|So|S|;Kosaka|Hisashi|H|;Inoue|Kentaro|K|;Hashimoto|Yuki|Y|;Matsui|Yoichi|Y|;Kon|Masanori|M|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": "10.1002/jhbp.447",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1868-6974",
"issue": "24(5)",
"journal": "Journal of hepato-biliary-pancreatic sciences",
"keywords": "Intra-peritoneal chemotherapy; Paclitaxel; Pancreatic ductal adenocarcinoma; Peritoneal metastasis; S-1",
"medline_ta": "J Hepatobiliary Pancreat Sci",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic; D021441:Carcinoma, Pancreatic Ductal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007564:Japan; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel; D010534:Peritoneal Neoplasms; D010537:Peritoneum; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101528587",
"other_id": null,
"pages": "289-296",
"pmc": null,
"pmid": "28301088",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Survival benefit of intravenous and intraperitoneal paclitaxel with S-1 in pancreatic ductal adenocarcinoma patients with peritoneal metastasis: a retrospective study in a single institution.",
"title_normalized": "survival benefit of intravenous and intraperitoneal paclitaxel with s 1 in pancreatic ductal adenocarcinoma patients with peritoneal metastasis a retrospective study in a single institution"
} | [
{
"companynumb": "JP-PFIZER INC-2017216945",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo report a case of metabolic acidosis and coma in a severe acetaminophen overdose.\n\n\nMETHODS\nA 29-year-old white woman was admitted to the emergency department with a diminished level of consciousness and metabolic acidosis. The toxicology screen revealed a serum acetaminophen concentration of 1072 microg/mL, and she was consequently treated with intravenous acetylcysteine. Despite the elevated concentration, the patient did not manifest signs of hepatotoxicity.\n\n\nCONCLUSIONS\nMetabolic acidosis and coma are rare manifestations in acetaminophen overdoses. In published case reports, severe acetaminophen ingestion independently causes metabolic acidosis and coma in the absence of hepatotoxicity. The mechanism by which metabolic acidosis occurs is not clearly defined. Studies conducted on animals demonstrated that in severe overdoses, acetaminophen may cause lactic acidosis by inhibiting mitochondrial respiration. The mechanism by which acetaminophen can cause coma is still unknown.\n\n\nCONCLUSIONS\nSevere acetaminophen overdoses can independently cause metabolic acidosis and coma in the absence of hepatotoxicity.",
"affiliations": "Department of Pharmacy, Ottawa Hospital, Ontario, Canada.",
"authors": "Koulouris|Z|Z|;Tierney|M G|MG|;Jones|G|G|",
"chemical_list": "D000082:Acetaminophen",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.18404",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "33(11)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000082:Acetaminophen; D000138:Acidosis; D000328:Adult; D003128:Coma; D062787:Drug Overdose; D005260:Female; D006801:Humans",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1191-4",
"pmc": null,
"pmid": "10573319",
"pubdate": "1999-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metabolic acidosis and coma following a severe acetaminophen overdose.",
"title_normalized": "metabolic acidosis and coma following a severe acetaminophen overdose"
} | [
{
"companynumb": "CA-RANBAXY-2013US-65188",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe immunosuppressant agents in kidney transplantation (KT) may lead to various complications such as opportunistic infections and malignancies. BK virus associated nephropathy is a significant complication following KT, and it can result in graft failure. BK virus causes tubulointerstitial nephritis, ureter stenosis, and even graft failure in KT recipients with impaired immune system. We described a 63-year-old woman, who was a hepatitis C carrier and on dialysis for 22 years before KT, who received cadaveric-donor KT 2 years previously. She reported decreasing urine output and general weakness. The serum creatinine level was slightly increased from 2.94 to 4.38 mg/dL.\n\n\nMETHODS\nImmunosuppressant medications including prednisolone, everolimus, cyclosporin, and mycophenolate sodium were continued as maintenance therapy post KT. Kidney biopsy was performed due to deterioration of graft function.\n\n\nRESULTS\nThe kidney biopsy showed consistent results with early-stage polyomavirus nephropathy, characterized by focal viral cytopathic changes with positive immunohistochemical signals and mesangial proliferative glomerulonephritis, immune-complex-mediated (Fig 1 and Fig 2). Negative C4d staining at peritubular capillary was reported. The dosage of mycophenolate sodium was tapered from 720 to 360 mg daily and that of everolimus increased from 0.5 to 1.0 mg daily due to BK viral infection with BK nephropathy. The serum creatinine level was 2.75 mg/dL after treatment.\n\n\nCONCLUSIONS\nEarly detection of BK nephropathy and decreasing immunosuppressant agents are the mainstay of treatment. Substituting leflunomide for mycophenolate sodium and increasing dosage of everolimus has been proposed to solve BK nephropathy. We presented that the use of leflunomide in such situation is in a timely manner.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan; Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Primary Care, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.;Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan; Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.;Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.;Department of Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.;Department of General Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.;Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan; Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.;Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan; Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: maiszuwu@gmail.com.",
"authors": "Wu|Mei-Yi|MY|;Chen|Yu-Wei|YW|;Hung|Lie-Yee|LY|;Lee|Chii-Hong|CH|;Chen|Hsin-An|HA|;Hsu|Yung-Ho|YH|;Wu|Mai-Szu|MS|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068338:Everolimus; D000077339:Leflunomide; D009173:Mycophenolic Acid",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2019.01.146",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "51(5)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D001739:BK Virus; D000068338:Everolimus; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D000077339:Leflunomide; D008875:Middle Aged; D009173:Mycophenolic Acid; D009395:Nephritis, Interstitial; D009894:Opportunistic Infections; D027601:Polyomavirus Infections; D014184:Transplantation, Homologous; D014412:Tumor Virus Infections",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1472-1474",
"pmc": null,
"pmid": "31084921",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Treatment for BK Virus Nephropathy by Leflunomide in a Kidney Transplant Patient: A Case Report.",
"title_normalized": "successful treatment for bk virus nephropathy by leflunomide in a kidney transplant patient a case report"
} | [
{
"companynumb": "TW-BAUSCH-BL-2019-015259",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nThe features of paradoxical reactions (PR) that occurred in non-HIV infected patients are rare and not well known.\n\n\nMETHODS\nThe authors reported the case of a 21years old, non-immunocompromised, and HIV negative patient treated for disseminated tuberculosis. PR occurred after 8months after initiation of antituberculous treatment. PR presented as left cervical lymphadenopathy, pulmonary, pleural, costal and spinal location of the tuberculosis. The antituberculous drugs were prolonged. Patient's clinical symptoms improved initially. However, left inguinal lymphadenopathy appeared after 20months of antituberculous therapy. Inguinal lymph node biopsy revealed tuberculous lymphadenitis. The patient has a good compliance to the treatment. The patient was continued on same antituberculous treatment for a total of 28months. The cervical and inguinal lymphadenopathy disappeared and CT scan showed regression of thoracic, abdominal, costal and spinal lesions.\n\n\nCONCLUSIONS\nPR during antituberculous treatment must be considered after exclusion of other causes. No consensus on the therapeutic management of this entity has been developed to date.",
"affiliations": "Service de pneumologie, hôpital Abderrahmane Mami, pavillon 2 Ariana, Tunisie. Electronic address: saoussenbacha@yahoo.fr.;Service de pneumologie, hôpital Abderrahmane Mami, pavillon 2 Ariana, Tunisie.;Service de pneumologie, hôpital Abderrahmane Mami, pavillon 2 Ariana, Tunisie.;Service de radiologie, hôpital Abderrahmane Mami, Ariana, Tunisie.;Service de pneumologie, hôpital Abderrahmane Mami, pavillon 2 Ariana, Tunisie.;Service de pneumologie, hôpital Abderrahmane Mami, pavillon 2 Ariana, Tunisie.;Service de pneumologie, hôpital Abderrahmane Mami, pavillon 2 Ariana, Tunisie.;Service de pneumologie, hôpital Abderrahmane Mami, pavillon 2 Ariana, Tunisie.",
"authors": "Bacha|S|S|;Khemiri|M|M|;Racil|H|H|;Hantous|S|S|;Chaouch|N|N|;Cheikhrouhou|S|S|;Chabbou|A|A|;Megdiche|M L|ML|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "France",
"delete": false,
"doi": "10.1016/j.pneumo.2016.09.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0761-8417",
"issue": "72(6)",
"journal": "Revue de pneumologie clinique",
"keywords": "Adénopathie paradoxale; Antituberculeux; Antituberculous treatment; Management; Paradoxical lymphadenopathy; Paradoxical reaction; Prise en charge; Réaction paradoxale; Tuberculose; Tuberculosis",
"medline_ta": "Rev Pneumol Clin",
"mesh_terms": "D000995:Antitubercular Agents; D006801:Humans; D007121:Immunocompetence; D008198:Lymph Nodes; D008297:Male; D009333:Neck; D010388:Pelvis; D014388:Tuberculosis, Lymph Node; D014391:Tuberculosis, Miliary; D055815:Young Adult",
"nlm_unique_id": "8406312",
"other_id": null,
"pages": "367-372",
"pmc": null,
"pmid": "27776947",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Paradoxical reaction following antituberculosis therapy in immunocompetent patient.",
"title_normalized": "paradoxical reaction following antituberculosis therapy in immunocompetent patient"
} | [
{
"companynumb": "TN-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-133588",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PYRAZINAMIDE"
},
"dr... |
{
"abstract": "OBJECTIVE\nTo assess ECG changes in patients with tramadol-induced seizure(s) and compare these changes in lower and higher than 500 mg tramadol doses as a main goal.\n\n\nMETHODS\nIn an analytical-cross sectional manner over 1 year, 170 patients with idiosyncratic seizure(s) after using tramadol, were studied. Full data were recorded for each patient. ECGs were taken from all the patients on admission and 1 h later and were assessed for findings.\n\n\nRESULTS\n70 of 170 patients (41.2%) had used lower than 500 mg doses of tramadol while 90 patients (52.9%) were included in the high dose group. Rate of female patients in the high dose group was significantly higher. The average age of patients in the high dose group was significantly lower (22.04 vs 25.76). The high dose group had significantly higher heart rates. There was no history of cardiovascular diseases; two patients had previous history of seizure. No significant difference was shown between low dose and high dose groups from the point of ECG changes.\n\n\nCONCLUSIONS\nUsing doses higher than 500 mg is more frequently seen in women, young people and those who have not experienced previous use of tramadol. Terminal S wave, sinus tachycardia, and terminal R wave in the lead aVR are among the most common ECG changes in tramadol users.",
"affiliations": "Emergency Medicine Management Research Center, Iran University of Medical Sciences, Hazrat Rasoul Akram Complex Emergency Department, Tehran, Iran.;Emergency Medicine Management Research Center, Iran University of Medical Sciences, Hazrat Rasoul Akram Complex Emergency Department, Tehran, Iran.;Emergency Medicine Management Research Center, Iran University of Medical Sciences, Hazrat Rasoul Akram Complex Emergency Department, Tehran, Iran.;Emergency Medicine Management Research Center, Iran University of Medical Sciences, Hazrat Rasoul Akram Complex Emergency Department, Tehran, Iran.;Emergency Medicine Management Research Center, Iran University of Medical Sciences, Hazrat Rasoul Akram Complex Emergency Department, Tehran, Iran.;Emergency Medicine Management Research Center, Iran University of Medical Sciences, Hazrat Rasoul Akram Complex Emergency Department, Tehran, Iran.;Emergency Medicine Management Research Center, Iran University of Medical Sciences, Hazrat Rasoul Akram Complex Emergency Department, Tehran, Iran.",
"authors": "Hafezi Moghadam|Peyman|P|;Zarei|Najmeh|N|;Farsi|Davood|D|;Abbasi|Saeed|S|;Mofidi|Mani|M|;Rezai|Mahdi|M|;Mahshidfar|Babak|B|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1016/j.tjem.2016.08.005",
"fulltext": "\n==== Front\nTurk J Emerg MedTurk J Emerg MedTurkish Journal of Emergency Medicine2452-2473Elsevier S2452-2473(16)30084-X10.1016/j.tjem.2016.08.005Original ArticleElectrocardiographic changes in patients with tramadol-induced idiosyncratic seizures Hafezi Moghadam Peyman hafezimoghadam@yahoo.comZarei Najmeh znajme@gmail.comFarsi Davood davoodfa2004@yahoo.comAbbasi Saeed saieedabbasi@yahoo.comMofidi Mani manimofidi@yahoo.comRezai Mahdi mah_re@yahoo.comMahshidfar Babak bmahshidfar@gmail.com∗Emergency Medicine Management Research Center, Iran University of Medical Sciences, Hazrat Rasoul Akram Complex Emergency Department, Tehran, Iran∗ Corresponding author. bmahshidfar@gmail.com16 9 2016 12 2016 16 9 2016 16 4 151 154 13 3 2016 22 8 2016 29 8 2016 Copyright © 2016 The Emergency Medicine Association of Turkey. Production and hosting by Elsevier B.V. on behalf of the Owner.2016The Emergency Medicine Association of TurkeyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Objectives\nTo assess ECG changes in patients with tramadol-induced seizure(s) and compare these changes in lower and higher than 500 mg tramadol doses as a main goal.\n\nMaterial and methods\nIn an analytical-cross sectional manner over 1 year, 170 patients with idiosyncratic seizure(s) after using tramadol, were studied. Full data were recorded for each patient. ECGs were taken from all the patients on admission and 1 h later and were assessed for findings.\n\nResults\n70 of 170 patients (41.2%) had used lower than 500 mg doses of tramadol while 90 patients (52.9%) were included in the high dose group. Rate of female patients in the high dose group was significantly higher. The average age of patients in the high dose group was significantly lower (22.04 vs 25.76). The high dose group had significantly higher heart rates. There was no history of cardiovascular diseases; two patients had previous history of seizure. No significant difference was shown between low dose and high dose groups from the point of ECG changes.\n\nDiscussion and conclusion\nUsing doses higher than 500 mg is more frequently seen in women, young people and those who have not experienced previous use of tramadol. Terminal S wave, sinus tachycardia, and terminal R wave in the lead aVR are among the most common ECG changes in tramadol users.\n\nKeywords\nECG changesTramadolSeizure\n==== Body\n1 Introduction\nTramadol is a synthetic analog of codeine1 with a 10-fold weaker affinity for opium receptors (resulting in analgesic effects) compared to morphine.2 It is absorbed rapidly and almost completely, following oral intake.3 There are also, slow-releasing forms of tramadol in which the free portion is being released within 12 h and the highest concentration is being achieved within 4.9 h.4 20% of tramadol gets bound to plasma proteins.5 Tramadol is distributed in blood, kidney, and brain, but it cannot be found in muscles. Like morphine, tramadol is significantly accumulated in bile rather than in kidneys and liver and its clearance takes 6 h.4 First, tramadol was claimed to be a safe agent with a low potential for being abused,6 but later, adverse reactions were reported. Its complications are inappropriately higher in overdose. Published cases of overdoses are mainly in an acute, oral, and intentional setting. Majority of cases become symptomatic within the first 4 h and the symptoms disappear after 24 h. It is reported that up to 20% of cases need intensive care unit (ICU) admission. Tramadol overdose generally involves young people in third decade of their lives, on average.7 Central nervous system complications are the most frequently reported manifestations ranging from agitation to deep coma.5 Seizure has been considered to have an important role in tramadol toxicity as declared by studies and the literature.5, 7, 8, 9, 10, 11 Nausea/vomiting and respiratory depression have also been reported.5, 7, 8 Of cardiac issues, hypotension, especially affecting systolic blood pressure (SBP) and sinus tachycardia have been listed as tramadol toxicity complications.5, 7, 8, 12, 13, 14\n\nManagement of tramadol toxicity is focused on supportive care, including oxygen, fluid therapy, and diazepam for controlling agitation or seizure.\n\nFew studies have been conducted to investigate electrocardiographic (ECG) changes after idiosyncratic seizures following tramadol use. Our study was performed to evaluate ECG changes in this category of patients.\n\n2 Material and methods\nThis study was conducted in an analytical cross sectional manner since January 2013 to January 2014. The study was approved by ethics committee of Iran University of Medical Sciences (IUMS) and all ethical issues regarding research were fulfilled during the study. Informed consent was taken from each patient or his/her companion(s). 170 patients, admitted to a teaching Hospital because of an idiosyncratic seizure after using tramadol, were included in the study. Inclusion criteria were age between 16 and 80 years, complaints following tramadol abuse. Exclusion criteria included cardiovascular disease, proof of other drugs and substances abuse with tests and use of drugs affecting cardiovascular system before admission. A checklist including age, sex, frequency of seizures during admission, history of seizure, and dose and duration of tramadol use was filled. ECG was taken from all the patients 1 h after admission. QT interval prolongation, QRS widening, terminal S wave in the lead D1, terminal R wave in the lead aVR, and sinus tachycardia were assessed in ECGs by trained emergency room physician. The group of patients who had used doses lower than 500 mg of tramadol, was named “low dose” group and patients who had used doses higher than 500 mg, were included in the so-named “high dose” group.15, 16, 17 Acquired data were analyzed in SPSS V.16 with independent sample t-test for quantitative and chi-square test for qualitative comparison.\n\n3 Results\n170 patients were included in the study; In low dose group there were 70 (41.2%) patients, including 68 men and 2 women, while 90 (52.9%) of patients, including 76 men, 13 women and unknown sex of one patient, entered the high dose group. Dose of tramadol used, has not been recorded for 10 patients (5.9%).\n\nThere was no difference in respiratory rates (RRs) between two groups but a significant difference between pulse rates (PRs) of two groups has been observed. PRs were lower in the high dose group compared to the low dose group (92.94 ± 17.80 vs. 101.06 ± 20.03; p = 0.009) (Table 1).\n\nThere was not even one positive history of heart disease in the participants. 157 patients denied any history of cardiac problems and in 13 patients there was no recorded document supporting their cardiac history. Two cases had a positive previous history of seizure; one of them was due to previous use of tramadol.\n\nNumber of seizure attacks was 1.18 ± 0.615 and 1.26 ± 0.604 in the low and high dose groups, respectively (p = 0.169). Fig. 1 shows the frequency of seizure attacks in patients after tramadol use.\n\nThe time interval between using tramadol and occurrence of seizure(s) was measured in both groups. It was 150 min in the low dose group, compared to 235 min in the high dose group; there was no statistically significant difference between two groups (p = 0.113).\n\nThe positive history of previous tramadol use was significantly more frequent in the low dose group (p = 0.002), as 47 of patients reported previous use of tramadol, while 21 of them denied any history of previous use (compared to 38 and 48 patients, respectively, in the high dose group).\n\nOverall, 68 patients (42.5%) showed sinus tachycardia and 4 patients (2.4%) had sinus bradycardia; sinus tachycardia was significantly much more frequent in the high dose group (47 vs. 21 patients; p = 0.005).\n\nThere was no statistically meaningful difference between two groups from the point of bradycardia (3 patients in the high dose group vs. just 1 patient in the low dose group; p = 0.632).\n\nThe most frequent ECG changes were terminal S wave, sinus tachycardia, terminal R wave in the lead aVR, T wave inversion, right bundle branch block (RBBB), and QRS widening, respectively. No left bundle branch block (LBBB), QT interval prolongation (Fig. 2), second or third degree atrio-ventricular (AV) block were seen. Table 2 demonstrates ECG changes in details.\n\n4 Discussion\nSeizure is a critical issue in tramadol toxicity. While population-based reports speculate the frequency of seizure from 8 to 14%,5, 7 hospital reports declare a higher risk for seizure, from 15 to 35%.8, 9 It is seen that tramadol leads to seizure if it's used in doses higher than therapeutic ranges or in combination with antidepressants10; it has not been reported after standard and appropriate doses. More than half of tramadol abusers (54%) have experienced at least one episode of tonic-clonic seizure in a 3-year follow-up period.11 Different amounts have been mentioned in various studies as the minimum dose of tramadol needed to cause seizure, ranges from 200 mg7–350 mg8 and even higher. In our study, 9 patients had used 100 mg of tramadol and it was the least dose used by our cases.\n\nThe average age of people experiencing tramadol overdose, is around 30 years according to different studies, which is consistent with our findings. The average age of patients was 23.69 years in our study. Different studies have reported the average interval of seizure occurrence after using tramadol to be 4 h which was almost the same (3.26 h) in our study.5, 18\n\nIn our study which was done among patients with tramadol toxicity and seizure, number of men was significantly higher than the women, but association of women with doses higher than 500 mg was stronger. Maybe the reason is that men usually abuse Tramadol as substance but women abuse it to commit suicide. It has been reported in previous studies that tramadol toxicity in non-hospital setting is a little bit higher in women than men, but it's not true for in-hospital setting.8, 9\n\nHypotension, especially affecting SBP and sinus tachycardia are the cardiac complications5, 7 resembling findings caused by other opioids. In majority of toxicities, no arrhythmia was reported except to tachycardia.8 There are a few case reports of Brugada ECG pattern, right-sided heart failure (HF), refractory shock, and asystole.12, 13, 14 Interestingly, hypertension is seen in some cases.5 As said before, higher HRs and sinus tachycardia were seen in high dose group and no hypotension or any considerable ECG changes or arrhythmias were found. One study showed an association between seizure and male gender, chronic use, intentional use, and tachycardia,18 but other studies didn't support it. In one recent study, the most common types of ECG changes were sinus tachycardia, a deep S wave in leads I and aVL, right axis deviation, and long QTc interval, respectively. Brugada pattern and sinus bradycardia were rarely presented.19 As in our study, most of studies have not reported any arrhythmia beyond tachycardia or any serious cardiovascular toxicity. Overall, abnormal R or S waves were not seen in the aVR. There are just one or two case reports of serious abnormalities like Brugada pattern, acute right-sided HF, refractory shock, and asystole. We didn't observe any case of hypertension, although it was reported in some studies.\n\nWe showed people who have not used tramadol before, are more likely to use higher doses in cases of overdose in comparison to those who have experienced it, before; this could be due to the cautions taken by experienced users of tramadol.\n\n5 Limitations\nWe faced some limitations in our study including the unknown dose of tramadol used in some patients, inability to follow-up the patients who were transferred to ICU or left the hospital, incomplete data in some patients, and unawareness of concomitant drugs used in some cases.\n\n6 Conclusion\nUsing doses higher than 500 mg was seen significantly more frequent in women, young people, and those who had not previously used tramadol. Terminal S wave, sinus tachycardia, and terminal R wave in the lead aVR are among the most common ECG changes seen in tramadol users. It is important to consider abovementioned findings in addition to drug history in the young patients who are admitted with seizure(s) following tramadol use.\n\nPeer review under responsibility of The Emergency Medicine Association of Turkey.\n\nFig. 1 Number of seizure episodes in the individuals.\n\nFig. 1Fig. 2 One of patients ECG demonstrating sinus tachycardia and QT prolongation (Corrected QT is about 0.50 msec).\n\nFig. 2Table 1 Basic patients' characteristics.\n\nTable 1\tLow dose group\tHigh dose group\tp-value\t\nAge\t25.76 ± 7.30\t22.04 ± 6.21\t0.001\t\nGender\t68 males (97.14%), 2 females (2.85%)\t76 males (85.39%), 13 females (14.60%)\t0.012\t\nSystolic blood pressure\t124 ± 14.25\t120.90 ± 15.17\t0.190\t\nDiastolic blood pressure\t77.94 ± 8.20\t75.40 ± 10.55\t0.103\t\nRespiratory rate (RR)\t23.31 ± 2.61\t22.76 ± 2.61\t0.106\t\nPulse rate (PR)\t101.06 ± 20.03\t92.94 ± 17.80\t0.009\t\nTable 2 ECG changes in the patients.\n\nTable 2ECG changes\tLow dose groups\tHigh dose group\tTotal\tp-value\t\nTerminal S\tPresent\t53\t61\t114\t0.271\t\nAbsent\t17\t29\t46\t\nTerminal R in aVR\tPresent\t19\t36\t55\t0.089\t\nAbsent\t51\t54\t105\t\nST depression\tPresent\t2\t2\t4\t0.799\t\nAbsent\t68\t88\t156\t\nT inversion\tPresent\t6\t14\t20\t0.185\t\nAbsent\t64\t76\t140\t\nRBBB\tPresent\t5\t12\t17\t0.207\t\nAbsent\t65\t78\t143\t\nQRS widening\tPresent\t5\t6\t11\t0.906\t\nAbsent\t65\t84\t149\t\nAV Block Type I\tPresent\t0\t1\t1\t0.376\t\nAbsent\t70\t89\t159\t\nSinus Tachycardia\tPresent\t21\t47\t68\t0.005\t\nAbsent\t49\t43\t92\t\nSinus Bradycardia\tPresent\t1\t2\t3\t0.632\t\nAbsent\t69\t88\t157\t\nECG: electrocardiography, RBBB: right bundle branch block, AV: atrio-ventricular.\n==== Refs\nReferences\n1 Kovelowski C.J. Raffa R.B. Porreca F. Tramadol and its enantiomers differentially suppress c-fos-like immunoreactivity in rat brain and spinal cord following acute noxious stimulus Eur J Pain 2 1998 211 219 15102381 \n2 Sansone R.A. Sansone L.A. Tramadol: seizures, serotonin syndrome, and coadministered antidepressants Psychiatry (Edgmont) 6 2009 17 21 \n3 Grond S. Sablotzki A. Clinical pharmacology of tramadol Clin Pharmacokinet 43 2004 879 923 15509185 \n4 Klingmann A. Skopp G. Pedal I. Distribution of morphine and morphine glucuronides in body tissue and fluids— postmortem findings in brief survival Arch Kriminol 206 2000 38 49 11006825 \n5 Spiller H.A. Gorman S.E. Villalobos D. Prospective multicenter evaluation of tramadol exposure J Toxicol Clin Toxicol 35 1997 361 364 9204095 \n6 Moore P.A. Pain management in dental practice: tramadol vs. codeine combinations J Am Dent Assoc 130 1999 1075 1079 10422401 \n7 Marquardt K.A. Alsop J.A. Albertson T.E. Tramadol exposures reported to statewide poison control system Ann Pharmacother 39 2005 1039 1044 15870139 \n8 Tashakori A. Afshari R. Tramadol overdose as a cause of serotonin syndrome: a case series Clin Toxicol (Phila) 48 2010 337 341 20367390 \n9 Shadnia S. Soltaninejad K. Heydari K. Tramadol intoxication: a review of 114 cases Hum Exp Toxicol 27 2008 201 205 18650251 \n10 Ripple M.G. Pestaner J.P. Levine B.S. Smialek J.E. Lethal combination of tramadol and multiple drugs affecting serotonin Am J Forensic Med Pathol 21 2000 370 374 11111800 \n11 Jovanovic-Cupic V. Marinovic Z. Nesic N. Seizures associated with intoxication and abuse of tramadol Clin Toxicol (Phila) 44 2006 143 146 16615669 \n12 Daubin C. Quentin C. Goullé J.P. Refractory shock and asystole related to tramadol overdose Clin Toxicol (Phila) 45 2007 961 964 17852155 \n13 Afshari R. Tashakori A. Shakiba A.H. Tramadol overdose induced CPK rise, haemodynamic, and electrocardiographic changes, and seizure Clin Toxicol 46 5 2008 369 \n14 Cole J.B. Sattiraju S. Bilden E.F. Isolated tramadol overdose associated with Brugada ECG pattern Pacing Clin Electrophysiol 35 8 2012 e219 e221 21039643 \n15 Reeves R.R. Burke R.S. Tramadol: basic pharmacology and emerging concepts Drugs Today (Barc) 44 2008 827 19180260 \n16 Hassanian-Moghaddam H. Farajidana H. Sarjami S. Tramadol-induced apnea Am J Emerg Med 31 2013 26 22809771 \n17 Rahimi H.R. Soltaninejad K. Shadnia S. Acute tramadol poisoning and its clinical and laboratory findings J Res Med Sci 19 9 2014 855 859 25535500 \n18 Wang S.Q. Li C.S. Song Y.G. Multiply organ dysfunction syndrome due to tramadol intoxication alone Am J Emerg Med 27 7 2009 903.e5-7 \n19 Alizadeh Ghamsari A. Dadpour B. Najari F. Frequency of electrocardiographic abnormalities in tramadol poisoned patients; a brief report Emergency 4 3 2016 151 154 27299145\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2452-2473",
