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"abstract": "This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a publication available from Wolters Kluwer Health. Off-Label Drug Facts is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding Off-Label Drug Uses to jgeneral@ku.edu.",
"affiliations": null,
"authors": "McEvoy|Theresa|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1310/hpj5106-450",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-5787",
"issue": "51(6)",
"journal": "Hospital pharmacy",
"keywords": null,
"medline_ta": "Hosp Pharm",
"mesh_terms": null,
"nlm_unique_id": "0043175",
"other_id": null,
"pages": "450-1",
"pmc": null,
"pmid": "27354745",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article",
"references": "21477849;17919504;12524397;23567357;26485101;21674173",
"title": "Montelukast: Eosinophilic Esophagitis.",
"title_normalized": "montelukast eosinophilic esophagitis"
} | [
{
"companynumb": "US-009507513-1609USA009478",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MONTELUKAST SODIUM"
},
"drugadditional": "3"... |
{
"abstract": "Lemierre syndrome (LS) is an acute oropharyngeal infection with secondary septic thrombophlebitis and distant septic embolisation. A 29-year-old woman with sore throat, dyspnoea and left shoulder pain, who was on levofloxacin for 3 days, presented with worsening symptoms. She was tachycardic, tachypneic and hypoxic on presentation. CT of neck and chest revealed multiple loculated abscesses on her left lower neck and shoulder, right peritonsillar abscess, thrombosis of the right external jugular vein and multiple bilateral septic emboli to the lungs. She was started on clindamycin and ampicillin sulbactam for LS. She developed septic shock and required intubation due to respiratory failure. Drainage of the left shoulder abscess grew Fusobacterium nucleatum After 2 weeks of a complicated intensive care unit stay, her haemodynamic status improved and she was transferred to the floor. LS has variable presentations, but regardless of the presentation, it is a potentially fatal disease-requiring prompt diagnosis and management.",
"affiliations": "Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, USA dilpat.kumar@med.wmich.edu.;Internal Medicine, Western Michigan University School of Medicine, Kalamazoo, Michigan, USA.;Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, USA.;Interfaith Medical Center, Brooklyn, New York, USA.",
"authors": "Kumar|Dilpat|D|http://orcid.org/0000-0001-8462-4627;Shamsi|Wasif Elahi|WE|http://orcid.org/0000-0002-7364-3694;Gomes|Thales|T|;Warsha|Fnu|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-242468",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(6)",
"journal": "BMJ case reports",
"keywords": "adult intensive care; ear; infectious diseases; nose and throat/otolaryngology; pleural infection; pulmonary embolism",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D005260:Female; D005674:Fusobacterium Infections; D005675:Fusobacterium necrophorum; D016967:Fusobacterium nucleatum; D006801:Humans; D007601:Jugular Veins; D057831:Lemierre Syndrome; D000039:Peritonsillar Abscess; D010612:Pharyngitis; D013924:Thrombophlebitis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34187798",
"pubdate": "2021-06-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Forgotten disease: an atypical case of Lemierre syndrome presenting as a soft tissue abscess.",
"title_normalized": "forgotten disease an atypical case of lemierre syndrome presenting as a soft tissue abscess"
} | [
{
"companynumb": "US-SPC-000010",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMPICILLIN SODIUM"
},
"drugadditional": "3",
"d... |
{
"abstract": "Erythema induratum (EI), or nodular vasculitis (NV), is a type of panniculitis that is often associated with vasculitis affecting various-sized veins, venules, and arteries in reaction to various causative factors. Historically, EI was highly linked to tuberculosis, but in 1946, Montgomery first proposed the term NV to describe cases of EI not associated with tuberculosis. Only 2 reports of NV associated with inflammatory bowel disease have been reported in the literature. The authors report a 60-year-old woman with Crohn's disease presenting with exacerbation of NV in the setting of vedolizumab therapy.",
"affiliations": "Division of Dermatology, University of California, Los Angeles, CA.;Department of Dermatology, University of California, Irvine, Irvine, CA.;Department of Dermatology, University of California, Irvine, Irvine, CA.;Department of Dermatology, University of California, Irvine, Irvine, CA.;Department of Dermatology, University of California, Irvine, Irvine, CA.;Department of Dermatology, University of California, Irvine, Irvine, CA.",
"authors": "Pouldar|Delila|D|;Elsensohn|Ashley|A|;Ortenzio|Francesca|F|;Shiu|Jessica|J|;McLeod|Michael|M|;de Feraudy|Sébastien|S|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D005765:Gastrointestinal Agents; C543529:vedolizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/DAD.0000000000001003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-1091",
"issue": "40(3)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D003424:Crohn Disease; D004891:Erythema Induratum; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D008875:Middle Aged",
"nlm_unique_id": "7911005",
"other_id": null,
"pages": "e36-e37",
"pmc": null,
"pmid": "28953016",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18251747;28337471;22172959;26512176;28276855",
"title": "Nodular Vasculitis in a Patient With Crohn's Disease on Vedolizumab.",
"title_normalized": "nodular vasculitis in a patient with crohn s disease on vedolizumab"
} | [
{
"companynumb": "US-MYLANLABS-2018M1084177",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CLOBETASOL"
},
"drugadditional": null,
... |
{
"abstract": "Tularemia is a rare and potentially life-threatening infection caused by the highly infectious gram-negative coccobacillus Francisella tularensis. We present the case of an 11-year old girl who presented with erythema multiforme minor in the setting of an indolent but progressive soft tissue infection and was found to have tularemia. We review the role of dermatologists in identifying the features of and complications associated with this rare zoonosis and discuss the potential effect of climate change on its incidence.",
"affiliations": "Department of Dermatology, University of California, San Francisco, CA, USA.;Department of Pediatric Infectious Diseases, University of California, San Francisco, CA, USA.;Department of Dermatology, University of California, San Francisco, CA, USA.",
"authors": "Coates|Sarah J|SJ|http://orcid.org/0000-0002-9872-5602;Briggs|Benjamin|B|;Cordoro|Kelly M|KM|http://orcid.org/0000-0001-9158-2111",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.13501",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "35(4)",
"journal": "Pediatric dermatology",
"keywords": "erythema multiforme; infection-bacterial; inflammatory disorders; skin signs of systemic disease; tularemia",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002648:Child; D004892:Erythema Multiforme; D005260:Female; D005604:Francisella tularensis; D006801:Humans; D017282:Tick-Borne Diseases; D014406:Tularemia",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "478-481",
"pmc": null,
"pmid": "29582465",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tularemia-induced erythema multiforme minor in an 11-year-old girl.",
"title_normalized": "tularemia induced erythema multiforme minor in an 11 year old girl"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/18/0103258",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": "1",... |
{
"abstract": "Locally advanced basal cell carcinoma (laBCC) represents a rare but possible occurrence in the vast scenario of dermatological diseases. It is well known that most BCC has a pathological activation of the hedgehog pathway, making them susceptible to targeted therapy with selective inhibitors. Sonidegib, approved for the treatment of laBCC on the basis of the results of the basal cell carcinoma outcomes with LDE225 treatment study, demonstrated rapid efficacy and a manageable safety profile. Here, we describe the case of a patient affected by multiple laBCC treated with Sonidegib. The patient experienced an important regression of tumors after only 2 months of therapy, with few side effects. This result confirms the role of Sonidegib as a valid and well-tolerated therapeutic option for laBCC.",
"affiliations": "Department of Health Science.;Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy.;Department of Health Science.;Department of Health Science.;Department of Health Science.",
"authors": "Tarantino|Vanessa|V|;Zavattaro|Elisa|E|;Veronese|Federica|F|;Gironi|Laura C|LC|;Savoia|Paola|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000001054",
"fulltext": "\n==== Front\nAnticancer Drugs\nAnticancer Drugs\nACD\nAnti-Cancer Drugs\n0959-4973\n1473-5741\nLippincott Williams & Wilkins\n\n33534224\n00013\n10.1097/CAD.0000000000001054\nCase Reports\nRapid and exceptional response to Sonidegib in a patient with multiple locally advanced basal cell carcinomas\nTarantino Vanessa a\nZavattaro Elisa b\nVeronese Federica a\nGironi Laura C. a\nSavoia Paola a\na Department of Health Science\nb Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy\nCorrespondence to Paola Savoia, MD, Department of Health Science, University of Eastern Piedmont, Novara, Italy, Tel: +39 0321 3733387; e-mail: paola.savoia@med.uniupo.it\n29 1 2021\n4 2021\n32 4 465468\n21 9 2020\n11 1 2021\nCopyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nThis is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.\n\nLocally advanced basal cell carcinoma (laBCC) represents a rare but possible occurrence in the vast scenario of dermatological diseases. It is well known that most BCC has a pathological activation of the hedgehog pathway, making them susceptible to targeted therapy with selective inhibitors. Sonidegib, approved for the treatment of laBCC on the basis of the results of the basal cell carcinoma outcomes with LDE225 treatment study, demonstrated rapid efficacy and a manageable safety profile. Here, we describe the case of a patient affected by multiple laBCC treated with Sonidegib. The patient experienced an important regression of tumors after only 2 months of therapy, with few side effects. This result confirms the role of Sonidegib as a valid and well-tolerated therapeutic option for laBCC.\n\nhedgehog pathway inhibitors\nlocally advanced basal cell carcinoma\nnonmelanoma skin cancer\nsonidegib\ntreatment\nOPEN-ACCESSTRUE\n==== Body\nIntroduction\n\nBasal cell carcinoma (BCC) is the most common form of skin cancer, making up approximately 80% of all nonmelanoma skin cancers [1]. The vast majority of BCCs can be effectively cured by complete histopathology controlled excision, which is the gold standard for BCC treatment. However, about 1–10% of lesions evolve towards advanced forms, including laBCC and Metastatic BCC [2]; in these cases, surgery may not represent a possible therapeutic option, because curing is unlikely and surgery might result in substantial deformity [3].\n\nIn order to avoid unreasonable postsurgical cosmetic changes, alternative approaches such as radiation, electrochemotherapy or systemic treatment [4] can be required, as specified by the European guidelines for the management of BCC [5]. Particularly, these approaches are indicated in patient affected by multiple comorbidities, numerous lesions or Gorlin–Goltz syndrome.\n\nHowever, about 90% of BCCs have a pathologic activation of the Sonic hedgehog pathway, making them susceptible to targeted therapy with selective hedgehog pathway inhibitors (HPI) [6,7]. Notably, Sonidegib (Odomzo) demonstrated a sustained and clinically relevant efficacy and a manageable safety profile in phase II randomized, double-blind basal cell carcinoma outcomes with LDE225 treatment (BOLT) study [8,9].\n\nHerein, we describe a rapid and exceptional response to Sonidegib in a patient affected by multiple disfiguring laBCC.\n\nCase report\n\nAn otherwise healthy 71-year-old male patient comes to our attention for the sudden bleeding of an ulcerated abdominal lesion of 8 cm × 5 cm (Fig. 1a). Complete physical examination allowed us to identify about 30 other pink or reddish papules and plaques of different shapes and sizes (up to 15 cm) located on the face, trunk and limb; clinical and dermoscopic characteristics were compatible with BCCs (Fig. 1b–d).\n\nFig. 1 (a) Deep ulcerated abdominal lesion; (b) Basal cell carcinoma (BCC) of 15 cm × 8 cm located on the left shoulder; (c) multiple BCCs of different shapes and sizes on the anterior trunk, with a detail of the voluminous nodule at the internal cantus; (d) multiple BCC on the posterior trunk.\n\nWe collected the patient’s medical history, which was negative for comorbidity, chronic therapy or radiotherapy treatments; he reported a previous surgical treatment to remove a BCC on nasal dorsum without any dermatological follow-up for over 10 years. A skin biopsy was performed on the abdominal lesion, and the histological examination confirmed the diagnosis of BCC. The skull X-ray and the orthopantomography showed no evidence of calcification of the falx cerebri or odontogenic keratocysts; the patient did not appear to have skeletal anomalies or intellectual deficit; he also denies family history of skin cancers. All other criteria for a possible Gorlin–Goltz syndrome have been excluded.\n\nConsidering the extensive dimensions of the lesions on the abdomen and back, the numerousness of tumors, and the involvement of critical sites, we excluded the possibility of a surgical approach and decided, on the basis of the results of the BOLT study [8] and the evidence reported by Dummer et al. [10], to start systemic therapy with Sonidegib 200 mg, 1 cp per day.\n\nTherapy was well-tolerated by the patient, except for a transient CTCAE grade I increase in the creatine phosphokinase, less than 2.5 × ULN, observed at the end of the first month of treatment, which did not require a dose adjustment. The other grades 1–2 side effects observed were dysgeusia and nocturnal muscle cramps resolving in a few minutes. Already at the end of the second month of treatment, the abdominal lesion appeared considerably reduced in size and depth (Fig. 2a). Furthermore, a similar clinical improvement was observed in other lesions; notably, the lesion on the back was less infiltrated and the size of the nodule at the internal cantus decreased significantly (Fig. 2b).\n\nFig. 2 (a) Abdominal basal cell carcinoma (BCC) considerably reduced in size and depth; (b) internal cantus BCC, significantly decreased.\n\nAt the end of the sixth month, there was no clinical or dermatoscopic evidence of BCC: the abdominal ulcerated lesion was healed (Fig. 3a), the nodule in the inner corner of the eye was not palpable and the lesions localized in the trunk assumed a scar-like appearance (Fig. 3b–d).\n\nFig. 3 (a) Ulcerated abdominal lesion healed; (b) scar appearance of the lesion localized in the left shoulder; (c) appearance of the anterior trunk and face lesions after 6 months of therapy; (d) appearance of the posterior trunk lesions after 6 months of therapy.\n\nCurrently, the treatment is ongoing, and the excellent clinical response persists.\n\nDiscussion\n\nAlthough BCC is the most common skin cancer, the finding of laBCC is rather infrequent, often related to tumors with a long-term course, located in midface or on ears, with aggressive histopathologic subtype, perivascular or perineural infiltration, history of radiation exposure or previous surgical treatment failure. Patients with immunosuppressive status or multiple comorbidities are more affected [11]. In particular, neglected patients are one of the major contributing factors for the development of mutilating and aggressive BCC.\n\nBCC occurs in the head area in 85–90% of cases [12] and can cause, when the tumor reaches a considerable size, social isolation in affected people. Here, the use of alternative therapeutic strategies is mandatory, to avoid cosmetically unacceptable postsurgical outcomes.\n\nIn phase II randomized double-blind BOLT study, which led to the approval of Sonidegib [8], the median time of response assessed by investigators was 1.9 months. Even in our patient, we observed a quick response to the treatment, with a significant improvement of all skin lesions after only 2 months. Already during the first weeks of therapy, in addition to an obvious reduction in the size of the tumors, the patient experienced a significative improvement of symptoms; in particular, the bleeding stopped and the patient reported a progressive reduction in the visual discomfort given by the BCC located at the inner corner of the eye. The rapidity of these events is very important as it promotes patient adherence to treatment, limiting the risk of spontaneous drop-out.\n\nThe good tolerability profile of Sonidegib detected by the BOLT study [8] was also confirmed in the long-term observations [10,13,14]. Also, in our experience, dysgeusia appeared as the first and main adverse event, whereas muscle cramps (reported as the first side effect in the patients received the 200 mg dose) arose later. However, also a slight spontaneously resolved increase in the CK value was observed.\n\nNevertheless, this value should be monitored, to evaluate any dose adjustment as required by the drug data sheet [8,9,13,14].\n\nEven if the usefulness of HPI in the treatment of laBCC is widely confirmed [15], there are still few real-life experiences on Sonidegib [16,17] and anecdotal reports on multiple laBCC.\n\nOur observations confirm the efficacy and safety of Sonidegib in this setting, suggesting it as an excellent therapeutic choice in neglected and laBCC.\n\nConclusion\n\nIn our real-life experience, Sonidegib has fulfilled its main goal, which is to obtain a rapid improvement of lesions and related symptoms, to avoid the risk of infection and anemia, to promote patient compliance towards the treatment and to reduce their social isolation improving his quality of life. The safety and effectiveness of the treatment will be confirmed by the long-term follow-up.\n\nAcknowledgements\n\nThe authors are grateful to the patient for agreeing to share photos contributing to extend medical knowledge on this topic. The study received unrestricted grant from Sun Pharmaceutical Industries.\n\nConflicts of interest\n\nWe thank SunPharma for the non-conditioning contribution. There are no conflicts of interest.\n==== Refs\nReferences\n\n1 Rubin AI Chen EH Ratner D . Basal-cell carcinoma. N Engl J Med. 2005; 353 :2262–2269.16306523\n2 Migden M Xie J Wei J Tang W Herrera V Palmer JB . Burden and treatment patterns of advanced basal cell carcinoma among commercially insured patients in a United States database from 2010 to 2014. J Am Acad Dermatol. 2017; 77 :55–62.e3.28392293\n3 Peris K Licitra L Ascierto PA Corvò R Simonacci M Picciotto F . Identifying locally advanced basal cell carcinoma eligible for treatment with vismodegib: an expert panel consensus. Future Oncol. 2015; 11 :703–712.25686123\n4 Espeli V Ruegg E Hottinger AF Modarressi A Dietrich PY . Weekly multi-agent chemotherapy (CMF-b) for advanced non-melanoma skin cancer. Anticancer Res. 2016; 36 :2359–2364.27127144\n5 Peris K Fargnoli MC Garbe C Kaufmann R Bastholt L Seguin NB ; European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization for Research and Treatment of Cancer (EORTC). Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines. Eur J Cancer. 2019; 118 :10–34.31288208\n6 Daya-Grosjean L Couvé-Privat S . Sonic hedgehog signaling in basal cell carcinomas. Cancer Lett. 2005; 225 :181–192.15978322\n7 Campione E Di Prete M Lozzi F Lanna C Spallone G Mazzeo M . High-risk recurrence basal cell carcinoma: focus on hedgehog pathway inhibitors and review of the literature. Chemotherapy. 2020; 65 :2–10.32777789\n8 Migden MR Guminski A Gutzmer R Dirix L Lewis KD Combemale P . Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015; 16 :716–728.25981810\n9 Dummer R Guminksi A Gutzmer R Lear JT Lewis KD Chang ALS . Long-term efficacy and safety of sonidegib in patients with advanced basal cell carcinoma: 42-month analysis of the phase II randomized, double-blind BOLT study. Br J Dermatol. 2020; 182 :1369–1378.31545507\n10 Dummer R Ascierto PA Basset-Seguin N Dréno B Garbe C Gutzmer R . Sonidegib and vismodegib in the treatment of patients with locally advanced basal cell carcinoma: a joint expert. J Eur Acad Dermatol Venereol. 2020; 34 :1944–1956.31990414\n11 Wollina U Pabst F Krönert C Schorcht J Haroske G Klemm E . High-risk basal cell carcinoma: an update. Expert Rev Dermatol. 2010; 5 :357–368.\n12 Lovatt TJ Lear JT Bastrilles J Wong C Griffiths CE Samarasinghe V . Associations between ultraviolet radiation, basal cell carcinoma site and histology, host characteristics, and rate of development of further tumors. J Am Acad Dermatol. 2005; 52 :468–473.15761425\n13 Dummer R Guminski A Gutzmer R Dirix L Lewis KD Combemale P . The 12-month analysis from Basal Cell Carcinoma Outcomes with LDE225 Treatment (BOLT): a phase II, randomized, double-blind study of sonidegib in patients with advanced basal cell carcinoma. J Am Acad Dermatol. 2016; 75 :113–125.e5.27067394\n14 Lear JT Migden MR Lewis KD Chang ALS Guminski A Gutzmer R . Long-term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30-month analysis of the randomized phase 2 BOLT study. J Eur Acad Dermatol Venereol. 2018; 32 :372–381.28846163\n15 Rodon J Tawbi HA Thomas AL Stoller RG Turtschi CP Baselga J . A phase I, multicenter, open-label, first-in-human, dose-escalation study of the oral smoothened inhibitor Sonidegib (LDE225) in patients with advanced solid tumors. Clin Cancer Res. 2014; 20 :1900–1909.24523439\n16 Hou X Rokohl AC Ortmann M Heindl LM . Effective treatment of locally advanced periocular basal cell carcinoma with oral hedgehog pathway inhibitor? Graefes Arch Clin Exp Ophthalmol. 2020; 258 :2335–2337.32514773\n17 Yoon J Apicelli AJ 3rd Pavlopoulos TV . Intracranial regression of an advanced basal cell carcinoma using sonidegib and itraconazole after failure with vismodegib. JAAD Case Rep. 2018; 4 :10–12.29387745\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0959-4973",
"issue": "32(4)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": null,
"nlm_unique_id": "9100823",
"other_id": null,
"pages": "465-468",
"pmc": null,
"pmid": "33534224",
"pubdate": "2021-04-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Rapid and exceptional response to Sonidegib in a patient with multiple locally advanced basal cell carcinomas.",
"title_normalized": "rapid and exceptional response to sonidegib in a patient with multiple locally advanced basal cell carcinomas"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-324333",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SONIDEGIB"
},
"druga... |
{
"abstract": "Almost all epidermal growth factor receptor (EGFR)-mutant lung cancers develop resistance to EGFR-tyrosine kinase inhibitors. Several mechanisms for this acquired resistance have been identified, including development of an EGFR T790M mutation, MET amplification, hepatocyte growth factor overexpression, loss of phosphatase and tensin homolog expression, epithelial-mesenchymal transition, and transformation to small cell lung cancer. Herein, we report a case of a lung cancer patient with EGFR exon 19 deletion who was resistant to EGFR-tyrosine kinase inhibitor treatment during disease progression. Using histological and gene sequencing analysis, we observed that the primary adenocarcinoma acquired T790M mutation in EGFR exon 20, and a secondary sarcomatoid carcinoma developed in the vicinity. Assessment of E-cadherin and Vimentin expression confirmed that the sarcomatoid carcinoma had undergone an epithelial-mesenchymal transition. Therefore, it is important to perform a tissue re-biopsy after the development of resistance to identify the best treatment options. Surgical resection might be a better \"salvage\" treatment in cases of oligometastatic progression.",
"affiliations": "Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China.;Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin, China.;Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China.;Department of Pathology, Tianjin Medical University General Hospital, Tianjin, China.;Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China.;Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China.;Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin, China.;Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China.;Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China.",
"authors": "Xu|Song|S|;Liu|Xia|X|;Liu|Renwang|R|;Shi|Tao|T|;Li|Xiongfei|X|;Zhong|Diansheng|D|;Wang|Yan|Y|;Chen|Gang|G|;Chen|Jun|J|",
"chemical_list": "D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "Singapore",
"delete": false,
"doi": "10.1111/1759-7714.12484",
"fulltext": "\n==== Front\nThorac CancerThorac Cancer10.1111/(ISSN)1759-7714TCAThoracic Cancer1759-77061759-7714John Wiley & Sons Australia, Ltd Melbourne 10.1111/1759-7714.12484TCA12484Case ReportCase ReportsConcurrent epidermal growth factor receptor T790M secondary mutation and epithelial‐mesenchymal transition in a lung adenocarcinoma patient with EGFR‐TKI drug resistance T790M and EMT in EGFR TKI resistanceS. Xu et al.Xu Song \n1\n\n2\n\n†\nLiu Xia \n3\n\n†\nLiu Renwang \n1\n\n†\nShi Tao \n4\n\n†\nLi Xiongfei \n1\nZhong Diansheng \n2\n\n3\nWang Yan wangyan5701@sohu.com \n3\nChen Gang \n1\nChen Jun huntercj2004@yahoo.com \n1\n\n2\n\n1 \nDepartment of Lung Cancer Surgery\nTianjin Medical University General Hospital\nTianjin\nChina\n\n2 \nTianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute\nTianjin Medical University General Hospital\nTianjin\nChina\n\n3 \nDepartment of Medical Oncology\nTianjin Medical University General Hospital\nTianjin\nChina\n\n4 \nDepartment of Pathology\nTianjin Medical University General Hospital\nTianjin\nChina\n* Correspondence\n\nYan Wang, Department of Medical Oncology, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, No. 154 Anshan Road, Heping District, 300052 Tianjin, China.\n\nTel: +86 22 6081 7007\n\nFax: +86 22 6036 3013\n\nEmail: wangyan5701@sohu.com\n\nJun Chen, Department of Lung Cancer Surgery, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, No. 154 Anshan Road, Heping District, 300052 Tianjin, China.\n\nTel: +86 22 6081 4803\n\nFax: +86 22 6036 3013\n\nEmail: huntercj2004@yahoo.com\n† These authors contributed equally to this work.\n\n08 8 2017 11 2017 8 6 10.1111/tca.2017.8.issue-6693 697 02 6 2017 26 6 2017 27 6 2017 © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, LtdThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Almost all epidermal growth factor receptor (EGFR)‐mutant lung cancers develop resistance to EGFR‐tyrosine kinase inhibitors. Several mechanisms for this acquired resistance have been identified, including development of an EGFR T790M mutation, MET amplification, hepatocyte growth factor overexpression, loss of phosphatase and tensin homolog expression, epithelial–mesenchymal transition, and transformation to small cell lung cancer. Herein, we report a case of a lung cancer patient with EGFR exon 19 deletion who was resistant to EGFR‐tyrosine kinase inhibitor treatment during disease progression. Using histological and gene sequencing analysis, we observed that the primary adenocarcinoma acquired T790M mutation in EGFR exon 20, and a secondary sarcomatoid carcinoma developed in the vicinity. Assessment of E‐cadherin and Vimentin expression confirmed that the sarcomatoid carcinoma had undergone an epithelial–mesenchymal transition. Therefore, it is important to perform a tissue re‐biopsy after the development of resistance to identify the best treatment options. Surgical resection might be a better “salvage” treatment in cases of oligometastatic progression.\n\nAdenocarcinomadrug resistanceEMTsarcomatoid carcinomaT790MNational Natural Science Foundation of China8130181281172233Tianjin Medical University General Hospital Young Incubation FoundationZYYFY2015015Tianjin Educational Committee Foundation20120117Science & Technology Foundation for Selected Overseas Chinese Scholar, Ministry of Personnel of ChinaScience & Technology Foundation for Selected Overseas Chinese Scholar, Bureau of Personnel of China TianjinTianjin Key Project of Natural Science Foundation17JCZDJC36200Specialized Research Fund for the Doctoral Program of Higher Education20131202120004 source-schema-version-number2.0component-idtca12484cover-dateNovember 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.2.1 mode:remove_FC converted:03.11.2017\n==== Body\nIntroduction\nDrug resistance is the most challenging problem with epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI) treatment in non‐small cell lung cancer (NSCLC) patients. The major mechanisms giving rise to EGFR‐TKI resistance in NSCLC have been demonstrated, including secondary mutation of EGFR T790M, MET amplification, epithelial–mesenchymal transition, activation of alternative oncogenic pathways, and transformation to small cell lung cancer (SCLC).1 Herein, we present a rare case of EGFR T790M secondary mutation accompanied with the phenotype of sarcomatoid carcinoma after EGFR‐TKI treatment.\n\nCase Report\nA non‐smoking 60‐year‐old woman was diagnosed via a left supraclavicular lymph node biopsy in December 2012 with left upper lung adenocarcinoma. A gene mutation test indicated EGFR exon 19 deletion without an exon 20 T790M mutation. After two cycles of gemcitabine plus cisplatin chemotherapy, abdominal computed tomography showed liver metastasis; therefore from January 2013, the patient was administered erlotinib. By October 2015, following erlotinib treatment, the metastatic tumors in the liver and supraclavicular lymph nodes had disappeared and the primary lung tumor had reduced. However, the original lung tumor started to enlarge and bred an adjacent secondary nodule (Fig 1). Although drug resistance had occurred, the patient refused any other treatment and continued to take erlotinib. In July 2016, a left upper lobectomy plus systematic mediastinal lymphadenectomy by video‐assisted thoracoscopic surgery was performed after a comprehensive evaluation showed no sign of extrapulmonary abnormalities and negative T790M mutation from a blood circulating tumor (ct)DNA test. Surgery was approved after multiple disciplinary team‐based evaluation and informed consent was acquired from the patient. The pathological diagnosis of the original lung tumor was confirmed to be adenocarcinoma according to the typical morphology and positivity of thyroid transcription factor 1 and cytokeratin (CK)7. The secondary lung tumor had sarcomatoid histology showing a more spindle‐like mesenchymal morphology with CK and Vimentin positivity (Fig 2). N1 but not N2 lymph nodes were involved. Next generation sequencing confirmed that the original lung adenocarcinoma retained EGFR exon 19 deletion but also detected T790M mutation in EGFR exon 20 (File S1, Table S1). The secondary sarcomatoid carcinoma also displayed EGFR exon 19 deletion and genetic mutations on FANCL and BCL2L2, and amplification on CDK4, MDM2, APFRP1, GNAS, CIC, FANCE, Notch4, and AKT2 (Table 1). Additional histological E‐cadherin and Vimentin staining were performed on the primary biopsy specimen and TKI‐resistant postoperative specimens. In comparison to the adenocarcinoma, the sarcomatoid tumor was strongly positive for Vimentin and almost negative for E‐cadherin, indicating that the sarcomatoid probably underwent EMT (Fig 3). A postoperative ctDNA test did not show any driver gene mutation in the blood, including EGFR exon 20 T790M mutation or exon 19 deletion (Burning Rock Dx, Guangzhou, China). Moreover, postoperative circulating tumor cell analysis showed a value of 4.29 (cut‐off 8.70 FU) (Geno, Shanghai, China) (File S1); therefore, we continued to administer erlotinib. The patient has received thorough imaging evaluations and ct cell tests twice every three months, with no sign of relapse. She continues to take erlotinib and is intensively followed‐up.\n\nFigure 1 (a) Computed tomography scan and (b) gross specimen. Blue arrow: sarcomatoid carcinoma; red arrow: adenocarcinoma. EGFR‐TKI, epidermal growth factor receptor‐tyrosine kinase inhibitor.\n\nFigure 2 Histology of the two pulmonary nodules after surgical resection. The original lung tumor was confirmed to be adenocarcinoma according to the typical morphology and positivity of thyroid transcription factor 1 (TTF1) and cytokeratin (CK)7. The secondary lung tumor has sarcomatoid histology showing a more spindle‐like mesenchymal morphology with CK and Vimentin positivity (magnification ×100). Adeno, adenocarcinoma; HE, hematoxylin and eosin; Sarco, sarcomatoid carcinoma.\n\nTable 1 Gene analysis of primary adenocarcinoma and secondary lung sarcomatoid carcinoma from surgical resection (July 2016)\n\nGene\tLocation\tMutation type\tFrequency (%)\t\nAdenocarcinoma\tSarcomatoid carcinoma\t\nEGFR\texon 19\tE746_A750 deletion mut\n\t27.70\t28.90\t\nBCL2L2\texon 3\tA65T missense mut\n\t16.60\t49.30\t\nFANCL\texon 1\tS30L missense mut\n\t15.50\t51.30\t\nARFRP1\t20q13.33\tcn_amplification\t6.19\t16.99\t\nEGFR\texon 20\tT790M missense mut\n\t15.20\t0\t\nTGFBR2\texon 8\tR553H missense mut\n\t29.10\t0\t\nTRRAP\texon 43\tV2098A missense mut\n\t24.70\t0\t\nFLT1\texon 13\tV211 synonymous mut\n\t17.40\t0\t\nNF1\texon 17\tA208 synonymous mut\n\t8.80\t0\t\nTBX3\texon 12\tP63 synonymous mut\n\t7.00\t0\t\nSMO\texon 7\tF252 synonymous mut\n\t0\t23.10\t\nCDK4\t12q14.1\tcn_amplification\t0\t11.38\t\nMDM2\t12q15\tcn_amplification\t0\t18.66\t\nAKT2\t19q13.2\tcn_amplification\t0\t3.8\t\nCIC\t19q13.2\tcn_amplification\t0\t4.31\t\nGNAS\t20q13.32\tcn_amplification\t0\t6.76\t\nFANCE\t6p21.31\tcn_amplification\t0\t4.12\t\nNOTCH4\t6p21.32\tcn_amplification\t0\t3.87\t\nGreen denotes gene alterations common to adenocarcinoma and sarcomatoid carcinoma; blue denotes gene alterations in adenocarcinoma only; pink: denotes gene alterations in sarcomatoid carcinoma only.\n\nFigure 3 Histological staining of E‐cadherin and Vimentin on the primary biopsy specimen and tyrosine kinase inhibitor‐resistant postoperative specimen (adenocarcinoma and sarcomatoid carcinoma, July 2016). In the adenocarcinoma biopsy (December 2012) and surgical resection (July 2016) specimens, adenocarcinoma cells were strongly positive for E‐cadherin and almost negative for Vimentin, while the surrounding stromal tissues were positive for Vimentin. By contrast, the sarcomatoid histology showed a more spindle‐like mesenchymal morphology with diffuse positivity of Vimentin but lacked E‐cadherin expression (magnification ×100). Adeno, adenocarcinoma; Sarco, sarcomatoid carcinoma.\n\nDiscussion\nIn this case, two pulmonary tumors that acquired resistance to EGFR inhibitors had very distinct phenotypes after EGFR‐TKI treatment. Using in‐depth genetic and histological analyses, two major mechanisms were identified in this patient. The adenocarcinoma exhibited a secondary EGFR exon 20 T790M mutation and the newly developed pulmonary nodule was confirmed to be a sarcomatoid carcinoma, which explains why the primary pulmonary tumor grew more aggressively after effective erlotinib treatment. Secondary EGFR T790M mutation is a well‐known mechanism of EGFR‐TKI resistance, while the development of sarcomatoid carcinoma after EGFR‐TKI treatment is not frequently reported.\n\nThree possible pathophysiological mechanisms underlying the development of sarcomatoid carcinoma might be involved: (i) intra‐patient tumor heterogeneity, in which the sarcomatoid carcinoma may already be present and gradually becomes dominant after EGFR‐TKI therapy; (ii) metachronous development of the secondary cancer; or (iii) direct transformation from adenocarcinoma to sarcomatoid carcinoma. It is difficult to explain the reasons by pathological diagnosis alone. Thus, next generation sequencing was performed with a broad gene panel. The genetic sequencing data explicitly shows that the sarcomatoid carcinoma shared the same genetic phenotype as the primary adenocarcinoma, including EGFR 19 deletion (with comparable mutation frequency) and three other genes (Table 1). In view of the computed tomography imaging and sequencing results, it seems logical that the sarcomatoid carcinoma retaining the original EGFR mutation may have been directly derived from the primary adenocarcinoma. Sequist et al. reported sarcomatoid morphology with an EMT phenotype at the time of EGFR‐TKI resistance.2 In our case, an assessment of E‐cadherin and Vimentin expression confirmed that the sarcomatoid carcinoma had also undergone EMT. EMT indicates that a cancer cell has lost its epithelial morphology and thus develops a more spindle‐like mesenchymal morphology, and is often associated with a more invasive phenotype. Previous studies have shown that EMT is a well‐established mechanism for acquired resistance in EGFR‐mutant NSCLC.3, 4, 5 However, concurrent EGFR T790M secondary mutation and EMT in a lung adenocarcinoma patient with EGFR‐TKI drug resistance has rarely been reported in the literature.\n\nAlthough blood biopsy techniques have developed significantly, tissue re‐biopsy is still very important after EGFR‐TKI resistance and should not be replaced by liquid biopsy in these cases. Before the surgery, a blood ctDNA test was performed and only EGFR 19 deletion was detected, with a frequency of 0.08%; T790M was not found. If tissue re‐biopsy and surgery had not been performed, we would not have information on the underlying mechanisms of acquired resistance and this patient might have been treated with chemotherapy or radiotherapy. As sarcomatoid carcinomas are less sensitive to chemotherapy or radiotherapy, we can presume that the treatment response would have been poor. This case also indicates the necessity of multiple disciplinary team‐based evaluation and treatment, especially for patients with EGFR‐TKI acquired resistance. If performance status and pulmonary function are good, a complete surgical resection may be the best alternative for a patient with local disease progression or oligometastasis. Because of the patient's refusal, we did not perform a biopsy of the lung mass and only tested for EGFR mutation on the left supraclavicular lymph nodes. Although the patient has responded well to TKI treatment, a secondary lung biopsy may be necessary because of the heterogeneity between the primary lung tumor and metastatic lymph nodes.\n\nThe clinical implications of this case provide significant insight that two or more mechanisms may be simultaneously involved in EGFR‐TKI resistance. Therefore, if possible, tumor biopsies should be performed after the development of resistance to identify the best treatment option for patients.\n\nDisclosure\nNo authors report any conflict of interest.\n\nSupporting information\n\nFile S1. Next generation sequencing (NGS) and circulating tumor cell (ctC) analysis.\n\nClick here for additional data file.\n\n \nTable S1. The OncoScreen panel captures and sequences all exons of a panel of 287 cancer‐related genes simultaneously, along with intronic regions from 22 genes from which we want to catch all fusion/translocation events. All of the tested genes cover the most important solid tumor related signaling pathways and targeted therapeutics.\n\nClick here for additional data file.\n\n Acknowledgments\nThis work was supported by grants from the National Natural Science Foundation of China (81301812, 81172233); the Specialized Research Fund for the Doctoral Program of Higher Education (20131202120004); the Science & Technology Foundation for Selected Overseas Chinese Scholar, Ministry of Personnel of China; the Science & Technology Foundation for Selected Overseas Chinese Scholar, Bureau of Personnel of China Tianjin; the Tianjin Key Project of Natural Science Foundation (17JCZDJC36200); the Tianjin Educational Committee Foundation (20120117); and the Tianjin Medical University General Hospital Young Incubation Foundation (ZYYFY2015015).\n==== Refs\nReferences\n1 \n\nSuda \nK \n, \nBunn \nPA \nJr\n, \nRivard \nCJ \n, \nMitsudomi \nT \n, \nHirsch \nFR \n. Primary double‐strike therapy for cancers to overcome EGFR kinase inhibitor resistance: Proposal from the bench . J Thorac Oncol \n2017 ; 12 : 27 –35 .27642065 \n2 \n\nSequist \nLV \n, \nWaltman \nBA \n, \nDias‐Santagata \nD \n\net al.\nGenotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors . Sci Transl Med \n2011 ; 3 : 75ra26 .\n3 \n\nChung \nJH \n, \nRho \nJK \n, \nXu \nX \n\net al.\nClinical and molecular evidences of epithelial to mesenchymal transition in acquired resistance to EGFR‐TKIs . Lung Cancer \n2011 ; 73 : 176 –82 .21168239 \n4 \n\nSuda \nK \n, \nTomizawa \nK \n, \nFujii \nM \n\net al.\nEpithelial to mesenchymal transition in an epidermal growth factor receptor‐mutant lung cancer cell line with acquired resistance to erlotinib . J Thorac Oncol \n2011 ; 6 : 1152 –61 .21597390 \n5 \n\nUramoto \nH \n, \nIwata \nT \n, \nOnitsuka \nT \n, \nShimokawa \nH \n, \nHanagiri \nT \n, \nOyama \nT \n. Epithelial‐mesenchymal transition in EGFR‐TKI acquired resistant lung adenocarcinoma . Anticancer Res \n2010 ; 30 : 2513 –7 .20682976\n\n",