"issue": "16(4)",
"journal": "Turkish journal of emergency medicine",
"keywords": "ECG changes; Seizure; Tramadol",
"medline_ta": "Turk J Emerg Med",
"mesh_terms": null,
"nlm_unique_id": "101681782",
"other_id": null,
"pages": "151-154",
"pmc": null,
"pmid": "27995207",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": "15870139;17852155;19724727;20367390;15509185;11111800;9204095;11006825;10422401;27299145;18650251;25535500;16615669;22809771;21039643;19683139;19180260;15102381",
"title": "Electrocardiographic changes in patients with tramadol-induced idiosyncratic seizures.",
"title_normalized": "electrocardiographic changes in patients with tramadol induced idiosyncratic seizures"
} | [
{
"companynumb": "IR-JNJFOC-20170108388",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRAMADOL HYDROCHLORIDE"
},
"drugadditional": "3",... |
{
"abstract": "Cavernous sinus thrombosis (CST) is a rare and potentially fatal complication of acute sinusitis. Timely diagnosis and management is, therefore, essential in preventing death and neurological disability. Here, we describe the case of a paediatric patient with bilateral CST secondary to acute unilateral pansinusitis that presented with rapidly progressing bilateral periorbital oedema. Initial imaging was negative. This case serves to emphasise the importance of maintaining a high index of suspicion when managing paediatric patients with suspected CST with persistent symptoms. Expeditious investigation and management of our patient in this case resulted in a positive outcome, with resolution of symptoms and no residual neurological deficit.",
"affiliations": "Otolaryngology, University Hospital Crosshouse, Kilmarnock, UK timothy.davies@nhs.net.;Otolaryngology, University Hospital Crosshouse, Kilmarnock, UK.;Radiology, University Hospital Crosshouse, Kilmarnock, UK.;Otolaryngology, University Hospital Crosshouse, Kilmarnock, UK.",
"authors": "Davies|Timothy Charles|TC|;Alatsatianos|Anton|A|;Nowak|Magdalena|M|;Fraser|Lyndsay|L|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000925:Anticoagulants",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-237758",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(12)",
"journal": "BMJ case reports",
"keywords": "ear; nose and throat/otolaryngology; radiology; venous thromboembolism",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D061605:Administration, Intravenous; D000293:Adolescent; D000900:Anti-Bacterial Agents; D000925:Anticoagulants; D002426:Cavernous Sinus; D020226:Cavernous Sinus Thrombosis; D003937:Diagnosis, Differential; D004359:Drug Therapy, Combination; D004724:Endoscopy; D006261:Headache; D006801:Humans; D018810:Magnetic Resonance Angiography; D008297:Male; D012852:Sinusitis; D013290:Streptococcal Infections; D034367:Streptococcus intermedius; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33370987",
"pubdate": "2020-12-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bilateral cavernous sinus thrombosis complicating acute unilateral pansinusitis in a 15-year-old boy.",
"title_normalized": "bilateral cavernous sinus thrombosis complicating acute unilateral pansinusitis in a 15 year old boy"
} | [
{
"companynumb": "GB-MYLANLABS-2021M1025720",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": null,
... |
{
"abstract": "This report describes esophageal ulcer as a novel adverse event associated with crizotinib therapy. Although crizotinib is generally well tolerated, physicians should be aware of the possibility of this adverse event.",
"affiliations": "Department of Thoracic Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.;Department of Thoracic Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.;Department of Thoracic Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.;Department of Thoracic Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.;Department of Thoracic Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.;Department of Gastroenterology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.;Department of Thoracic Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. Electronic address: 107974@aichi-cc.jp.",
"authors": "Park|Jangchul|J|;Yoshida|Kimihide|K|;Kondo|Chiaki|C|;Shimizu|Junichi|J|;Horio|Yoshitsugu|Y|;Hijioka|Susumu|S|;Hida|Toyoaki|T|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.lungcan.2013.06.017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "81(3)",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "Adverse event; Anaplastic lymphoma kinase; Crizotinib; Inhibitor; Non-small-cell lung cancer; Ulceration",
"medline_ta": "Lung Cancer",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D002289:Carcinoma, Non-Small-Cell Lung; D000077547:Crizotinib; D016145:Endoscopy, Digestive System; D004935:Esophageal Diseases; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D014456:Ulcer",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "495-496",
"pmc": null,
"pmid": "23891512",
"pubdate": "2013-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Crizotinib-induced esophageal ulceration: a novel adverse event of crizotinib.",
"title_normalized": "crizotinib induced esophageal ulceration a novel adverse event of crizotinib"
} | [
{
"companynumb": "JP-PFIZER INC-2017267819",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CRIZOTINIB"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nWe compared the clinical outcomes and toxicity profile among a retrospective cohort of patients with primary major salivary gland carcinomas (SGCs) treated with surgery followed by adjuvant radiation therapy (S+RT) versus surgery and adjuvant chemoradiotherapy (S+CRT).\n\n\nMETHODS\nTwenty patients (71%) underwent S+RT and eight (29%) S+CRT at our Institution between 2006 and 2015. Microscopic positive margins were present in 54% of the patients.\n\n\nRESULTS\nThe 3-year overall survival (OS) was 100% with S+RT and 87.5% with S+CRT (p=0.141) and locoregional control (LRC) was 95% with S+RT and 87.5% with S+CRT (p=0.383). There were no significant differences in the rate of acute (p=0.801) and late (p=0.714) toxicities.\n\n\nCONCLUSIONS\nWhile we await randomized data, adjuvant CRT may be considered as a viable therapeutic option for patients at high-risk of local or regional recurrence, especially in those with a positive microscopic margin where further surgery may result in functional cranial neuropathies.",
"affiliations": "University of Vermont, College of Medicine, Burlington, VT, U.S.A.;Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, U.S.A.;Department of Otolaryngology-Head and Neck Surgery, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, U.S.A.;Department of Otolaryngology-Head and Neck Surgery, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, U.S.A.;Department of Otolaryngology-Head and Neck Surgery, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, U.S.A.;Department of Pathology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, U.S.A.;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, U.S.A.;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, U.S.A.;Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, U.S.A.;Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, U.S.A. Richard.Bakst@mountsinai.org.",
"authors": "Sayan|Mutlay|M|;Vempati|Prashant|P|;Miles|Brett|B|;Teng|Marita|M|;Genden|Eric|E|;Demicco|Elizabeth G|EG|;Misiukiewicz|Krzysztof|K|;Posner|Marshall|M|;Gupta|Vishal|V|;Bakst|Richard L|RL|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "36(8)",
"journal": "Anticancer research",
"keywords": "Salivary gland carcinoma; adjuvant therapy; chemoradiotherapy; radiotherapy",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003528:Carcinoma, Adenoid Cystic; D059186:Chemoradiotherapy, Adjuvant; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012468:Salivary Gland Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "4165-70",
"pmc": null,
"pmid": "27466526",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Adjuvant Therapy for Salivary Gland Carcinomas.",
"title_normalized": "adjuvant therapy for salivary gland carcinomas"
} | [
{
"companynumb": "US-HQ SPECIALTY-US-2017INT000013",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "Hepatoblastoma treatment with curative intent requires surgical resection, but only about a third of newly diagnosed patients with hepatoblastoma have resectable disease at diagnosis. Patients who have upfront resection typically receive a total of 4-6 cycles of adjuvant chemotherapy post-surgery, with the combination of cisplatin, fluorouracil, and vincristine. We aimed to investigate whether event-free survival in children with hepatoblastoma who had complete resection at diagnosis could be maintained with two cycles of adjuvant chemotherapy.\n\n\n\nIn this Children's Oncology Group, multicentre, phase 3 trial, patients were enrolled in four risk groups on the basis of Evans surgical stage, tumour histology, and levels of α-fetoprotein at diagnosis to receive risk-adapted therapy. Here, we report on the low-risk stratum of the trial. Eligible patients were younger than 21 years and had histologically confirmed, stage I or II hepatoblastoma without 100% pure fetal stage I or small-cell undifferentiated histology; elevated serum α-fetoprotein level (>100 ng/mL); a complete resection at diagnosis; at least 50% Karnofsky (patients >16 years) or Lansky (patients ≤16 years) performance status; and had received no previous chemotherapy or other hepatoblastoma-directed therapy. Patients received two 21-day cycles of cisplatin, fluorouracil, and vincristine within 42 days of resection, consisting of cisplatin (100 mg/m2 per dose or 3·3 mg/kg per dose for children <10 kg) intravenously over 6 h on day 1; fluorouracil (600 mg/m2 per dose or 20 mg/kg per dose for children <10 kg) intravenous push on day 2; and vincristine (1·5 mg/m2 per day to a maximum dose of 2 mg, or 0·05 mg/kg per day for children <10 kg) intravenous push on days 2, 9, and 16. The primary outcome was investigator-assessed event-free survival. As prespecified by protocol, we analysed the primary endpoint 6 years after enrolment (cutoff date June 30, 2017). This trial is registered with ClinicalTrials.gov, number NCT00980460, and is now permanently closed to accrual.\n\n\n\nBetween May 18, 2010, and May 28, 2014, 51 patients in 32 centres in two countries were enrolled into the low-risk stratum of this trial, of whom 49 received c hemotherapy treatment after surgery and were evaluable for activity and safety. Median follow-up time for all evaluable patients was 42 months (IQR 36-62). 4-year event-free survival was 92% (95% CI 79-97) and 5-year event-free survival was 88% (72-95). Two (4%) of 49 patients had surgical complications (bile leaks). The most common grade 3-4 adverse events were febrile neutropenia in seven (14%) patients, decreased neutrophil count in three (6%) patients, infections in four (8%) patients, and diarrhoea in four (8%) patients. Ototoxicity occurred in one (2%) patient. One (2%) patient of the three who relapsed in this cohort died from disease. Two (4%) patients died in clinical remission after therapy discontinuation. One patient died of pneumonia and bacterial sepsis 1 year after therapy discontinuation and another patient died of unrelated causes 57 months after therapy completion. There were no treatment-related deaths.\n\n\n\nMinimal postoperative chemotherapy with two cycles of cisplatin, fluorouracil, and vincristine can ensure disease control in patients with hepatoblastoma resected at diagnosis. Our results show that dose reduction of ototoxic agents is a safe, effective treatment for these children.\n\n\n\nNational Institutes of Health.",
"affiliations": "Nemours Children's Specialty Care and Wolfson Children's Hospital, Jacksonville, FL, USA. Electronic address: howard.katzenstein@nemours.org.;University of Tennessee Health Science Center, Memphis, TN, USA; St Jude Children's Research Hospital, Memphis, TN, USA.;University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.;University of Southern California Keck School of Medicine, Los Angeles, CA, USA.;Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.;University of Tennessee Health Science Center, Memphis, TN, USA; St Jude Children's Research Hospital, Memphis, TN, USA.;Baylor College of Medicine, Houston, TX, USA.;Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.;AI Dupont Hospital for Children, Wilmington, DE, USA.;University of Virginia Hospital, Charlottesville, VA, USA.;Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.;Dana-Farber Cancer Institute, and Boston Children's Hospital, Boston, MA, USA.;Children's Healthcare of Atlanta, Atlanta, GA, USA.;University of Tennessee Health Science Center, Memphis, TN, USA; St Jude Children's Research Hospital, Memphis, TN, USA.;Children's Oncology Group, Monrovia, CA, USA.;University of Tennessee Health Science Center, Memphis, TN, USA; St Jude Children's Research Hospital, Memphis, TN, USA.;Primary Children's Hospital, Salt Lake City, UT, USA.",
"authors": "Katzenstein|Howard M|HM|;Langham|Max R|MR|;Malogolowkin|Marcio H|MH|;Krailo|Mark D|MD|;Towbin|Alexander J|AJ|;McCarville|Mary Beth|MB|;Finegold|Milton J|MJ|;Ranganathan|Sarangarajan|S|;Dunn|Stephen|S|;McGahren|Eugene D|ED|;Tiao|Gregory M|GM|;O'Neill|Allison F|AF|;Qayed|Muna|M|;Furman|Wayne L|WL|;Xia|Caihong|C|;Rodriguez-Galindo|Carlos|C|;Meyers|Rebecka L|RL|",
"chemical_list": "D014750:Vincristine; D002945:Cisplatin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1016/S1470-2045(18)30895-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "20(5)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000367:Age Factors; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin; D018450:Disease Progression; D005260:Female; D005472:Fluorouracil; D006498:Hepatectomy; D018197:Hepatoblastoma; D006801:Humans; D007223:Infant; D008113:Liver Neoplasms; D008297:Male; D009367:Neoplasm Staging; D000077982:Progression-Free Survival; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014481:United States; D014750:Vincristine",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "719-727",
"pmc": null,
"pmid": "30975630",
"pubdate": "2019-05",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "10894865;11905674;12037748;14746860;19588519;19846851;21768450;22648979;22887704;24362406;26164096;29924955;8380296;8889347",
"title": "Minimal adjuvant chemotherapy for children with hepatoblastoma resected at diagnosis (AHEP0731): a Children's Oncology Group, multicentre, phase 3 trial.",
"title_normalized": "minimal adjuvant chemotherapy for children with hepatoblastoma resected at diagnosis ahep0731 a children s oncology group multicentre phase 3 trial"
} | [
{
"companynumb": "US-MYLANLABS-2019M1049157",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": "3",
... |
{
"abstract": "This report is related to the unusual case of an 11-year-old boy presenting with acute gastric dilatation after the intake of excessive food and carbonated beverages after a 12-hour fasting who died of complications of acute reperfusion syndrome after decompression of the stomach with gastrotomy. An enormously distended stomach was encountered without volvulus and obstruction in the operation. Autopsy and histological findings revealed a severely distended stomach, the walls of which were notably thin and displayed transmural necrosis. The reported case demonstrated that enormous food and beverage intake may cause acute gastric dilatation and gastric necrosis, and subsequently, sudden death may develop in children. The subject reported here is the youngest child in literature dying from acute gastric dilatation and necrosis without any underlying disorders and exposed to autopsy.",
"affiliations": "From the *Department of Pediatric Surgery, Konya Education and Research Hospital; †Department of Pediatric Surgery, Faculty of Medicine, Baskent University; and ‡Department of Pediatric Surgery, Faculty of Medicine, Selcuk University, Konya, Turkey.",
"authors": "Kocaoglu|Canan|C|;Akillioglu|Ishak|I|;Gunduz|Metin|M|;Sekmenli|Tamer|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000000699",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "33(11)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000208:Acute Disease; D001344:Autopsy; D002253:Carbonated Beverages; D002648:Child; D003645:Death, Sudden; D019299:Decompression, Surgical; D004108:Dilatation, Pathologic; D017809:Fatal Outcome; D013271:Gastric Dilatation; D005774:Gastrostomy; D006801:Humans; D008297:Male; D009336:Necrosis; D013270:Stomach",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "e131-e133",
"pmc": null,
"pmid": "27164319",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unexpected Death Due to Acute Gastric Dilatation and Gastric Necrosis in an 11-Year-Old Boy.",
"title_normalized": "unexpected death due to acute gastric dilatation and gastric necrosis in an 11 year old boy"
} | [
{
"companynumb": "TR-GLENMARK PHARMACEUTICALS-2017GMK030123",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATROPINE"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nImmune checkpoint inhibitors have potential applications in treating various cancers but are associated with immune-related adverse events, such as inflammation, in a wide range of organs; however, allergic inflammation caused by these agents has not been extensively studied.\n\n\nMETHODS\nA 65-year-old man was diagnosed with a kidney neuroendocrine carcinoma. Three months after kidney resection surgery, the tumor cells had metastasized to his liver and lymph nodes. Subsequently, the patient started chemotherapy; however, regardless of treatment, the tumor grew, and the patient experienced a series of adverse effects, such as taste disorder, anorexia, and general fatigue. Finally, he was administered a programmed cell death (PD)-1 inhibitor, nivolumab (biweekly, toal 200 mg/body), which was effective against kidney carcinoma. However, the patient had a bronchial asthma attack at 22 cycles of nivolumab treatment and chest computed tomography (CT) revealed an abnormal bilateral shadow after 37 cycles of nivolumab treatment. Bronchoscopy findings revealed eosinophil infiltration in the lungs along with severe alveolar hemorrhage. Paranasal sinus CT scanning indicated sinusitis and nerve conduction analysis indicated a decrease in his right ulnar nerve conduction velocity. Based on these findings, the patient was diagnosed with eosinophilic granulomatosis with polyangiitis; he was treated with prednisolone, which alleviated his bronchial asthma. To restart nivolumab treatment, the dose of prednisolone was gradually tapered, and the patient was administered a monthly dose of mepolizumab and biweekly dose of nivolumab. To date, there have been no bronchial attacks or CT scan abnormalities upon follow up.\n\n\nCONCLUSIONS\nWe present a rare case in which a patient with cancer was diagnosed with eosinophilic granulomatosis with polyangiitis following treatment with a PD-1 inhibitor. Blockade of PD-1 and the programmed cell death ligand (PD-L) 1/PD-1 and PD-L2/PD-1 signaling cascade may cause allergic inflammation. Further studies are needed to identify the specific mechanisms underlying allergic inflammation after PD-1 blockade.",
"affiliations": "Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda City, Shizuoka Province, Japan. mharada202@gmail.com.;Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda City, Shizuoka Province, Japan.;Department of Pathology, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda City, Shizuoka Province, Japan.;Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda City, Shizuoka Province, Japan.;Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda City, Shizuoka Province, Japan.;Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda City, Shizuoka Province, Japan.;Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda City, Shizuoka Province, Japan.;Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda City, Shizuoka Province, Japan.;Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda City, Shizuoka Province, Japan.;Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda City, Shizuoka Province, Japan.;Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda City, Shizuoka Province, Japan.;Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda City, Shizuoka Province, Japan.",
"authors": "Harada|Masanori|M|;Naoi|Hyogo|H|;Yasuda|Kazuyo|K|;Ito|Yutaro|Y|;Kagoo|Namio|N|;Kubota|Tsutomu|T|;Ichijo|Koshiro|K|;Mochizuki|Eisuke|E|;Uehara|Masahiro|M|;Matsuura|Shun|S|;Tsukui|Masaru|M|;Koshimizu|Naoki|N|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors; D000077594:Nivolumab; D011239:Prednisolone",
"country": "England",
"delete": false,
"doi": "10.1186/s12890-020-01375-5",
"fulltext": "\n==== Front\nBMC Pulm Med\nBMC Pulm Med\nBMC Pulmonary Medicine\n1471-2466 BioMed Central London \n\n1375\n10.1186/s12890-020-01375-5\nCase Report\nProgrammed cell death-1 blockade in kidney carcinoma may induce eosinophilic granulomatosis with polyangiitis: a case report\nHarada Masanori mharada202@gmail.com 1 Naoi Hyogo 1 Yasuda Kazuyo 2 Ito Yutaro 1 Kagoo Namio 1 Kubota Tsutomu 1 Ichijo Koshiro 1 Mochizuki Eisuke 1 Uehara Masahiro 1 Matsuura Shun 1 Tsukui Masaru 1 Koshimizu Naoki 1 1 grid.415119.90000 0004 1772 6270Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda City, Shizuoka Province Japan \n2 grid.415119.90000 0004 1772 6270Department of Pathology, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda City, Shizuoka Province Japan \n6 1 2021 \n6 1 2021 \n2021 \n21 614 7 2020 14 12 2020 © The Author(s) 2021Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nImmune checkpoint inhibitors have potential applications in treating various cancers but are associated with immune-related adverse events, such as inflammation, in a wide range of organs; however, allergic inflammation caused by these agents has not been extensively studied.\n\nCase presentation\nA 65-year-old man was diagnosed with a kidney neuroendocrine carcinoma. Three months after kidney resection surgery, the tumor cells had metastasized to his liver and lymph nodes. Subsequently, the patient started chemotherapy; however, regardless of treatment, the tumor grew, and the patient experienced a series of adverse effects, such as taste disorder, anorexia, and general fatigue. Finally, he was administered a programmed cell death (PD)-1 inhibitor, nivolumab (biweekly, toal 200 mg/body), which was effective against kidney carcinoma. However, the patient had a bronchial asthma attack at 22 cycles of nivolumab treatment and chest computed tomography (CT) revealed an abnormal bilateral shadow after 37 cycles of nivolumab treatment. Bronchoscopy findings revealed eosinophil infiltration in the lungs along with severe alveolar hemorrhage. Paranasal sinus CT scanning indicated sinusitis and nerve conduction analysis indicated a decrease in his right ulnar nerve conduction velocity. Based on these findings, the patient was diagnosed with eosinophilic granulomatosis with polyangiitis; he was treated with prednisolone, which alleviated his bronchial asthma. To restart nivolumab treatment, the dose of prednisolone was gradually tapered, and the patient was administered a monthly dose of mepolizumab and biweekly dose of nivolumab. To date, there have been no bronchial attacks or CT scan abnormalities upon follow up.\n\nConclusions\nWe present a rare case in which a patient with cancer was diagnosed with eosinophilic granulomatosis with polyangiitis following treatment with a PD-1 inhibitor. Blockade of PD-1 and the programmed cell death ligand (PD-L) 1/PD-1 and PD-L2/PD-1 signaling cascade may cause allergic inflammation. Further studies are needed to identify the specific mechanisms underlying allergic inflammation after PD-1 blockade.\n\nKeywords\nProgrammed cell death-1Programmed cell death ligand 1Programmed cell death ligand 2Airway hyper-reactivityNivolumabissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\nImmune checkpoint inhibitors (ICIs) have been employed to treat several cancers. The ICI nivolumab shows inhibitory effects by blocking immune system suppressors, such as programmed cell death protein 1 (PD-1), and decreasing T helper cell signaling [1]. However, nivolumab is also associated with several immune-related adverse events (irAEs) [2]. Among them, immune-related eosinophilia cases in patients treated with anti-PD-1 or anti-programmed cell death ligand (PD-L) 1 are rare, with an estimated frequency of only 2.9–3.3% [3, 4]. Eosinophil-induced adverse events (Eo-irAEs) occur in almost half of these cases. The most frequently damaged organ is the skin, followed by the lungs; eosinophilic pneumonia or bronchitis occurs in only 0.3% of cases. These allergic irAEs associated with ICIs have rarely been reported in the literature.\n\nHere, we report a case of a patient with cancer who was treated with nivolumab and subsequently developed eosinophilic granulomatosis with polyangiitis (EGPA).\n\nCase presentation\nA 65-year-old Japanese man was diagnosed with kidney large cell neuroendocrine carcinoma (G3 grade, 52.1% Ki67-positive stained cells, PD-L1 TPS 70%), and had undergone total left kidney resection and descending colectomy 3 years prior to visiting our hospital. Three months after surgery, the tumor cells had metastasized to his liver and lymph nodes around the abdominal aorta. At the time, there was no established treatment against neuroendocrine cell carcinoma of the renal cells in Japan. The patient provided written informed consent and started chemotherapy. First, he was administered two courses of carboplatin plus irinotecan; however, the tumor size increased. The patient then started second-line treatment with sunitinib, which was discontinued after 3 months because he developed a taste disorder and watery diarrhea. Next, the patient was administered everolimus as a third-line therapy; however, the patient developed anorexia and general fatigue, and treatment with everolimus was discontinued. Because there were no other standard therapies for treating neuroendocrine kidney carcinoma, bi-weekly nivolumab (200 mg/body) treatment was administered to the patient. After nivolumab treatment, the tumor gradually disappeared, and no adverse events other than a mildly increased peripheral absolute eosinophil count (300–500/μL) were observed after 5 cycles of nivolumab treatment.\n\nThe patient experience his first bronchial asthma attack at 22 cycles of nivolumab treatment and was treated with a short course of corticosteroid burst therapy with 20 mg prednisolone along with inhalation therapy with budesonide/formoterol fumarate. This bronchial asthma attack was thought to be an adverse event associated with nivolumab; however, the patient continued the same dose of nivolumab treatment until 37 cycles because a good response against the kidney neuroendocrine carcinoma had been achieved. This clinical course is summarized in the Additional file 1: supplementary figure. Although nivolumab treatment had been discontinued until 37 cycles, the absolute eosinophil count remained high (26.6%, 1782.2 cells/μL) and his serum immunoglobulin E (IgE) levels were increased (924 IU/mL). Titers of anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies remained in the normal range. An IgE-radioallergosorbent test detected normal IgE levels, except against Japanese cedar and white cedar pollen. His fractional exhaled nitric oxide level was elevated to 107 ppb (normal range: 15–37 ppb). The patient had no history of allergy: however, all of his children had allergic bronchial asthma. He also showed dyspnea on exertion, developed sputum, and exhibited swelling and pain in his bilateral fingers. There were no other physical findings, including wheezing. Chest X-ray and computed tomography (CT) scanning detected a bilateral linear shadow which was not detected at his first visit to our hospital (Fig. 1a–d), and paranasal sinus CT scanning showed inflamed ethmoid, frontal, and maximal sinuses, indicating sinusitis (Fig. 1e–g). Although he had a normal respiratory function before initiating nivolumab treatment (FEV1.0 = 3.08 L, FEV1.0/FVC = 71.0%), his respiratory function test indicated an obstructive ventilation disorder (FEV1.0 = 1.63 L, FEV1.0/FVC = 50.6%). These results suggested that he had either eosinophilic pneumonia or EGPA. To confirm our hypothesis, we performed a bronchoscopy; the bronchoalveolar lavage fluid collected from the right B5 contained 40% lymphocytes and 3% eosinophils. Histopathological examination of a transbronchial lung biopsy sample from the right B8 showed small blood vessel hyperplasia with neutrophil infiltration and thickening of the alveolar septa with prominent eosinophil infiltration. Large numbers of red blood cells were observed on the lung tissue along with intra-alveolar bleeding (Fig. 2a, b), suggesting distinct alveolar hemorrhage with eosinophilic pneumonia. However hemosiderin-laden macrophages were not detected by Berlin blue staining, suggesting that the alveolar hemorrhage was an occasional event. Because he had experienced several bronchial asthma attacks and was already being treated with medication, the representative clinical findings needed for the bronchial asthma diagnosis were likely masked. To confirm the pathological findings of bronchial asthma, transbronchial mucosal biopsy was conducted. A bronchial mucosal lesion of the secondary carina also showed smooth muscle hyperplasia and thickening of the basement membrane with eosinophil infiltration (Fig. 2c). These findings suggested that the patient had bronchial asthma, eosinophilic pneumonia, and small vessel vasculitis. Finally, nerve conduction analysis showed that his right ulnar nerve conduction velocity was slightly decreased. There were no brain metastatic diseases, cervical spondylosis, or abnormalities related to rheumatoid arthritis. Although we could not definitively diagnose his neurological abnormalities, EGPA was thought to be one cause of the neuropathy. According to these findings with small vessel vasculitis, the patient was diagnosed with EGPA as per the American College of Rheumatology criteria for EGPA [5]. Distinct alveolar hemorrhage was not severe in the clinical setting and no heart involvement was detected; thus, treatment with 20 mg/day oral prednisolone was started. After 3 months, his bronchial asthma was improved, and bilateral infiltration had disappeared, as shown in Fig. 3. Steroid therapy was gradually tapered; during its discontinuation to less than 10 mg/day, a biweekly dose of mepolizumab (300 mg/day) was started to treat the EGPA. Currently, the patient is being treated with both nivolumab and mepolizumab, his peripheral eosinophilia has almost disappeared, and his respiratory function has improved (FEV1.0 = 2.94 L, FEV1.0/FVC = 71.2%), with paranasal sinus CT scanning showed normal findings (Fig. 3) after a year of treatment. He appears to be stable except for his neuropathy; to date, there have been no bronchial asthma attacks or CT scan abnormalities (Fig. 3).Fig. 1 Thoracic radiogram and computed tomography (CT) scan at the bronchoscopy exam. Chest radiogram (a) showed bilateral linear shadow. Thoracic CT scan of upper (b, c) and lower lobes (d) showed bilateral ground-glass opacity. e–g Paranasal sinus CT scan; Ethmoid sinus (e), frontal sinus (f) and maxillary sinus (g). Each arrow indicates nasal mucosa thickening and fluid collection in the sinus. These appearances suggest paranasal sinusitis\n\nFig. 2 a, b Transbronchial lung biopsy sample from right lower lung (right B8); sample stained with hematoxylin and eosin (HE) and viewed at high power. c Airway mucosal biopsy sample from secondary carina; sample stained with HE and viewed at high power. Bar indicates 200 μm. a shows small blood vessel with neutrophil and eosinophil infiltration. Alveolar septa are thickened. b Shows lots of red blood cells on the lung tissue and intra-alveolar bleeding with septal edema. c Shows smooth muscle hyperplasia and thickened basement membrane with eosinophil infiltration\n\nFig. 3 Thoracic radiogram (a), CT scans of chest (b–d) and ethmoid sinus (e), frontal sinus (f) and maxillary sinus (g) after a year from initiation of treatment for EGPA. Chest radiogram (a) shows no any abnormal shadows. Thoracic CT scan of upper (b, c) and lower lobes (d) also does not show any ground-glass opacity. Each arrow in e–g indicates nasal mucosa thickening and fluid collection that was shown in e–g\n\n\n\nDiscussion and conclusions\nWe report a rare case in which a patient with kidney neuroendocrine carcinoma was diagnosed with EGPA after treatment with nivolumab (a PD-1 checkpoint inhibitor). ICIs, such as nivolumab, are used to treat several cancers and have been associated with immune-related eosinophilia. The exact mechanisms mediating Eo-irAEs are not fully understood but a few clinical cases related to Eo-irAEs have been reported [6–8] (Table 1). Eo-irAEs can occur in systemic organs after ICI therapy and damage various organs, including the skin, lung, kidney, heart, and biliary ducts [4]. In the cases shown in Table 1, the Eo-irAEs were limited to the respiratory tract and showed a duration of development of 2–12 months. In the current case, the initial Eo-irAE was bronchial asthma, which occurred 9 months after starting nivolumab treatment; however, eosinophil infiltration was systemic and damaged the lungs, paranasal sinus, and peripheral nervous system. Before treatment with nivolumab, the patient’s absolute eosinophil count was normal; therefore, nivolumab was thought to be the main cause of the Eo-irAE. In a recent case, ipilimumab and nivolumab therapy (which was continued after Eo-ir) led to systemic infiltration of peripheral eosinophils [9]; however, there was a lack of sufficient pathological evidence of lung eosinophil infiltration. In our case, pathological evidence revealed eosinophil infiltration around the small vessels in the lung tissues and severe alveolar hemorrhage. These findings indicated eosinophilic vasculitis and eosinophilic pneumonia and were confirmed by CT scanning, although the damage to the paranasal sinus and peripheral nervous system in the pathological findings may differ from the damage to the lungs.Table 1 Clinical appearances of previous case reports and our case\n\nCase reports\tJohdai et al. 2018 [4]\tMaeno et al. 2017 [5]\tDonato et al. 2019 [3]\tThis case\t\nAge/sex\t62/M\t50/M\t47/M\t67/M\t\nDiagnosis\tAEP\tBA\tABPA\tEGPA\t\nBA histoly\t−\t−\t + \t−\t\nLength to AE\t2 M\t6 M\t12 M\t9 M\t\nTumor\tLung-sq\tLung-adeno\tLung-adeno\tKidney-NEC\t\nPD-L1\tN.F\tN.F\t50%\t70%\t\nICI\tNivo\tNivo\tPembro\tNivo\t\nTreatment\tPSL\tPSL\tPSL/VRCZ\tPSL/mepolizumab\t\nEfficacy\timp\timp\timp\timp\t\nAEP: acute eosinophilic pneumonia, BA: bronchial asthma, ABPA: allergic bronchopulmonary aspergillaosis, EGPA: Eosinophlic Granulomatosis with Polyangitis, lung-sq: lung squamous cell carcinoma, lung-adeno: lung adenocarcinoma, kidney-NEC: kidney neuroendocrine carcinoma, N.F: no findings, Nivo: nivolumab, Pembro: pembrolizumab, PSL: prednisolone, VRCZ: voriconazol, imp: improvement\n\n\n\nProlonged nivolumab treatment induced not only bronchial asthma but also systemic eosinophilic infiltration in our patient. The Eo-irAEs were thought to be an allergic reaction due to PD-1 inhibition. The underlying pathological mechanisms remain unclear; however, recent evidence suggests several hypotheses such as PD-L2/PD-1 signaling inhibition or PD-L2 intrinsic dysfunction.\n\nPD-1 is a negative regulator of CD4-positive T-cells. The ligands for PD-1 are PD-L1 (B7-H1) and PD-L2 (B7-DC), both of which belong to the B7-CD28 family [10]. PD-L1 is expressed by different resting cells, such as dendritic cells, macrophages, T-cells, and B-cells, whereas PD-L2 expression appears to be restricted to activated dendritic cells and macrophages [11]. Furthermore, only 40% homology has been reported among the two ligands [12]. Studies of the roles of PD-1 and its ligands PD-L1 and PD-L2 have yielded conflicting results in allergen-induced inflammation and airway hyper-reactivity (AHR). AHR is one of the characteristics of bronchial asthma; PD-L1 and PD-L2 show opposing functions in airway modulation. PD-L1/PD-1 induces AHR, whereas PD-L2/PD-1 blocks the initiation and progression of airway inflammation [13]. In our case, PD-1 blockade induced peripheral eosinophilia and bronchial asthma attacks. Therefore, the interaction of PD-L2 with PD-1 may be stronger than that of PD-L1.\n\nMatsumoto et al. reported that PD-L2 blockade induced not only AHR and eosinophilia, but also increased the production of interleukin (IL)-5 and IL-13 and decreased the production of interferon-γ [14]. Oflazoglu et al. reported that exogenous PD-L2 administration in an in vivo mouse asthma model resulted in elevation of serum IgE levels, eosinophilic and lymphocytic infiltration, and production of IL-5 and IL-13 [15]. In our case, PD-1 blockade by nivolumab induced an increase in the production of both interferon-γ and Th2-type immune cytokines. In addition to PD-L2 intrinsic regulation, allergen-driven enhancement of PD-L2 also limits the secretion of IL-12 and leads to exacerbation of AHR via a PD-1 independent mechanism [16]. These results suggest unknown signaling cascades (other than PD-1 signaling) underlying the AHR mechanisms.\n\nFinally, in our case, mepolizumab (an IL-5 inhibitor) was useful during nivolumab discontinuation. Because the IL-5 signaling cascade is thought to be an important factor related to Eo-irAEs [6], the use of mepolizumab may have prevented nivolumab from inducing Eo-irAEs in the patient. Therefore, it is necessary to investigate the effects of Eo-irAEs on systemic organs.\n\nIn summary, we reported a rare case in which nivolumab treatment for kidney neuroendocrine carcinoma induced recurrent bronchial asthma attacks and led to systemic eosinophilic inflammation and EGPA. Although the exact mechanisms underlying allergic inflammation after PD-1 blockade remain unclear, PD-L1/PD-1 and PD-L2/PD-1 signaling may be key in deciphering the mechanisms mediating allergic inflammation.\n\nSupplementary information\n\nAdditional file 1. A clinical coarse after initiation of nivolumab treatment. Treatment cycles of nivolumab shows on the upper black bar. Black triangle represents oral 30mg/day prednisolone treatments for bronchial asthma attacks. BA-AE: bronchial asthma attack, BUD/FP: budesonide/formoterol fumarate, Tio: Tiotropium bromide, solid line represents peripheral absolute eosinophil count (EOS). Tumor size of live metastasis was represented as maximum diameter in the bottom rectangle area.\n\n \n\nAbbreviations\nCTComputed tomography\n\nEGPAEosinophilic granulomatosis with polyangiitis\n\nEo-irImmune-related eosinophilia\n\nEo-irAEEosinophil-induced adverse event\n\nICIImmune checkpoint inhibitor\n\nILInterleukin\n\nIgEImmunoglobulin E\n\nirAEImmune-related adverse event\n\nPD-1Programmed cell death 1\n\nPD-L1Programmed cell death ligand 1\n\nPD-L2Programmed cell death ligand 2\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nThe online version contains supplementary material available at 10.1186/s12890-020-01375-5.\n\nAcknowledgements\nWe would like to thank the staff of the Department of Endoscopy and Pathology. We would also like to thank Editage (www.editage.com) for English language editing.\n\nAuthors’ contributions\nMH managed the patient, created the figures, and collected laboratory data. MH and NK wrote the manuscript. MH, HN, KY, YI, NK, TK, EM, MU, SM, MT, and NK contributed to the discussion of results and reviewed the manuscript. All authors read and approved the final manuscript.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nNot applicable.\n\nEthical approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for the publication of this case report and of the accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Chen DS Irving BA Hodi FS Molecular pathways: next-generation immunotherapy–inhibiting programmed death-ligand 1 and programmed death-1 Clin Cancer Res 2012 18 24 6580 6587 10.1158/1078-0432.ccr-12-1362 23087408 \n2. Postow MA Hellmann MD Adverse events associated with immune checkpoint blockade N Engl J Med 2018 378 12 1165 10.1056/NEJMc1801663 29562154 \n3. Bernard-Tessier A Jeanville P Champiat S Lazarovici J Voisin AL Mateus C Lambotte O Annereau M Michot JM Immune-related eosinophilia induced by anti-programmed death 1 or death-ligand 1 antibodies Eur J Cancer 2017 81 135 137 10.1016/j.ejca.2017.05.017 28624693 \n4. Scanvion Q Béné J Gautier S Grandvuillemin A Le Beller C Chenaf C Etienne N Brousseau S Cortot AB Mortier L Moderate-to-severe eosinophilia induced by treatment with immune checkpoint inhibitors: 37 cases from a national reference center for hypereosinophilic syndromes and the French pharmacovigilance database Oncoimmunology 2020 9 1 1722022 10.1080/2162402x.2020.1722022 32313716 \n5. Masi AT Hunder GG Lie JT Michel BA Bloch DA Arend WP Calabrese LH Edworthy SM Fauci AS Leavitt RY The American college of rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis) Arthritis Rheum 1990 33 8 1094 1100 10.1002/art.1780330806 2202307 \n6. Jodai T Yoshida C Sato R Kakiuchi Y Sato N Iyama S Kimura T Saruwatari K Saeki S Ichiyasu H A potential mechanism of the onset of acute eosinophilic pneumonia triggered by an anti-PD-1 immune checkpoint antibody in a lung cancer patient Immunity Inflammat Dis 2019 7 1 3 6 10.1002/iid3.238 \n7. Maeno K Fukuda S Oguri T Niimi A Nivolumab-induced asthma in a patient with non-small-cell lung cancer Ann Oncol 2017 28 11 2891 10.1093/annonc/mdx455 28945837 \n8. Donato AA Krol R Allergic bronchopulmonary aspergillosis presumably unmasked by PD-1 inhibition BMJ Case Rep 2019 10.1136/bcr-2018-227814 30765445 \n9. Roger A Groh M Lorillon G Le Pendu C Maillet J Arangalage D Tazi A Lebbe C Baroudjian B Delyon J Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) induced by immune checkpoint inhibitors Ann Rheum Dis 2019 78 8 e82 10.1136/annrheumdis-2018-213857 29936437 \n10. Singh AK Stock P Akbari O Role of PD-L1 and PD-L2 in allergic diseases and asthma Allergy 2011 66 2 155 162 10.1111/j.1398-9995.2010.02458.x 20722638 \n11. Yamazaki T Akiba H Iwai H Matsuda H Aoki M Tanno Y Shin T Tsuchiya H Pardoll DM Okumura K Expression of programmed death 1 ligands by murine T cells and APC J Immunol 2002 169 10 5538 5545 10.4049/jimmunol.169.10.5538 12421930 \n12. Okazaki T Honjo T PD-1 and PD-1 ligands: from discovery to clinical application Int Immunol 2007 19 7 813 824 10.1093/intimm/dxm057 17606980 \n13. Akbari O Stock P Singh AK Lombardi V Lee WL Freeman GJ Sharpe AH Umetsu DT Dekruyff RH PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions Mucosal Immunol 2010 3 1 81 91 10.1038/mi.2009.112 19741598 \n14. Matsumoto K Inoue H Nakano T Tsuda M Yoshiura Y Fukuyama S Tsushima F Hoshino T Aizawa H Akiba H B7-DC regulates asthmatic response by an IFN-gamma-dependent mechanism J Immunol 2004 172 4 2530 2541 10.4049/jimmunol.172.4.2530 14764726 \n15. Oflazoglu E Swart DA Anders-Bartholo P Jessup HK Norment AM Lawrence WA Brasel K Tocker JE Horan T Welcher AA Paradoxical role of programmed death-1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo Eur J Immunol 2004 34 12 3326 3336 10.1002/eji.200425197 15484188 \n16. Lewkowich IP Lajoie S Stoffers SL Suzuki Y Richgels PK Dienger K Sproles AA Yagita H Hamid Q Wills-Karp M PD-L2 modulates asthma severity by directly decreasing dendritic cell IL-12 production Mucosal Immunol 2013 6 4 728 739 10.1038/mi.2012.111 23149662\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2466",
"issue": "21(1)",
"journal": "BMC pulmonary medicine",
"keywords": "Airway hyper-reactivity; Nivolumab; Programmed cell death ligand 1; Programmed cell death ligand 2; Programmed cell death-1",
"medline_ta": "BMC Pulm Med",
"mesh_terms": "D000368:Aged; D018278:Carcinoma, Neuroendocrine; D015267:Churg-Strauss Syndrome; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007680:Kidney Neoplasms; D008297:Male; D000077594:Nivolumab; D011239:Prednisolone; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "100968563",
"other_id": null,
"pages": "6",
"pmc": null,
"pmid": "33407304",
"pubdate": "2021-01-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23149662;17606980;28945837;19741598;29562154;14764726;32313716;30461210;28624693;23087408;15484188;30765445;12421930;2202307;20722638;29936437",
"title": "Programmed cell death-1 blockade in kidney carcinoma may induce eosinophilic granulomatosis with polyangiitis: a case report.",
"title_normalized": "programmed cell death 1 blockade in kidney carcinoma may induce eosinophilic granulomatosis with polyangiitis a case report"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-295335",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SUNITINIB"
},
"druga... |
{
"abstract": "Haemophagocytic lymphohistiocytosis (HLH) in the context of malignancy is mainly considered a challenge of adult haematology. While this association is also observed in children, little is known regarding inciting factors, appropriate treatment and prognosis. We retrospectively analysed 29 paediatric and adolescent patients for presenting features, type of neoplasm or preceding chemotherapy, treatment and outcome. Haemophagocytic lymphohistiocytosis was considered triggered by the malignancy (M-HLH) in 21 patients, most of whom had T- (n = 12) or B-cell neoplasms (n = 7), with Epstein-Barr virus as a co-trigger in five patients. In eight patients, HLH occurred during chemotherapy (Ch-HLH) for malignancy, mainly acute leukaemias (n = 7); an infectious trigger was found in seven. In M- and Ch-HLH, median overall survival was 1·2 and 0·9 years, and the 6 month survival rates were 67% and 63%, respectively. Seven of 11 deceased M-HLH patients exhibited active malignancy and HLH at the time of death, while only two out of five deceased Ch-HLH patients had evidence of active HLH. To overcome HLH, malignancy- and HLH-directed treatments were administered in the M-HLH cohort; however, it was not possible to determine superiority of one approach over the other. For Ch-HLH, treatment ranged from postponement of chemotherapy to the use of etoposide-containing regimens.",
"affiliations": "Paediatric Haematology and Oncology, University Medical Centre Hamburg Eppendorf, Hamburg, Germany.;Paediatric Haematology and Oncology, University Medical Centre Hamburg Eppendorf, Hamburg, Germany.;Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.;Paediatric Haematology and Oncology, University Hospital Giessen, Giessen, Germany.;Paediatric Haematology and Oncology, University Medical Centre Hamburg Eppendorf, Hamburg, Germany.;Paediatric Haematology and Oncology, University Hospital Dresden, Dresden, Germany.;Paediatric Haematology and Oncology, University Hospital Halle, Halle, Germany.;Paediatric Haematology and Oncology, Clinical Centre Schwabing and München Rechts der Isar, Technical University Munich, Munich, Germany.;Centre of Chronic Immunodeficiency, University of Freiburg, Freiburg, Germany.;Paediatric Haematology and Oncology, University Hospital Jena, Jena, Germany.;Paediatric Haematology and Oncology, Elisabeth-Hospital Oldenburg, Oldenburg, Germany.;Gemeinschaftskrankenhaus Herdecke, University of Witten/Herdecke, Herdecke, Germany.;Paediatric Haematology and Oncology, Rudolfstiftung Hospital Vienna, Vienna, Austria.;Paediatric Oncology and Haematology, Olgahospital, Klinikum Stuttgart, Stuttgart, Germany.;Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.;Paediatric Haematology and Oncology, University Hospital Kiel, Kiel, Germany.;Centre of Chronic Immunodeficiency, University of Freiburg, Freiburg, Germany.;Paediatric Haematology and Oncology, University Medical Centre Hamburg Eppendorf, Hamburg, Germany.;Paediatric Haematology and Oncology, University Medical Centre Hamburg Eppendorf, Hamburg, Germany.",
"authors": "Lehmberg|Kai|K|;Sprekels|Björn|B|;Nichols|Kim E|KE|;Woessmann|Wilhelm|W|;Müller|Ingo|I|;Suttorp|Meinolf|M|;Bernig|Toralf|T|;Beutel|Karin|K|;Bode|Sebastian F N|SF|;Kentouche|Karim|K|;Kolb|Reinhard|R|;Längler|Alfred|A|;Minkov|Milen|M|;Schilling|Freimut H|FH|;Schmid|Irene|I|;Vieth|Simon|S|;Ehl|Stephan|S|;Zur Stadt|Udo|U|;Janka|Gritta E|GE|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bjh.13462",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "170(4)",
"journal": "British journal of haematology",
"keywords": "Hodgkin lymphoma; T-cell lymphoma; anaplastic large cell lymphoma; hemophagocytic syndrome; macrophage activation syndrome",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D020031:Epstein-Barr Virus Infections; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007938:Leukemia; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "539-49",
"pmc": null,
"pmid": "25940575",
"pubdate": "2015-08",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Malignancy-associated haemophagocytic lymphohistiocytosis in children and adolescents.",
"title_normalized": "malignancy associated haemophagocytic lymphohistiocytosis in children and adolescents"
} | [
{
"companynumb": "PHHY2015DE094973",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
"d... |
{
"abstract": "The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab ± vincristine in patients with relapsed/refractory aggressive B-NHL.\n\n\n\nPatients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 + 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine [1.4 mg/m2 (maximum 2 mg) days 1, 8] for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/BCL2 IHC was performed on available archival tissue.\n\n\n\nForty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV (n = 32), the RP2D was determined as 40 mg b.i.d. [1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg]. Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL).\n\n\n\nThe combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.",