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"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D001706:Biopsy; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors",
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"title": "Concurrent epidermal growth factor receptor T790M secondary mutation and epithelial-mesenchymal transition in a lung adenocarcinoma patient with EGFR-TKI drug resistance.",
"title_normalized": "concurrent epidermal growth factor receptor t790m secondary mutation and epithelial mesenchymal transition in a lung adenocarcinoma patient with egfr tki drug resistance"
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"abstract": "HIV-associated lymphomas (HAL) remain an important cause of morbidity and mortality in HIV patients, especially in the setting of treatment-refractory disease. Hematopoietic cell transplantation (HCT) is considered a curative option for patients with refractory HAL.\n\n\n\nWe report the efficacy of autologous HCT in 20 patients with HAL [non-Hodgkin lymphoma = 14 (70%), Hodgkin lymphoma = 6 (30%)]. At the time of transplantation, the median peripheral blood CD4+ count was 226 cells/μL. HIV virus load was undetectable in 14 (70%) of 20 patients.\n\n\n\nThe median follow-up of surviving patients was 47 months (range, 20-119 months). The median time to neutrophil engraftment was 11 days. The median progression-free survival and median overall survival have not been reached. At 4 years after transplantation, progression-free survival and overall survival were 65% and 70%, respectively. Six patients died from disease relapse or progression (n = 5) and infection (n = 1). Nonrelapse mortality was 0 and 5% at 100 days and 4 years after transplantation, respectively.\n\n\n\nAutologous HCT is an effective therapy for refractory/relapsed HAL with manageable toxicity, similar to non-HIV patients.",
"affiliations": "Department of Blood and Marrow Transplantation and Cellular Immune Therapies, Moffitt Cancer Center, Tampa, FL.;Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL. Electronic address: julio.c.chavez@moffitt.org.;Department of Blood and Marrow Transplantation and Cellular Immune Therapies, Moffitt Cancer Center, Tampa, FL.;Department of Blood and Marrow Transplantation and Cellular Immune Therapies, Moffitt Cancer Center, Tampa, FL.;Program for Comparative Effectiveness Research, University of South Florida Morsani College of Medicine, Tampa, FL.;Department of Blood and Marrow Transplantation and Cellular Immune Therapies, Moffitt Cancer Center, Tampa, FL.",
"authors": "Ayala|Ernesto|E|;Chavez|Julio C|JC|;Gomez|Alexandra|A|;Sleiman|Elsa|E|;Kumar|Ambuj|A|;Kharfan-Dabaja|Mohamed A|MA|",
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"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Autologous transplantation; HAART; HIV; Lymphoma; Non-relapse mortality",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D023241:Antiretroviral Therapy, Highly Active; D018450:Disease Progression; D005240:Feasibility Studies; D005260:Female; D005431:Florida; D006678:HIV; D018380:Hematopoietic Stem Cell Transplantation; D006689:Hodgkin Disease; D006801:Humans; D016483:Lymphoma, AIDS-Related; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D000077982:Progression-Free Survival; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D014182:Transplantation, Autologous; D019562:Viral Load",
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"title": "Feasibility and Efficacy of High-Dose Chemotherapy and Autologous Hematopoietic Cell Transplantation for HIV-Associated Lymphoma: A Single-Institution Experience.",
"title_normalized": "feasibility and efficacy of high dose chemotherapy and autologous hematopoietic cell transplantation for hiv associated lymphoma a single institution experience"
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"abstract": "Delirium, or acute confusional syndrome, is a set of symptoms whose care involves not only psychiatry, but also many other medical specialties. Being as how the syndrome is caused by multiple factors, it is important to recognize each risk factor affecting the patient in order to anticipate and prevent it. In case of diagnosis, identifying and treating the root cause that triggered is important, given that it has a high rate of comorbidity and an elevated cost of medical care. We describe a case where a patient with hypothyroidism began suffering from delirium due to an abrupt discontinuation of levothyroxine treatment. Previously, the patient was seemingly healthy. After the medical treatment was interrupted, sensory processing and behavior were altered, and symptoms fluctuated, for a short period of time, showing disorientation and memory and language impairment.",
"affiliations": "Primary Care Physician and Emergency Medical Department, Clínica Integral de Tibás, Coopesain R.L., San José , Costa Rica.;Primary Care Physician and Emergency Medical Department, Clínica Integral de Tibás, Coopesain R.L., San José , Costa Rica.;Primary Care Physician and Emergency Medical Department, Clínica Integral de Tibás, Coopesain R.L., San José , Costa Rica.",
"authors": "Hernández-Sandí|Alejandro|A|;Quirós-Baltodano|David|D|;Oconitrillo-Chaves|Michelle|M|",
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"doi": "10.4081/mi.2016.6787",
"fulltext": "\n==== Front\nMent IllnMent IllnMIMental Illness2036-74572036-7465PAGEPress Publications, Pavia, Italy 2799483510.4081/mi.2016.6787Case ReportDelirium, Caused by Suspending Treatment of Hypothyroidism Hernández-Sandí Alejandro Quirós-Baltodano David Oconitrillo-Chaves Michelle Primary Care Physician and Emergency Medical Department, Clínica Integral de Tibás, Coopesain R.L., San José, Costa RicaUrbanización El Marino, casa #12, San Pablo, Heredia, 3019, Costa Rica. +506.8729.2328. +506.2279.4460. Aleomark@yahoo.comAuthors’ Contributions: AHS, designed the study and wrote the first draft of the manuscript and had the overall supervision and corrected the final draft; DQB and author MOC also contributed to the first draft of the manuscript and managed the literature searches of the manuscript.\n\nConflict of interest: the authors declare no potential conflict of interest.\n\n23 11 2016 23 11 2016 8 2 678718 7 2016 20 8 2016 23 8 2016 ©Copyright A. Hernández-Sandí et al., 20162016Licensee 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.Delirium, or acute confusional syndrome, is a set of symptoms whose care involves not only psychiatry, but also many other medical specialties. Being as how the syndrome is caused by multiple factors, it is important to recognize each risk factor affecting the patient in order to anticipate and prevent it. In case of diagnosis, identifying and treating the root cause that triggered is important, given that it has a high rate of comorbidity and an elevated cost of medical care. We describe a case where a patient with hypothyroidism began suffering from delirium due to an abrupt discontinuation of levothyroxine treatment. Previously, the patient was seemingly healthy. After the medical treatment was interrupted, sensory processing and behavior were altered, and symptoms fluctuated, for a short period of time, showing disorientation and memory and language impairment.\n\nKey words\nDeliriumConfusionDrug Recalls\n==== Body\nIntroduction\nDelirium is a complex neuropsychiatric syndrome with a multi factorial etiology.1,2 One of the most prominently affected populations are elderly adults, but delirium can occur at any age.2 Delirium is characterized by a disturbance of consciousness and attention, in addition to changes in cognition, thought, memory, emotions and in the sleep cycle (inversions of the cycle).3-5 The symptoms tend to worsen during the night or in the early hours of the morning.\n\nOnset of delirium occurs acutely, its symptoms tend to fluctuate, and it has a duration of a few hours to a few days. If the underlying cause is properly identified, symptoms can rapidly improve.1,6 There are certain factors that increase the possibility of developing delirium. Among its predisposing factors are: hospitalization, preexisting brain damage, polypharmacy, old age, dehydration, malnutrition, history of delirium, and male gender, among others.1,7 Some important precipitating factors are: complex surgical intervention, acute sickness, infections (especially in the urinary tract), immobilization, stressful environment, changes in medication and hyponatremia. The incidence is higher in hospitalized patients and in patients that recently came out of surgery.\n\nCase Report\nA 81-year-old female patient, living with her nephew, who is absent most of the time. One of her primary caregivers is her neighbor, who looks after her daily and makes sure that she is in good health and that she does not need anything. The neighbor and the patient, upon being interviewed, indicated that the patient usually has a good cognitive level, and that there are no major difficulties with her superior mental functions. Moreover, they claimed she has no problems doing housework or other activities. They consulted with a doctor because they were worried the patient may be developing early symptoms of dementia.\n\nThe patient has a history of chronic hyperthyroidism and hypertriglyceridemia. At the moment, these conditions are under control, as her primary caregiver treats the conditions with 0.1 mg of levothyroxine medication and 600 mg of gemfibrozil, administered daily. She denies having a family history of psychiatric illness and consuming any kind of substance or medication, other than those indicated by her primary physician.\n\nThe patient, at the moment of her mental examination, was dressed according to her age and gender, exhibited a good attitude and was very collaborative with the interviewer. She used an adequate tone of voice, normal verbal language, was capable of rational thought and adequate course and content, had sensorial perceptions without alterations, was conscious, seemed well oriented and alert, showed a slight difficulty with calculations, proved to have an adequate memory and proper capacity of abstraction, had adequate judgment and adequate illness perception. She displayed no reason to doubt her story.\n\nThe patient claimed that a month ago she suffered an episode of Senile Dementia, which lasted for 3 days, by that name she refers to cognitive impairments and alterations of consciousness, the list of signs and symptoms shown was corroborated by her neighbor. Previously she was seemingly healthy. The symptoms were apparent because she was leaving her activities unfinished for no apparent reason; for example, if she was eating she would stop all of a sudden with no explanation. She wanted to sleep only during the day, presented serious memory defects: she did not remember what had just been said to her and did not recognize her life-long neighbors. She forgot to shower, even though she used to do it daily, and she would have difficulty thinking clearly. She was not speaking clearly and others could not understand her. These symptoms would not last all day, but rather would present themselves in certain periods during these 3 days.\n\nThe patient mentioned she stopped taking levothyroxine weeks before that period claiming she had forgotten where she stored her medication and that her symptoms went away when she resumed her treatment as indicated in a first consultation in the emergency medical service, a Mini-Mental State Examination (MMSE) practiced in the same query showed a score of 22 points. She seemed worried this episode might repeat itself and might become permanent in the future.\n\nDiscussion\nThe patient who inspired this case review, is an 81-year-old seemingly healthy female, sensory processing and usual behavior were suddenly altered. This lasted for a short period of time, with constant fluctuations, showing symptoms of memory impairment, disorientation and language impairment, as stated by the patient. The patient requested a consultation after an episode of unusual behaviors that had started suddenly and developed in a 3-day period. As far as she can remember and as confirmed by her neighbor, she seemed disorganized, leaving her activities unfinished for no apparent reason and forgetting to resume them, showing significant memory loss (she could not remember who her neighbors were, people who she has known for decades), a potential inversion of the sleep cycle, wakefulness and a state of confusion. All these symptoms fluctuated and were not considered to be related to any other cognitive disorder.\n\nAlthough during that period the patient appeared to be in a state that would fall under psychotic, she actually presented a rather typical case of delirium in accordance with the DSM-5 criteria for delirium. There is a set of criteria that is difficult to detect: family history, medical exams or analyses that suggest the episode is a direct physiological consequence of a condition, intoxication or withdrawal syndrome, or the exposure to a certain toxin (or a combination thereof).2 Symptoms described may resemble catatonia, but she only was having agitation no influenced by external stimuli, and the diagnostic criteria for catatonia needs three (or more) symptoms of catatonia.\n\nDuring the actual interview, the patient was feeling better. The results of her medical exam were within the expected limits. Her mental assessment only revealed a slight difficulty with calculations, a new MMSE practiced showed a score of 27 points. The patient is a known carrier of hyperthyroidism and normally takes her medication on a daily basis. This treatment was interrupted abruptly, as she forgot to take her medication and, within 10 days, started to show the above-mentioned symptoms, which can be attributed to the seven-day half-life of levothyroxine. The thyroid-stimulating hormone and Thyroxine libre lab tests could not be performed because the patient attended the next consultation after she resumed her medication. That resuming the consumption of levothyroxine made her symptoms disappear supports the diagnosis of delirium caused by the sudden interruption of the treatment.\n\nThe sudden interruption of the chronic levothyroxine treatment triggered delirium symptoms, of which stress was the main trigger. The relationship between delirium and medication withdrawal was made more apparent due to the fast disappearance of the symptoms once the treatment was resumed.\n\nLiterature defines thyroid hormones as responsible for regulating the metabolism.8 A decrease in the level of thyroid hormones produces significant changes in the receptors of noradrenaline, serotonin, and GABAergic agents, but its psychiatric illness-producing mechanism is not clear.9 Accordingly, altering one of these neurotransmitters, in addition to variations of the thyroid hormone may cause delirium, as alterations in the function of neurotransmitters have been described, among others, as the physiopathological cause of delirium.10,11\n\nThe onset of symptoms caused by the sudden interruption of the levothyroxine treatment evidences that the decrease in thyroid hormone levels in the patient, in addition to her reduced capacity to cope with change and stressors common of her age, may have been the cause of delirium, which may reappear should the treatment be interrupted yet again.\n\nConclusions\nDelirium is a multifactorial syndrome; therefore, identifying the triggering factor is vital to provide treatment. Once the initial problem is fixed, delirium is resolved. Identification is crucial for adequate diagnosis and treatment.\n==== Refs\nReferences\n1. Sanchez RS Beltran C Lara SA Chiquete E. \nDelirium en adultos que reciben cuidados paliativos: revisión de la literatura con un enfoque sistemático . Rev Psiquiatr Salud Ment \n2014 ;7 :48 -58 .23911280 \n2. Restrepo D Niño J Ortiz D. \nPrevención del delirium . Rev Col Psiqui \n2016 ;45 :37 -45 .\n3. American Psychiatric Association . Diagnostic and statistical manual of mental disorders . 5th ed. \nWashington, DC : American Psychiatric Publishing ; 2013 .\n4. World Health Organization . The ICD-10 classification of mental and behavioral disorders: Clinical descriptions and diagnostic guidelines . 1st ed. \nGeneva : World Health Organization ; 1992 .\n5. Deksnyte A Ramunas A Valmantas B \nDelirium: its historical evolution and current interpretation . Eur J Intern Med \n2012 ;23 :482 -5 .\n6. Sadock BJ Sadock VA Ruiz P. \nKaplan and Sadock’s synopsis of psychiatry: behavioral sciences/clinical psychiatry . 11th ed. \nPhiladelphia PA : Wolters Kluwer ; 2015 .\n7. Valencia C Heredia R Moreno A. \nEnvejecimiento y delirium: un viejo conocido en el Departamento de Urgencias . Revista Médicas UIS \n2014 ;27 :85 -92 .\n8. Restrepo D Niño J Ortiz D. \nPrevención del delirium . Rev Col Psiqui \n2016 ;45 :37 -45 .\n9. González E Gil Y Younes T \nDisfunción tiroidea y su relación con el perfil lipídico e índices aterogénicos en individuos antes y después de la tiroidectomía . Rev Venez Endocrinol Metab \n2014 ;12 :4 -11 .\n10. Ortiz-Pérez L de la Espriella M \nHormonas tiroideas y trastornos afectivos . Rev Col Psiqui \n2004 ;33 :98 -107 .\n11. Ganuza Z González-Torres M Gaviria M. \nEl delirium. Una revisión orientada a la práctica clínica . Rev Asoc Esp Neuropsiq \n2012 ;32 :247 -59 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2036-7457",