"affiliations": "USC Norris Comprehensive Cancer Center, Los Angeles, California (previously University of Texas Health Science Center at San Antonio, San Antonio, Texas). kevin.kelly@med.usc.edu.;University of Rochester Medical Center, Rochester, New York.;Levine Cancer Institute and Carolinas Healthcare System, Charlotte, North Carolina.;Vanderbilt University, Nashville, Tennessee (previously University of Kentucky Markey Cancer Center, Lexington, Kentucky).;University of Kentucky Markey Cancer Center, Lexington, Kentucky.;University of Arizona, Tucson, Arizona.;Weill Cornell Medical College, New York, New York.;University of Arizona, Tucson, Arizona.;Providence St Joseph Medical Center, Disney Family Cancer Center, Burbank, California.;Methodist Hospital, Houston, Texas.;University of Miami Miller School of Medicine, Sylvester Cancer Center, Miami, Florida.;University of Rochester Medical Center, Rochester, New York.;University of Texas Health Science Center at San Antonio, San Antonio, Texas.;University of Texas Health Science Center at San Antonio, San Antonio, Texas.;University of Kentucky Markey Cancer Center, Lexington, Kentucky.;University of Tennessee Health Science Center and West Clinic, Memphis, Tennessee.;Providence St Joseph Medical Center, Disney Family Cancer Center, Burbank, California.;Department of Pathology, College of Medicine, University of Arizona, Tucson, Arizona.;Department of Pathology, College of Medicine, University of Arizona, Tucson, Arizona.;USC Norris Comprehensive Cancer Center, Los Angeles, California (previously University of Texas Health Science Center at San Antonio, San Antonio, Texas).;Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.;Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.;Bluebird Bio, Cambridge, Massachusetts (previously Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited).;Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.;University of Arizona, Tucson, Arizona.",
"authors": "Kelly|Kevin R|KR|;Friedberg|Jonathan W|JW|;Park|Steven I|SI|;McDonagh|Kevin|K|;Hayslip|John|J|;Persky|Daniel|D|;Ruan|Jia|J|;Puvvada|Soham|S|;Rosen|Peter|P|;Iyer|Swaminathan Padmanabhan|SP|;Stefanovic|Alexandra|A|;Bernstein|Steven H|SH|;Weitman|Steven|S|;Karnad|Anand|A|;Monohan|Gregory|G|;VanderWalde|Ari|A|;Mena|Raul|R|;Schmelz|Monika|M|;Spier|Catherine|C|;Groshen|Susan|S|;Venkatakrishnan|Karthik|K|;Zhou|Xiaofei|X|;Sheldon-Waniga|Emily|E|;Leonard|E Jane|EJ|;Mahadevan|Daruka|D|",
"chemical_list": "D001381:Azepines; C550258:MLN 8237; D011743:Pyrimidines; D000069283:Rituximab; D014750:Vincristine; D064096:Aurora Kinase A",
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-18-0286",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0432",
"issue": "24(24)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D064096:Aurora Kinase A; D001381:Azepines; D018450:Disease Progression; D016903:Drug Monitoring; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011743:Pyrimidines; D012008:Recurrence; D019233:Retreatment; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "6150-6159",
"pmc": null,
"pmid": "30082475",
"pubdate": "2018-12-15",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "20231299;12559175;21556291;24597851;27083466;29313949;24398326;24893165;24352795;17715155;14523000;14504078;18628459;22864622;24043741;22016509;28615297;22753585;19107951;17541033;21623171;11423671;18765795;26077240;15896667;18311783;16080195;11807147;22374334;17242396;26240231;27526684;21658615;14693746;15781834;28891222;25302940;25174022;25728526;9606188;22767670;25431238;20382844;12716366;25068104;24879333",
"title": "Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma.",
"title_normalized": "phase i study of the investigational aurora a kinase inhibitor alisertib plus rituximab or rituximab vincristine in relapsed refractory aggressive b cell lymphoma"
} | [
{
"companynumb": "US-PFIZER INC-2019415337",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Tamoxifen-induced ocular complications including cataracts, keratopathies, retinopathy, impaired visual acuity, ocular irritation, optical neuritis, and retinal vein occlusion are uncommonly reported in the literature. Herein, we report on a premenopausal patient with right-side breast carcinoma who received adjuvant tamoxifen therapy (20 mg/day) for 1.5 years and developed sudden visual loss. Fundal examination revealed an obstruction in the branch of the retinal vein. The diagnosis was confirmed by fluorescein angiography and optical coherence tomography. Thus, tamoxifen was switched to an aromatase inhibitor. Tamoxifen-induced ocular complications should be kept in mind when visual symptoms are seen in patients undergoing tamoxifen therapy. In such cases, a complete ocular examination should be performed.",
"affiliations": "Department of Medical Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey.;Department of Medical Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey.;Department of Ophthalmology, Ankara Numune Training and Research Hospital, Ankara, Turkey.;Department of Medical Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey.;Department of Medical Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey.;Department of Medical Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey.;Department of Medical Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey.",
"authors": "Demirci|Nebi Serkan|NS|;Erdem|Gokmen Umut|GU|;Uçgun|Nil İrem|Nİ|;Bozkaya|Yakup|Y|;Ozdemir|Nuriye Yildirim|NY|;Dogan|Mutlu|M|;Zengin|Nurullah|N|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen",
"country": "India",
"delete": false,
"doi": "10.4103/0973-1482.204888",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1998-4138",
"issue": "15(3)",
"journal": "Journal of cancer research and therapeutics",
"keywords": "Breast cancer; ocular toxicity; retinal vein occlusion; tamoxifen therapy",
"medline_ta": "J Cancer Res Ther",
"mesh_terms": "D018931:Antineoplastic Agents, Hormonal; D001943:Breast Neoplasms; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D008875:Middle Aged; D012170:Retinal Vein Occlusion; D013629:Tamoxifen; D041623:Tomography, Optical Coherence",
"nlm_unique_id": "101249598",
"other_id": null,
"pages": "722-724",
"pmc": null,
"pmid": "31169251",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "A rare case: Branch retinal vein occlusion associated with the use of tamoxifen.",
"title_normalized": "a rare case branch retinal vein occlusion associated with the use of tamoxifen"
} | [
{
"companynumb": "TR-TEVA-2019-TR-1081453",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TAMOXIFEN"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nBullous pemphigoid (BP) is the most common blistering autoimmune skin disease. Combination methotrexate (MTX) and prednisone therapy is an effective short-term treatment for BP.\n\n\nOBJECTIVE\nTo determine the average length and frequency with which MTX and prednisone combination therapy leads to long-term remission off therapy.\n\n\nMETHODS\nA retrospective chart review of 16 of our patients with BP was conducted. Patients were treated with the combination regimen of MTX and prednisone, followed by us for at least 1 year, and had long-term follow-up data.\n\n\nRESULTS\nThe average length of time from initiating MTX and prednisone therapy to complete disease control was 3.8 months. Eight of 16 patients were in remission off BP therapy with combination MTX and prednisone therapy. The average length of treatment in this subgroup was 25.3 months and patients were followed for a mean of 5.5 years since initiating therapy. Three additional patients were in remission (with a mean treatment time short of the 25.3 month average) undergoing tapering of BP therapy.\n\n\nCONCLUSIONS\nTwo year MTX and prednisone combination therapy is a safe, inexpensive, and effective treatment for BP that can result in long-term remission off therapy.",
"affiliations": "Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. skwatra@wfubmc.edu",
"authors": "Kwatra|Shawn G|SG|;Jorizzo|Joseph L|JL|",
"chemical_list": "D003879:Dermatologic Agents; D011241:Prednisone; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.3109/09546634.2012.660519",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-6634",
"issue": "24(5)",
"journal": "The Journal of dermatological treatment",
"keywords": null,
"medline_ta": "J Dermatolog Treat",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003879:Dermatologic Agents; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D010391:Pemphigoid, Bullous; D011241:Prednisone; D012074:Remission Induction; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8918133",
"other_id": null,
"pages": "327-31",
"pmc": null,
"pmid": "22268701",
"pubdate": "2013-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Bullous pemphigoid: a case series with emphasis on long-term remission off therapy.",
"title_normalized": "bullous pemphigoid a case series with emphasis on long term remission off therapy"
} | [
{
"companynumb": "US-ROXANE LABORATORIES, INC.-2014-RO-01574RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugaddit... |
{
"abstract": "Nevirapine resistance mutations arise commonly following single or extended-dose nevirapine (ED-NVP) prophylaxis to prevent mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV), but decay within 6-12 months of single-dose exposure. Use of ED-NVP prophylaxis in infants is expected to rise, but data on decay of nevirapine resistance mutations in infants in whom ED-NVP failed remain limited. We assessed, in Ethiopian infants participating in the Six-Week Extended Nevirapine (SWEN) Trial, the prevalence and persistence of nevirapine resistance mutations at 6 and 12 months following single-dose or up to 6 weeks of ED-NVP, and correlated their presence with the timing of infection and the type of resistance mutations. Standard population genotyping followed by high-throughput cloning were done on dried blood spot samples collected during the trial. More infants who received ED-NVP had nevirapine resistance detected by standard population genotyping (high frequencies) at age 6 months compared with those who received single-dose nevirapine (SD-NVP) (58% of 24 vs. 26% of 19, respectively; p = 0.06). Moreover, 56% of ED-NVP-exposed infants with nevirapine resistance at age 6 months still had nevirapine resistance mutations present at high frequencies at age 1 year. Infants infected before 6 weeks of age who received either SD- or ED-NVP were more likely to have Y181C or K103N; these mutations were also more likely to persist at high frequencies through 1 year of age. HIV-infected infants in whom ED-NVP prophylaxis fails are likely to experience delayed clearance of nevirapine-resistant virus in the first year of life, which in turn places them at risk for early selection of multidrug-resistant HIV after initial therapy with nonnucleoside reverse transcriptase inhibitor-based regimens.",
"affiliations": "Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. dpers@jhmi.edu",
"authors": "Persaud|Deborah|D|;Bedri|Abubaker|A|;Ziemniak|Carrie|C|;Moorthy|Anitha|A|;Gudetta|Berhanu|B|;Abashawl|Aida|A|;Mengistu|Yohannes|Y|;Omer|Saad B|SB|;Isehak|Abdulhamid|A|;Kumbi|Solomon|S|;Adamu|Rahel|R|;Lulseged|Sileshi|S|;Ashworth|Roxann|R|;Hassen|Elham|E|;Ruff|Andrea|A|;|||",
"chemical_list": "D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D054303:HIV Reverse Transcriptase",
"country": "United States",
"delete": false,
"doi": "10.1089/AID.2010.0346",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0889-2229",
"issue": "27(8)",
"journal": "AIDS research and human retroviruses",
"keywords": null,
"medline_ta": "AIDS Res Hum Retroviruses",
"mesh_terms": "D001483:Base Sequence; D001942:Breast Feeding; D002648:Child; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral; D005002:Ethiopia; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D015658:HIV Infections; D054303:HIV Reverse Transcriptase; D015497:HIV-1; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D008969:Molecular Sequence Data; D058889:Molecular Typing; D009154:Mutation; D019829:Nevirapine; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D018894:Reverse Transcriptase Inhibitors; D019562:Viral Load",
"nlm_unique_id": "8709376",
"other_id": null,
"pages": "823-9",
"pmc": null,
"pmid": "21241214",
"pubdate": "2011-08",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "19438605;19552593;20942667;20554983;17457089;11600822;13678973;19504753;18525035;11598834;17533166;17262714;19119321;17117145;18684096;20068260;20554982;19020325;16773030;10485720;15942889;20823434;15247339;16828172;19133804;19338474;20057308;18657709;8599114;19210162;17215531;21258105;16641095;20942666;10983633;17725424",
"title": "Slower clearance of nevirapine resistant virus in infants failing extended nevirapine prophylaxis for prevention of mother-to-child HIV transmission.",
"title_normalized": "slower clearance of nevirapine resistant virus in infants failing extended nevirapine prophylaxis for prevention of mother to child hiv transmission"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP003024",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
},
"drugadditional... |
{
"abstract": "Central nervous system (CNS) relapse is an infrequent but severe complication for DLBCL patients, associated with poor prognosis. Intravenous prophylaxis with high-dose methotrexate has shown promising results but is rarely feasible in elderly and/or nephropathic patients. A 83 years old woman with CNS relapse occurred 6 months after chemoimmunotherapy. The patient was defined ineligible for radiotherapy (RT) and started oral Temozolomide 250mg daily for 5 consecutive days without any improvement after 1st cycle. We administered lenalidomide 25mg daily for 21 days every 28 days together with temozolomide 250mg daily for 5 days every 28 days. The patient experienced a rapid improvement of general and cognitive conditions; Gadolinium-enhanced brain MRI showed a wide reduction of neoplastic tissue. The patients maintained good clinical conditions with mild treatment toxicity until the end of the 6th cycle, when brain MRI showed disease progression and the patient died 1 month later. We suggest lenalidomide could be a feasible option for CNS relapse in elderly DLBCL patients and it could be associated in future studies with other cytotoxic agents such as temozolomide.",
"affiliations": "Unit of Hematology, Azienda Ospedaliera Universitaria Senese, Siena, Italy.;Unit of Hematology, Azienda Ospedaliera Universitaria Senese, Siena, Italy.;Unit of Neuroimaging and Neurointervention, Department of Neurological and Sensorineural Sciences, Azienda Ospedaliera Università Senese, \"Santa Maria alle Scotte\" University and NHS Hospital, Siena, Italy.;Unit of Neuroimaging and Neurointervention, Department of Neurological and Sensorineural Sciences, Azienda Ospedaliera Università Senese, \"Santa Maria alle Scotte\" University and NHS Hospital, Siena, Italy.;Unit of Hematology, Azienda Ospedaliera Universitaria Senese, Siena, Italy.",
"authors": "Cencini|Emanuele|E|;Fabbri|Alberto|A|;Arrigucci|Umberto|U|;Cerase|Alfonso|A|;Bocchia|Monica|M|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4084/MJHID.2017.040",
"fulltext": "\n==== Front\nMediterr J Hematol Infect DisMediterr J Hematol Infect DisMediterranean Journal of Hematology and Infectious DiseasesMediterranean Journal of Hematology and Infectious Diseases2035-3006Università Cattolica del Sacro Cuore 10.4084/MJHID.2017.040mjhid-9-1-e2017040Case ReportsLenalidomide and Temozolomide Combination in a Very Elderly Patient with CNS Relapse of Diffuse Large B-Cell Lymphoma Cencini Emanuele 12Fabbri Alberto 1Arrigucci Umberto 3Cerase Alfonso 3Bocchia Monica 121 Unit of Hematology, Azienda Ospedaliera Universitaria Senese, Siena, Italy2 University of Siena, Siena, Italy3 Unit of Neuroimaging and Neurointervention, Department of Neurological and Sensorineural Sciences, Azienda Ospedaliera Università Senese, “Santa Maria alle Scotte” University and NHS Hospital, Siena, ItalyCorrespondence to: Dr. Emanuele Cencini, MD. Unit of Hematology, University Hospital. Viale Bracci, 16 - 53100 Siena, Italy. tel: + 39 0577 586798, fax:+ 39 0577 586185. E-mail: cencioema@libero.it2017 16 6 2017 9 1 e201704013 3 2017 10 5 2017 2017This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Central nervous system (CNS) relapse is an infrequent but severe complication for DLBCL patients, associated with poor prognosis. Intravenous prophylaxis with high-dose methotrexate has shown promising results but is rarely feasible in elderly and/or nephropathic patients.\n\nA 83 years old woman with CNS relapse occurred 6 months after chemoimmunotherapy. The patient was defined ineligible for radiotherapy (RT) and started oral Temozolomide 250mg daily for 5 consecutive days without any improvement after 1st cycle.\n\nWe administered lenalidomide 25mg daily for 21 days every 28 days together with temozolomide 250mg daily for 5 days every 28 days. The patient experienced a rapid improvement of general and cognitive conditions; Gadolinium-enhanced brain MRI showed a wide reduction of neoplastic tissue. The patients maintained good clinical conditions with mild treatment toxicity until the end of the 6th cycle, when brain MRI showed disease progression and the patient died 1 month later.\n\nWe suggest lenalidomide could be a feasible option for CNS relapse in elderly DLBCL patients and it could be associated in future studies with other cytotoxic agents such as temozolomide.\n\nLenalidomideCNS lymphomatherapysurvival\n==== Body\nIntroduction\nCentral nervous system (CNS) relapse is an infrequent but severe complication for diffuse large B-cell lymphoma (DLBCL) patients, associated with poor prognosis.1 Several risk factors have been identified for CNS recurrences, such as localizations at testis, orbit, paranasal sinuses, more than 1 extranodal involved site and elevated lactate dehydrogenase (LDH). A new prognostic model has recently been proposed, called CNS international prognostic index (IPI), including kidney and/or adrenal localization.2,3 However, CNS prophylaxis with intrathecal methotrexate and/or cytarabine is not possible in all patients, and current guidelines and recent studies suggest it is not sufficient in a majority of cases due to a prevalent parenchymal and not meningeal involvement in most relapsed DLBCL patients.4,5 Intravenous prophylaxis with high-dose methotrexate has shown promising results but is rarely feasible in elderly and/or nephropathic patients.4,5\n\nOverall, very few agents pass through blood brain barrier (BBB), such as temozolomide, but long-term remissions in primary CNS lymphoma are seldom observed with this drug.6\n\nLenalidomide has a pleiotropic effect and has been widely used in relapsed DLBCL;7 there are some interesting reports about its efficacy in CNS relapse and its capacity to cross BBB.8–11\n\nAccording to this background, we would like to report our experience in a case of CNS relapse in an elderly patient.\n\nCase Report\nIn 2015, April, an 83 years old woman was referred to our institution because of a diagnosis of DLBCL was made by a biopsy of a right orbit injury. Physical examination showed no enlarged lymph nodes, blood cell count was normal, LDH was mildly increased (249IU/l, normal value 135–225 IU/l). Bone marrow biopsy revealed no infiltration, computed tomography (CT) scan showed multiple mediastinal and celiac enlarged lymph nodes, together with parenchymal splenic localizations. ECOG performance status was 2. The patient was considered ineligible for i.v. high-dose methotrexate (MTX) and, according to conflicting results of i.t. prophylaxis, recent data by Muravski and colleagues and patient’s willing, did not receive i.t. MTX.12\n\nImmunochemotherapy with etoposide, mitoxantrone, cyclophosphamide, vincristine, prednisone, and bleomycin (VNCOP-B) was administered, in association with rituximab.13,14 The patient received chemotherapy weekly and rituximab every 2 weeks for 12 weeks, as previously published. The regimen was completed without dose delays or dose reductions; total body CT scan showed a complete remission (CR). Treatment toxicity was mild with only grade 1 peripheral neuropathy that disappeared after treatment completion; thank primary prophylaxis with filgrastim no neutropenia occurred.\n\nThe patient maintained CR for 6 months when she came to the emergency department because of a headache and cognitive impairment. Brain CT scan showed CNS relapse with a right frontal mass that extended to the ipsilateral frontal-basal areas, a wide ipsilateral vasogenic edema with ventricular compression and initial trans-falcial herniation. The patient was defined ineligible for radiotherapy (RT) because of age, wide vasogenic edema and high risk of neurotoxicity and started intramuscular dexamethasone 8mg daily and oral temozolomide 250mg daily for 5 consecutive days without any improvement after 1st cycle; total body CT scan (Figure 1A) showed a further increase of the right frontal mass (diameter 7cm) without other disease localizations.\n\nGiven the promising data of lenalidomide use for CNS lymphoma and the lack of other treatment options, we decided to administer lenalidomide 25mg daily for 21 days every 28 days together with temozolomide 250mg daily for 5 days every 28 days. The patient experienced a rapid improvement in general and cognitive conditions after the 1st cycle, headache disappeared, both Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) improved. We decided to continue this association; Gadolinium-enhanced brain MRI (Figure 1B) was performed after the 2nd cycle and showed a wide reduction of neoplastic tissue (diameter 37 mm), vasogenic edema, and mass effect. In accordance with these promising results, the patients received other 4 cycles. Therapy was well tolerated, grade 2 neutropenia without infections and grade 2 thrombocytopenia that recovered after one-week dose delay were observed; no extra-hematological toxicity was observed, and no hospitalization was needed.\n\nThe patients maintained good clinical conditions until the end of the 6th cycle when a headache recurred. Gadolinium-enhanced brain MRI (Figure 1C) showed disease progression. Clinical conditions rapidly worsened, the patient came to the hospital, we tried to administer steroid therapy, mannitol, and oral procarbazine, but the patient did not respond to treatment and died.\n\nDiscussion\nCNS relapse in elderly DLBCL patients is an unmet clinical need to date.1 These patients are usually not eligible for HD-MTX and/or HD cytarabine and have a dismal prognosis, mainly because there is a lack of cytotoxic agents that cross BBB with manageable toxicity. Whole brain RT is characterized by a substantial neurotoxicity, that limits its feasibility especially in older patients.15\n\nProcarbazine, lomustine, and vincristine (PCV) was administered to 8 recurrent CNS lymphoma patients (age 36–72 years old) and showed an overall response rate (ORR) of 50% with a median progression-free survival (PFS) of 7 months.16 Temozolomide, an alkylating agent that can penetrate into the brain, demonstrated promising results both as first-line treatment and for recurrent primary CNS lymphoma. In a retrospective series of 17 elderly patients CR rate was 47%, median PFS and overall survival (OS) were 5 and 21 months, respectively.6\n\nThe possibility for lenalidomide to accumulate in the cerebrospinal fluid was reported in a case of blastoid mantle cell lymphoma (9). Lenalidomide as salvage therapy for recurrent primary CNS lymphoma was administered to 6 elderly patients (median age 73.5 years, range 64–78), 2/6 patients achieved CR and 1/6 achieved partial remission (PR).8 Salati and colleagues showed a leptomeningeal relapse in a patient with DLBCL successfully treated with lenalidomide monotherapy.11 The patient was elderly, had an early relapse after first-line chemoimmunotherapy of a double-hit DLBCL and received high-dose MTX and cytarabine as salvage treatment, alternating with bi-weekly liposomal cytarabine. MRI showed a significant reduction of leptomeningeal contrast enhancement, the patient refused RT and was successfully consolidated with lenalidomide 15mg daily for 21 every 28 days, achieving a complete and durable response (month+9).\n\nMoreover, an interesting phase I study of lenalidomide was presented at last International Conference on Malignant Lymphoma (ICML) meeting, 6 out of 8 patients achieved at least PR, in 2 patients a duration of response of more than 1 year was reported.17\n\nLenalidomide in combination has shown an unexpected toxicity, and a dose of 5 mg has been suggested.18,19 It is important to note that in our case the combination with temozolomide of lenalidomide daily dose of 15 mg was well tolerated.\n\nConclusions\nAccording to these promising results and our experience in a very elderly patient, we suggest lenalidomide could be a feasible option for CNS relapse in aged DLBCL patients, and it could be associated in future studies with other cytotoxic agents such as temozolomide.\n\nCompeting interests: The authors have declared that no competing interests exist.\n\nFigure 1 Neuroradiological follow-up: a) iodine contrast-enhanced computed tomography axial image obtained in 2016, March, at relapse; b) and c) gadolinium-enhanced T1-weighted magnetic resonance axial images obtained after the 2nd and the 6th cycle, respectively.\n==== Refs\nReferences\n1 Orfao A Spanish Lymphoma Group (GELTAMO) Guidelines for diagnosis, prevention and management of central nervous system involvement in diffuse large B-cell lymphoma patients by the Spanish Lymphoma Group (GELTAMO) Haematologica 2017 102 235 245 https://doi.org/10.3324/haematol.2016.149120 27846613 \n2 Schmitz N Zeynalova S Nickelsen M Kansara R Villa D Sehn LH Glass B Scott DW Gascoyne RD Connors JM Ziepert M Pfreundschuh M Loeffler M Savage KJ CNS International Prognostic Index: A Risk Model for CNS Relapse in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP J Clin Oncol 2016 34 3150 3156 https://doi.org/10.1200/JCO.2015.65.6520 27382100 \n3 Cheah CY Seymour JF Central nervous system prophylaxis in non-Hodgkin lymphoma: who, what, and when? Curr Oncol Rep 2015 17 25 https://doi.org/10.1007/s11912-015-0450-4 25912004 \n4 Tilly H Gomes da Silva M Vitolo U Jack A Meignan M Lopez-Guillermo A Walewski J André M Johnson PW Pfreundschuh M Ladetto M ESMO Guidelines Committee Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 2015 26 116 125 https://doi.org/10.1093/annonc/mdv304 26314773 \n5 Ferreri AJ Bruno-Ventre M Donadoni G Ponzoni M Citterio G Foppoli M Vignati A Scarfò L Sassone M Govi S Caligaris-Cappio F Risk-tailored CNS prophylaxis in a mono-institutional series of 200 patients with diffuse large B-cell lymphoma treated in the rituximab era Br J Haematol 2015 168 654 662 https://doi.org/10.1111/bjh.13194 25312994 \n6 Kurzwelly D Glas M Roth P Weimann E Lohner H Waha A Schabet M Reifenberger G Weller M Herrlinger U Primary CNS lymphoma in the elderly: temozolomide therapy and MGMT status J Neurooncol 2010 97 389 392 https://doi.org/10.1007/s11060-009-0032-0 19841864 \n7 Witzig TE Vose JM Zinzani PL Reeder CB Buckstein R Polikoff JA Bouabdallah R Haioun C Tilly H Guo P Pietronigro D Ervin-Haynes AL Czuczman MS An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma Ann Oncol 2011 22 1622 1627 10.1093/annonc/mdq626 https://doi.org/10.1093/annonc/mdq626 21228334 \n8 Houillier C Choquet S Touitou V Martin-Duverneuil N Navarro S Mokhtari K Soussain C Hoang-Xuan K Lenalidomide monotherapy as salvage treatment for recurrent primary CNS lymphoma Neurology 2015 84 325 326 https://doi.org/10.1212/WNL.0000000000001158 25527263 \n9 Cox MC Mannino G Lionetto L Naso V Simmaco M Spiriti MA Lenalidomide for aggressive B-cell lymphoma involving the central nervous system? Am J Hematol 2011 86 957 10.1002/ajh.22148 No abstract available https://doi.org/10.1002/ajh.22148 21990093 \n10 Rubenstein JL Treseler PA Stewart PJ Regression of refractory intraocular large B-cell lymphoma with lenalidomide monotherapy J Clin Oncol 2011 29 595 597 https://doi.org/10.1200/JCO.2011.34.7252 21519022 \n11 Salati M Tarantino V Maiorana A Bettelli S Luminari S Durable remission in a patient with leptomeningeal relapse of a MYC/BCL6-positive double-hit DLBCL treated with lenalidomide monotherapy Hematol Oncol 2016 [Epub ahead of print] https://doi.org/10.1002/hon.2315 27301994 \n12 Murawski N Held G Ziepert M Kempf B Viardot A Hänel M Witzens-Harig M Mahlberg R Rübe C Fleckenstein J Zwick C Glass B Schmitz N Zeynalova S Pfreundschuh M The role of radiotherapy and intrathecal CNS prophylaxis in extralymphatic craniofacial aggressive B-cell lymphomas Blood 2014 124 720 728 https://doi.org/10.112/bl8ood-2013-10-535021 24939657 \n13 Fina M Tani M Stefoni V Musuraca G Marchi E Pellegrini C Alinari L Derenzini E Bacci F Pileri S Baccarani M Zinzani PL VNCOP-B plus rituximab in the treatment of diffuse large B-cell lymphoma in the elderly Leuk Lymphoma 2007 48 2167 2171 https://doi.org/10.1080/10428190701642102 17990178 \n14 Ishii K Urase F Nagare Y Kimura H Manabe M Yagi T Teshima H Hayashi K Shibano M Tsukaguchi M Katsurada T Mugitani A Kitayama H Nomura S VNCOP- B plus rituximab therapy in elderly patients with aggressive B-cell non-Hodkin lymphoma: A multicenter experience Arch Gerontol Geriatr 2010 51 209 215 https://doi.org/10.1016/j.archger.2009.10 19926148 \n15 Kasenda B Loeffler J Illerhaus G Ferreri AJ Rubenstein J Batchelor TT The role of whole brain radiation in primary CNS lymphoma Blood 2016 128 32 66 https://doi.org/10.1182/blood-2016-01-650101 27207798 \n16 Kim YJ Choe JH Park JH Hong YK Efficacy of Procarbazine, Lomustine, and Vincristine Chemotherapy for Recurrent Primary Central Nervous System Lymphomas Brain Tumor Res Treat 2015 3 75 80 https://doi.org/10.14791/btrt.2015.3.2.75 26605261 \n17 Rubenstein JL Formaker P Wang X Chen N Fraser E Munster P Damato B Lenalidomide is highly active in recurrent CNS lymphomas: phase I investigation of lenalidomide plus rituximab and outcomes of lenalidomide as maintenance monotherapy Hematol Oncol (ICML abstracts) 2015 33 175 \n18 Quach H Fernyhough L Henderson R Corbett G Baker B Browett P Blacklock Martín A Redondo AM Dlouhy I Salar A González-Barca E Canales M Montes-Moreno S Ocio EM López-Guillermo A Caballero D Spanish Group for Lymphomas and Autologous Bone Marrow (GELTAMO Lenalidomide in combination with R-ESHAP in patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 1b study from GELTAMO group Br J Haematol 2016 4 173 2 245 52 https://doi.org/10.1111/bjh.13945 26847165 \n19 H Forsyth C Underhill C Cannell P Trotman J Neylon A Harrison S Link E Swern A Cowan L Dimopoulos MA Miles Prince H Upfront lower dose lenalidomide is less toxic and does not compromise efficacy for vulnerable patients with relapsed refractory multiple myeloma: final analysis of the phase II RevLitestudy Br J Haematol 2017 5 177 3 441 448 Epub 2017 Feb 15 https://doi.org/10.1111/bjh.14562 28197996\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2035-3006",