"issue": "8(2)",
"journal": "Mental illness",
"keywords": "Confusion; Delirium; Drug Recalls",
"medline_ta": "Ment Illn",
"mesh_terms": null,
"nlm_unique_id": "101634942",
"other_id": null,
"pages": "6787",
"pmc": null,
"pmid": "27994835",
"pubdate": "2016-11-23",
"publication_types": "D002363:Case Reports",
"references": "22795469;23911280;26896403",
"title": "Delirium, Caused by Suspending Treatment of Hypothyroidism.",
"title_normalized": "delirium caused by suspending treatment of hypothyroidism"
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"abstract": "Cerebral sinovenous thrombosis (CSVT) is a rare but not a negligible complication in pediatric brain tumor. An 11-year-old male with suprasellar germ cell tumor developed treatment-related vascular complications of CSVT and subdural hematoma. The underlying mechanism of CSVT was attributed to multiple risk factors, such as adipsic diabetes insipidus, obesity, central apnea, and chemotherapy-induced endothelial injury. In an attempt to minimize the possible risk of vascular complications, including late effect in pediatric brain tumors, we would like to stress the importance of individualized supportive therapy, i.e., hormone replacement, fluid management, thromboprophylaxis, and bi-level positive airway pressure therapy.",
"affiliations": "Department of Pediatric Hematology and Oncology, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan, kobayashi-kn@ncchd.go.jp.;Department of Pediatric Hematology and Oncology, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan.;Department of Pediatrics, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan.;Department of Pediatric Hematology and Oncology, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan.;Department of Neurology, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan.;Department of Pediatric Neurology, Osaka City General Hospital, Osaka, Japan.;Department of Pediatrics, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan.",
"authors": "Kobayashi|Kenichiro|K|;Suehiro|Minoru|M|;Maihara|Toshiro|T|;Usami|Ikuya|I|;Kageyama|Yasufumi|Y|;Okazaki|Shin|S|;Heike|Toshio|T|",
"chemical_list": "D000925:Anticoagulants",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000501044",
"fulltext": null,
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"issn_linking": "1016-2291",
"issue": "54(4)",
"journal": "Pediatric neurosurgery",
"keywords": "Adipsic diabetes insipidus; Central apnea; Cerebral sinovenous thrombosis; Chemotherapy; Endothelial injury",
"medline_ta": "Pediatr Neurosurg",
"mesh_terms": "D000925:Anticoagulants; D002648:Child; D003919:Diabetes Insipidus; D004358:Drug Therapy; D018237:Germinoma; D006408:Hematoma, Subdural; D006801:Humans; D008297:Male; D009765:Obesity; D010911:Pituitary Neoplasms; D012851:Sinus Thrombosis, Intracranial",
"nlm_unique_id": "9114967",
"other_id": null,
"pages": "288-292",
"pmc": null,
"pmid": "31291634",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Cerebral Sinovenous Thrombosis and Subdural Hematoma as Treatment-Related Complications in Suprasellar Germ Cell Tumor Associated with Adipsic Diabetes Insipidus.",
"title_normalized": "cerebral sinovenous thrombosis and subdural hematoma as treatment related complications in suprasellar germ cell tumor associated with adipsic diabetes insipidus"
} | [
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"abstract": "Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist used for the treatment of type 2 diabetes mellitus. We are reporting the second case of liraglutide-induced liver injury, with complete resolution of liver injury after discontinuation of the drug.",
"affiliations": "Department of Internal Medicine, Geisinger Lewistown Hospital, Lewiston, Pennsylvania, USA.;Department of Gastroenterology, Brooklyn Hospital Center, Brooklyn, New York, USA.;Department of Gastroenterology, Brooklyn Hospital Center, Brooklyn, New York, USA.;St. George's University, St. George, Grenada.;Department of Gastroenterology, Blanchard Valley Health System, Findlay, Ohio, USA.",
"authors": "Parvataneni|Swetha|S|https://orcid.org/0000-0002-5932-2237;Ramachandran|Rajarajeshwari|R|https://orcid.org/0000-0001-5367-869X;Then|Eric|E|https://orcid.org/0000-0003-3649-1190;Grantham|Tyler|T|https://orcid.org/0000-0002-9213-9880;Gaduputi|Vinaya|V|https://orcid.org/0000-0002-3789-5392",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/6306149",
"fulltext": "\n==== Front\nCase Rep Gastrointest Med\nCase Rep Gastrointest Med\nCRIGM\nCase Reports in Gastrointestinal Medicine\n2090-6528\n2090-6536\nHindawi\n\n10.1155/2021/6306149\nCase Report\nAn Exceedingly Rare Case of Liraglutide-Induced Liver Injury\nhttps://orcid.org/0000-0002-5932-2237\nParvataneni Swetha 1\nhttps://orcid.org/0000-0001-5367-869X\nRamachandran Rajarajeshwari rajeeeram@gmail.com\n2\nhttps://orcid.org/0000-0003-3649-1190\nThen Eric 2\nhttps://orcid.org/0000-0002-9213-9880\nGrantham Tyler 3\nhttps://orcid.org/0000-0002-3789-5392\nGaduputi Vinaya 4\n1Department of Internal Medicine, Geisinger Lewistown Hospital, Lewiston, Pennsylvania, USA\n2Department of Gastroenterology, Brooklyn Hospital Center, Brooklyn, New York, USA\n3St. George's University, St. George, Grenada\n4Department of Gastroenterology, Blanchard Valley Health System, Findlay, Ohio, USA\nAcademic Editor: Marcel Cerqueira Cesar Machado\n\n2021\n23 8 2021\n2021 630614911 7 2021\n12 8 2021\nCopyright © 2021 Swetha Parvataneni et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This 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.\nLiraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist used for the treatment of type 2 diabetes mellitus. We are reporting the second case of liraglutide-induced liver injury, with complete resolution of liver injury after discontinuation of the drug.\n==== Body\n1. Introduction\n\nDiabetes mellitus is a major health burden, affecting about 34.2 million adults in the United States [1, 2]. Several classes of drugs have been developed and approved by the Food and Drug Administration for the treatment of type 2 diabetes mellitus. Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as a promising treatment for individuals with type 2 diabetes mellitus who have poor glycemic control with oral medications [3]. GLP-1 receptors are present in pancreatic cells, adipose tissue, gastrointestinal tract, central nervous system, and cardiovascular system. Activation of these receptors results in slowed gastric emptying and activation of the satiety center resulting in decreased food intake [4, 5]. These effects underlie the mechanism of GLP-1 agonist in achieving adequate glycemic control and weight loss. Clinical trials demonstrated safety of the drug and its effectiveness in glycemic control when used in combination with other oral antidiabetic medications [6–11]. The most common adverse events reported in these trials were nausea, vomiting, and diarrhea, and rare cases of pancreatitis and thyroid cancer were reported in animal models when exposed to high doses of liraglutide. To our knowledge, this is the second case report of drug-induced liver injury (DILI) directly related to liraglutide, with complete resolution of liver injury upon cessation of the drug.\n\n2. Case Report\n\nA 64-year-old woman with hypertension, diabetes mellitus, hyperlipidemia, and history of cholecystectomy presented to the hospital for the evaluation of 4-day history of diffuse abdominal pain. Her home medications were lisinopril, metformin, and liraglutide. She denied alcohol use, illicit drug use, and use of over-the-counter supplements and herbal preparations. On examination, she had epigastric tenderness. She did not exhibit features of liver failure. Her laboratory tests were remarkable for alanine aminotransferase (ALT): 1359 U/L; aspartate aminotransferase (AST): 565 U/L; alkaline phosphatase (ALP): 405 U/L; total bilirubin (TB): 2.9 mg/dL; and INR: 0.9. R factor was consistent with hepatocellular injury. Hepatitis A IgM, hepatitis B surface antigen, hepatitis B surface antibodies, hepatitis B core antibodies and hepatitis C RNA, CMV viral load, and EBV viral load were negative. Immunoglobulin G, antinuclear antibodies, anti-smooth muscle antibodies, antimitochondrial antibodies, anti-liver-kidney microsomal antibodies, ferritin, iron saturation, alpha-1 antitrypsin, ceruloplasmin, and 24-hour urinary copper were normal. Abdominal ultrasound demonstrated fatty changes of the liver, without evidence of biliary obstruction. Her liver tests were normal 6 months prior to presentation, when the patient was started on liraglutide. Due to concern for DILI, liraglutide was discontinued and N-acetylcysteine was administered. On the third day of hospitalization, the patient's symptoms resolved, and her liver tests demonstrated gradual improvement. On the day of discharge, her liver tests were ALT: 335 U/L; AST: 58 U/L; ALP: 286 U/L; and TB: 1.3 mg/dL. 2 months after discharge, her liver tests normalized.\n\n3. Discussion\n\nThe liver is the major site for first-pass metabolism of medications. DILI is the most common cause of acute liver failure in the United States [12, 13]. The incidence of idiosyncratic DILI has risen because of increased emergence of new medications with the growing chronic medical problems.\n\nLiraglutide is evolving as a promising treatment option for patients with type 2 diabetes mellitus. It is a recombinant human GLP-1 analog with 97% amino acid sequence homologous with human GLP-1 [14]. Mechanism of liver injury due to liraglutide use is unknown, and the medication label includes elevation of liver enzymes based on postmarketing experiences. Approximately 8% of patients exposed to liraglutide will develop antiliraglutide antibodies; however, in the study by Buse et al., the antiliraglutide antibodies were found to have no effect on the safety of medication use [14].\n\nIn our literature search, we identified a case of liraglutide-induced autoimmune hepatitis reported by Kern et al; however, the patient's condition did not improve after stopping liraglutide, and the patient eventually needed long-term corticosteroid therapy [15]. Lack of improvement after discontinuation of the drug in this case suggests autoimmune hepatitis independent of the drug use or liraglutide triggered underlying liver condition [16]. Maor et al. reported the first care of liraglutide-induced hepatotoxicity in a 53-year-old woman taking the medication as part of her weight loss program, with complete resolution of liver injury after discontinuation of the medication [17].\n\nOur patient had a hepatocellular pattern of liver injury in the setting of recent initiation of liraglutide. Liver biopsies are not required to make the diagnosis of DILI. Based on the temporal relationship between the use of liraglutide and development of liver injury, we suspected liraglutide-induced liver injury. Our patient was advised to discontinue liraglutide leading to normalization of liver tests and this further supported our diagnosis of liraglutide-induced liver injury.\n\nAbbreviations\n\nGLP-1: Glucagon-like peptide-1\n\nDILI: Drug-induced liver injury.\n\nConsent\n\nInformed consent was obtained from the patient for the publication of this article with anonymized information.\n\nConflicts of Interest\n\nThe authors have no conflicts of interest to declare.\n==== Refs\n1 Center for Disease Control and Prevention National Diabetes Statistics Report 2020 Atlanta, GA, USA Center for Disease Control and Prevention https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf\n2 Gray N. Picone G. Sloan F. Yashkin A. Relation between BMI and diabetes mellitus and its complications among US older adults Southern Medical Journal 2015 108 1 29 36 10.14423/smj.0000000000000214 2-s2.0-84925032493 25580754\n3 Koliaki C. Doupis J. Incretin-based therapy: a powerful and promising weapon in the treatment of type 2 diabetes mellitus Diabetes Therapy 2011 2 2 101 121 10.1007/s13300-011-0002-3 2-s2.0-79955930032 22127804\n4 Nagell C. F. Wettergren A. Ørskov C. Holst J. J. Inhibitory effect of GLP-1 on gastric motility persists after vagal deafferentation in pigs Scandinavian Journal of Gastroenterology 2006 41 6 667 672 10.1080/00365520500408253 2-s2.0-33745700396 16716964\n5 Williams D. L. Baskin D. G. Schwartz M. W. Evidence that intestinal glucagon-like peptide-1 plays a physiological role in satiety Endocrinology 2009 150 4 1680 1687 10.1210/en.2008-1045 2-s2.0-63849248275 19074583\n6 Marre M. Shaw J. Brändle M. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU) Diabetic Medicine 2009 26 3 268 278 10.1111/j.1464-5491.2009.02666.x 2-s2.0-62449129181 19317822\n7 Nauck M. Frid A. Hermansen K. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes Diabetes Care 2009 32 1 84 90 10.2337/dc08-1355 2-s2.0-62449169287 18931095\n8 Garber A. Henry R. Ratner R. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial Lancet 2009 373 9662 473 481 10.1016/s0140-6736(08)61246-5 2-s2.0-59449101432 18819705\n9 Zinman B. Gerich J. Buse J. B. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD) Diabetes Care 2009 32 7 1224 1230 10.2337/dc08-2124 2-s2.0-67650066860 19289857\n10 Russell-Jones D. Vaag A. Schmitz O. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial Diabetologia 2009 52 10 2046 2055 10.1007/s00125-009-1472-y 2-s2.0-69949117621 19688338\n11 Buse J. B. Rosenstock J. Sesti G. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6) Lancet 2009 374 9683 39 47 10.1016/s0140-6736(09)60659-0 2-s2.0-67649666737 19515413\n12 Ostapowicz G. Fontana R. J. Schioødt F. V. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States Annals of Internal Medicine 2002 137 12 947 954 10.7326/0003-4819-137-12-200212170-00007 2-s2.0-0037126649 12484709\n13 Reuben A. Koch D. G. Lee W. M. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study Hepatology 2010 52 6 2065 2076 10.1002/hep.23937 2-s2.0-78649625452 20949552\n14 Buse J. B. Garber A. Rosenstock J. Liraglutide treatment is associated with a low frequency and magnitude of antibody formation with no apparent impact on glycemic response or increased frequency of adverse events: results from the liraglutide effect and action in diabetes (LEAD) trials Journal of Clinical Endocrinology & Metabolism 2011 96 6 1695 1702 10.1210/jc.2010-2822 2-s2.0-79956328908 21450987\n15 Kern E. Van Wagner L. B. Yang G. Y. Rinella M. E. Liraglutide-induced autoimmune hepatitis JAMA Internal Medicine 2014 174 6 984 987 10.1001/jamainternmed.2014.674 2-s2.0-84902137985 24733687\n16 LiverTox Clinical and Research Information on Drug-Induced Liver Injury 2012 Bethesda, MD, USA National Institute of Diabetes and Digestive and Kidney Diseases https://www.ncbi.nlm.nih.gov/books/NBK548472/\n17 Maor Y. Ergaz D. Malnick S. D. H. Melzer E. Neuman M. G. Liraglutide-induced hepatotoxicity Biomedicines 2021 9 2 p. 106 10.3390/biomedicines9020106\n\n",
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"issue": "2021()",
"journal": "Case reports in gastrointestinal medicine",
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"nlm_unique_id": "101580185",
"other_id": null,
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"pmc": null,
"pmid": "34471551",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "24733687;18819705;16716964;19688338;19074583;19317822;20949552;21450987;25580754;18931095;22127804;12484709;19515413;33498980;19289857",
"title": "An Exceedingly Rare Case of Liraglutide-Induced Liver Injury.",
"title_normalized": "an exceedingly rare case of liraglutide induced liver injury"
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"abstract": "Late peripheral arterial stent thrombosis usually occurs due to haemodynamically relevant in-stent restenosis. However, late stent thrombosis may be multicausal. We report here the well-documented case of a 69-year-old man with acute thrombosis of the stented superficial femoral artery after a long-distance bicycle tour. Catheter-directed thrombolysis revealed a residual stenosis located at a stent fracture site. In addition, platelet function tests revealed an inadequate platelet response to clopidogrel. In conclusion, stent fracture, strenuous exercise and hyporesponsiveness to clopidogrel may have contributed to the development of late peripheral stent thrombosis.",
"affiliations": "Division of Vascular Medicine, Department of Internal Medicine, J.W. Goethe University Hospital, Frankfurt/Main, Germany. Birgit.Linnemann@kgu.de",
"authors": "Linnemann|Birgit|B|;Thalhammer|Axel|A|;Wolf|Zsuzsanna|Z|;Tirneci|Vanessa|V|;Vogl|Thomas J|TJ|;Edelgard Lindhoff-Last|And|A|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine",
"country": "Switzerland",
"delete": false,
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"issue": "41(2)",
"journal": "VASA. Zeitschrift fur Gefasskrankheiten",
"keywords": null,
"medline_ta": "Vasa",
"mesh_terms": "D000368:Aged; D017130:Angioplasty; D001157:Arterial Occlusive Diseases; D001642:Bicycling; D000077144:Clopidogrel; D003251:Constriction, Pathologic; D004351:Drug Resistance; D015444:Exercise; D005263:Femoral Artery; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors; D010979:Platelet Function Tests; D011474:Prosthesis Design; D011475:Prosthesis Failure; D011859:Radiography; D012307:Risk Factors; D015607:Stents; D015912:Thrombolytic Therapy; D013927:Thrombosis; D013988:Ticlopidine; D016896:Treatment Outcome",
"nlm_unique_id": "0317051",
"other_id": null,
"pages": "136-44",
"pmc": null,
"pmid": "22403133",
"pubdate": "2012-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Late peripheral stent thrombosis due to stent fracture, vigorous exercise and hyporesponsiveness to clopidogrel.",
"title_normalized": "late peripheral stent thrombosis due to stent fracture vigorous exercise and hyporesponsiveness to clopidogrel"
} | [
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"companynumb": "DE-SA-2014SA118681",
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"activesubstancename": "CLOPIDOGREL BISULFATE"
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{
"abstract": "BACKGROUND\nIn West and Central Africa Buruli ulcer (BU) and HIV co-infection is increasingly recognised and management of these two diseases combined is an emerging challenge for which there is little published information. In this case we present a severe paradoxical reaction occurring after commencing antibiotic treatment for BU combined with antiretroviral therapy for HIV, and describe its clinical features and management. This includes to our knowledge the first reported use of prednisolone in Africa to manage a severe paradoxical reaction related to BU treatment.\n\n\nMETHODS\nA 30 year old immunosuppressed HIV positive man from Cameroon developed a severe paradoxical reaction 24 days after commencing antibiotic treatment for BU and 14 days after commencing antiretroviral therapy for HIV. Oral prednisolone was successfully used to settle the reaction and prevent further tissue loss. The antiretroviral regimen was continued unchanged and the BU antibiotic treatment not prolonged beyond the recommended duration of 8 weeks. A second small local paradoxical lesion developed 8 months after starting antibiotics and settled with conservative treatment only. Complete healing of lesions occurred and there was no disease recurrence 12 months after commencement of treatment.\n\n\nCONCLUSIONS\nClinicians should be aware that severe paradoxical reactions can occur during the treatment of BU/HIV co-infected patients. Prednisolone was effectively and safely used to settle the reaction and minimize the secondary tissue damage.",
"affiliations": "Manson Unit, Médecins Sans Frontières, London, UK. daniel.obrien@amsterdam.msf.org.",
"authors": "Wanda|Franck|F|;Nkemenang|Patrick|P|;Ehounou|Genevieve|G|;Tchaton|Marie|M|;Comte|Eric|E|;Toutous Trellu|Laurence|L|;Masouyé|Isabelle|I|;Christinet|Vanessa|V|;O'Brien|Daniel P|DP|",
"chemical_list": "D000900:Anti-Bacterial Agents; D019380:Anti-HIV Agents",
"country": "England",
"delete": false,
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"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 25073531371910.1186/1471-2334-14-423Case ReportClinical features and management of a severe paradoxical reaction associated with combined treatment of Buruli ulcer and HIV co-infection Wanda Franck MSFCH-Akonolinga-Medical@geneva.msf.org Nkemenang Patrick MSFCH-Akonolinga-Medical@geneva.msf.org Ehounou Genevieve MSFCH-Yaounde-Medco@geneva.msf.org Tchaton Marie MSFCH-Akonolinga-Rmt@geneva.msf.org Comte Eric Eric.COMTE@geneva.msf.org Toutous Trellu Laurence Laurence.Trellu@hcuge.ch Masouyé Isabelle Isabelle.Masouye@hcuge.ch Christinet Vanessa vchristinet@hotmail.com O’Brien Daniel P daniel.obrien@amsterdam.msf.org Médecins Sans Frontières, Akonolinga, Cameroon Medical Unit, Médecins Sans Frontières, Geneva, Switzerland Department of Dermatology, University Hospitals of Geneva, Geneva, Switzerland Manson Unit, Médecins Sans Frontières, London, UK Department of Infectious Diseases, Geelong Hospital, Geelong, Australia Department of Medicine and Infectious Diseases, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia 30 7 2014 30 7 2014 2014 14 42321 3 2014 15 7 2014 © Wanda et al.; licensee BioMed Central Ltd. 2014This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nIn West and Central Africa Buruli ulcer (BU) and HIV co-infection is increasingly recognised and management of these two diseases combined is an emerging challenge for which there is little published information. In this case we present a severe paradoxical reaction occurring after commencing antibiotic treatment for BU combined with antiretroviral therapy for HIV, and describe its clinical features and management. This includes to our knowledge the first reported use of prednisolone in Africa to manage a severe paradoxical reaction related to BU treatment.\n\nCase presentation\nA 30 year old immunosuppressed HIV positive man from Cameroon developed a severe paradoxical reaction 24 days after commencing antibiotic treatment for BU and 14 days after commencing antiretroviral therapy for HIV. Oral prednisolone was successfully used to settle the reaction and prevent further tissue loss. The antiretroviral regimen was continued unchanged and the BU antibiotic treatment not prolonged beyond the recommended duration of 8 weeks. A second small local paradoxical lesion developed 8 months after starting antibiotics and settled with conservative treatment only. Complete healing of lesions occurred and there was no disease recurrence 12 months after commencement of treatment.\n\nConclusions\nClinicians should be aware that severe paradoxical reactions can occur during the treatment of BU/HIV co-infected patients. Prednisolone was effectively and safely used to settle the reaction and minimize the secondary tissue damage.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/1471-2334-14-423) contains supplementary material, which is available to authorized users.\n\nKeywords\nMycobacterium ulceransBuruli ulcerHIVParadoxical reactionAntibioticsAntiretroviral treatmentPrednisoloneissue-copyright-statement© The Author(s) 2014\n==== Body\nBackground\nMycobacterium ulcerans causes severe destructive lesions of skin, soft-tissue and bone mediated through its potent exotoxin mycolactone that are known as Buruli ulcers (BU). They are most commonly found in Central and West Africa but have been reported from Australia, Asia, South America and the Pacific [1]. It predominantly affects children in rural and remote regions and often results in permanent disability. Co-infection with HIV is increasingly recognised and is thought to result in more severe disease and slower healing times following treatment [2–4]. Paradoxical reactions have recently been recognised to complicate up to 20% of patients receiving antibiotics for BU, [5] and can lead to significant secondary tissue destruction [6]. Prednisolone has been used to successfully minimize tissue destruction from severe paradoxical reactions in Australia, [7] but its use in Africa for this indication has not been reported. It is not known whether the incidence of paradoxical reactions is affected by BU/HIV co-infection or antiretroviral treatment (ART), and there is a lack of information to guide their management in BU/HIV co-infected patients [8].\n\nIn this case we present a severe paradoxical reaction occurring in a patient co-infected with BU/HIV after commencing antibiotic treatment for BU concomitantly with ART for HIV. We describe its clinical features and management including to our knowledge the first reported use of prednisolone to manage a severe paradoxical reaction related to BU treatment in Africa.\n\nCase presentation\nCase details\nA 30 year old man living in rural Cameroon presented to the Buruli ulcer treatment center in Akonolinga, Cameroon, in January 2013 with a 7-month history of plaque-like lesions over the lateral aspect of this left ankle and posterior aspect of his left leg both of which later ulcerated. The ulcer on the lateral aspect of the left ankle measured 14 cm x 9 cm with some small areas of necrosis and inflammation in the surrounding tissue. The second ulcerative lesion on the left leg measured 6 cm x 4 cm with minimal surrounding inflammation. Xrays of the left ankle and left leg revealed no evidence of osteomyelitis deep to the lesions. His weight was 65 kg and Body Mass Index 25. Further examination was unremarkable with specifically no clinical evidence of co-infection with tuberculosis and a chest X-ray was normal.\n\nHe had been previously diagnosed elsewhere with HIV infection and received 2 months of ART from January 2012 but had then interrupted it. A HIV antibody test on presentation to Akonolinga was positive and a CD4 count was 212 cells/mm3. Baseline viral load was not available.\n\nThe diagnosis of BU was made on the basis of a positive AFB stain and compatible histopathology showing a granulomatous infiltrate on tissue biopsies, and a positive IS2404 PCR and AFB stain on swab specimens, of both the ankle and leg lesions.\n\nHe was hospitalised and commenced on BU treatment with oral rifampicin 600 mg daily and intramuscular streptomycin (STM) 1 gram daily on 9/1/13. Within 24 hours he developed a fever to 39.5 degrees and a generalised pustular and itchy rash. A diagnosis of a STM hypersensitivity reaction was made and the STM was replaced by clarithromycin 500 mg twice daily. Prednisolone 30 mg orally daily was also given for 10 days and the reaction resolved.\n\nAntiretroviral treatment (ART) was commenced on 19/1/13 with a regimen containing zidovudine, lamivudine and efavirenz. Co-trimoxazole 960 mg/day was also commenced at the same time. Antibiotic and ART adherence was directly supervised in the hospital.Two weeks after ART initiation the tissue around the ulcer became inflamed, with significant oedema extending across the dorsum of the foot to the toes with evidence of extending necrosis and ulceration from the wound margins. (Figure 1) A provisional clinical diagnosis of a severe paradoxical reaction was made and 2 tissue biopsy specimens were performed for histological and microbiological examination; one from the edge of the lesion and one from the centre of the oedematous dorsum of the foot. Whilst awaiting the results the patient was commenced on oral prednisolone (50 mg daily) with the aim to reduce the severity of the paradoxical reaction and prevent further ulceration of the tissue on the dorsum of the foot. Prednisolone was continued at 50 mg daily for 2 weeks then weaned to 30 mg daily for 1 week, then 20 mg daily for 2 weeks and then 10 mg daily for 2 weeks (total 7 weeks). Albendazole 400 mg daily for 3 days was given at prednisolone commencement to treat any possible strongyloides co-infection. ART was continued unchanged.Histopathological examination of the tissue biopsy revealed diffuse inflammation with lymphoid granulomas (Figure 2) and was negative on examination for acid fast bacilli (AFB) consistent with a paradoxical reaction. Mycobacterial cultures were not performed on the tissue. Following prednisolone treatment the tissue oedema rapidly settled and no further ulceration of the skin on the adjacent dorsum of the foot occurred (Figures 3 and 4). The prednisolone treatment was well tolerated.Figure 1 \nBU ulcer on lateral aspect of the left ankle complicated by a severe paradoxical reaction with extending necrosis and swelling of skin and subcutaneous tissue of the forefoot.\n\n\nFigure 2 \nBiopsy of oedematous forefoot lesion 2 weeks after commencing ART showing a dense inflammatory reaction with lymphoid granulomas consistent with a paradoxical reaction.\n\n\nFigure 3 \nBU ulcer on lateral aspect of the left ankle showing significant reduction in swelling of skin and subcutaneous tissue of the forefoot with preservation of tissue following 10 days of prednisolone treatment.\n\n\nFigure 4 \nBU ulcer on lateral aspect left ankle showing significant reduction in swelling of skin and subcutaneous tissue of the forefoot with preservation of tissue following 30 days of prednisolone treatment.\n\n\n\n\nThe BU antibiotics were ceased on 3/3/13 after 53 days of treatment with no further adverse effects. The ankle lesion underwent surgical debridement to remove hypergranulation tissue on 13/3/13. The skin defect underwent further surgical debridement and was closed with a split skin graft on 4/7/2013. The graft healed well (Figure 5). The patient had excellent adherence to his ART which he tolerated well. After 6 months of ART the viral load was undetectable and after 8 months the CD4 count had increased to 416 cells/mm3.A further 1 cm ulcerated lesion on the retromalleolar region of the left ankle appeared 8 months after the start of BU antibiotic treatment. (Figure 6) This was diagnosed as a late paradoxical reaction clinically and was confirmed as such by a biopsy revealing significant inflammation with no AFB seen on histology, and mycobacterial cultures of a swab of the lesion were negative despite the PCR of the swab remaining positive. The lesion healed 12 weeks later with dressings as the only treatment.Figure 5 \nHealed BU lesion 10 months after commencement of antibiotics and 2 months post split skin graft.\n\n\nFigure 6 \nSecond paradoxical lesion developing in retromalleolar region of left ankle 8 months after commencing BU antibiotic treatment.\n\n\n\n\nThe patient was discharged from hospital 11 months after starting antibiotics. Twelve months after completing antibiotic treatment all the lesions remain healed with no evidence of BU recurrence.\n\nDiscussion of case\nWe present a case of a severe paradoxical reaction occurring in an HIV-infected patient receiving combined BU antibiotic treatment and ART. The severity of the reaction threatened the viability of tissue around the BU lesion, especially across the dorsum of the left foot. The diagnosis of a paradoxical reaction was initially based on a consistent clinical picture where the lesion and surrounding tissue deteriorated after 3 weeks of antibiotics [5, 6]. This was later supported by the histological appearances that showed evidence of an intense inflammatory reaction consistent with previous descriptions of paradoxical reactions [6, 9]. Paradoxical reactions, also known as immune reconstitution reactions, [9] are proposed to result from a reversal of the mycolactone toxin induced immune-inhibitory state via the antibiotic mediated killing of M. ulcerans organisms allowing an intense immunological reaction to develop against the persisting mycobacterial antigens [10, 11]. As has been reported in HIV-negative patients following the completion of antibiotics, [12, 13] a second paradoxical lesion developed on the retromalleolar region of the left ankle 6 months after antibiotics were ceased. Late reactions may account for up to 24% of paradoxical cases, [6] and this reaction was likely due to enhanced immune responses to a previously undetected disease focus.\n\nIt is not known whether paradoxical reactions are increased in HIV patients with BU, whether this is influenced by the baseline level of immune suppression or whether it is further potentiated when the generalised immune suppressed state is partially reversed by ART. However it is known that paradoxical reactions are common in HIV patients commencing ART with a variety of other microorganisms including tuberculosis (TB) [14], cryptococcus [15] and Mycobacterium avium complex [16], and that the rate increases with increasing immunosuppression at ART baseline [17]. Furthermore in TB/HIV co-infection, the incidence of TB associated immune reconstitution disease is increased in those who commence ART within 30 days of commencing TB treatment [14]. If these findings can be extrapolated to BU treatment, then in our case some factors existed that may have increased the paradoxical reaction risk: the baseline level of immune suppression was significant (CD4 220 cells/mm3) and ART was commenced early (2 weeks) after the start of BU treatment. Furthermore the good response to his ART with a robust increase in his CD4 cell count and reduction in viral load to undetectable levels may have contributed. A recent report from Ivory Coast also describes further multifocal BU lesions developing in a HIV positive patient with severe immunosuppression (baseline CD4 count of 51 cells/mm3) one month after starting both BU antibiotic treatment and ART [18]. Further studies on the incidence and risk factors for paradoxical reactions during treatment of patients co-infected with BU/HIV are needed to investigate these issues [8].\n\nOral prednisolone was used in this patient to settle a severe paradoxical reaction. We believe it prevented further skin and subcutaneous tissue loss on the dorsum of the foot, which commonly occurs during treatment of oedematous BU lesions and with severe paradoxical reactions [6]. Evidence from the mouse model suggests that the use of corticosteroids does not increase the risk of BU treatment failure, [19] and it has been used successfully in an Australian setting to minimise damage from severe paradoxical reactions [6, 7, 20]. Potential risks of prednisolone administration in an African setting, such as worsening TB or disseminated strongyloides infection, were minimised by active screening of the patient for TB and administration of albendazole at initiation of prednisolone treatment. The prednisolone was well tolerated and did not result in any adverse effects. The usual recommended dose is 0.5-1.0 mg/kg daily tapered over 4-8 weeks [21]. Of note, despite the use of prednisolone, the duration of BU antibiotic treatment was not prolonged and the antiretroviral regimen was not ceased or altered and this did not appear to adversely affect outcomes.\n\nThis case also illustrates a number of important issues relevant to the patient co-infected with BU and HIV. Firstly the patient presented with large, multiple and ulcerated lesions consistent with previous reports of more severe BU disease at presentation in those co-infected with HIV [2, 4]. Secondly, due to a hypersensitivity reaction to streptomycin, the patient was treated with the all oral antibiotic combination of rifampicin and clarithromycin with good success. Although oral combinations have been effective in observational studies of HIV negative patients with BU, [22, 23] this case provides preliminary evidence that they may also be effective in HIV co-infected patients. Thirdly, although effective and safe in this case, there are concerns regarding the interaction of clarithromycin and efavirenz that may lead to reduced effectiveness and increased toxicity of BU treatment [24]. This potential interaction requires further study.\n\nConclusions\nSevere paradoxical reactions can occur during the antibiotic treatment of BU/HIV co-infected patients. Prednisolone was effectively and safely used to settle the reaction and minimize the secondary tissue damage. Further study on the incidence, risk factors and management of paradoxical reactions in HIV/BU co-infected populations is needed.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nAuthors’ original submitted files for images\nBelow are the links to the authors’ original submitted files for images.Authors’ original file for figure 1\n\nAuthors’ original file for figure 2\n\nAuthors’ original file for figure 3\n\nAuthors’ original file for figure 4\n\nAuthors’ original file for figure 5\n\nAuthors’ original file for figure 6\n\n\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nFW: Managed the case, collected the data, revised the manuscript. PN: Managed the case, collected the data, revised the manuscript. GE: Managed the case, revised the manuscript. EC: Managed the case, revised the manuscript. LTT: Performed the pathological analyses, revised the manuscript. IM: Performed the pathological analyses, revised the manuscript. VC: Critically revised the manuscript. DPOB: Managed the case, devised the concept for the article, wrote the first draft of the article. All authors read and approved the final manuscript.