"issue": "9(1)",
"journal": "Mediterranean journal of hematology and infectious diseases",
"keywords": "CNS lymphoma; Lenalidomide; survival; therapy",
"medline_ta": "Mediterr J Hematol Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101530512",
"other_id": null,
"pages": "e2017040",
"pmc": null,
"pmid": "28698783",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "21990093;19926148;28197996;26314773;27846613;19841864;25912004;25312994;21519022;26605261;26847165;17990178;21228334;27207798;24939657;25527263;27382100;27301994",
"title": "Lenalidomide and Temozolomide Combination in a Very Elderly Patient with CNS Relapse of Diffuse Large B-Cell Lymphoma.",
"title_normalized": "lenalidomide and temozolomide combination in a very elderly patient with cns relapse of diffuse large b cell lymphoma"
} | [
{
"companynumb": "IT-CELGENEUS-ITA-20170705274",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThromboembolic complications are the primary risks of stent-coiling of cerebral aneurysms. The utility of platelet function testing in stent-assisted aneurysm coiling remains controversial. This study aimed to assess a pharmacy-mediated antiplatelet management protocol for stent-assisted coiling.\n\n\nMETHODS\nStent-coiled aneurysms at an academic institution in the United States between 2015 and 2018 were retrospectively reviewed. All patients were managed using a pharmacy-mediated antiplatelet protocol, which required repeated platelet function testing and subsequent dose adjustments. Medication dosage, number of adjustments, aspirin reaction units (ARU) and P2Y12 reaction units (PRU), as well as complication rates, angiographic and functional outcome were analyzed.\n\n\nRESULTS\nA total of 56 aneurysms (median size 5 mm, range 2.6-14.0 mm) in 54 patients (median age 58.5 years) were treated with stent-assisted coil embolization. Most aneurysms were located at the basilar tip (28.6%). Median pre-procedure ARU and PRU were 442.5 (range 363-594) and 123.5 (range 1-252), respectively. Approximately two-thirds of all procedures required at least one aspirin dose adjustment and 88.5% of procedures required at least one clopidogrel dose adjustment. There were two (3.6%) thromboembolic complications. One of the thromboembolic complications occurred in a patient where the pharmacy-mediated protocol was violated. There were no hemorrhagic complications. Last imaging follow-up demonstrated complete aneurysm occlusion in 83.9%.\n\n\nCONCLUSIONS\nIn patients where the pharmacy-mediated antiplatelet protocol was followed, the thromboembolic complication rate was 1.8%. This complication rate compares favorably to those reported in large contemporary series. Nevertheless, the pharmacy-mediated protocol places a significant burden on both the patient and healthcare system.",
"affiliations": "Department of Neurosurgery, Geisinger, Danville, PA, USA.;Department of Neurosurgery, Geisinger, Danville, PA, USA.;Department of Neurosurgery, Geisinger, Danville, PA, USA.;Department of Neurosurgery, Geisinger, Danville, PA, USA.;Department of Neurosurgery, Geisinger, Danville, PA, USA.;Department of Neurosurgery, Geisinger, Danville, PA, USA.;Department of Neurosurgery, Geisinger, Danville, PA, USA.;Department of Neurosurgery, Geisinger, Danville, PA, USA.",
"authors": "Wirtz|Mirja M|MM|;Schirmer|Clemens M|CM|;Goren|Oded|O|;Bohan|Christian O|CO|https://orcid.org/0000-0001-5079-6674;Dalal|Shamsher|S|;Weiner|Gregory|G|;Foreman|Paul M|PM|https://orcid.org/0000-0001-8743-5119;Griessenauer|Christoph J|CJ|https://orcid.org/0000-0002-2952-3812",
"chemical_list": "D010975:Platelet Aggregation Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1177/1591019919894140",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1591-0199",
"issue": "26(3)",
"journal": "Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences",
"keywords": "Cerebral; aneurysm; antiplatelet; coil; embolization",
"medline_ta": "Interv Neuroradiol",
"mesh_terms": "D002533:Cerebral Angiography; D004621:Embolization, Therapeutic; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D010979:Platelet Function Tests; D012189:Retrospective Studies; D015607:Stents",
"nlm_unique_id": "9602695",
"other_id": null,
"pages": "275-282",
"pmc": null,
"pmid": "31856647",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": "26520845;28411263;23886748;22363312;29608747;25281703;28985662;25385746;29526063;26926583;21113358;24898735;15313699;28233076;25733843;30201813;29352056;23512976;7863971",
"title": "Utility of platelet function testing in stent-assisted coiling of cerebral aneurysms.",
"title_normalized": "utility of platelet function testing in stent assisted coiling of cerebral aneurysms"
} | [
{
"companynumb": "US-ACCORD-167878",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": "1",
"drugadmi... |
{
"abstract": "There is limited data suggesting that recovery from severe pulmonary infection with Coccidioides may be hastened by the addition of systemic corticosteroids.\n\n\n\nWe present a case report of 2 patients with persistent and progressive coccidioidomycosis who demonstrated a dramatic response to adjunctive corticosteroid therapy.\n\n\n\nBoth patients had Coccidioides immitis cultured from respiratory samples. One was a 69-year-old man who had been treated with combination fluconazole and liposomal amphotericin for over 6 weeks, with persistent fever and pneumonia. The other was a 61-year-old man treated with fluconazole and then amphotericin for 3 weeks, with progression to acute respiratory distress syndrome and shock. Both received short courses of intravenous methylprednisolone and recovered to be discharged home.\n\n\n\nAs opposed to associated hypersensitivity, corticosteroid treatment in these cases was directed at modulating the ongoing destructive effects of unchecked inflammation. Rapid improvement was noted in both cases and raises the possibility that the addition of systemic corticosteroids may hasten recovery in patients with severe coccidioidomycosis.",
"affiliations": "Pulmonary, Critical Care and Sleep Section, Infectious Diseases Section, VA Greater Los Angeles Healthcare System, David Geffen School of Medicine at UCLA, Los Angeles, Calif. Electronic address: Melisa.Chang@va.gov.;Pulmonary, Critical Care and Sleep Section, Infectious Diseases Section, VA Greater Los Angeles Healthcare System, David Geffen School of Medicine at UCLA, Los Angeles, Calif.;Pulmonary, Critical Care and Sleep Section, Infectious Diseases Section, VA Greater Los Angeles Healthcare System, David Geffen School of Medicine at UCLA, Los Angeles, Calif.;Pulmonary, Critical Care and Sleep Section, Infectious Diseases Section, VA Greater Los Angeles Healthcare System, David Geffen School of Medicine at UCLA, Los Angeles, Calif.;Pulmonary, Critical Care and Sleep Section, Infectious Diseases Section, VA Greater Los Angeles Healthcare System, David Geffen School of Medicine at UCLA, Los Angeles, Calif.",
"authors": "Chang|Melisa R|MR|;Chopra|Neha|N|;Beenhouwer|David|D|;Goetz|Matthew B|MB|;Hoo|Guy W Soo|GWS|",
"chemical_list": "D005938:Glucocorticoids; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjmed.2018.09.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9343",
"issue": "132(1)",
"journal": "The American journal of medicine",
"keywords": "Coccidioidomycosis; Corticosteroids; Pneumonia; Respiratory failure",
"medline_ta": "Am J Med",
"mesh_terms": "D000368:Aged; D003047:Coccidioidomycosis; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged",
"nlm_unique_id": "0267200",
"other_id": null,
"pages": "110-113",
"pmc": null,
"pmid": "30290191",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Corticosteroids in the Management of Severe Coccidioidomycosis.",
"title_normalized": "corticosteroids in the management of severe coccidioidomycosis"
} | [
{
"companynumb": "PHHY2019US001205",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Allogeneic hematopoietic stem cell transplant patients are at risk for common and atypical infections. Superior diagnostics can decrease infection-related morbidity and mortality. A novel plasma cell-free DNA next-generation sequencing test detected an uncommon presentation of Chlamydia trachomatis and recurrent and metastatic complications of Staphylococcus aureus bacteremia before standard microbiology.",
"affiliations": "Division of Infectious Diseases, University of California San Francisco, San Francisco, California.;Karius, Inc., Redwood City, California.;Karius, Inc., Redwood City, California.;Karius, Inc., Redwood City, California.;Karius, Inc., Redwood City, California.;Karius, Inc., Redwood City, California.;Karius, Inc., Redwood City, California.;School of Medicine, University of California Davis, Sacramento, California.;Division of Infectious Diseases, University of California San Francisco, San Francisco, California.;Division of Infectious Diseases, University of California San Francisco, San Francisco, California.;Division of Hematology and Blood and Marrow Transplantation, University of California San Francisco, San Francisco, California.;Division of Infectious Diseases, University of California San Francisco, San Francisco, California.",
"authors": "Fung|Monica|M|;Zompi|Simona|S|;Seng|Hon|H|;Hollemon|Desiree|D|;Parham|Adama|A|;Hong|David K|DK|;Bercovici|Sivan|S|;Dolan|Estelle|E|;Lien|Kathy|K|;Teraoka|Justin|J|;Logan|Aaron C|AC|;Chin-Hong|Peter|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofy301",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n30581881\n10.1093/ofid/ofy301\nofy301\nBrief Report\nPlasma Cell–Free DNA Next-Generation Sequencing to Diagnose and Monitor Infections in Allogeneic Hematopoietic Stem Cell Transplant Patients\nFung Monica 1 Zompi Simona 2 Seng Hon 2 Hollemon Desiree 2 Parham Adama 2 Hong David K 2 Bercovici Sivan 2 Dolan Estelle 3 Lien Kathy 1 Teraoka Justin 1 Logan Aaron C 4 Chin-Hong Peter 1 1 \nDivision of Infectious Diseases, University of California San Francisco, San Francisco, California\n\n2 \nKarius, Inc., Redwood City, California\n\n3 \nSchool of Medicine, University of California Davis, Sacramento, California\n\n4 \nDivision of Hematology and Blood and Marrow Transplantation, University of California San Francisco, San Francisco, California\n\nCorrespondence: M. Fung, MD, MPH, 513 Parnassus Avenue, S-380, San Francisco, CA 94143 (monica.fung@ucsf.edu).\n12 2018 \n16 11 2018 \n16 11 2018 \n5 12 ofy30112 9 2018 12 11 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2018This 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 reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract\nAllogeneic hematopoietic stem cell transplant patients are at risk for common and atypical infections. Superior diagnostics can decrease infection-related morbidity and mortality. A novel plasma cell–free DNA next-generation sequencing test detected an uncommon presentation of Chlamydia trachomatis and recurrent and metastatic complications of Staphylococcus aureus bacteremia before standard microbiology.\n\nimmunocompromisedmolecular diagnosticsnext-generation sequencingstem cell transplantKarius, Inc.\n==== Body\nAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is a life-saving treatment for patients with hematologic malignancy. However, it increases the risk of infections, which cause significant morbidity and mortality in this population [1]. Diagnosing infections in allo-HSCT patients is challenging due to uncommon causative pathogens and atypical clinical presentations of disease.\n\nNext-generation sequencing (NGS) holds promise as an infectious disease diagnostic that can quickly and accurately detect a wide range of pathogens to help guide therapy and monitor response [2]. Karius, Inc., has developed a novel plasma NGS platform that provides rapid and unbiased identification of >1000 pathogens [3]. We present a series of allo-HSCT cases where plasma NGS detected pathogens or complications of infection before standard microbiology.\n\nMETHODS\nAdult patients undergoing allo-HSCT for hematologic malignancy at the University of California, San Francisco (UCSF) were consented and enrolled in the Diagnosis of Infection in Stem Cell Transplant Patients OVER Time (DISCOVER) trial (NCT02804464). The protocol was approved by the UCSF Institutional Review Board (IRB#1518026). Patients were free of known active infections at initiation of their transplant conditioning. Patients underwent plasma sampling before conditioning, at the time of graft infusion, and at standard weekly intervals post-transplant, with additional sampling during acute illness.\n\nSamples were transferred to the Karius CLIA/CAP Laboratory (Redwood City, CA) for processing. Cell-free DNA was extracted from plasma, NGS libraries were prepared, and sequencing was performed on an Illumina NextSeq 500 (Figure 1A). Sequencing reads identified as human were removed, and the remaining sequences were aligned to a curated pathogen database. Validated organisms found to be present above a predefined statistical threshold were reported as previously described [3–5]. The process from sample receipt to result typically takes 28 hours.\n\nFigure 1.\n A, Workflow of Karius diagnostic test for infectious disease using NGS of plasma cell-free DNA. B, Timeline of events for Case 1. C, Timeline of events for Case 2. D, Timeline of events for Case 3. For the plasma NGS test, the day of plasma collection is shown. Abbreviations: AKI, acute kidney injury; allo-HSCT, allogeneic hematopoietic stem cell transplant; ATG, antithymocyte globulin; BK PCR, BK virus polymerase chain reaction test; Bu, busulfan; CT, computed tomography; Flu, fludarabine; GC/CT NAAT, gonorrhea and chlamydia nucleic acid amplification test; ICU, intensive care unit; Mel, melphalan; MRI, magnetic resonance imaging; MRSA, methicillin-resistant Staphylococcus aureus; MUD, matched unrelated donor; NGS, next-generation sequencing; PCR, polymerase chain reaction; RIC, reduced intensity conditioning; TTE, transthoracic echocardiogram; US, ultrasound.\n\nCases were selected from the first 20 subjects (70 total) enrolled in the DISCOVER trial. Research study results were not made available to the clinical providers in real time and were not applied in clinical decision-making. For details, see the Supplementary Data.\n\nCASE REPORTS\nCase 1\nA 21-year-old man with acute myelogenous leukemia and horseshoe kidney underwent human leukocyte antigen–matched unrelated donor myeloablative allo-HSCT. He was admitted on post-transplant days 40–44 for flank pain, hematuria, and low-grade fever (Figure 1B). History was negative for sexual activity in the prior 6 months. Work-up was notable for urinalysis showing hemoglobin and leukocyte esterase, urine culture without growth, and negative urine and serum BK virus polymerase chain reaction (PCR). Computed tomography (CT) of the abdomen and pelvis demonstrated a 3-mm nonobstructive stone in the superior pole of the right kidney and dilated right calyx with layering stones without hydronephrosis. Urology considered nephrolithiasis the most likely explanation for the patient’s symptoms, and he was discharged on alpha-1 antagonist treatment.\n\nThe patient was readmitted on post-transplant days 53–62 for ongoing dysuria and hematuria (Figure 1B). Labwork was notable for mild acute kidney injury; urinalysis showing hemoglobin, protein, and leukocyte esterase; urine culture without growth; and negative urine and serum BK virus PCRs. Renal ultrasound revealed a dilated right calyx with small stone fragments without hydronephrosis. Ureteroscopy was performed and revealed diffuse bladder inflammation with mild to moderate dilation of the intrarenal collecting system. Placement of a right-sided ureteral stent did not improve the patient’s symptoms, so it was removed 48 hours later. On discharge, the etiology of the patient’s symptoms remained unclear, so a urine gonorrhea/chlamydia nucleic acid amplification test was sent, returning positive for Chlamydia trachomatis. At outpatient follow-up 2 days postdischarge, the patient was started on a 14-day course of doxycycline with resolution of his urinary symptoms.\n\nPlasma NGS was positive for Chlamydia trachomatis 7 days before initial symptoms and 30 days before standard microbiologic diagnosis (post-transplant day 32), as well as a day before discharge from the first admission (post-transplant day 43).\n\nCase 2\nA 69-year-old woman with myelodysplastic syndrome/myeloproliferative neoplasm underwent intermediate-intensity mismatched unrelated donor allo-HSCT. Her post-transplant course was complicated by engraftment failure, Clostridium difficile infection, veno-occlusive disease, renal failure, and respiratory failure, requiring a prolonged course of intensive care (Figure 1C).\n\nOn post-transplant day 22, the patient developed methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. After starting intravenous (IV) vancomycin, blood cultures cleared within 1 day (post-transplant day 23), and she received a 2-week course that ended on post-transplant day 39. On post-transplant day 49, blood cultures drawn for worsening hemodynamic instability showed recurrent MRSA bacteremia. Given poor oncologic prognosis, the patient was transitioned to comfort-focused care and died.\n\nPlasma NGS testing was positive for S. aureus the day before initial MRSA bacteremia (post-transplant day 21), throughout the vancomycin course (post-transplant days 27 and 35), after stopping vancomycin (post-transplant day 42), and on the same day as recurrent MRSA bacteremia.\n\nCase 3\nA 56-year-old woman with JAK2 V617F+ postpolycythemia vera myelofibrosis underwent reduced-intensity conditioning unrelated donor allo-HSCT, with her immediate post-transplant course complicated by neutropenic fever and C. difficile colitis (Figure 1D). On post-transplant days 70–82, the patient was readmitted for neutropenic fever and found to have MRSA bacteremia. After starting IV vancomycin, blood cultures cleared within 48 hours. The patient’s Hickman catheter was removed, and transthoracic echocardiogram and magnetic resonance imaging of the spine showed no endocarditis or osteomyelitis/discitis. Due to subtherapeutic serum levels, vancomycin was changed to daptomycin, and the patient completed a 4-week course of antibiotic therapy (through post-transplant day 99).\n\nOn post-transplant day 118, the patient presented to clinic reporting a right chest wall mass. On post-transplant day 134, ultrasound showed soft tissue thickening/hyperemia surrounding a 2.6 × 0.7 × 2.7-cm fluid collection, and chest CT demonstrated stranding and soft tissue swelling of the right anterior chest wall. Bacterial culture from same-day ultrasound-guided aspiration preliminarily identified Staphylococcus epidermidis. On post-transplant day 137, speciation was corrected to MRSA, and the patient was started on a 14-day course of oral doxycycline with improvement in chest wall tenderness.\n\nPlasma NGS remained positive for S. aureus after completion of daptomycin for bacteremia (post-transplant day 110) and preceding the clinical and microbiological diagnosis of chest wall abscess (post-transplant day 139), becoming negative after drainage and antibiotics for abscess.\n\nDISCUSSION\nAmong allo-HSCT recipients, infections are often severe but lack classic symptoms such as fever and leukocytosis [1]. Current laboratory methods are frequently unable to establish a microbiologic diagnosis [1, 6]. We describe 3 cases where plasma NGS could have facilitated early identification of an uncommon presentation of Chlamydia trachomatis and indicated persistent MRSA infection before microbiologic diagnosis of recurrent bacteremia and metastatic infection.\n\nIn Case 1, given the patient’s atypical presentation, directed chlamydia testing was not sent until the end of his second admission. Although urethritis with dysuria and leukocyturia is the most common presentation of chlamydia infection in men, hematuria and proteinuria have been described in pediatric and adolescent males with chlamydia urethritis [7, 8]. Plasma NGS testing was positive 19 and 30 days before standard microbiology and could have potentially prevented a 10-day hospitalization with invasive ureteroscopy with stent placement.\n\nIn Case 2, plasma NGS remained positive for S. aureus after completion of therapy for MRSA bacteremia and before identification of recurrent bacteremia by standard culture. The incidence of bacteremia among allo-HSCT patients is estimated to be as high as 39% [9]. S. aureus bacteremia, in particular, is associated with significant morbidity and mortality, with recurrence occurring in 2%–17% of cases, especially among patients with MRSA [10]. Among allo-HSCT recipients, risk factors for recurrent S. aureus bacteremia include graft-vs-host disease, corticosteroid treatment, liver dysfunction, and prolonged hospitalization [11]. As plasma NGS may detect pathogens 2–5 days before bacteremia and remains positive on average 3 days longer than blood culture, plasma NGS results could have provided an early indication of recurrent or relapsed bacteremia [12, 13].\n\nIn Case 3, plasma NGS remained positive after treatment for MRSA bacteremia and before clinical diagnosis of chest wall abscess. Metastatic infection is a common complication of S. aureus bacteremia, occurring in up to 39% of patients [14, 15]. This immunocompromised patient exhibited limited symptoms, and the causative organism was initially erroneously identified as S. epidermidis, contributing to delayed treatment. Persistent positive plasma NGS testing for S. aureus despite completion of antibiotics could have indicated persistent occult infection.\n\nBeyond the detection of active infection, plasma NGS testing reports other relevant pathogens for allo-HSCT monitoring. In Case 1, routine plasma NGS was positive for cytomegalovirus (CMV) on post-transplant days 14–32, coinciding with standard CMV PCR. In Case 2, plasma NGS detected human herpes virus 6B, Pneumocystis jirovecii, and CMV on post-transplant day 42. Due to a decision not to escalate care, standard microbiology tests were not obtained. In Case 3, plasma NGS showed CMV on post-transplant days 35–64 and Epstein-Barr virus (EBV) on post-transplant day 42, corresponding to standard CMV and EBV PCRs, respectively.\n\nIn summary, plasma NGS is a rapid, noninvasive, and unbiased test that detects a broad range of pathogens from a single plasma sample [3–5]. Here, we describe cases where plasma NGS not only identified compartmentalized non-bloodstream infections, but also detected persistent pathogen DNA after bacteremia that could have served as early indications of recurrent or occult infection. In immunocompromised patients such as allo-HSCT recipients, plasma NGS may aid in the diagnosis of infections caused by uncommon pathogens and in situations of atypical clinical presentations, potentially allowing for early targeted therapy to improve clinical outcomes and decrease antimicrobial resistance and drug toxicity. Further study is needed to fully define the test characteristics of plasma NGS.