\n==== Refs\nReferences\n1. World Health Organisation Treatment of Mycobacterium Ulcerans Disease (Buruli ulcer): Guidance for Health Workers 2012 Switzerland Geneva \n2. Christinet V Rossel L Serafini M Delhumeau C Odermatt P Ciaffi L Impact of HIV on the Severity of Buruli Ulcer Disease: Results from a Retrospective Study in Cameroon Open Forum Infect Dis 2014 1 1 10.1093/ofid/ofu021 \n3. Johnson RC Nackers F Glynn JR de Biurrun Bakedano E Zinsou C Aguiar J Tonglet R Portaels F Johnson RC Nackers F Glynn JR de Biurrun Bakedano E Zinsou C Aguiar J Tonglet R Portaels F Association of HIV infection and Mycobacterium ulcerans disease in Benin AIDS (London, England) 2008 22 7 901 903 10.1097/QAD.0b013e3282f7690a \n4. Kibadi K Colebunders R Muyembe-Tamfum JJ Meyers WM Portaels F Buruli ulcer lesions in HIV-positive patient Emerg Infect Dis 2010 16 4 738 739 10.3201/eid1604.091343 20350411 \n5. Nienhuis WA Stienstra Y Abass KM Tuah W Thompson WA Awuah PC Awuah-Boateng NY Adjei O Bretzel G Schouten JP van der Werf TS Paradoxical responses after start of antimicrobial treatment in Mycobacterium ulcerans infection Clin Infect Dis 2012 54 4 519 526 10.1093/cid/cir856 22156855 \n6. O’Brien DP Robson M Friedman ND Walton A McDonald A Callan P Hughes A Rhadon R Athan E Incidence, clinical spectrum, diagnostic features, treatment and predictors of paradoxical reactions during antibiotic treatment of Mycobacterium ulcerans infections BMC Infect Dis 2013 13 416 10.1186/1471-2334-13-416 24007371 \n7. Friedman ND McDonald A Robson M O’Brien DP Corticosteroid use for paradoxical reactions during antibiotic treatment for Mycobacterium ulcerans PLoS Neglected Trop Dis 2012 6 9 e1769 10.1371/journal.pntd.0001767 \n8. O’Brien DP Comte E Serafini M Ehounou G Antierens A Vuagnat H Christinet V Hamani MD du Cros P The urgent need for clinical, diagnostic, and operational research for management of Buruli ulcer in Africa Lancet Infect Dis 2014 14 5 435 440 10.1016/S1473-3099(13)70201-9 24309480 \n9. O’Brien DP Robson ME Callan PP McDonald AH “Paradoxical” immune-mediated reactions to Mycobacterium ulcerans during antibiotic treatment: a result of treatment success, not failure Med J Aust 2009 191 10 564 566 19912091 \n10. Phillips R Sarfo FS Guenin-Mace L Decalf J Wansbrough-Jones M Albert ML Demangel C Immunosuppressive signature of cutaneous Mycobacterium ulcerans infection in the peripheral blood of patients with buruli ulcer disease J Infect Dis 2009 200 11 1675 1684 10.1086/646615 19863437 \n11. Schutte D Pluschke G Immunosuppression and treatment-associated inflammatory response in patients with Mycobacterium ulcerans infection (Buruli ulcer) Expet Opin Biol Ther 2009 9 2 187 200 10.1517/14712590802631854 \n12. Ruf MT Chauty A Adeye A Ardant MF Koussemou H Johnson RC Pluschke G Secondary Buruli ulcer skin lesions emerging several months after completion of chemotherapy: paradoxical reaction or evidence for immune protection? PLoS Neglected Trop Dis 2011 5 8 e1252 10.1371/journal.pntd.0001252 \n13. Beissner M Piten E Maman I Symank D Jansson M Nitschke J Amekuse K Kobara B Wiedemann F Hoffmann H Diefenhardt A Badziklou K Banla Kere A Loscher T Bretzel G Spontaneous clearance of a secondary Buruli ulcer lesion emerging ten months after completion of chemotherapy–a case report from Togo PLoS Neglected Trop Dis 2012 6 7 e1747 10.1371/journal.pntd.0001747 \n14. Tansuphasawadikul S Saito W Kim J Phonrat B Dhitavat J Chamnachanan S Pitisuttithum P Outcomes in HIV-infected patients on antiretroviral therapy with tuberculosis Southeast Asian J Trop Med Publ Health 2007 38 6 1053 1060 \n15. Chang CC Dorasamy AA Gosnell BI Elliott JH Spelman T Omarjee S Naranbhai V Coovadia Y Ndung’u T Moosa MY ILewin SR French MA Clinical and mycological predictors of cryptococcosis-associated immune reconstitution inflammatory syndrome AIDS (London, England) 2013 27 13 2089 2099 10.1097/QAD.0b013e3283614a8d \n16. Phillips P Bonner S Gataric N Bai T Wilcox P Hogg R O’Shaughnessy M Montaner J Nontuberculous mycobacterial immune reconstitution syndrome in HIV-infected patients: spectrum of disease and long-term follow-up Clin Infect Dis 2005 41 10 1483 1497 10.1086/497269 16231262 \n17. Muller M Wandel S Colebunders R Attia S Furrer H Egger M Ie DEAS Central A Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis Lancet Infect Dis 2010 10 4 251 261 10.1016/S1473-3099(10)70026-8 20334848 \n18. Komenan K Elidje EJ Ildevert GP Yao KI Kanga K Kouame KA Abdoulaye S Hamdam KS Yao YP Jean-Marie K Multifocal Buruli ulcer associated with secondary infection in HIV positive Patient Case Rep Med 2013 2013 348628 24454398 \n19. Martins TG Trigo G Fraga AG Gama JB Longatto-Filho A Saraiva M Silva MT Castro AG Pedrosa J Corticosteroid-induced immunosuppression ultimately does not compromise the efficacy of antibiotherapy in murine Mycobacterium ulcerans infection PLoS Neglected Trop Dis 2012 6 11 e1925 10.1371/journal.pntd.0001925 \n20. Trevillyan JM Johnson PD Steroids control paradoxical worsening of Mycobacterium ulcerans infection following initiation of antibiotic therapy Med J Aust 2013 198 8 443 444 10.5694/mja12.11559 23641997 \n21. O’Brien DP Jenkin G Buntine J Steffen CM McDonald A Horne S Friedman ND Athan E Hughes A Callan PP Johnson PD Treatment and prevention of Mycobacterium ulcerans infection (Buruli ulcer) in Australia: guideline update Med J Aust 2014 200 5 267 270 10.5694/mja13.11331 24641151 \n22. Friedman ND Athan E Hughes AJ Khajehnoori M McDonald A Callan P Rahdon R O’Brien DP Mycobacterium ulcerans disease: experience with primary oral medical therapy in an Australian cohort PLoS Neglected Trop Dis 2013 7 7 e2315 10.1371/journal.pntd.0002315 \n23. Chauty A Ardant MF Marsollier L Pluschke G Landier J Adeye A Goundote A Cottin J Ladikpo T Ruf T Ji B Oral treatment for Mycobacterium ulcerans infection: results from a pilot study in Benin Clin Infect Dis 2011 52 1 94 96 10.1093/cid/ciq072 21148526 \n24. O’Brien DP Comte E Ford N Christinet V du Cros P Moxifloxacin for Buruli ulcer/HIV coinfected patients: kill two birds with one stone? AIDS (London, England) 2013 27 14 2177 2179 10.1097/QAD.0b013e32836268f4\n\n",
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"references": null,
"title": "Unusual pattern of leukoencephalopathy after morphine sulphate intoxication.",
"title_normalized": "unusual pattern of leukoencephalopathy after morphine sulphate intoxication"
} | [
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"companynumb": "DE-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-144274",
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"activesubstancename": "MORPHINE SULFATE\\NALTREXONE HYDROCHLORI... |
{
"abstract": "BACKGROUND\nA significant proportion of patients with multiple sclerosis (MS) show cognitive impairment.\n\n\nOBJECTIVE\nTo evaluate the effect of 2-year treatment with oral dimethyl fumarate (DMF) on cognition in relapsing remitting MS (RRMS).\n\n\nMETHODS\nIn this prospective single-arm study RRMS patients treated with DMF underwent a wide battery of tests, including an extensive neuropsychological evaluation, clinical and patient-reported outcomes (PROs) and quality of life (QoL). Primary endpoints were the proportion of patients with cognitive impairment at baseline and of patients with cognitive worsening over 2 years.\n\n\nRESULTS\nOverall, 217 patients (74.2% females, mean age 37.3 years) receiving DMF were recruited, and 156 (67.2%) completed the study. Of the 49 patients with cognitive impairment at baseline, 34 had 2-year data: 15 (44.1%) patients worsened and 19 (55.9%) did not. The cognitive impairment index improved in one third of patients at 2 years. Less than 20% of patients had relapses at 2 years (annualized relapse rate: 0.190). Few patients had disability progression. PROs (fatigue, depression, impairment in work/social activities), QoL, and most of neuropsychological tests significantly improved vs. baseline.\n\n\nCONCLUSIONS\nThe 2-year treatment with DMF was associated with slowing of cognitive impairment and with significant improvements in QoL and psychosocial function.",
"affiliations": "Department NEUROFARBA, University of Florence, Florence, Italy. mariapia.amato@unifi.it.;Department NEUROFARBA, University of Florence, Florence, Italy.;University Federico II Napoli, Naples, Italy.;Azienda Ospedaliera di Padova, Padua, Italy.;Centro Sclerosi Multipla, ASST della Valle Olona, Gallarate, Italy.;Ospedale Policlinico Ss. Annunziata di Chieti, Chieti, Italy.;Ospedale Binaghi, Cagliari, Italy.;Neurological Centre of Latium, Rome, Italy.;Biogen Italy, Milan, Italy.;Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy.",
"authors": "Amato|Maria Pia|MP|;Goretti|Benedetta|B|;Brescia Morra|Vincenzo|V|;Gallo|Paolo|P|;Zaffaroni|Mauro|M|;Onofrj|Marco|M|;Cocco|Eleonora|E|;Borriello|Giovanna|G|;Zipoli|Valentina|V|;Trojano|Maria|M|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069462:Dimethyl Fumarate",
"country": "Italy",
"delete": false,
"doi": "10.1007/s10072-020-04320-w",
"fulltext": null,
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"issn_linking": "1590-1874",
"issue": "41(11)",
"journal": "Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology",
"keywords": "Cognition; Dimethyl fumarate; Relapsing remitting multiple sclerosis",
"medline_ta": "Neurol Sci",
"mesh_terms": "D000328:Adult; D003071:Cognition; D000069462:Dimethyl Fumarate; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D009103:Multiple Sclerosis; D020529:Multiple Sclerosis, Relapsing-Remitting; D011446:Prospective Studies; D011788:Quality of Life",
"nlm_unique_id": "100959175",
"other_id": null,
"pages": "3185-3193",
"pmc": null,
"pmid": "32358701",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": "28607719;22513513",
"title": "Effects of 2-year treatment with dimethyl fumarate on cognition and functional impairment in patients with relapsing remitting multiple sclerosis.",
"title_normalized": "effects of 2 year treatment with dimethyl fumarate on cognition and functional impairment in patients with relapsing remitting multiple sclerosis"
} | [
{
"companynumb": "IT-BIOGEN-2020BI00876696",
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"activesubstance": {
"activesubstancename": "DIMETHYL FUMARATE"
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"drugadditional": "3",
... |
{
"abstract": "Microscopic colitis (MC) is a chronic inflammation condition of the colon characterized by watery diarrhea and normal appearing mucosa. A 75-year-old female presented with one-year history of chronic diarrhea while taking cannabidiol (CBD) for pain. Colonoscopy with random colon biopsies revealed collagenous colitis. She started budesonide and stopped CBD. At six-week follow-up, her diarrhea improved, and the budesonide dose was decreased. She restarted CBD oil twice but had diarrhea both times. Her diarrhea resolved after taking budesonide and stopping CBD. We report a case of CBD-associated MC to make clinicians aware of this potential adverse effect in patients who chronically use CBD.",
"affiliations": "Internal Medicine, Loyola University Medical Center, Maywood, USA.;Internal Medicine, Loyola University Medical Center, Maywood, USA.;Gastroenterology, Loyola University Medical Center, Maywood, USA.;Pathology, Loyola University Medical Center, Maywood, USA.;Gastroenterology, Loyola University Medical Center, Maywood, USA.",
"authors": "Oruganti|Poornima|P|;Betcher|Stephanie|S|;Wakade|Zuie|Z|;Ding|Xianzhong|X|;Abegunde|Ayokunle T|AT|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.10528",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.10528\nInternal Medicine\nPathology\nGastroenterology\nCannabidiol Oil-Associated Microscopic Colitis\nMuacevic Alexander Adler John R Oruganti Poornima 1 Betcher Stephanie 1 Wakade Zuie 2 Ding Xianzhong 3 Abegunde Ayokunle T 2 \n1 \nInternal Medicine, Loyola University Medical Center, Maywood, USA \n\n2 \nGastroenterology, Loyola University Medical Center, Maywood, USA \n\n3 \nPathology, Loyola University Medical Center, Maywood, USA \n\nPoornima Oruganti poornima.oruganti9692@gmail.com\n18 9 2020 \n9 2020 \n12 9 e105287 8 2020 18 9 2020 Copyright © 2020, Oruganti et al.2020Oruganti 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/39171-cannabidiol-oil-associated-microscopic-colitisMicroscopic colitis (MC) is a chronic inflammation condition of the colon characterized by watery diarrhea and normal appearing mucosa. A 75-year-old female presented with one-year history of chronic diarrhea while taking cannabidiol (CBD) for pain. Colonoscopy with random colon biopsies revealed collagenous colitis. She started budesonide and stopped CBD. At six-week follow-up, her diarrhea improved, and the budesonide dose was decreased. She restarted CBD oil twice but had diarrhea both times. Her diarrhea resolved after taking budesonide and stopping CBD. We report a case of CBD-associated MC to make clinicians aware of this potential adverse effect in patients who chronically use CBD.\n\ncannabisdiarrheamicroscopic colitisThe 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\nMicroscopic colitis (MC) is a chronic inflammation condition of the colon characterized by watery, non-bloody diarrhea and generally normal appearing colonic mucosa on colonoscopy. Colon biopsy is required to confirm the diagnosis and differentiate between the two subtypes: lymphocytic and collagenous colitis (CC) [1]. Many drugs have been associated with MC. However, the pathophysiology is incompletely understood. Drugs that have been implicated in MC include non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, proton-pump inhibitors (PPIs), selective serotonin reuptake inhibitors (SSRIs), clozapine, and acarbose [2]. Studies examining the etiology of MC are limited and mostly consist of case reports and observational studies. Cannabidiol (CBD) is a concentrated oily residue of the plant Cannabis sativa. Recent changes in the legality of CBD have led to an increased acceptance of its use by the medical community. The Controlled Substances Act (CSA) of 1970 made the growth of hemp and marijuana illegal in the United States, but in 2014, the Agricultural Act allowed for industrial growth of hemp [3]. CBD and hemp are different from marijuana because they have low tetrahydrocannabinol (THC) levels [3]. This provides patients with the medical benefits of Cannabis without the intoxicating effects of marijuana [3]. CBD has found some popularity in the search for an alternative to opioids for the treatment of pain [4]. CBD is not regulated by the U.S. Food and Drug Administration (FDA), and there are no determinations on appropriate dosage, safety, efficacy, or interactions with other drugs or food [3]. There are currently no reports in the medical literature that CBD is a risk factor for the development of MC. We report a case of CBD-associated MC to make clinicians aware of this potential adverse effect in patients who chronically use CBD. The patient agreed to the use and publication of her disease process and case with her personal health information deleted.\n\nCase presentation\nA 75-year-old Caucasian female with a history of anemia, hypothyroidism, and migraines presented to the gastroenterology clinic with a one-year history unexplained diarrhea. The patient started taking CBD oil for lumbosacral pain about one year prior to presentation. She endorsed watery, non-bloody, nocturnal diarrhea, left lower quadrant abdominal pain, and unintentional weight loss of eight pounds. The patient also endorsed urgency, tenesmus, fecal incontinence, and a small amount of blood when wiping after bowel movements (BMs). She had already tried loperamide and bismuth subsalicylate. She also tried the BRAT (bananas, rice, applesauce, and toast) diet and probiotic yogurt, but neither diet nor over-the-counter medications were effective in reducing her diarrhea. Prior to onset of diarrhea, the patient had constipation, which required her to take metamucil to have one BM daily. However, she began to have two loose BMs daily, and then her stool frequency increased to five times daily and three to four times at night. Colonoscopy performed for polyp surveillance six months prior to presentation and symptom onset revealed decreased anal sphincter tone and multiple colon polyps; grossly, mucosa appeared normal and random biopsies were not taken. Repeat colonoscopy with random biopsies six months later (at symptom onset) revealed CC (Figures 1, 2). She was still taking CBD oil at the time of her second colonoscopy demonstrating MC. She was not taking NSAIDs or any other agent associated with MC at the time of her second colonoscopy. Stool PCR was negative for enteric pathogens. Budesonide therapy was started, and she was advised her to continue a high fiber diet and to avoid artificial sweeteners and sugar alcohols. She was advised to avoid NSAIDs and discontinue CBD oil. During follow-up six weeks later, her diarrhea had improved. Her gastroenterologist reduced the dose of budesonide. After her six-week follow-up, the patient started taking CBD oil again at home and had a recurrence of diarrhea. She stopped CBD oil, and her diarrhea resolved. One week later, she restarted CBD oil and experienced diarrhea again. She then stopped CBD oil completely and completed a tapering course of budesonide. Eventually, diarrhea turned to constipation. She was advised to continue fiber supplements and high fiber diet. About three months after the initial presentation, she was able to stop budesonide. There was no recurrence of diarrhea after she stopped taking CBD oil and completed budesonide therapy.\n\nFigure 1 H&E stain showing increased intraepithelial lymphocytes (black arrow) and subepithelial collagen band > 10 microns (red arrow) consistent with collagenous colitis.\nFigure 2 H&E stain showing increased intraepithelial lymphocytes (black arrow) and subepithelial collagen band >10 microns (red arrow) consistent with collagenous colitis.\nDiscussion\nThe cause-effect relationship between drugs and MC is difficult to define. The patient in this case used a CBD soft gel made with hemp oil, extra virgin olive oil, vegetarian soft gel (vegetable cellulose, water), and silica. However, there are multiple different formulations of CBD oil and capsules, as well as other products including honey, vape pens, teas, gelatin snacks, baked goods, and beverages. Experimental studies on murine colitis suggest that physiologically relevant concentrations of exogenous CBD can reduce gut inflammation by stimulating CB1/CB2 cannabinoid receptors and endogenous cannabinoids N-arachidonoyl-ethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG) [5,6]. However, data are limited on dose-related adverse effects of CBD. As the popularity of CBD products increases, more research is necessary regarding their safety and efficacy in humans. The World Health Organization (WHO) has proposed a method that establishes causality based on temporal sequence, prior information on the drug, dose-response relationship, pattern of response to the drug, the re-challenge, exclusion of other alternative etiologic candidates, and exposure to concomitant drugs. The events are then classified as “certain, probable, possible, unlikely, and not assessable” (Table 1) [2,7]. This case demonstrates a temporal relationship between exposure to CBD oil and onset of diarrhea, resolution of diarrhea after withdrawal of CBD oil, and reoccurrence of diarrhea with two re-challenge attempts with CBD oil while the patient was taking budesonide. Therefore, we can surmise that her CC resulted from chronic ingestion of CBD oil. The mechanism by which CBD oil induced MC in this case is unclear; however, we hypothesize that elevation of tissue levels of endocannabinoids may cause colonic inflammation by stimulating the vanilloid receptor subtype 1 (VR1) to release substance P [8]. Based on the WHO method, we believe that this case establishes a causal link between CBD and MC that can be classified as \"probable or likely\". To our knowledge there are currently no other case reports that describe such a relationship between CBD and MC. We recommend that physicians educate themselves on CBD containing products, and encourage open communication with patients regarding dietary supplements and their potential clinical adverse effects. \n\nTable 1 WHO Drug Causality Assessment System (Adapted From WHO-UMC*)\n*WHO-UMC, World Health Organization-Uppsala Monitoring Centre\n\nCausality Term\tAssessment Criteria\t\nCertain\tPlausible time relationship between event and drug intake and response to withdrawal\t\nEvent definitive objectively, meaning pharmacologically or phenomenologically\t\nEvent cannot be explained by disease or other drugs\t\nRe-challenge satisfactory, if necessary\t\nProbable/Likely\tReasonable time relationship between event and drug intake and response to withdrawal\t\nUnlikely to be explained by disease or other drugs\t\nRe-challenge not required\t\nPossible\tReasonable time relationship between event and drug intake and response to withdrawal\t\nCould also be explained by disease or other drugs\t\nUnlikely\tImprobable, but not impossible, time relationship between event and drug intake\t\nDisease or other drugs provide plausible explanation\t\nConditional/Unclassified\tEvent occurred, but more information is required\t\nUnclassifiable\tInsufficient data\t\nConclusions\nMultiple drugs have been implicated in the development of MC. CBD oil is a relatively new dietary supplement that is gaining popularity as an alternative to opioids for the treatment of pain. To our knowledge, there are currently no other case reports that describe such a relationship between CBD and MC. Physicians should suspect CBD-associated MC in patients taking CBD who develop diarrhea for which no other causes can be identified. We recommend that physicians educate themselves on CBD containing products and encourage open communication with patients regarding dietary supplements and their potential clinical adverse effects.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n\nAuthors P Oruganti and S Betcher contributed equally to this work and should be considered co-first authors.\n==== Refs\nReferences\n1 American Gastroenterological Association Institute guideline on the medical management of microscopic colitis Gastroenterology Nguyen GC Smalley WE Vege SS Carrasco-Labra A 242 246 150 2016 26584605 \n2 Drug exposure and the risk of microscopic colitis: a critical update Drugs R D Lucendo AJ 79 89 17 2017 28101837 \n3 Clinicians’ guide to cannabidiol and hemp oils Mayo Clin Proc VanDolah HJ Bauer BA Mauck KF 1840 1851 94 2019 31447137 \n4 Management of chronic pain in the aftermath of the opioid backlash JAMA Kroenk K Cheville A 2365 2366 317 2017 28494058 \n5 Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a murine model of colitis J Mol Med (Berl) Borrelli F Aviello G Romano B 1111 1121 87 2009 19690824 \n6 Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis PLoS One De Filippis D Esposito G Cirillo C 0 6 2011 \n7 World Health Organization UMC. The use of the WHO-UMC system for standardized case panel causality assessment 6 2020 2015 https://www.who.int/medicines/areas/quality_safety/safety_efficacy/WHOcausality_assessment.pdf \n8 Endocannabinoids induce ileitis in rats via the capsaicin receptor (VR1) J Pharmacol Exp Ther McVey DC Schmid PC Schmid HH Vigna SR 713 722 304 2003 12538826\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(9)",
"journal": "Cureus",
"keywords": "cannabis; diarrhea; microscopic colitis",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e10528",
"pmc": null,
"pmid": "33094069",
"pubdate": "2020-09-18",
"publication_types": "D002363:Case Reports",
"references": "26584605;28101837;22163000;12538826;31447137;28494058;19690824",
"title": "Cannabidiol Oil-Associated Microscopic Colitis.",
"title_normalized": "cannabidiol oil associated microscopic colitis"
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"companynumb": "US-TEVA-2021-US-1867300",
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{
"abstract": "The combination of Pegylated Liposomal Doxorubicin (PLD) plus Gemcitabine (GEM) has been previously investigated in the treatment of metastatic breast cancer (MBC). PLD is a doxorubicin formulation with prolonged circulation time and better tissue distribution. GEM is a nucleoside analog with nonoverlapping toxicity compared to PLD. The aim of our study was to assess efficacy, toxicity, and long-term outcome of this combination. Patients with heavily treated MBC were retrospectively analyzed. Chemotherapy consisted of PLD 25 mg/m2 and GEM 800 mg/m2 day 1, on a three-week schedule. Cardiac function was evaluated baseline and during treatment. Radiological response was graded according to RECIST criteria v1.1. Toxicity was scored according to CTCAE v4.0. Progression-free survival (PFS) and overall survival (OS) were evaluated. From 2001 to 2014, 122 pts were included. Median age was 55 (range: 28-84). Median previous treatment schedules in the metastatic scenario were 3 (range: 1-15). Most patients received prior anthracyclines (85%). Median number of metastatic sites was 2 (range: 1-7). Median number of cycles delivered was 5 (range: 1-36). Overall response rate was 31% (5% complete responses; 26% partial responses). Stable and progressive diseases were observed in 32% and 26% of patients. Grade ≥3 neutropenia was observed in 29 patients (24%). Grade ≥3 hand-foot syndrome was detected in 17 patients (14%), mostly since cycle 3 (88%). Median cumulative PLD dose was 125 mg/m2 . At a median follow-up of 101 months, median PFS and OS were 7 and 22 months, respectively. PLD-GEM combination achieves remarkable long-term outcomes with an acceptable toxicity profile in patients with MBC.",
"affiliations": "Department of Medical Oncology. Clínica, Universidad de Navarra, Pamplona, Navarra, Spain.;Department of Medical Oncology. Clínica, Universidad de Navarra, Pamplona, Navarra, Spain.;Department of Medical Oncology. Clínica, Universidad de Navarra, Pamplona, Navarra, Spain.;Department of Medical Oncology. Clínica, Universidad de Navarra, Pamplona, Navarra, Spain.;Department of Medical Oncology. Clínica, Universidad de Navarra, Pamplona, Navarra, Spain.;Department of Medical Oncology. Clínica, Universidad de Navarra, Pamplona, Navarra, Spain.;Department of Medical Oncology. Clínica, Universidad de Navarra, Pamplona, Navarra, Spain.;Department of Medical Oncology. Clínica, Universidad de Navarra, Pamplona, Navarra, Spain.",
"authors": "Martin-Romano|Patricia|P|;Baraibar|Iosune|I|;Espinós|Jaime|J|;Legaspi|Jairo|J|;López-Picazo|Jose M|JM|;Aramendía|Jose Manuel|JM|;Fernández|Oscar A|OA|;Santisteban|Marta|M|0000-0003-0625-686X",
"chemical_list": "D000903:Antibiotics, Antineoplastic; C506643:liposomal doxorubicin; D003841:Deoxycytidine; D011092:Polyethylene Glycols; D004317:Doxorubicin; C056507:gemcitabine",
"country": "United States",
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"issue": "24(4)",
"journal": "The breast journal",
"keywords": "chemotherapy combination; gemcitabine; metastatic breast cancer; pegylated liposomal doxorubicin",
"medline_ta": "Breast J",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D003841:Deoxycytidine; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017063:Outcome Assessment, Health Care; D011092:Polyethylene Glycols; D011446:Prospective Studies; D012189:Retrospective Studies",
"nlm_unique_id": "9505539",
"other_id": null,
"pages": "473-479",
"pmc": null,
"pmid": "29286192",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Combination of pegylated liposomal doxorubicin plus gemcitabine in heavily pretreated metastatic breast cancer patients: Long-term results from a single institution experience.",
"title_normalized": "combination of pegylated liposomal doxorubicin plus gemcitabine in heavily pretreated metastatic breast cancer patients long term results from a single institution experience"
} | [
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"companynumb": "ES-JNJFOC-20190709268",
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"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
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"abstract": "We report herein a case of 35-years-old woman in whom portal hypertension (esophageal varix and splenomegaly) developed after 12 cycles of oxaliplatin based adjuvant chemotherapy for rectal cancer. She was transferred for the evaluation of etiology of new-onset portal hypertension. The esophageal varix and splenomegaly were absent before the oxaliplatin based adjuvant chemotherapy. Thorough history taking and serological exam revealed no evidence of chronic liver disease. Liver biopsy was done and there was no cirrhotic nodule formation. Instead, perivenular fibrosis was noted. Considering new development of esophageal varices and splenomegaly after 12 cycles of oxaliplatin-based adjuvant chemotherapy, we could conclude that portal hypertension in this patient were due to sinusoidal injury by oxaliplatin. Finally, we recommend regular follow-up with endoscopy and radiologic examination for checking the development of varices and for screening of varices and splenomegaly in patients with colo-rectal cancer who receive oxaliplatin-based chemotherapy.",
"affiliations": "Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea.",
"authors": "Heo|Jun|J|;Shin|Keun Young|KY|;Kwon|Yong Hwan|YH|;Park|Soo Young|SY|;Jung|Min Kyu|MK|;Cho|Chang Min|CM|;Tak|Won Young|WY|;Kweon|Young Oh|YO|",
"chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"country": "Korea (South)",
"delete": false,
"doi": "10.4166/2011.57.4.253",
"fulltext": null,
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"issn_linking": "1598-9992",
"issue": "57(4)",
"journal": "The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi",
"keywords": null,
"medline_ta": "Korean J Gastroenterol",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D017024:Chemotherapy, Adjuvant; D004932:Esophageal and Gastric Varices; D005260:Female; D005355:Fibrosis; D006801:Humans; D006975:Hypertension, Portal; D008099:Liver; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D049268:Positron-Emission Tomography; D012004:Rectal Neoplasms; D013163:Splenomegaly; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101189416",
"other_id": null,
"pages": "253-7",
"pmc": null,
"pmid": "21519180",
"pubdate": "2011-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of portal hypertension after the treatment of oxaliplatin based adjuvant chemotherapy for rectal cancer.",
"title_normalized": "a case of portal hypertension after the treatment of oxaliplatin based adjuvant chemotherapy for rectal cancer"
} | [
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"companynumb": "KR-BPIPOOL-BPILit36779",
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"activesubstancename": "OXALIPLATIN"
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"abstract": "We present nine cases of systemic lupus erythematosus with refractory disease that we treated with the chimeric monoclonal anti-CD20 antibody rituximab. Three patients had renal disease, three neurological involvement with transverse myelitis and vasculitis of the central nervous system, one thrombocytopenia, one skin involvement with generalized erythema and one patient had constitutional, haematological and immunological symptoms. Two patients with renal disease, the patient with immune thrombocytopenia and the three patients with neurological disease, who stayed in remission despite a reduction of immunosuppressive therapy, responded particularly well to the therapy. Five of nine patients showed an improvement in ECLAM of at least two points. During therapy only minor adverse events were observed. One patient died during follow-up which was unrelated to the therapy. The selective depletion of B-lymphocytes in the therapy of systemic lupus erythematosus seems to be an effective and safe treatment option for different manifestations.",
"affiliations": "Rheumazentrum Düsseldorf, Klinik für Endokrinologie, Diabetologie und Rheumatologie, Heinrich-Heine Universität Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf. chehab@rheumanet.org",
"authors": "Chehab|G|G|;Sander|O|O|;Fischer-Betz|R|R|;Schneider|M|M|",
"chemical_list": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D007155:Immunologic Factors; D000069283:Rituximab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00393-007-0164-6",
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"issn_linking": "0340-1855",
"issue": "66(4)",
"journal": "Zeitschrift fur Rheumatologie",
"keywords": null,
"medline_ta": "Z Rheumatol",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D008180:Lupus Erythematosus, Systemic; D008875:Middle Aged; D000069283:Rituximab; D055502:Secondary Prevention; D016896:Treatment Outcome",
"nlm_unique_id": "0414162",
"other_id": null,
"pages": "328, 330-6",
"pmc": null,
"pmid": "17440741",
"pubdate": "2007-07",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": "9324032;15693003;15059147;15795920;16188950;16649186;16550390;1458711;12384926;10498591;15334472;9551955;7931063;16269424;4117792;15550531;1458709;10330443;7138600;15494350;1458710",
"title": "Anti-CD20 therapy for inducing and maintaining remission in refractory systemic lupus erythematosus.",
"title_normalized": "anti cd20 therapy for inducing and maintaining remission in refractory systemic lupus erythematosus"
} | [
{
"companynumb": "NVSC2020DE049594",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "1",
... |
{
"abstract": "We report the case of a 64-year-old man who presented with back pain, anorexia, and weight loss 9 months following bacillus Calmette-Guérin immunotherapy for high-grade transitional cell carcinoma of the bladder. A FDG PET/CT was performed, which demonstrated osteolysis and intense FDG avidity of the T6/T7 and T8/T9 vertebral endplates. In addition, an aneurysm with FDG-avid soft tissue was present of the distal left common iliac artery. The provisional diagnosis was disseminated bacillus Calmette-Guérin infection, resulting in spondylodiscitis and a mycotic aneurysm. A CT-guided vertebral biopsy confirmed the presence of Mycobacterium tuberculosis DNA on polymerase chain reaction testing.",
"affiliations": "From the Queensland X-Ray, Greenslopes Private Hospital, Greenslopes.",
"authors": "Curley|Michael|M|;Bhardwaj|Hemant|H|",
"chemical_list": "D001500:BCG Vaccine; D019788:Fluorodeoxyglucose F18",
"country": "United States",
"delete": false,
"doi": "10.1097/RLU.0000000000003046",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0363-9762",
"issue": "45(7)",
"journal": "Clinical nuclear medicine",
"keywords": null,
"medline_ta": "Clin Nucl Med",
"mesh_terms": "D000283:Administration, Intravesical; D001500:BCG Vaccine; D002295:Carcinoma, Transitional Cell; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D000072078:Positron Emission Tomography Computed Tomography; D014376:Tuberculosis; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "7611109",
"other_id": null,
"pages": "e323-e324",
"pmc": null,
"pmid": "32433172",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated Bacillus Calmette-Guérin Infection Detected on FDG PET/CT Following Intravesical Bacillus Calmette-Guérin Therapy.",
"title_normalized": "disseminated bacillus calmette gu rin infection detected on fdg pet ct following intravesical bacillus calmette gu rin therapy"
} | [
{
"companynumb": "AU-009507513-2006AUS002382",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN"
... |
{
"abstract": "Only limited data are available on whether glatiramer acetate exposure during pregnancy has an effect on perinatal outcome.\n\n\n\nTo determine the effect of glatiramer acetate exposure during pregnancy on pregnancy outcomes in women with multiple sclerosis.\n\n\n\nWe compared the outcome of pregnancies of women with multiple sclerosis exposed to glatiramer acetate with pregnancies unexposed to disease-modifying therapies. Women were enrolled into the German Multiple Sclerosis and Pregnancy registry. A standardized questionnaire was administered during pregnancy and postpartum. Detailed information on course of multiple sclerosis and pregnancy, concomitant medications, labor, delivery, and outcome of pregnancy was obtained.\n\n\n\nWe collected data on 246 multiple sclerosis pregnancies, 151 exposed to glatiramer acetate and 95 unexposed to disease-modifying therapies during pregnancy. Three (2.2%) congenital anomalies occurred in the exposed and 6 (6.7%) in the control group. We did not observe an increase in other adverse pregnancy or delivery outcomes including spontaneous abortions, preterm birth, Cesarean sections, or reduced birth weight in the exposed group.\n\n\n\nOur data provide further evidence that glatiramer acetate exposure during the first trimester of pregnancy appears safe and without teratogenic effect. These findings provide important additive knowledge to better counsel women with multiple sclerosis in planning a pregnancy.",
"affiliations": "Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany/Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich Heine University, Duesseldorf, Germany.;Kaiser Permanente Southern California, Pasadena, CA, USA.;Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.;Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.;Centre of Paediatrics and Youth Medicine, Johannes Gutenberg-University Mainz, Mainz, Germany.;Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.;Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, 44791 Bochum, Germany k.hellwig@klinikum-bochum.de.",
"authors": "Herbstritt|Sandra|S|;Langer-Gould|Annette|A|;Rockhoff|Milena|M|;Haghikia|Aiden|A|;Queisser-Wahrendorf|Annette|A|;Gold|Ralf|R|;Hellwig|Kerstin|K|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068717:Glatiramer Acetate",
"country": "England",
"delete": false,
"doi": "10.1177/1352458515623366",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-4585",
"issue": "22(6)",
"journal": "Multiple sclerosis (Houndmills, Basingstoke, England)",
"keywords": "Multiple sclerosis; disease-modifying therapies; glatiramer acetate; pregnancy; pregnancy outcomes; safety",
"medline_ta": "Mult Scler",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000022:Abortion, Spontaneous; D000328:Adult; D001724:Birth Weight; D002585:Cesarean Section; D005260:Female; D005858:Germany; D000068717:Glatiramer Acetate; D006801:Humans; D007166:Immunosuppressive Agents; D007231:Infant, Newborn; D009103:Multiple Sclerosis; D011247:Pregnancy; D011248:Pregnancy Complications; D047928:Premature Birth; D011446:Prospective Studies; D012042:Registries",
"nlm_unique_id": "9509185",
"other_id": null,
"pages": "810-6",
"pmc": null,
"pmid": "26754804",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Glatiramer acetate during early pregnancy: A prospective cohort study.",
"title_normalized": "glatiramer acetate during early pregnancy a prospective cohort study"
} | [
{
"companynumb": "DE-TEVA-629203GER",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GLATIRAMER ACETATE"
},
"drugadditional": null,
... |
{
"abstract": "Few effective therapeutic options exist for patients with metastatic paraganglioma (PGL). We report the case of a 16-year-old male who developed acute myeloid leukemia (AML) 30 months following the treatment for metastatic PGL. PGL had been refractory to 131 I-meta-iodobenzylguanidine and temozolomide therapy. However, there was a major reduction in primary tumor allowing its gross total resection, and complete resolution of metastatic disease following AML-directed therapy that included daunorubicin, cytarabine, and etoposide. He remains in remission for both AML and PGL, 48 months post AML chemotherapy. Alternative chemotherapeutic agents should be considered for metastatic PGL resistant to conventional therapy.",
"affiliations": "Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York.;Department of Radiology, Memorial Sloan Kettering Cancer Center, New York.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York.",
"authors": "Sait|Sameer|S|;Kobos|Rachel|R|;LaQuaglia|Michael P|MP|;Pandit-Taskar|Neeta|N|;Modak|Shakeel|S|",