\n\nSupplementary Data\nSupplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.\n\nofy301_suppl_supplementary_appendix Click here for additional data file.\n\n Acknowledgments\nThe authors would like to thank Sumedha Sinha for assistance in preparation of the manuscript.\n\n\nFinancial support. This work was supported by Karius, Inc.\n\n\nPotential conflicts of interest. M.F., E.D., K.L., J.T., and A.C.L. have no relevant conflicts of interest. S.Z., H.S., D.H., A.P., D.K.H., and S.B. are employees of Karius, Inc. P.C.H. receives research funding from Karius, Inc. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1. \nWingard JR , Hsu J , Hiemenz JW \nHematopoietic stem cell transplantation: an overview of infection risks and epidemiology\n. Infect Dis Clin North Am 2010 ; 24 :257 –72\n.20466269 \n2. \nSimner PJ , Miller S , Carroll KC \nUnderstanding the promises and hurdles of metagenomic next-generation sequencing as a diagnostic tool for infectious diseases\n. Clin Infect Dis 2018 ; 66 :778 –88\n.29040428 \n3. \nBlauwkamp TA , Thair S , Rosen MJ , et al \nAnalytical and clinical validation of a microbial cell-free DNA sequencing test for infectious disease\n. Nat Microbiol . In press .\n4. \nHong DK , Blauwkamp TA , Kertesz M , Bercovici S , Truong C , Banaei N \nLiquid biopsy for infectious diseases: sequencing of cell-free plasma to detect pathogen DNA in patients with invasive fungal disease\n. Diagn Microbiol Infect Dis 2018 ; 92 (3 ):210 –3\n.30017314 \n5. \nAbril MK , Barnett AS , Wegermann K , et al \nDiagnosis of Capnocytophaga canimorsus sepsis by whole-genome next-generation sequencing\n. Open Forum Infect Dis 2016 ; 3 :1 –4\n.\n6. \nSerody JS , Berrey MM , Albritton K , et al \nUtility of obtaining blood cultures in febrile neutropenic patients undergoing bone marrow transplantation\n. Bone Marrow Transplant 2000 ; 26 :533 –8\n.11019843 \n7. \nMegli A , Bojan HH \nChlamydial infection of the urinary tract in children and adolescents with hematuria\n. Pediatr Nephrol 2000 ; 15 :132 –133\n.11095030 \n8. \nTaube OM \nChlamydia trachomatis urethritis presenting as hematuria in an adolescent male\n. J Adolesc Health Care 1988 ; 9 :505 –6\n.3182369 \n9. \nDandoy CE , Ardura MI , Papanicolaou GA , Auletta JJ \nBacterial bloodstream infections in the allogeneic hematopoietic cell transplant patient: new considerations for a persistent nemesis\n. Bone Marrow Transplant 2017 ; 52 :1091 –106\n.28346417 \n10. \nKreisel K , Boyd K , Langenberg P , Roghmann MC \nRisk factors for recurrence in patients with Staphylococcus aureus infections complicated by bacteremia\n. Diagn Microbiol Infect Dis 2006 ; 55 :179 –84\n.16631340 \n11. \nMihu CN , Schaub J , Kesh S , et al \nRisk factors for late Staphylococcus aureus bacteremia after allogeneic hematopoietic stem cell transplantation: a single-institution, nested case-controlled study\n. Biol Blood Marrow Transplant 2008 ; 14 :1429 –33\n.19041067 \n12. \nWanda L , Ruffin F , Jonathan Hill-Rorie J , et al \nDirect detection and quantification of bacterial cell-free DNA in patients with bloodstream infection (BSI) using the karius plasma next generation sequencing (NGS) test\n. Open Forum Infect Dis 2017 ; 4 :S613 .\n13. \nGoggin K , Inaba Y , Gonzalez-Pena V , et al \nPrediction of bloodstream infection prior to onset of symptoms by plasma metagenomic sequencing in pediatric patients with relapsed or refractory malignancy (PREDSEQ) . Abstract #1756 presented at: IDWeek ; October 3–7, 2018 ; San Francisco, CA .\n14. \nHorino T , Sato F , Hosaka Y , et al \nPredictive factors for metastatic infection in patients with bacteremia caused by methicillin-sensitive Staphylococcus aureus\n. Am J Med Sci 2015 ; 349 :24 –8\n.25250988 \n15. \nCuijpers ML , Vos FJ , Bleeker-Rovers CP , et al \nComplicating infectious foci in patients with Staphylococcus aureus or Streptococcus species bacteraemia\n. Eur J Clin Microbiol Infect Dis 2007 ; 26 :105 –13\n.17211607\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2328-8957",
"issue": "5(12)",
"journal": "Open forum infectious diseases",
"keywords": "immunocompromised; molecular diagnostics; next-generation sequencing; stem cell transplant",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofy301",
"pmc": null,
"pmid": "30581881",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": "27704003;25250988;28346417;11095030;17211607;29040428;30742071;19041067;3182369;11019843;16631340;30017314;20466269",
"title": "Plasma Cell-Free DNA Next-Generation Sequencing to Diagnose and Monitor Infections in Allogeneic Hematopoietic Stem Cell Transplant Patients.",
"title_normalized": "plasma cell free dna next generation sequencing to diagnose and monitor infections in allogeneic hematopoietic stem cell transplant patients"
} | [
{
"companynumb": "US-PFIZER INC-2019311401",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": "3... |
{
"abstract": "Cervical carcinoma is associated with high-risk human papillomavirus (HPV) DNA integration and usually occurs after age 21 (peak 45 years), as reflected in screening guidelines. Between 1999 and 2008, cervical carcinoma rate in adolescents aged 15-19 years was 0.15 per 100,000. HPV-negative cervical carcinoma is rare in adolescents. The youngest previously reported case was 15 years old. Treatment options for cervical carcinoma are limited after first-line therapy. Immune checkpoint inhibitors blocking programmed death receptor (PD-1) and its ligand, PD-L1, have shown objective clinical responses and are tolerable in adults with gynecologic cancers. This class of agents is well tolerated in pediatric patients. PD-1/PD-L1 is commonly expressed in gynecologic cancers but its expression may not predict clinical response. We describe an exceptional response to single agent nivolumab postradiation therapy in a 13-year-old adolescent with poorly differentiated cervical carcinoma and widespread metastatic disease.",
"affiliations": "Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.;Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania.;Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Clinical Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Clinical Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.;Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.",
"authors": "Oved|Joseph H|JH|;Graul|Ashley|A|;Burger|Robert A|RA|;Schwartz|Lauren E|LE|;Reyes|M Carolina|MC|;Balis|Frank M|FM|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000077594:Nivolumab; D016190:Carboplatin; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1089/dna.2019.4650",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1044-5498",
"issue": "38(10)",
"journal": "DNA and cell biology",
"keywords": "cervical carcinoma; immunotherapy; pediatric oncology",
"medline_ta": "DNA Cell Biol",
"mesh_terms": "D000293:Adolescent; D000074322:Antineoplastic Agents, Immunological; D016190:Carboplatin; D002277:Carcinoma; D005260:Female; D005720:Gamma Rays; D006801:Humans; D007044:Hysterectomy; D008113:Liver Neoplasms; D008175:Lung Neoplasms; D008197:Lymph Node Excision; D000077594:Nivolumab; D010052:Ovariectomy; D017239:Paclitaxel; D027383:Papillomaviridae; D058994:Salpingectomy; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "9004522",
"other_id": null,
"pages": "1143-1146",
"pmc": null,
"pmid": "31464522",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29095678;28094262;17250453;23090530;15520206;30643254;16636135",
"title": "Exceptional Response to Nivolumab in a 13-Year-Old Female with Metastatic HPV-Negative Cervical Carcinoma.",
"title_normalized": "exceptional response to nivolumab in a 13 year old female with metastatic hpv negative cervical carcinoma"
} | [
{
"companynumb": "NVSC2019US034861",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "1",
"drug... |
{
"abstract": "Drug-induced injury (DILI) is a frequent cause of abnormal liver tests and a leading cause of liver failure in the United States. Colchicine has long been used as a systemic anti-inflammatory agent for treatment of gout by inhibiting mitotic activity and neutrophil function. We present the first case of colchicine-induced hepatoxicity, supported by histopathologic findings characteristic of colchicine-induced injury and resolution of liver enzyme abnormalities after its discontinuation. Colchicine-associated DILI has implications for the evaluation of patients with abnormal liver tests and gout, especially for patients with alcoholism and non-alcoholic fatty liver disease, in whom there is an increased incidence of gout.",
"affiliations": "Division of Gastroenterology, Department of Internal Medicine, New York University School of Medicine, New York, NY.;Department of Pathology, New York University School of Medicine, New York, NY.;Division of Gastroenterology, Department of Internal Medicine, New York University School of Medicine, New York, NY.",
"authors": "Abbott|Collette E|CE|;Xu|Ruliang|R|;Sigal|Samuel H|SH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.14309/crj.2017.120",
"fulltext": "\n==== Front\nACG Case Rep JACG Case Rep JcrjACG Case Reports Journal2326-3253American College of Gastroenterology crj.2017.12010.14309/crj.2017.120Case ReportLiverColchicine-Induced Hepatotoxicity Abbott et alColchicine-Induced HepatotoxicityAbbott Collette E. MD1Xu Ruliang MD2Sigal Samuel H. MD11 Division of Gastroenterology, Department of Internal Medicine, New York University School of Medicine, New York, NY2 Department of Pathology, New York University School of Medicine, New York, NYCorrespondence: Samuel H. Sigal, Montefiore Medical Center, 111 East 210th St, Bronx, NY 10468 (ssigal@montefiore.org).2017 22 11 2017 4 e12015 5 2017 21 9 2017 Copyright © Abbott et al.2017This is an open-access article. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/Drug-induced injury (DILI) is a frequent cause of abnormal liver tests and a leading cause of liver failure in the United States. Colchicine has long been used as a systemic anti-inflammatory agent for treatment of gout by inhibiting mitotic activity and neutrophil function. We present the first case of colchicine-induced hepatoxicity, supported by histopathologic findings characteristic of colchicine-induced injury and resolution of liver enzyme abnormalities after its discontinuation. Colchicine-associated DILI has implications for the evaluation of patients with abnormal liver tests and gout, especially for patients with alcoholism and non-alcoholic fatty liver disease, in whom there is an increased incidence of gout.\n==== Body\nIntroduction\nDrug-induced liver injury (DILI) accounts for 10% of all episodes of acute hepatitis and is the most common cause of liver failure in the United States.1,2 DILI can cause either hepatocellular or cholestatic injury, and its severity ranges from asymptomatic mild elevations in liver tests, to nonspecific symptoms with nausea, anorexia, and fatigue, and even to fulminant hepatic failure with jaundice and hepatic encephalopathy. Proposed mechanisms of DILI include direct cellular injury and immune-mediated injury. Most cases subside after cessation of the drug, which serves as an important diagnostic and therapeutic aide.3\n\nColchicine is used as a treatment for gout, and the biologic effects of colchicine are based on its ability to bind to tubulin. Colchicine forms a tight complex with tubulin and induces a conformational change in the protein that inhibits its polymerization into microtubules, thereby leading to mitotic arrest in metaphase and disruption of cellular division.4 Its anti-inflammatory effect is attributed to its ability to disrupt neutrophil microtubules and inhibit neutrophil migration and adhesion.5 Colchicine demonstrates the greatest anti-mitotic activity on rapidly dividing tissues, so toxicity initially presents with gastrointestinal (GI) symptoms, but patients can develop bone marrow hypoplasia, cardiac arrhythmias, cardiovascular collapse, respiratory distress, and shock, which can lead to multisystem organ failure.6-8 Colchicine has only infrequently been associated with hepatotoxicity. It has usually been associated with cases of overdose in which the hepatic injury has been self-limited and overshadowed by the other toxicities.\n\nCase Report\nA 41-year-old, non-obese man was started on 0.6 mg oral colchicine and allopurinol daily for treatment of chronic gout. Liver tests immediately prior to starting therapy were not available, but such tests were noted to be mildly abnormal at 6 months after starting colchicine and remained so after discontinuing allopurinol. The tests were remarkable for aspartate aminotransferase (AST) 50 IU/L, alanine aminotransferase (ALT) 47 IU/L, and alkaline phosphatase 76 IU/L. Serologic evaluation was remarkable for anti-mitochondrial antibody 74.9. Anti-nuclear antibody, anti-smooth muscle antibody, liver-kidney microsomal antibody, celiac serologies, and immunoglobulin levels, as well as α-1-antitrypsin and ferritin levels were normal. M2 subtype was not measured, but the patient was not taking any antibiotics, and, as described below, histopathology was inconsistent with primary biliary cirrhosis (PBC). Physical examination was unremarkable without stigmata of chronic liver disease. Abdominal ultrasound was normal. Liver biopsy was remarkable for focal hepatocytes with glycogenated nuclei, 1% macrovesicular steatosis, occasional ceroid macrophages, and significant anisonucleosis with enlarged nuclei, multiple nucleoli, and frequent mitotic figures (Figure 1). This is indirectly suggestive of mitotic arrest, which is colchicine’s mechanism of action. The liver biopsy did not have features suggestive of primary biliary cholangitis or granulomatous features suggestive of allopurinol-induced liver injury. After discontinuing colchicine, liver tests normalized within 3 weeks (AST 33 IU/L, ALT 40 IU/L).\n\nFigure 1 (A) Histological features of liver biopsy, showing significant anisonucleosis, mild liver cell plate disarray, loss of nuclear polarity, hepatocytes and glycogenated nuclei, and focal macrovesicular steatosis (hematoxylin and eosin stain, 40× magnification). (B) Frequent mitotic figures (arrow) (hematoxylin and eosin stain, 40x magnification). (C) Trichrome stain highlighting peri-centrovenular fibrosis (40× magnification). (D) Trichrome stain highlighting peri-sinusoidal/peri-hepatocellular fibrosis (40× magnification).\n\nDiscussion\nThe abnormal liver tests in our patient can be attributed to colchicine-associated liver injury due to its resolution after colchicine was discontinued and other etiologies were excluded. Although the presence of anti-mitochondrial antibody raised the possibility of PBC, the liver test pattern was hepatocellular rather than cholestatic, the immunoglobulin M (IgM) level was normal, and the liver biopsy lacked features of this condition. Nearly half of newly detected anti-mitochondrial antibodies in clinical practice do not lead to PBC, and there was no clinical evidence to suggest that this patient had PBC.9 Although allopurinol is associated with minor liver test abnormalities and has been linked to acute liver injury with features of a hypersensitivity reaction, liver tests in our patient remained elevated despite discontinuing allopurinol, and the histopathology was inconsistent with the granulomatous disease characteristic of allopurinol-induced liver injury.10\n\nThe histopathologic changes observed in the liver biopsy were consistent with colchicine’s mechanism of action, in which mitotic activity and cellular division is disrupted. These changes include anisonucleosis with enlarged nuclei, multiple nucleoli, and frequent mitotic figures, which is suggestive of mitotic arrest. These changes are similar to histological changes seen in GI, bronchiolar, and cardiac biopsies in patients with colchicine toxicity, which show endothelial cell injury, mitotic figures arrested in metaphase (\"ring\" mitoses), nuclear swelling, and loss of nuclear polarity.11,12\n\nThe majority of cases of hepatotoxicity associated with colchicine are in the setting of multisystem organ failure with hepatic histologic findings consistent with sepsis.13 Reports of chronic colchicine hepatotoxicity are limited to 2 case reports of patients taking the agent for gout. Liver biopsy in a patient with chronic hepatitis C who had been taking colchicine for more than 10 years presented with mildly elevated liver tests and loose stools revealed \"ring\" mitotic figures that were not present on a previous biopsy 7 years earlier when he was also taking the agent.14 Colchicine is most toxic to highly proliferative tissues. It is unclear why ring mitoses were not initially present in this case and ours. One explanation is that it is a feature of only chronic toxicity. Results of liver tests after the discontinuation of colchicine were not reported in this case. In a second case, a patient with gout presented with transient loose stools, sub-acute painless jaundice, and elevated liver tests after taking 0.5 mg colchicine twice daily for 6 days, all of which gradually improved after discontinuing colchicine.15 A liver biopsy was not performed in this case.\n\nWhen evaluating elevated liver tests in patients with gout, important considerations in the differential diagnosis include DILI (allopurinol, non-steroidal anti-inflammatory drug), and fatty liver disease. Alcohol abuse is a frequent causative factor for gout among those with regular alcohol use.16,17 Additionally, gout is an independent risk factor for non-alcoholic fatty liver disease (NAFLD).18,19 Given the increasing worldwide epidemic of NAFLD, it is anticipated that abnormal liver tests associated with colchicine therapy in patients with fatty liver and gout will be more commonly encountered. Our case, which is the first biopsy-proven case of colchicine-induced hepatotoxicity, highlights the importance of considering colchicine-DILI in patients with abnormal liver tests and gout.\n\nDisclosures\nAuthor contributions: CE Abbott wrote the manuscript. R. Xu edited the manuscript. SH Sigal edited the manuscript and is the article guarantor.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nReferences\n1 Kaplowitz N \nDrug-induced liver injury . Clin Infect Dis . 2004 ;38 (Supplement 2 ):S44 –8 .14986274 \n2 Zimmerman HJ \nDrug-induced liver disease . Clin Liver Dis . 2000 ;4 (1 ):73 –96 .11232192 \n3 Russmann S , Kullak-Ublick GA , Grattagliano I \nCurrent concepts of mechanisms in drug-induced hepatotoxicity . Curr Med Chem . 2009 ;16 :3041 –53 .19689281 \n4 Sackett DL , Varma JK \nMolecular mechanism of colchicine action: Induced local unfolding of beta-tubulin . Biochemistry . 1993 ;32 (49 ):13560 –5 .8257691 \n5 Cronstein BN , Molad Y , Reibman J , Balakhane E , Levin RI , Weissman G \nColchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils . J Clin Invest . 1995 ;96 (2 ):994 –1002 .7543498 \n6 Milne ST , Meek PD \nFatal colchicine overdose: Report of a case and review of the literature . Am J Emerg Med . 1998 ;16 (6 ):603 –8 .9786547 \n7 Maxwell MJ , Muthu P , Pritty PE \nAccidental colchicine overdose. A case report and literature review . Emerg Med J . 2002 ;19 (3 ):265 –6 .11971849 \n8 Domínguez de Villota ED , Galdos P , Mosquera JM , Tomás MI \nColchicine overdose: An unusual origin of multiorgan failure . Crit Care Med . 1979 ;7 (6 ):278 –9 .446061 \n9 Dahlqvist G , Gaouar F , Carrat F , et al \nLarge-scale characterization study of patients with antimitochondrial antibodies but nonestablished primary biliary cholangitis . Hepatology . 2017 ;65 (1 ):152 –63 .27688145 \n10 Chawla SK , Patel HD , Parrino GR , Soterakis J , Lopresti PA , D’Angelo WA \nAllopurinol hepatotoxicity. Case report and literature review . Arthritis Rheum . 1977 ;20 (8 ):1546 –9 .921828 \n11 Iacobuzio-Donahue CA , Lee EL , Abraham AC , Yardley JH , Wu TT \nColchicine toxicity: Distinct morphologic findings in gastrointestinal biopsies . Am J Surg Pathol . 2001 ;25 (8 ):1067 –73 .11474292 \n12 Mikaelian I , Buness A , de Vera-Mudry M-C , et al \nPrimary endothelial damage is the mechanism of cardiotoxicity of tubulin-binding drugs . Toxicol Sci . 2010 ;117 (1 ):144 –51 .20624997 \n13 Stemmerman GN , Hayashi T \nColchicine intoxication: A reappraisal of its pathology based on a study of three fatal cases . Hum Pathol . 1971 ;2 (2 ):321 –32 .5095674 \n14 Kamath A , Mehal W , Jain D \nColchicine-associated ring mitosis in liver biopsy and their clinical implications . J Clin Gastroenterol . 2008 ;42 (9 ):1060 –62 .18391833 \n15 Ali T , Khan S , Kalim A , Riazuddin M \nA case of colchicine associated hepatotoxicity. Walsall Healthcare NHS Trust . http://www.acutemedicine.org.uk/wp-content/uploads/2013/10/cr1%20-%20a%20case%20of%20colchicine%20associated%20hepatotoxicity.pdf. 2013. Accessed June 16, 2016.\n16 Choi HK , Mount DB , Reginato AM \nPathogenesis of gout . Ann Intern Med . 2005 ;143 (7 ):499 –516 .16204163 \n17 Choi HK , Atkinson K , Karlson EW , Willett W , Curhan G \nAlcohol intake and risk of incident gout in men: A prospective study . Lancet . 2004 ;363 (9417 ):1277 –81 .15094272 \n18 Obika M , Noguchi H \nDiagnosis and evaluation of nonalcoholic fatty liver disease . Exp Diabetes Res . 2012 ;2012 :145754. 22110476 \n19 Kuo C-F , Yu K-H , Luo S-F , et al \nGout and risk of non-alcoholic fatty liver disease . Scand J Rheumatol . 2010 ;29 (6 ):466 –71 .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2326-3253",
"issue": "4()",
"journal": "ACG case reports journal",
"keywords": null,
"medline_ta": "ACG Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101638398",
"other_id": null,
"pages": "e120",
"pmc": null,
"pmid": "29201931",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "921828;14986274;11474292;446061;7543498;18391833;20560813;5095674;19689281;20624997;15094272;11971849;8257691;27688145;16204163;9786547;11232192;22110476",
"title": "Colchicine-Induced Hepatotoxicity.",
"title_normalized": "colchicine induced hepatotoxicity"
} | [
{
"companynumb": "US-INGENUS PHARMACEUTICALS NJ, LLC-ING201801-000002",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LISINOPRIL"
},
"dr... |
{
"abstract": "The association between growth hormone (GH) treatment and cancer risk has not been thoroughly evaluated and there are questions about any increased risk of bone tumors. We examined cancer risk and especially bone tumor risk in a population-based cohort study of 6874 patients treated with recombinant GH in France for isolated GH deficiency, short stature associated with low birth weight or length or idiopathic short stature. Adult mortality and morbidity data obtained from national databases and from questionnaires. Case ascertainment completeness was estimated with capture-recapture methods. Standardized mortality and incidence ratios were calculated using national reference data. 111 875 person-years of observation were analyzed and patients were followed for an average of 17.4 ± 5.3 years to a mean age of 28.4 ± 6.2 years. For cancer overall, mortality and incidence were not different from expected figures. Five patients developed bone tumors (chondrosarcoma, 1, Ewing sarcoma, 1, osteosarcoma, 3) of whom 3 died (Ewing sarcoma, 1, osteosarcoma, 2), whereas only 1.4 case and 0.6 deaths were expected: standardized mortality ratio, 5.0 and standardized incidence ratio from 3.5 to 3.8 accounting or not accounting for missed cases. Most patients received conventional doses of GH, although one patient with osteosarcoma had received high dose GH (60 μg/kg/d). This study confirms an increased risk of bone tumors but not overall cancer risk in subjects treated with GH in childhood for isolated GH deficiency or childhood short stature. Further work is needed to elucidate the mechanisms involved.",
"affiliations": "Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Robert-Debré, Department of Pediatric Endocrinology and Diabetology, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Paris, France.;Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Robert-Debré, Department of Pediatric Endocrinology and Diabetology, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Paris, France.;Assistance Publique-Hôpitaux de Paris, Biostatistics and Epidemiology Unit, Hôtel Dieu, Paris, France.;Institut Curie, Paris, France.;Institut Curie, Paris, France.;Assistance Publique-Hôpitaux de Paris, Biostatistics and Epidemiology Unit, Hôtel Dieu, Paris, France.",
"authors": "Poidvin|Amélie|A|;Carel|Jean-Claude|JC|;Ecosse|Emmanuel|E|;Levy|Dominique|D|;Michon|Jean|J|;Coste|Joël|J|http://orcid.org/0000-0001-7674-7192",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/cam4.1602",
"fulltext": "\n==== Front\nCancer MedCancer Med10.1002/(ISSN)2045-7634CAM4Cancer Medicine2045-7634John Wiley and Sons Inc. Hoboken 10.1002/cam4.1602CAM41602Original ResearchCancer PreventionOriginal ResearchIncreased risk of bone tumors after growth hormone treatment in childhood: A population‐based cohort study in France POIDVIN et al.Poidvin Amélie \n1\n\n2\nCarel Jean‐Claude \n1\n\n2\nEcosse Emmanuel \n3\nLevy Dominique \n4\nMichon Jean \n4\nCoste Joël http://orcid.org/0000-0001-7674-7192joel.coste@parisdescartes.fr \n3\n\n5\n\n1 \nAssistance Publique‐Hôpitaux de Paris (AP‐HP)\nHôpital Universitaire Robert‐Debré\nDepartment of Pediatric Endocrinology and Diabetology\nCentre de Référence des Maladies Endocriniennes Rares de la Croissance\nParis\nFrance\n\n2 \nPROTECT\nINSERM\nUniversité Paris Diderot\nSorbonne Paris Cité\nParis\nFrance\n\n3 \nAssistance Publique‐Hôpitaux de Paris, Biostatistics and Epidemiology Unit\nHôtel Dieu\nParis\nFrance\n\n4 \nInstitut Curie\nParis\nFrance\n\n5 \nUniversité Paris Descartes\nSorbonne Paris Cité\nParis\nFrance\n* Correspondence\n\nJoël Coste, Biostatistics and Epidemiology Unit, Hôtel Dieu, Paris, France.\n\nEmail: joel.coste@parisdescartes.fr\n14 6 2018 7 2018 7 7 10.1002/cam4.2018.7.issue-73465 3473 15 3 2018 13 5 2018 15 5 2018 © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nThe association between growth hormone (GH) treatment and cancer risk has not been thoroughly evaluated and there are questions about any increased risk of bone tumors. We examined cancer risk and especially bone tumor risk in a population‐based cohort study of 6874 patients treated with recombinant GH in France for isolated GH deficiency, short stature associated with low birth weight or length or idiopathic short stature. Adult mortality and morbidity data obtained from national databases and from questionnaires. Case ascertainment completeness was estimated with capture‐recapture methods. Standardized mortality and incidence ratios were calculated using national reference data. 111 875 person‐years of observation were analyzed and patients were followed for an average of 17.4 ± 5.3 years to a mean age of 28.4 ± 6.2 years. For cancer overall, mortality and incidence were not different from expected figures. Five patients developed bone tumors (chondrosarcoma, 1, Ewing sarcoma, 1, osteosarcoma, 3) of whom 3 died (Ewing sarcoma, 1, osteosarcoma, 2), whereas only 1.4 case and 0.6 deaths were expected: standardized mortality ratio, 5.0 and standardized incidence ratio from 3.5 to 3.8 accounting or not accounting for missed cases. Most patients received conventional doses of GH, although one patient with osteosarcoma had received high dose GH (60 μg/kg/d). This study confirms an increased risk of bone tumors but not overall cancer risk in subjects treated with GH in childhood for isolated GH deficiency or childhood short stature. Further work is needed to elucidate the mechanisms involved.\n\nBone tumorschildhoodgrowth hormone treatmentAFSSAPS (the French drug safety agency)Direction Générale de la Santé (French Ministry of Health)Institut National du CancerCommission of European Communities GrantHEALTH‐F2‐2009‐223497 source-schema-version-number2.0component-idcam41602cover-dateJuly 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.3 mode:remove_FC converted:18.07.2018\n\n\nPoidvin \nA \n, \nCarel \nJ‐C \n, \nEcosse \nE \n, \nLevy \nD \n, \nMichon \nJ \n, \nCoste \nJ \n. Increased risk of bone tumors after growth hormone treatment in childhood: A population‐based cohort study in France . Cancer Med . 2018 ;7 :3465 –3473 . 10.1002/cam4.1602\n==== Body\n1 INTRODUCTION\nThe risk of malignancy after growth hormone treatment during childhood remains unclear. In experimental studies, growth hormone (GH) and insulin‐like growth factors (IGFs) have mitogenic, antiapoptotic, and proliferative properties.1, 2, 3 High levels of circulating IGF‐I have been shown to be associated with increased risks of several common cancers, including breast, prostate, and colorectal cancers 3, 4, 5 and GH itself could also play a direct role in carcinogenesis6, 7; notably, patients with acromegaly have consistently been found to have increased risks of several cancers, especially colorectal cancer.8 Also, patients with GH resistance and IGF‐I deficiency due to GH resistance have a significantly decreased risk of cancer.9, 10 The risk of several cancers is linked to height with taller people having a higher risk.11, 12, 13, 14, 15, 16, 17, 18\n\n\nFew studies have addressed growth hormone therapy and cancer, however, and their systematic review by Deodati et al19 suggests that cancer mortality is not increased although cancer incidence is increased; these conclusions are not definitive, given the size and the methodology of the studies. An increased risk of second neoplasm in GH‐treated patients has also been reported, in particular for bone tumors.20\n\n\nThe Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) project is a multinational European study that aims to evaluate long‐term mortality and cancer morbidity in subjects who were treated with recombinant GH in childhood. A preliminary report in 2012 describing the French cohort of the SAGhE study indicated that all‐type cancer‐related mortality was not higher among those treated for idiopathic short stature or isolated GH deficiency than in the general population (standardized mortality ratio [SMR] 1.02, 95% CI 0.41‐2.09). Nevertheless, the bone tumor‐related mortality was high (SMR 5.00, 95% CI 1.01‐14.63).21 More recently, the European consortium published results for cancer mortality in all eight country cohorts and results for cancer incidence for five countries (not France, Germany, and Italy).22 In GH‐treated patients without previous cancer, there was no increased risk of cancer or cancer mortality overall but there was an excess risk of cancer mortality and incidence for bone cancer, an increased mortality by prostate cancer (1 case) and an increased incidence of bladder cancer.\n\nThe French SAGhE study data is particularly high quality, being based on a national register of GH‐treated children (the France Hypophyse register), and completed by data extracted from the Center for Epidemiology on Medical Causes of Death and from the French national health insurance information system. These data allow us to examine in more detail cancer morbidity and mortality in this population.\n\n2 PATIENTS AND METHODS\n2.1 Patients\nAs described previously 21, 23, 24 we used the mandatory register of patients treated with GH in France [Association France‐Hypophyse] which was disbanded in 1996; we selected those patients had been treated exclusively with recombinant GH and who were born before 1 January 1990. Patients were assigned to three risk categories (low, medium, and high) for long‐term morbidity and mortality, based on the clinical condition leading to the initiation of GH treatment (Figure 1). Only low‐risk patients were included in this study, because their baseline risk of cancer is believed to be similar to or lower than that of the general population.\n\nFigure 1 Flow chart of the SAGhE study in France and number of cancer cases identified in the low‐risk group\n\n2.2 Data collected\n2.2.1 Childhood data\nData on patient characteristics, treatment, and growth progression in the France‐Hypophyse register were routinely collected at baseline and at regular follow‐up visits until 1996, and were obtained from pediatric endocrinologists. Additional follow‐up data on GH treatment were collected from clinical centers in 2008‐2010.\n\n2.2.2 Follow‐up data\nInformation on vital status was collected from the Répertoire National d'Identification des Personnes Physiques (http://www.insee.fr/fr/methodes) and the Répertoire National Inter‐régimes de l'Assurance Maladie. The cause of death indicated in death certificates was obtained from the French Center for Epidemiology on Medical Causes of Death (CépiDC, Institut National de la Santé et de la Recherche Médicale) and coded according to the 10th revision of the International Classification of Diseases (ICD‐10).\n\nMorbidity data were collected through a health questionnaire sent to all live patients (with a response rate of 46% after several reminders: the low response rate was expected, because questionnaires were sent to the parents’ address; there had been no prior contact between the researchers and the patients; and these patients generally do not feel “sick”). Data were also extracted using patient identifiers from the French national health insurance information system (Système National d'Information Inter‐régimes de l'Assurance Maladie; SNIIRAM); this system includes the French hospital discharge database (FHDD) also called Programme de Médicalisation des Systèmes d'Information from 1 January 2008 to 31 December 2010, and long‐lasting affection statements (LLA) which identify conditions with 100% reimbursement coverage (which include cancers). We set a censor date of 31 December 2010.\n\n2.2.3 Validation of events\nCancer events were validated using all medical and pathology reports obtained. Data about bone tumors were specifically reviewed by two oncologists specialized in these tumors (DL, JM).\n\n2.3 Statistical analyses\nThe overall risk of cancer was assessed by calculating standardized incidence ratios (SIR), with adjustment for age and sex, using reference rates for all cancer combined from population‐based registries of cancer in France, centralized by the FRANCIM (FRANce‐Cancer‐Incidence et Mortalité) network, between 1985 and 2010.25 The risk of bone tumor was assessed using data provided by FRANCIM combined six general registries of bone tumors in France. The number of person‐years at risk was calculated for GH‐treated subjects, for each 5‐years age class, separately for men and women, from the date of first administration of GH to the date of cancer, death, loss to follow‐up, or 31 December 2010. The expected number of events was then calculated for GH‐treated subjects by multiplying the age‐ and sex‐specific incidence rates by the number of person‐years at risk. SIRs were estimated by dividing the number of observed events by the number of expected events. Significance tests and 95% confidence intervals (CI) for the SIR were calculated with Byar's approximation to the exact Poisson test and the exact Poisson limits. Standardized mortality ratios (SMR) and 95% CIs were calculated as reported previously.21\n\n\nThe CépiDC source for fatal events is exhaustive but the three sources (SNIIRAM — LLA, SNIIRAM — FHDD — and questionnaires) used to identify nonfatal events are not and therefore some events could have been missed by all sources. We used capture‐recapture methods 26, 27 to estimate the number of nonfatal events missed by all three sources. These methods are commonly used in epidemiology to estimate the completeness of ascertainment of disease registries and to estimate the number of cases that could have been missed by all sources of ascertainment. Thus, they allow improved accuracy of estimation of disease or event rates. Log‐linear modeling was used to adjust for source dependence by including the corresponding interaction term into the model,23 and the significance of the interaction was assessed using likelihood ratio statistics. A confidence interval (CI) for the estimated number of cases missed was computed by the profile likelihood method. The Akaike Information Criterion (AIC) was used for selection of the model. Two analyses were carried out: one with observed events, giving the crude SIR, the other including estimated events using the capture‐recapture method, giving the corrected SIR. Because of the small number of events for bone tumors, the ratio of estimated/observed nonfatal events for the whole cancer group was used to estimate the number of nonfatal events of bone tumors.\n\nThis study was approved by the Comité Consultatif sur le Traitement de l'Information en Matière de Recherche dans le Domaine de la Santé and the Commission Nationale de l'Informatique et des Libertés (the national data protection agency). The use of the Registre National Inter‐Régimes de l'Assurance Maladie was approved by a specific statute.\n\n3 RESULTS\nMost of the low‐risk mortality and morbidity group (n = 6874) were patients treated for the indication of isolated GH deficiency, based on GH stimulation tests (peak below 10 ng/mL) (n = 4600, 67%) (Table 1). In this group, there were over 111 000 person‐years at risk and the mean follow‐up between the beginning of GH treatment and the date of last follow‐up, event, or death was 17.4 years. The mean (±SD) treatment duration was 3.9 (±2.6) years, with mean doses slightly below the current recommendations for isolated GH deficiency.\n\nTable 1 Main characteristics of patients and GH treatment for studied sample. N = 6874\n\nNumber of male patients (%)\t4510 (66)\t\nIndication for GH treatment. number (%)\t\nIsolated GH deficiency\t\nMaximum peak GH <3 μg/L\t295 (4)\t\nMaximum peak GH ≥3 μg/L and <7 μg/L\t1557 (23)\t\nMaximum peak GH ≥7 μg/L and <10 μg/L\t2748 (40)\t\nMissing value for maximum peak GH\t516 (8)\t\nMaximum peak GH ≥10 μg/L\t\nNeurosecretory dysfunction\t547 (8)\t\nIdiopathic short stature\t868 (13)\t\nSmall for gestational age\t343 (5)\t\nYear of treatment start. number (%)\t\n1985‐1987\t506 (7.4)\t\n1988‐1990\t2470 (36)\t\n1991‐1993\t2362 (34)\t\n1994‐1996\t1536 (22.6)\t\nBirth length (SDS for gestational age)\t−1.2 ± 1.2 (n = 4875)\t\nBirth weight (SDS for gestational age)\t−0.6 ± 1.2 (n = 5130)\t\nChildren born small for gestational age (birth weight or length ≤−2 SDS for gestational age)\t\nYes\t1298 (19)\t\nNo\t3864 (56)\t\nMissing data\t1712 (25)\t\nChronological age at start of treatment (y)\t11.0 ± 3.4 (n = 6874)\t\nHeight at start of treatment (SDS)\t−2.7 ± 0.8 (n = 6285)\t\nWeight at start of treatment (SDS)\t−1.6 ± 0.9 (n = 6242)\t\nMean dose (μg/kg/d)\t24.5 ± 12.3 (n = 6212)\t\nTreatment duration (y)\t3.9 ± 2.6 (n = 6380)\t\nChronological age at end of treatment (y)\t15.1 ± 2.7 (n = 6380)\t\nPerson‐years of observation (n)\t111 875\t\nChronological age at the time of census or event or death (y)\t28.4 ± 6.2\t\nDuration of follow‐up from start of GH to time of census or event or deaths (y)\t17.4 ± 5.3 (n = 6616)\t\nMean ± SD or n (%) are shown. GH, growth hormone; SDS, SD score.\n\nJohn Wiley & Sons, LtdTwenty‐four cancer events were identified in this group through the different sources, including one case which was not validated (Table 2). The most common cancers were bone tumors (n = 5), lymphoma (n = 4), and acute leukemia (n = 3). Overall, the patients were treated with conventional doses of GH (mean 23.4 μg/kg/d) with only one patient receiving high GH doses (60 μg/kg/d). None of the patients presented particularly severe short stature at the beginning of treatment or exhibited substantial height gain during treatment. Eight patients, including two with osteosarcoma and one with Ewing sarcoma, died at a mean age of 17.3 years.\n\nTable 2 Clinical characteristics and GH treatments in the 23 patients who developed cancer after GH treatment\n\n#\tType of cancer\tDied (Y/N)\tAge at event or death (y)a\n\tSex\tDiagnosis leading to GH treatment\tAge at start of GH treatment (y)\tHeight (SD) before treatment\tGH treatment duration (y)\tHeight (SD) at the end of treatment\tAdult height (SD)\tMean GH dose (μg/kg/d)\tSource of information for cancer\t\n1\tAcute leukemia\tY\t12.9\tF\tGHDI\t11.1\t‐\t1.4\t‐\t‐\t‐\tCépiDC\t\n2\tAcute leukemia\tY\t14.8\tM\tGHDI\t12.7\t−2.1\t0.8\t−1.8\t‐\t23.5\tCépiDC\t\n3\tAcute leukemia\tY\t16.5\tF\tGHDI\t9.2\t‐\t1.9\t‐\t‐\t‐\tCépiDC\t\n4\tLymphoma\tN\t29.0\tF\tGHDI\t12.0\t−2.5\t3.3\t−2.1\t−1.5\t19.2\tQuestionnaire\t\n5\tLymphoma\tN\t11.5\tM\tGHDI\t7.0\t−1.9\t3.7\t−1.0\t−2.1\t17.1\tQuestionnaire\t\n6\tLymphoma\tN\t24.4\tM\tGHDI\t9.9\t−2.2\t5.6\t−0.6\t‐\t23.4\tLLA. Questionnaire\t\n7\tLymphoma\tN\t22.4\tM\tGHDI\t8.6\t−2.0\t4.0\t−1.9\t‐\t21.1\tLLA. FHDD\t\n9\tEwing sarcoma\tY\t17.3\tM\tGHDI\t10.3\t−3.5\t5.1\t−2.4\t‐\t24.4\tCépiDC\t\n8\tOsteosarcoma\tY\t14.4\tM\tSGA\t8.5\t−3.6\t3.0\t−2.4\t‐\t60.0\tCépiDC\t\n10\tOsteosarcoma\tY\t20.2\tF\tGHDI\t4.5\t−2.7\t8.2\t‐\t‐\t26.6\tCépiDC\t\n11\tOsteosarcoma\tN\t7.4\tM\tGHDI\t6.1\t−3.3\t1.1\t−2.9\t−3.6\t24.1\tLLA. Questionnaire\t\n12\tChondrosarcoma\tN\t21.8\tM\tGHDI\t15.8\t−1.3\t1.2\t−0.7\t−0.7\t26.1\tQuestionnaire\t\n13\tMalignant brain tumor\tN\t18.2\tM\tGHDI\t2.4\t‐\t9.0\t‐\t‐\t‐\tLLA\t\n14\tMelanoma\tY\t28.1\tM\tGHDI\t11.1\t−2.6\t6.1\t−1.8\t−2.0\t17.3\tCépiDC\t\n15\tMelanoma\tN\t31.5\tF\tGHDI\t15.1\t‐\t1.9\t‐\t−1.5\t‐\tQuestionnaire\t\n16\tNasopharyngeal carcinoma\tY\t19.3\tM\tGHDI\t11.2\t‐\t1.4\t‐\t‐\t‐\tCépiDC\t\n17\tMalignant tumor of the mouth\tN\t26.4\tM\tGHDI\t8.5\t−2.0\t7.1\t−0.6\t−0.9\t21.5\tLLA. FHDD\t\n18\tMalignant tumor of the kidney\tN\t29.5\tF\tGHDI\t9.6\t‐\t2.4\t‐\t−2.7\t‐\tLLA. FHDD. Questionnaire\t\n19\tMalignant tumor of the testis\tN\t31.6\tM\tGHDI\t12.2\t‐\t2.0\t−1.8\t−0.9\t15.8\tLLA. FHDD. Questionnaire\t\n20\tMalignant tumor of the testis\tN\t15.0\tM\tGHDI\t12.7\t−1.9\t3.5\t−1.3\t\t27.9\tQuestionnaire\t\n21\tSweat gland carcinoma\tN\t32.6\tF\tGHDI\t13.9\t−2.7\t2.5\t−2.2\t−2.3\t28.0\tQuestionnaire\t\n22\tPulmonary carcinoma\tN\t26.9\tM\tGHDI\t8.0\t−1.7\t3.7\t−1.2\t−1.7\t17.2\tFHDD. Questionnaire\t\n23\tMalignant pancreatic tumor\tN\t19.4\tM\tGHDI\t8.2\t−2.2\t6.6\t−0.5\t−1.1\t16.7\tLLA. FHDD. Questionnaire\t\nLLA, long‐lasting affection; FHDD, French hospital discharge database; F, female; M, male; GHDI, idiopathic growth hormone deficiency; SGA, Born small for gestational age.\n\na Age at event was used for live patients, and age at death was used for those who died.\n\nJohn Wiley & Sons, LtdBone tumor characteristics are shown in Table 3. There were three osteosarcomas occurring 1.1, 2.9, and 15 years after the start of GH treatment; the diagnosis of cancer led to the interruption of GH treatment in the first two cases. Two of the patients with osteosarcoma died, 6 months‐3 years, after diagnosis. There was one fatal case of Ewing sarcoma, with bone and bone marrow metastases, 5.1 years after GH treatment initiation and 1.5 years after GH treatment interruption. There was one case of chondrosarcoma, 6 years after GH treatment initiation and 4.8 years after GH treatment interruption, and this patient is alive 8 years after surgery. One of the patients with osteosarcoma had received high GH doses (60 μg/kg/d).\n\nTable 3 Clinical characteristics, treatment and evolution related to GH and bone tumors in the 5 patients with bone tumors\n\n#\tType of cancer\tLocalization\tAge at diagnosis of cancer (y)\tDelay between start of GH and cancer diagnosis (y)\tClinical manifestations of cancer\tMetastasis\tMetastasis localization\tInitial cancer treatment\tComplete remission\tRelapse\tTreatment of cancer relapse\tDied\tMedical and pathology reports available\t\n8\tEwing sarcoma\tSacrum\t15.9\t6.6\tDysuria, constipation, pain\tY\tBone and bone marrow\tChemotherapy, surgery and radiotherapy\tY\tY\tOral chemotherapy (VP16)\tY\tY\t\n9\tOsteosarcoma\tLeft lower tibia\t11.5\t2.9\tPain\tN\t\tChemotherapy, surgery and radiotherapy\tY\tY\tCHD\tY\tY\t\n10\tOsteosarcoma\tIliac wing\t19.5\t15\tPain\tN\t\tChemotherapy and radiotherapy (no surgery because of deep vein thrombosis)\tN\t\t\tY\tY\t\n11\tOsteosarcoma\tLower end of the right femur\t7.4\t1.1\tU\tU\t\tU\tU\t\t\tN\tN\t\n12\tChondrosarcoma\tInter‐tibio‐fibular\t21.8\t6\tU\tN\t\tSurgery\tY\tN\t\tN\tY\t\nY, Yes; N, No; U, Unknown.\n\nJohn Wiley & Sons, LtdSIRs and SMRs for all cancers and bone tumors are presented in Table 4. The risk of cancer overall was not different from expected values in patients treated with GH (SIR 0.7, 95% CI 0.5‐1.1). The risk of bone tumor was significantly higher than expected in this population (SIR 3.5, 95% CI 1.1‐8.1). After capture‐recapture analysis (Table 4 and S1), the estimated number of missed cases of cancer overall was 3.5 (95% CI 0.8‐15.3) and the corrected SIR were 0.8 (95% CI 0.5‐1.2) for all cancers and 3.8 (95% CI 1.3‐8.6) for bone tumors. The SMR was 1.0 (95% CI 0.4‐2.1) for cancer overall and 5.0 (95% CI 1.0‐14.6) for bone tumors.\n\nTable 4 Crude SMR and SIR and corrected SIR for all‐type cancer and bone tumors in young adults treated with growth hormone in childhood\n\n\tCrude\tCorrected\t\nObserved deaths (n)\tExpected deaths (n)\tCrude SMR (95% CI)\tObserved events (n)\tExpected events (n)\tCrude SIR (CI 95%)\tEstimated events (n)\tExpected events (n)\tCorrected SIR (CI 95%)\t\nAll cancers\t7\t6.9\t1.0 (0.4‐2.1)\t23\t32.3\t0.7 (0.5‐1.1)\t26.5\t32.3\t0.8 (0.5‐1.2)\t\nBone tumors\t3\t0.6\t\n5.0 (1.0‐14.6)\n\t5\t1.4\t\n3.5 (1.1‐8.1)\n\t5.5\t1.4\t\n3.8 (1.3‐8.6)\n\t\nBold values indicate statistical significance.\n\nJohn Wiley & Sons, Ltd4 DISCUSSION\nWe report an analysis using the largest national population‐based register of patients treated with GH during childhood. Our study shows a 3.5‐3.8‐fold higher incidence of and a 5‐fold higher mortality from bone tumors in patients treated with GH for idiopathic isolated GH deficiency, idiopathic short stature, or short stature in children born short for gestational age, than in the general population. This raises issues about the mechanism, possible confounders, and causal effect of GH treatment. In contrast, the incidence and mortality of cancer overall were not different from those in the general population.\n\nGrowth hormone and IGF‐I act on bone and cartilage, specifically on chondrocytes and osteoblasts 28, 29, 30 and the GH receptor is strongly expressed on these cell types. Osteosarcomas occur preferentially in rapidly growing bones, during the rapid bone growth of puberty and in tall adolescents (patients are 0.3 SD taller than the general population).31, 32, 33 Observations of childhood cancer survivors indicate that GH treatment is associated with a large increase in the risk of osteosarcoma20: 15% of second neoplasms in this population are osteosarcomas.34, 35 The European SAGhE study has analyzed cancer morbidity using data from five countries (excluding France, due to methodological issues) 22 and also found an excess risk of bone tumors (SIR of 4.1) albeit without a clear dose‐effect relationship. Thus, evidence is growing that GH treatment may have a biological effect on bone tumor initiation, promotion, and/or progression.\n\nThe risk of cancer overall in our population of GH‐treated subjects with an SIR of 0.7‐0.8 and an SMR of 1.0 tended to be lower than that in the general population. This is consistent with the results of the meta‐analysis by Deodati et al19 — who provided summary tables of studies of cancer incidence and mortality following GH administration, with or without a cancer history — and those of the European SAGhE study.22 It is also consistent with the evidence that cancer incidence is lower in short stature than general populations, with hazard ratios applied to our cohort giving an estimated SIR of 0.8‐0.9.11, 12, 13, 14, 15, 16, 17, 18 Our observations for bone tumors are therefore even more striking, as the SIR would be expected to be lower than normal in a population of short individuals.\n\nOur study has several potential limitations. First, noncompleteness of the sources of ascertainment of cancer was a limitation for the analysis of the incidence of cancer. We addressed this limitation by using a capture‐recapture method which gave reassuring results on the validity of our crude analysis. Capture‐recapture methods have been successfully applied in a wide range of epidemiologic fields to estimate the completeness of ascertainment of registries. Such estimation of the potential number of cases (sometimes high) missed by all sources of ascertainment improves the accuracy of assessment of disease rates.27 The second limitation is that the numbers of events and especially of fatal events (both in the study cohort and in the reference registries) are small such that the CIs, in particular CIs of SMRs, were wide. The number of events was too small to allow testing for a relationship between the dose of GH treatment and the incidence of bone tumors. Another limitation was that we were unable to include a comparable reference group of short‐stature individuals not treated with GH. Also there is the issue of whether patients with a genetic predisposition to bone tumors were inadvertently included in our low‐risk group of patients; this issue is important because retrospective genetic analysis of families was not possible in our study for legal and ethical reasons. Several genetic syndromes, some of them associated with short stature (Bloom, Rothmund‐Thompson, Werner, hereditary retinoblastoma) are risk factors for osteosarcomas 32 but would not commonly be misdiagnosed for idiopathic isolated GH deficiency. Li‐Fraumeni syndrome, by contrast, could go clinically unnoticed if questions about familial history of tumor in childhood or young adults are not asked before beginning GH treatment but is generally not associated with short stature. Mild Fanconi anemia, which could be misdiagnosed for some time in short‐stature children, does not seem to be associated with an increased of bone tumors, contrary to other forms of malignancy (leukemias, myelodysplastic syndromes, solid tumors of head, neck, skin, gastrointestinal tract, and genitourinary tract).36 These rare genetic syndromes, none of which are strongly associated with both the risk of short stature and the risk of bone tumor, are therefore unlikely to confound our results. Finally, the reference data for bone tumors we used was based on six regional registries and not national data.\n\nIn conclusion, our analyses support the view that subjects treated with GH in childhood for isolated GH deficiency or childhood short stature are at increased risk of bone tumors but not of cancer overall. A causal relationship between GH treatment and bone tumors is biologically plausible but the mechanisms remain to be elucidated and the dose‐effect relationship, if any, is yet to be described. We believe that our results should be taken into consideration in the evaluation of the risk‐benefit balance of childhood GH treatments.\n\nCONFLICT OF INTEREST\nA. Poidvin received a master grant from the French Endocrine Society (Société Française d'Endocrinologie) funded by Lilly. J.C. Carel has the following conflicts of interest to declare, all outside the scope of this work: investigator in clinical trials using GH sponsored by Pfizer and Lilly and in postmarketing studies using several brands of GH, and support for travel to international meetings from several GH manufacturers. Emmanuel Ecosse, Dominique Levy, Jean Michon, and Joël Coste report no disclosures relevant to the manuscript.\n\nSupporting information\n \n\nClick here for additional data file.\n\n ACKNOWLEDGMENTS\nThe authors are indebted to Fabienne Landier for data collection and organization of the cohort study, Alain Weill and Philippe Ricordeau for help with the data from the French national health insurance information system (Système National d'Information Inter‐régimes de l'Assurance Maladie; SNIIRAM), and Grégoire Rey for help with the data from the French Center for Epidemiology on Medical Causes of Death (CépiDC, Institut National de la Santé et de la Recherche Médicale).\n==== Refs\nREFERENCES\n1 \n\nSamani \nAA \n, \nYakar \nS \n, \nLeRoith \nD \n, \nBrodt \nP \n. The role of the IGF system in cancer growth and metastasis: overview and recent insights . Endocr Rev . 2007 ;28 :20 ‐47 .16931767 \n2 \n\nSeccareccia \nE \n, \nBrodt \nP \n. The role of the insulin‐like growth factor‐I receptor in malignancy: An update . Growth Horm IGF Res . 2012 ;22 :193 ‐199 .23098677 \n3 \n\nClayton \nPE \n, \nBanerjee \nI \n, \nMurray \nPG \n, \nRenehan \nAG \n. Growth hormone, the insulin‐like growth factor axis, insulin and cancer risk . Nat Rev Endocrinol . 2011 ;7 :11 ‐24 .20956999 \n4 \n\nSwerdlow \nAJ \n. Does growth hormone therapy increase the risk of cancer? \nNat Clin Pract Endocrinol Metab . 2006 ;2 :530 ‐531 .17024146 \n5 \n\nPollak \nMN \n, \nSchernhammer \nES \n, \nHankinson \nSE \n. Insulin‐like growth factors and neoplasia . Nat Rev Cancer . 2004 ;4 :505 ‐518 .15229476 \n6 \n\nPerry \nJK \n, \nLiu \nD‐X \n, \nWu \nZ‐S \n, \nZhu \nT \n, \nLobie \nPE \n. Growth hormone and cancer: an update on progress . Curr Opin Endocrinol Diabetes Obes . 2013 ;20 :307 ‐313 .23807602 \n7 \n\nLea \nRW \n, \nDawson \nT \n, \nMartinez‐Moreno \nCG \n, \nEl‐Abry \nN \n, \nHarvey \nS \n. Growth hormone and cancer: GH production and action in glioma? \nGen Comp Endocrinol . 2015 ;220 :119 ‐123 .26163024 \n8 \n\nDal \nJ \n, \nLeisner \nMZ \n, \nHermansen \nK \n, et al. Cancer Incidence in Patients with Acromegaly: a cohort study and meta‐analysis of the literature . J Clin Endocrinol Metab . 2018 ; (in press). https://academic.oup.com/jcem/advance-article/doi/10.1210/jc.2017-02457/4951496.\n9 \n\nGuevara‐Aguirre \nJ \n, \nBalasubramanian \nP \n, \nGuevara‐Aguirre \nM \n, et al. Growth hormone receptor deficiency is associated with a major reduction in pro‐aging signaling, cancer and diabetes in humans . Sci Transl Med . 2011 ;3 :70ra13 .\n10 \n\nShevah \nO \n, \nLaron \nZ \n. Patients with congenital deficiency of IGF‐I seem protected from the development of malignancies: a preliminary report . Growth Horm IGF Res . 2007 ;17 :54 ‐57 .17166755 \n11 \n\nGreen \nJ \n, \nCairns \nBJ \n, \nCasabonne \nD \n, \nWright \nFL \n, \nReeves \nG \n, \nBeral \nV \n. Height and cancer incidence in the Million Women Study: prospective cohort, and meta‐analysis of prospective studies of height and total cancer risk . Lancet Oncol . 2011 ;12 :785 ‐794 .21782509 \n12 \n\nSung \nJ \n, \nSong \nY‐M \n, \nLawlor \nDA \n, \nSmith \nGD \n, \nEbrahim \nS \n. Height and site‐specific cancer risk: a cohort study of a korean adult population . Am J Epidemiol . 2009 ;170 :53 ‐64 .19403842 \n13 \n\nGunnell \nD \n, \nMay \nM \n, \nBen‐Shlomo \nY \n, \nYarnell \nJ \n, \nSmith \nGD \n. Height, leg length, and cancer: the Caerphilly Study . Nutr Cancer . 2003 ;47 :34 ‐39 .14769535 \n14 \n\nBatty \nGD \n, \nBarzi \nF \n, \nWoodward \nM \n, et al. Adult height and cancer mortality in Asia: the Asia Pacific Cohort Studies Collaboration . Ann Oncol . 2010 ;21 :646 ‐654 .19889610 \n15 \n\nBatty \nGD \n, \nShipley \nMJ \n, \nLangenberg \nC \n, \nMarmot \nMG \n, \nSmith \nGD \n. Adult height in relation to mortality from 14 cancer sites in men in London (UK): evidence from the original Whitehall study . Ann Oncol . 2006 ;17 :157 ‐166 .16249213 \n16 \nEmerging Risk Factors Collaboration \n. Adult height and the risk of cause‐specific death and vascular morbidity in 1 million people: individual participant meta‐analysis . Int J Epidemiol . 2012 ;41 :1419 ‐1433 .22825588 \n17 \n\nKabat \nGC \n, \nHeo \nM \n, \nKamensky \nV \n, \nMiller \nAB \n, \nRohan \nTE \n. Adult height in relation to risk of cancer in a cohort of Canadian women . Int J Cancer . 2013 ;132 :1125 ‐1132 .22753236 \n18 \n\nWalter \nRB \n, \nBrasky \nTM \n, \nBuckley \nSA \n, \nPotter \nJD \n, \nWhite \nE \n. Height as an explanatory factor for sex differences in human cancer . J Natl Cancer Inst . 2013 ;105 :860 ‐868 .23708052 \n19 \n\nDeodati \nA \n, \nFerroli \nBB \n, \nCianfarani \nS \n. Association between growth hormone therapy and mortality, cancer and cardiovascular risk: systematic review and meta‐analysis . Growth Horm IGF Res . 2014 ;24 :105 ‐111 .24818783 \n20 \n\nSklar \nCA \n, \nMertens \nAC \n, \nMitby \nP \n, et al. Risk of disease recurrence and second neoplasms in survivors of childhood cancer treated with growth hormone: a report from the Childhood Cancer Survivor Study . J Clin Endocrinol Metab . 2002 ;87 :3136 ‐3141 .12107213 \n21 \n\nCarel \nJ‐C \n, \nEcosse \nE \n, \nLandier \nF \n, et al. Long‐term mortality after recombinant growth hormone treatment for isolated growth hormone deficiency or childhood short stature: preliminary report of the French SAGhE study . J Clin Endocrinol Metab . 2012 ;97 :416 ‐425 .22238382 \n22 \n\nSwerdlow \nAJ \n, \nCooke \nR \n, \nBeckers \nD \n, et al. Cancer risks in patients treated with growth hormone in childhood: the SAGhE European cohort study . J Clin Endocrinol Metab . 2017 ;102 :1661 ‐1672 .28187225 \n23 \n\nPoidvin \nA \n, \nTouze \nE \n, \nEcosse \nE \n, et al. Growth hormone treatment for childhood short stature and risk of stroke in early adulthood . Neurology . 2014 ;83 :780 ‐786 .25122206 \n24 \n\nSwerdlow \nAJ \n, \nCooke \nR \n, \nAlbertsson‐Wikland \nK \n, et al. Description of the SAGhE cohort: a large European study of mortality and cancer incidence risks after childhood treatment with recombinant growth hormone . Horm Res Pædiatrics . 2015 ;84 :172 ‐183 .\n25 \nInVS > Cancers > Surveillance épidémiologique des cancers en France > Principaux acteurs et partenaires institutionnels . http://www.invs.sante.fr/surveillance/cancers/acteurs.htm#3 Accessed February 7, 2018.\n26 \n\nHook \nEB \n, \nRegal \nRR \n. Recommendations for presentation and evaluation of capture‐recapture estimates in epidemiology . J Clin Epidemiol . 1999 ;52 :917 ‐926 ; discussion 929‐933.10513754 \n27 \n\nHook \nEB \n, \nRegal \nRR \n. Capture‐recapture methods in epidemiology: methods and limitations . Epidemiol Rev . 1995 ;17 :243 ‐264 .8654510 \n28 \n\nSlootweg \nMC \n, \nvan Buul‐Offers \nSC \n, \nHerrmann‐Erlee \nMP \n, \nvan der Meer \nJM \n, \nDuursma \nSA \n. Growth hormone is mitogenic for fetal mouse osteoblasts but not for undifferentiated bone cells . J Endocrinol . 1988 ;116 :R11 ‐R13 .3351425 \n29 \n\nLindahl \nA \n, \nNilsson \nA \n, \nIsaksson \nOG \n. Effects of growth hormone and insulin‐like growth factor‐I on colony formation of rabbit epiphyseal chondrocytes at different stages of maturation . J Endocrinol . 1987 ;115 :263 ‐271 .3437249 \n30 \n\nGiustina \nA \n, \nMazziotti \nG \n, \nCanalis \nE \n. Growth hormone, insulin‐like growth factors, and the skeleton . Endocr Rev . 2008 ;29 :535 ‐559 .18436706 \n31 \n\nGelberg \nKH \n, \nFitzgerald \nEF \n, \nHwang \nS \n, \nDubrow \nR \n. Growth and development and other risk factors for osteosarcoma in children and young adults . Int J Epidemiol . 1997 ;26 :272 ‐278 .9169161 \n32 \n\nBroadhead \nML \n, \nClark \nJCM \n, \nMyers \nDE \n, \nDass \nCR \n, \nChoong \nPFM \n. The molecular pathogenesis of osteosarcoma: a review . Sarcoma . 2011 ;2011 :95924 .\n33 \n\nLonghi \nA \n, \nPasini \nA \n, \nCicognani \nA \n, et al. Height as a risk factor for osteosarcoma . J Pediatr Hematol Oncol . 2005 ;27 :314 ‐318 .15956884 \n34 \n\nBell \nJ \n, \nParker \nKL \n, \nSwinford \nRD \n, \nHoffman \nAR \n, \nManeatis \nT \n, \nLippe \nB \n. Long‐term safety of recombinant human growth hormone in children . J Clin Endocrinol Metab . 2010 ;95 :167 ‐177 .19906787 \n35 \n\nErgun‐Longmire \nB \n, \nMertens \nAC \n, \nMitby \nP \n, et al. Growth hormone treatment and risk of second neoplasms in the childhood cancer survivor . J Clin Endocrinol Metab . 2006 ;91 :3494 ‐3498 .16822820 \n36 \n\nMehta \nPA \n, \nTolar \nJ \n. Fanconi anemia In: Adam MP , Ardinger HH , Pagon RA , Wallace SE , Bean LJH , Stephens K , Amemiya A , eds. GeneReviews® [Internet]. Seattle, WA : University of Washington, Seattle ; 1993 ‐2018. https://www.ncbi.nlm.nih.gov/books/NBK1401/.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-7634",
"issue": null,
"journal": "Cancer medicine",
"keywords": "Bone tumors; childhood; growth hormone treatment",
"medline_ta": "Cancer Med",
"mesh_terms": null,
"nlm_unique_id": "101595310",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29905027",
"pubdate": "2018-06-14",
"publication_types": "D016428:Journal Article",
"references": "16822820;14769535;8654510;29590449;15956884;26163024;21559216;25122206;19906787;20956999;23098677;22238382;12107213;18436706;21782509;16931767;26227295;22753236;28187225;22825588;10513754;19403842;9169161;16249213;23807602;3351425;29905027;17024146;15229476;23708052;24818783;21325617;17166755;3437249;19889610",
"title": "Increased risk of bone tumors after growth hormone treatment in childhood: A population-based cohort study in France.",
"title_normalized": "increased risk of bone tumors after growth hormone treatment in childhood a population based cohort study in france"
} | [
{
"companynumb": "FR-PFIZER INC-2018251495",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SOMATROPIN"
},
"drugadditional": null,
... |
{
"abstract": "We report the magnetic resonance imaging (MRI) findings of metronidazole-induced encephalopathy in a 58-year-old man who was treated with metronidazole for hepatic encephalopathy. MRI is likely to be helpful in confirming the diagnosis of metronidazole toxicity in clinically suspected cases.",
"affiliations": null,
"authors": "Mulcahy|Hyojeong|H|;Chaddha|Shashi K B|SK|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.2484/rcr.v3i4.239",
"fulltext": "\n==== Front\nRadiol Case RepRadiol Case RepRadiology Case Reports1930-0433Elsevier S1930-0433(15)30306-X10.2484/rcr.v3i4.239239ArticleMRI of Metronidazole-Induced Encephalopathy Mulcahy Hyojeong M.D.hyomul@u.washington.edu1Chaddha Shashi K.B. M.D.21 Hyojeong Mulcahy, M.D., is in the Department of Radiology, University of Washington School of Medicine, Seattle, WA, USA.\n\n2 Shashi K.B. Chaddha, M.D., is in the Department of Radiology, St. Vincent’s Medical Center, Bridgeport, CT, USA.\n\n07 12 2015 2008 07 12 2015 3 4 239© 2008 The Authors.2008This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We report the magnetic resonance imaging (MRI) findings of metronidazole-induced encephalopathy in a 58-year-old man who was treated with metronidazole for hepatic encephalopathy. MRI is likely to be helpful in confirming the diagnosis of metronidazole toxicity in clinically suspected cases.\n\nAbbreviations\nMRI, magnetic resonance imaging\n==== Body\nIntroduction\nMetronidazole (Flagyl) is a common antimicrobial agent used in the treatment of anaerobic and protozoal infections. For the patients with hepatic encephalopathy, metronidazole is used to remove the nitrogenous load in the gastrointestinal tract. Dose and duration of metronidazole should be minimized as much as possible to avoid side effects such as peripheral neuropathy, cerebellar dysfunction, and seizures [1, 2]. We present a case of metronidazole-induced encephalopathy.\n\nCase Report\nA 58- year-old man presented with a chief complaint of increasing confusion, intermittent episodes of imbalance, and episodes of abnormal behavior. His medical history was significant for cirrhosis and hepatic encephalopathy secondary to congenital hepatic fibrosis. On neurologic examination, he had a horizontal nystagmus, demonstrated dysmetria on finger-to-nose test, and Romberg's sign was positive. He was on metronidazole 500 mg, orally twice a day, at home for his hepatic encephalopathy, and the dose was increased during admission to 750 mg orally twice a day.\n\nCT scan of the brain showed mild atrophy (not shown). The patient went on to further evaluation with MRI. MR imaging demonstrated strikingly increased signal intensity symmetrically involving the dentate nuclei bilaterally on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images (Fig 1A & B), with isointensity on T1-weighted images and no evidence of enhancement following administration of gadolinium (Fig 2A & B). Diffusion weighted imaging demonstrated corresponding high signal intensity within the dentate nuclei on the isotropic diffusion images (Fig 3). An apparent diffusion coefficient (ADC) map demonstrated an increase in the value of the diffusion coefficients in the regions of diffusion signal intensity abnormality, consistent with T2 shine-through (not shown).\n\nDiscussion\nMetronidazole (Flagyl) is a common antimicrobial agent used in the treatment of anaerobic and protozoal infections. For the patients with hepatic encephalopathy, metronidazole is used to remove the nitrogenous load in the gastrointestinal tract, and it's generally administered at 250 mg every 8 to 12 hours (500 to 750 mg daily) [3]. Dose and duration of metronidazole should be minimized as much as possible to avoid side effects associated with its long-term use such as peripheral neuropathy, cerebellar dysfunction, and seizures[1, 2]. Although this phenomenon has been described as a manifestation of drug toxicity, it is not clear why metronidazole causes these lesions in a small number of patients, and cases have been reported in which the serum levels of metronidazole were within the therapeutic range[4]. No serum or cerebrospinal fluid level of metronidazole was obtained in our patient, and the diagnosis of metronidazole toxicity was made clinically and supported by the MR imaging findings.\n\nDepending on their severity and chronicity, liver diseases have variable neurologic manifestations, and it is becoming widely recognized that patients with chronic liver disease exhibit typical abnormalities on MRI. High signal intensities in the globus pallidus on T1-weighted images have been established as a characteristic finding on MR images in chronic hepatic encephalopathy, and recent data have shown that white matter abnormalities can also be detected[5, 6]. However, cerebellar lesions have rarely been observed on MRI studies, and there are a few reports describing abnormal T2 high signal intensities in superficial and deep cerebellar white matter including the brachium pontis in patients with acquired hepatocerebral degeneration[7, 8].\n\nAfter Ahmed et al first described the imaging findings of metronidazole toxicity[9], there are only several reported cases describing imaging findings of metronidazole toxicity in literature. Imaging abnormalities associated with metronidazole toxicity have identified lesions in the dentate nuclei of the cerebellum, corpus callosum, basal ganglia, and frontal and subcortical white matter, and MR imaging findings of bilateral involvement of the dentate nuclei are a very characteristic feature of metronidazole-induced encephalopathy[4, 9, 10, 11, 12]. In our case, it was the only demonstrated lesion on MR imaging.\n\nThe mechanism of metronidazole toxicity has not been elucidated, and the apparent preferential involvement of the dentate nucleus remains puzzling. The signal intensity changes observed on the diffusion weighted images most likely represent interstitial edema[9, 11], even though it could represent cytotoxic edema in lesions of the corpus callosum[12]. The findings on MR spectroscopy suggest the possibility of a reversible mitochondrial dysfunction as a cause of the abnormalities in susceptible patients[13]. The imaging, spectroscopy, and clinical findings reverse after discontinuation of metronidazole therapy[4, 9, 10, 11, 12].\n\nPublished: October 7, 2008\n\nFigure 1 58-year-old man with metronidazole-induced encephalopathy. Axial T2-weighted (A), and FLAIR (B) MR images show markedly increased signal intensity symmetrically involving the dentate nuclei bilaterally without surrounding edema or mass effect.\n\nFigure 2 58-year-old man with metronidazole-induced encephalopathy. Axial pre- (A), and post-gadolinium (B) T1-weighted MR images show T1 isointensity and no evidence of enhancement following administration of gadolinium.\n\nFigure 3 58-year-old man with metronidazole-induced encephalopathy. Axial isotropic diffusion-weighted MR image shows corresponding high signal intensity within the dentate nuclei.\n==== Refs\nReferences\n1 Kusumi RK Plouffe JF Wyatt RH Fass RJ Central nervous system toxicity associated with metronidazole therapy Ann Intern Med 93 1980 59 60 [PubMed] 7396319 \n2 Halloran TJ Convulsions associated with high cumulative doses of metronidazole Drug Intell Clin Pharm 16 1982 409 [PubMed] 7084034 \n3 Blei AT Córdoba J Practice Parameters Committee of the American College of Gastroenterology. Hepatic encephalopathy Am J Gastroenterol 96 2001 1968 1976 [PubMed] 11467622 \n4 Woodruff BK Wijdicks EF Marshall WF Reversible metronidazole-induced lesions of the cerebellar dentate nuclei N Engl J Med 346 2002 68 69 [PubMed] 11778010 \n5 Brunberg JA Kanal E Hirsch W Van Thiel DH Chronic acquired hepatic failure: MR imaging of the brain at 1.5T Am J Neuroradiol 12 1991 909 914 [PubMed] 1950920 \n6 Matsusue E Kinoshita T Ohama E Ogawa T Cerebral Cortical and White Matter Lesions in Chronic Hepatic Encephalopathy: MR-Pathologic Correlations. Am J Neuroradiol 26:347–351 [PubMed] \n7 Lee J Lacomis D Comu S Jacobsohn J Kanal E Acquired hepatocerebral degeneration: MR and pathologic findings Am J Neuroradiol 19 1998 485 487 [PubMed] 9541303 \n8 Park SA Heo K Prominent cerebellar symptoms with unusual magnetic resonance imaging findings in acquired hepatocerebral degeneration Arch Neurol 61 2004 1458 1460 [PubMed] 15364694 \n9 Ahmed A Loes DJ Bressler EL Reversible magnetic resonance imaging findings in metronidazole-induced encephalopathy Neurology 45 1995 588 589 [PubMed] 7898724 \n10 Horlen CK Seifert CF Malouf CS Toxic metronidazole-induced MRI changes Ann Pharmacother 34 2000 1273 1275 [PubMed] 11098341 \n11 Heaney CJ Campeau NG Lindell EP MR imaging and diffusion-weighted imaging changes in metronidazole (flagyl)–induced cerebellar toxicity Am J Neuroradiol 24 2003 1615 1617 [PubMed] 13679281 \n12 Kim E Na DG Kim EY Kim JH Son KR Chang KH MR imaging of metronidazole-induced encephalopathy: lesion distribution and diffusion-weighted imaging findings Am J Neuroradiol 28 2007 1652 1658 [PubMed] 17885234 \n13 Cecil KM Halsted MJ Schapiro M Dinopoulos A Jones BV Reversible MR imaging and MR spectroscopy abnormalities in association with metronidazole therapy J Comput Assist Tomogr 26 6 2002 948 951 [PubMed] 12488741\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1930-0433",
"issue": "3(4)",
"journal": "Radiology case reports",
"keywords": "MRI, magnetic resonance imaging",
"medline_ta": "Radiol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101467888",
"other_id": null,
"pages": "239",
"pmc": null,
"pmid": "27303564",
"pubdate": "2008",
"publication_types": "D002363:Case Reports",
"references": "7898724;11098341;1950920;7396319;15709133;17885234;9541303;12488741;11778010;13679281;15364694;11467622;7084034",
"title": "MRI of Metronidazole-Induced Encephalopathy.",
"title_normalized": "mri of metronidazole induced encephalopathy"
} | [
{
"companynumb": "US-VIVIMED-2017SP015261",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "We describe a case of opportunistic coinfections with Coccidioides immitis and Pneumocystis jirovecii following treatment with idelalisib, a phosphoinositide 3-kinase inhibitor, for chronic lymphocytic leukaemia. This is the first case of pulmonary coccidioidomycosis reported in association with idelalisib. We review challenges related to diagnosis of opportunistic infections in this context. This report illustrates (1) the uncommon occurrence of two opportunistic infections concurrently or in rapid succession, (2) the importance of maintaining a broad differential diagnosis in the setting of an atypical imaging finding, slow clinical response or when immunomodulatory drugs are used, and (3) the challenges associated with non-invasive serological testing in individuals with haematological malignancy on immunomodulatory therapy.",
"affiliations": "University of California San Francisco School of Medicine, San Francisco, California, USA.;Division of HIV, Infectious Diseases, and Global Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, California, USA michael.peluso@ucsf.edu.;Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA.;Division of Radiology, University of California, San Francisco, California, USA.;Division of Infectious Diseases, University of California San Francisco, San Francisco, California, USA.;Division of Infectious Diseases, University of California San Francisco, San Francisco, California, USA.;Division of Infectious Diseases, University of California San Francisco, San Francisco, California, USA.",
"authors": "Ward|Lindsey M|LM|;Peluso|Michael J|MJ|http://orcid.org/0000-0001-5358-3535;Budak|Jehan Z|JZ|;Elicker|Brett M|BM|;Chin-Hong|Peter V|PV|;Lampiris|Harry|H|;Mulliken|Jennifer S|JS|",
"chemical_list": "D000970:Antineoplastic Agents; D011687:Purines; D052999:Quinazolinones; C552946:idelalisib",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-234113",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(4)",
"journal": "BMJ case reports",
"keywords": "TB and other respiratory infections; drugs: infectious diseases; infections; malignant and benign haematology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D003045:Coccidioides; D003047:Coccidioidomycosis; D060085:Coinfection; D003937:Diagnosis, Differential; D006801:Humans; D016867:Immunocompromised Host; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D011687:Purines; D052999:Quinazolinones; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32354764",
"pubdate": "2020-04-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Opportunistic coinfection with Pneumocystis jirovecii and Coccidioides immitis associated with idelalisib treatment in a patient with chronic lymphocytic leukaemia.",
"title_normalized": "opportunistic coinfection with pneumocystis jirovecii and coccidioides immitis associated with idelalisib treatment in a patient with chronic lymphocytic leukaemia"
} | [
{
"companynumb": "US-GILEAD-2020-0465965",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IDELALISIB"
},
"drugadditional": null,
... |
{
"abstract": "Gabapentin was used for the treatment of term and preterm infants with suspected visceral hyperalgesia caused by a variety of neurologic and gastrointestinal morbidities. Improved feeding tolerance and decreased irritability were seen, as well as decreased usage of opioids and benzodiazepines. Adverse events occurred with abrupt discontinuation of this medication.",
"affiliations": "Division of Neonatology, Department of Pediatrics, Duke University Medical Center, Durham, NC.;Division of Neonatology, Department of Pediatrics, Duke University Medical Center, Durham, NC.;Department of Pharmacy, Duke University Medical Center, Durham, NC.;Division of Neonatology, Department of Pediatrics, Duke University Medical Center, Durham, NC.;Division of Neonatology, Department of Pediatrics, Duke University Medical Center, Durham, NC.;Division of Pediatric Neurology, Department of Pediatrics, Duke University Medical Center, Durham, NC.;Department of Pediatrics, Children's Hospital Boston, Boston, MA.;Division of Neonatology, Department of Pediatrics, Duke University Medical Center, Durham, NC. Electronic address: margarita.bidegain@dm.duke.edu.",
"authors": "Edwards|Laura|L|;DeMeo|Stephen|S|;Hornik|Chi D|CD|;Cotten|C Michael|CM|;Smith|P Brian|PB|;Pizoli|Carolyn|C|;Hauer|Julie M|JM|;Bidegain|Margarita|M|",
"chemical_list": "D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3476",
"issue": "169()",
"journal": "The Journal of pediatrics",
"keywords": null,
"medline_ta": "J Pediatr",
"mesh_terms": "D000588:Amines; D000700:Analgesics; D001569:Benzodiazepines; D003509:Cyclohexanecarboxylic Acids; D005260:Female; D000077206:Gabapentin; D006801:Humans; D006930:Hyperalgesia; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D008297:Male; D012189:Retrospective Studies; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "0375410",
"other_id": null,
"pages": "310-2",
"pmc": null,
"pmid": "26578075",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "19637954;11483821;11361047;11479399;17272610;3730018;12077061;10530696;15798485;22871228",
"title": "Gabapentin Use in the Neonatal Intensive Care Unit.",
"title_normalized": "gabapentin use in the neonatal intensive care unit"
} | [
{
"companynumb": "US-DEPOMED, INC.-US-2016DEP009788",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BACLOFEN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nResearch suggests that maintaining treatment during pregnancy for women with bipolar affective disorder reduces the risk of relapse. However, one of the key questions for women and clinicians during pregnancy is whether there are implications of exposure to mood stabilizers for longer term child development. Despite these concerns, there are few recent systematic reviews comparing the impact on child developmental outcomes for individual mood-stabilizing agents to inform clinical decisions.\n\n\nOBJECTIVE\nTo examine the strengths and limitations of the existing data on child developmental outcomes following prenatal exposure to mood stabilizers and to explore whether there are any differences between agents for detrimental effects on child development.\n\n\nMETHODS\nUsing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a rigorous systematic search was carried out of four electronic databases from their respective years of inception to September 2016 to identify studies which examined the effects of mood stabilizers including sodium valproate, carbamazepine, lamotrigine, lithium and second-generation antipsychotics on child developmental outcomes.\n\n\nRESULTS\nWe identified 15 studies for critical review. Of these, 10 examined antiepileptic drugs, 2 studied lithium and 3 studied second-generation antipsychotics. The most consistent finding was a dose-response relationship for valproate with higher doses associated with poorer global cognitive abilities compared to other antiepileptic drugs. The limited data available for lithium found no adverse neurodevelopmental outcomes. The limited second-generation antipsychotic studies included a report of a transient early neurodevelopmental delay which resolved by 12 months of age.\n\n\nCONCLUSIONS\nThis review found higher neurodevelopmental risk with valproate. While the existing data on lithium and second-generation antipsychotics are reassuring, these data are both limited and lower quality, indicating that further research is required. The information from this review is relevant for patients and clinicians to influence choice of mood-stabilizing agent in childbearing women. This must be balanced against the known risks associated with untreated bipolar affective disorder.",
"affiliations": "1 Peel and Rockingham Kwinana Mental Health Service, Rockingham, WA, Australia.;2 School of Psychology and Exercise Science, Murdoch University, Murdoch, WA, Australia.",
"authors": "Haskey|Carolyn|C|;Galbally|Megan|M|",
"chemical_list": "D000927:Anticonvulsants; D018692:Antimanic Agents; D014150:Antipsychotic Agents",
"country": "England",
"delete": false,
"doi": "10.1177/0004867417726175",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-8674",
"issue": "51(11)",
"journal": "The Australian and New Zealand journal of psychiatry",
"keywords": "Pregnancy; bipolar affective disorder; child development; mood stabilizers",
"medline_ta": "Aust N Z J Psychiatry",
"mesh_terms": "D000927:Anticonvulsants; D018692:Antimanic Agents; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D002648:Child; D002657:Child Development; D005260:Female; D006801:Humans; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects",
"nlm_unique_id": "0111052",
"other_id": null,
"pages": "1087-1097",
"pmc": null,
"pmid": "28825316",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Mood stabilizers in pregnancy and child developmental outcomes: A systematic review.",
"title_normalized": "mood stabilizers in pregnancy and child developmental outcomes a systematic review"
} | [
{
"companynumb": "US-CIPLA (EU) LIMITED-STD201501-000034",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional"... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.