"chemical_list": "D007462:Iodobenzenes; D003561:Cytarabine; C004287:iodobenzylmalonate; D005047:Etoposide; D003606:Dacarbazine; D000077204:Temozolomide; D003630:Daunorubicin",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.26314",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "64(5)",
"journal": "Pediatric blood & cancer",
"keywords": "acute myeloid leukemia; chemotherapy; metastatic paraganglioma",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D059248:Chemoradiotherapy; D003561:Cytarabine; D003606:Dacarbazine; D003630:Daunorubicin; D019008:Drug Resistance, Neoplasm; D005047:Etoposide; D006801:Humans; D007462:Iodobenzenes; D015470:Leukemia, Myeloid, Acute; D008297:Male; D010235:Paraganglioma; D011836:Radiation Tolerance; D000077204:Temozolomide",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27804217",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16951005;9856686;21629739;2466547;26614373;12599242;8652810;23519741;25041164;10397082;22079789;19405123;23707781;20215394;22006217;12000816;24752622;16112304;24169644;26523625",
"title": "Acute myeloid leukemia therapy elicits durable complete response in chemoradio-resistant metastatic paraganglioma.",
"title_normalized": "acute myeloid leukemia therapy elicits durable complete response in chemoradio resistant metastatic paraganglioma"
} | [
{
"companynumb": "US-MYLANLABS-2017M1030879",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": "3",
... |
{
"abstract": "Flecainide is a class 1C antiarrhythmic drug especially used for the management of supraventricular arrhythmia. In overdose cases, flecainide can induce life treating ventricular arrhythmias and cardiogenic shock. We report the case of a 72-year-old woman admitted to our intensive care unit for a regular monomorphic wide complex tachycardia (QRS duration 240 ms, right bundle branch block and superior axis morphology) without apparent P waves. Clinical examination showed slight left congestive heart failure signs without cardiogenic shock. An intravenous bolus of 10 mg adenosine 5'-triphosphate (ATP) was ineffective to stop the tachycardia. The diagnosis of ventricular tachycardia induced by flecainide overdose was considered. 500 mL of intravenous 84‰ sodium bicarbonate was administrated. The patient's QRS narrowed immediately and 12-lead ECG showed sinus rhythm. Blood samples confirmed the flecainide overdose and the clinical status progressively improved.",
"affiliations": "pycourand@hotmail.com.",
"authors": "Courand|Pierre-Yves Nd|PY|;Sibellas|Franck|F|;Ranc|Sylvain|S|;Mullier|Audrey|A|;Kirkorian|Gilbert|G|;Bonnefoy|Eric|E|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D000255:Adenosine Triphosphate; D017693:Sodium Bicarbonate; D005424:Flecainide",
"country": "Poland",
"delete": false,
"doi": "10.5603/CJ.2013.0035",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1898-018X",
"issue": "20(2)",
"journal": "Cardiology journal",
"keywords": null,
"medline_ta": "Cardiol J",
"mesh_terms": "D000255:Adenosine Triphosphate; D000368:Aged; D000889:Anti-Arrhythmia Agents; D002037:Bundle-Branch Block; D004562:Electrocardiography; D005260:Female; D005424:Flecainide; D006801:Humans; D007275:Injections, Intravenous; D017693:Sodium Bicarbonate; D017180:Tachycardia, Ventricular; D016896:Treatment Outcome",
"nlm_unique_id": "101392712",
"other_id": null,
"pages": "203-5",
"pmc": null,
"pmid": "23558880",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Arrhythmogenic effect of flecainide toxicity.",
"title_normalized": "arrhythmogenic effect of flecainide toxicity"
} | [
{
"companynumb": "FR-WATSON-2014-20682",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": null,
... |
{
"abstract": "Seizures have been reported with tramadol monotherapy in animal and human studies, both at recommended and high doses. After tramadol abuse or overdose, neurotoxicity is speculated to be related to the reuptake inhibition of serotonin and norepinephrine, rather than its opioid effects. THE AIM OF THIS STUDY is to show three unusual cases of seizures provoked by tramadol.\n\n\nMETHODS\nA 56 year-old female was hospitalized with intensive lumbosacral pain. Because the standard therapy with non steroid anti-inflammatory drugs and diazepam did not show enough pain release, Tramadol ampoules were applied. Fifteen minutes later generalized tonic clonic seizure was noticed. A 24 year-old female was admitted to the Toxicology Clinic, one hour after ingestion of 1000 mg Tramadol (20 pills of 50 mg) in a suicide attempt. Five hours later generalized tonic clonic seizure was noticed. A 27 year-old male was hospitalized for detoxification procedure with buprenorphine. The patient was a more than four years heroin abuser, and in the last two years he mixed the heroin with high doses of tramadol. 16 hours later, after application of the first 2 mg of Buprenorphine, generalized tonic clonic seizure was noticed.\n\n\nCONCLUSIONS\nTramadol prescription, use and abuse are connected with the risk of developing seizures. The neurotoxicity of tramadol commonly manifests as seizures.",
"affiliations": "University Toxicology Clinic, Skopje, R. Macedonia.",
"authors": "Bekjarovski|N|N|;Chaparoska|D|D|;Radulovikj-Bekjarovska|S|S|",
"chemical_list": "D000701:Analgesics, Opioid; D014147:Tramadol",
"country": "Germany",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0351-3254",
"issue": "33(1)",
"journal": "Prilozi",
"keywords": null,
"medline_ta": "Prilozi",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D005260:Female; D006556:Heroin Dependence; D006801:Humans; D008297:Male; D008875:Middle Aged; D012640:Seizures; D013406:Suicide, Attempted; D014147:Tramadol",
"nlm_unique_id": "101189513",
"other_id": null,
"pages": "313-8",
"pmc": null,
"pmid": "22983066",
"pubdate": "2012",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Seizures after use and abuse of tramadol.",
"title_normalized": "seizures after use and abuse of tramadol"
} | [
{
"companynumb": "MK-LUPIN PHARMACEUTICALS INC.-2016-02077",
"fulfillexpeditecriteria": "1",
"occurcountry": "MK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TRAMADOL"
},
"drugadditional"... |
{
"abstract": "Vertebral fractures (VFs) are a frequent complication of acromegaly, but no studies have been so far published on effectiveness of antiosteoporotic drugs in this clinical setting.\n\n\n\nTo evaluate whether in real-life clinical practice bone active drugs may reduce the risk of VFs in patients with active or controlled acromegaly.\n\n\n\nRetrospective, longitudinal study including 9 tertiary care endocrine units.\n\n\n\nTwo hundred and forty-eight patients with acromegaly (104 males; mean age 56.00 ± 13.60 years) were evaluated for prevalent and incident VFs by quantitative morphometric approach. Bone active agents were used in 52 patients (20.97%) and the median period of follow-up was 48 months (range 12-132).\n\n\n\nDuring the follow-up, 65 patients (26.21%) developed incident VFs in relationship with pre-existing VFs (odds ratio [OR] 3.75; P < .001), duration of active acromegaly (OR 1.01; P = .04), active acromegaly at the study entry (OR 2.48; P = .007), and treated hypoadrenalism (OR 2.50; P = .005). In the entire population, treatment with bone active drugs did not have a significant effect on incident VFs (P = .82). However, in a sensitive analysis restricted to patients with active acromegaly at study entry (111 cases), treatment with bone active drugs was associated with a lower risk of incident VFs (OR 0.11; P = .004), independently of prevalent VFs (OR 7.65; P < .001) and treated hypoadrenalism (OR 3.86; P = .007).\n\n\n\nBone active drugs may prevent VFs in patients with active acromegaly.",
"affiliations": "Endocrinology, Diabetology and Medical Andrology Unit, Osteoporosis and Metabolic Bone Disease Section, Humanitas Clinical and Research Center, IRCCS, Rozzano-Milan, Italy.;Unit of Endocrinology, \"Casa Sollievo della Sofferenza\" Hospital, IRCCS, San Giovanni Rotondo (FG), Italy.;Endocrinology and Metabolism, Department of Medicine, ASST Spedali Civili Brescia, Italy.;Pituitary Unit, Department of Endocrinology and Metabolism, Fondazione Policlinico \"A. Gemelli\", IRCCS - Universita' Cattolica del Sacro Cuore, Rome, Italy.;Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Division of Endocrinology, Diabetology and Metabolism, Department of Medical Science, University of Turin, Italy.;Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy.;Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.;Endocrinology Unit, ASST Carlo Poma Hospital, Mantua, Italy.;Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Division of Endocrinology, Diabetology and Metabolism, Department of Medical Science, University of Turin, Italy.;Pituitary Unit, Department of Endocrinology and Metabolism, Fondazione Policlinico \"A. Gemelli\", IRCCS - Universita' Cattolica del Sacro Cuore, Rome, Italy.;Endocrinology, Diabetology and Medical Andrology Unit, Osteoporosis and Metabolic Bone Disease Section, Humanitas Clinical and Research Center, IRCCS, Rozzano-Milan, Italy.;Department of Clinical Sciences and Community Health, University of Milan, Italy.;Pituitary Unit, Department of Endocrinology and Metabolism, Fondazione Policlinico \"A. Gemelli\", IRCCS - Universita' Cattolica del Sacro Cuore, Rome, Italy.;Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy.;Endocrinology and Metabolism, Department of Clinical and Experimental Sciences, University of Brescia, Italy.;Division of Endocrinology, Diabetology and Metabolism, Department of Medical Science, University of Turin, Italy.;Pituitary Unit, Department of Endocrinology and Metabolism, Fondazione Policlinico \"A. Gemelli\", IRCCS - Universita' Cattolica del Sacro Cuore, Rome, Italy.;Division of Endocrinology, Diabetology and Metabolism, Department of Medical Science, University of Turin, Italy.;Endocrinology, Diabetology and Medical Andrology Unit, Osteoporosis and Metabolic Bone Disease Section, Humanitas Clinical and Research Center, IRCCS, Rozzano-Milan, Italy.;Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Department of Biomedical Sciences, Humanitas University, Milan, Italy.;Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy.;Endocrinology, Montichiari Hospital, ASST Spedali Civili Brescia.;Division of Endocrinology, Diabetology and Metabolism, Department of Medical Science, University of Turin, Italy.;Unit of Endocrinology, \"Casa Sollievo della Sofferenza\" Hospital, IRCCS, San Giovanni Rotondo (FG), Italy.;Unit of Endocrinology, \"Casa Sollievo della Sofferenza\" Hospital, IRCCS, San Giovanni Rotondo (FG), Italy.;Endocrinology, Diabetology and Medical Andrology Unit, Osteoporosis and Metabolic Bone Disease Section, Humanitas Clinical and Research Center, IRCCS, Rozzano-Milan, Italy.",
"authors": "Mazziotti|Gherardo|G|;Battista|Claudia|C|;Maffezzoni|Filippo|F|;Chiloiro|Sabrina|S|;Ferrante|Emanuele|E|;Prencipe|Nunzia|N|;Grasso|Ludovica|L|;Gatto|Federico|F|;Olivetti|Roberto|R|;Arosio|Maura|M|;Barale|Marco|M|;Bianchi|Antonio|A|;Cellini|Miriam|M|;Chiodini|Iacopo|I|;De Marinis|Laura|L|;Del Sindaco|Giulia|G|;Di Somma|Carolina|C|;Ferlin|Alberto|A|;Ghigo|Ezio|E|;Giampietro|Antonella|A|;Grottoli|Silvia|S|;Lavezzi|Elisabetta|E|;Mantovani|Giovanna|G|;Morenghi|Emanuela|E|;Pivonello|Rosario|R|;Porcelli|Teresa|T|;Procopio|Massimo|M|;Pugliese|Flavia|F|;Scillitani|Alfredo|A|;Lania|Andrea Gerardo|AG|",
"chemical_list": "D050071:Bone Density Conservation Agents",
"country": "United States",
"delete": false,
"doi": "10.1210/clinem/dgaa363",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-972X",
"issue": "105(9)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": "acromegaly; bisphosphonates; bone-active drugs; denosumab; osteoporosis; teriparatide; vertebral fractures",
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D000172:Acromegaly; D000328:Adult; D000368:Aged; D015519:Bone Density; D050071:Bone Density Conservation Agents; D001847:Bone Diseases; D005260:Female; D006801:Humans; D007558:Italy; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010818:Practice Patterns, Physicians'; D012189:Retrospective Studies; D016103:Spinal Fractures",
"nlm_unique_id": "0375362",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32511698",
"pubdate": "2020-09-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Treatment of Acromegalic Osteopathy in Real-life Clinical Practice: The BAAC (Bone Active Drugs in Acromegaly) Study.",
"title_normalized": "treatment of acromegalic osteopathy in real life clinical practice the baac bone active drugs in acromegaly study"
} | [
{
"companynumb": "IT-AMGEN-ITASP2020097180",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "REPAGLINIDE"
},
"drugadditional": null,
... |
{
"abstract": "In the United States, fibrin sealants have been used to achieve hemostasis for nearly two decades. Although their clinical utility was first demonstrated in cardiac surgery, their effectiveness and safety have since been demonstrated to extend to a wide array of procedures. Fibrin sealants typically contain two components-fibrinogen and thrombin-that are combined and delivered simultaneously to a target bleeding site in order to achieve hemostasis. However, many commercial formulations contain other additional components, such as antifibrinolytic agents, that have been associated with adverse outcomes. This subanalysis compares the safety and effectiveness of a fibrin sealant versus an absorbable hemostat for achieving hemostasis during urologic procedures with mild to moderate bleeding.",
"affiliations": "Associated Medical Professionals, Syracuse, NY.;Ethicon, Inc., Somerville, NJ.;Ethicon, Inc., Somerville, NJ.;Ethicon, Inc., Somerville, NJ.;Ethicon, Inc., Somerville, NJ.;Ethicon, Inc., Somerville, NJ.;Ethicon, Inc., Somerville, NJ.;Ethicon, Inc., Somerville, NJ.",
"authors": "Albala|David M|DM|;Riebman|Jerome B|JB|;Kocharian|Richard|R|;Ilie|Bogdan|B|;Albanese|John|J|;Shen|Jessica|J|;Ovington|Liza|L|;Batiller|Jonathan|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1523-6161",
"issue": "17(1)",
"journal": "Reviews in urology",
"keywords": "Fibrin tissue adhesive; Hemostasis; Hemostatics; Surgical technique; Urologic surgical procedures",
"medline_ta": "Rev Urol",
"mesh_terms": null,
"nlm_unique_id": "100889067",
"other_id": null,
"pages": "25-30",
"pmc": null,
"pmid": "26028998",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "17284697;11566470;2465646;21873356;12960574;12774314;11778063;1755137;15545559;12869982;9684674;18633016;2464722;18950843;11087168;12558776",
"title": "Hemostasis during urologic surgery: fibrin sealant compared with absorbable hemostat.",
"title_normalized": "hemostasis during urologic surgery fibrin sealant compared with absorbable hemostat"
} | [
{
"companynumb": "US-JNJFOC-20190504510",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FIBRINOGEN HUMAN\\THROMBIN HUMAN"
},
"drugadditio... |
{
"abstract": "Patients affected by Multiple Sclerosis are often treated by pulsed intravenous corticosteroids to manage acute relapses with positive outcomes. The intravenous administration is frequently associated to avascular necrosis of several bones, particularly the femur. The present report regards a case of an underage MS patient with a bilateral ANFH secondary to pulsed administrations of steroids, managed by a conservative approach on a hip, and by a novel surgical technique on the contralateral side.",
"affiliations": "Orthopaedic Clinic, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.;Orthopaedic Clinic, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.;Neurologic Unit, Department NEUROFARBA, Section Neurosciences, University of Florence, Florence, Italy.;Neurologic Unit, Department NEUROFARBA, Section Neurosciences, University of Florence, Florence, Italy.;Neurologic Unit, Department NEUROFARBA, Section Neurosciences, University of Florence, Florence, Italy.",
"authors": "Carulli|Christian|C|;Nistri|Lorenzo|L|;Bracco|Laura|L|;Giannini|Marta|M|;Amato|Maria Pia|MP|",
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"journal": "Clinical cases in mineral and bone metabolism : the official journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases",
"keywords": "avascular necrosis; bioceramics; core decompression; femur; fingolimod; forage; multiple sclerosis; stem cells; steroids",
"medline_ta": "Clin Cases Miner Bone Metab",
"mesh_terms": null,
"nlm_unique_id": "101250935",
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"title": "A steroid-induced bilateral avascular necrosis of the femoral head in an underage patient affected by multiple sclerosis.",
"title_normalized": "a steroid induced bilateral avascular necrosis of the femoral head in an underage patient affected by multiple sclerosis"
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"abstract": "Acute pancreatitis (AP) is considered one of the potentially rare complications of severe hypertriglyceridemia (HTG). Multiple treatment modalities have been suggested for patients with HTG-AP, such as permanent removal of TG by plasmapheresis, the use of insulin and heparin to enhance lipoprotein lipase activity and fibrate therapy, but the data remains limited.\nwe reported a case of 33-year-old women admitted for HTG-induced PA (HTG-AP). The patient had hypertriglyceridemia for 7 years under fibrate therapy as a medical history. On admission to our intensive care unit, his triglyceride level was 1060 mg/dl and the lipase level was 298 IU/L. An abdominal CT scan revealed stage E AP. The patient was treated with a low dose insulin infusion (0.05 unit/kg/h) with heparin and 5-day course of plasmapheresis, Fibrate therapy was maintained. His triglycerides went down to 130.9 mg/dl and she was discharged.\nEarly recognition of severe HTG can prevent progression to multiples diseases such as acute pancreatitis, can facilitate appropriate or even aggressive treatment to minimize complications of this.",
"affiliations": "Intensive Care Unit, Mohammed VI University Hospital Center, Oujda, Morocco.;Intensive Care Unit, Mohammed VI University Hospital Center, Oujda, Morocco.;Intensive Care Unit, Mohammed VI University Hospital Center, Oujda, Morocco.;Intensive Care Unit, Mohammed VI University Hospital Center, Oujda, Morocco.;Intensive Care Unit, Mohammed VI University Hospital Center, Oujda, Morocco.;Intensive Care Unit, Mohammed VI University Hospital Center, Oujda, Morocco.;Intensive Care Unit, Mohammed VI University Hospital Center, Oujda, Morocco.;Intensive Care Unit, Mohammed VI University Hospital Center, Oujda, Morocco.;Intensive Care Unit, Mohammed VI University Hospital Center, Oujda, Morocco.;Intensive Care Unit, Mohammed VI University Hospital Center, Oujda, Morocco.",
"authors": "Ghizlane|El Aidouni|EA|;Manal|Merbouh|M|;Salma|Taouihar|T|;Abderrahim|El Kaouini|EK|;Mohammed|Maarad|M|;Ikram|Zaid|Z|;Fatem-Zahra|Aftiss|A|;Sanae|El Mezzioui|EM|;Houssam|Bkiyar|B|;Brahim|Housni|H|",
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"fulltext": "\n==== Front\nAnn Med Surg (Lond)\nAnn Med Surg (Lond)\nAnnals of Medicine and Surgery\n2049-0801\nElsevier\n\nS2049-0801(21)00864-5\n10.1016/j.amsu.2021.102914\n102914\nCase Report\nHypertriglyceridemia revealing acute pancreatitis: A case report\nGhizlane El Aidouni elaidounighizlane@gmail.com\nabd∗\nManal Merbouh manal.mrb@gmail.com\nabd\nSalma Taouihar salma.taouihar@gmail.com\nabd\nAbderrahim El Kaouini abderrahimfmpo19@gmail.com\nabd\nMohammed Maarad maaradmohammed92@gmail.com\nabd\nIkram Zaid ikramzaid1993@gmail.com\nabd\nFatem-Zahra Aftiss fatimaaf-13@hotmail.com\nabd\nSanae El Mezzioui sanae.elmezzeoui@gmail.com\nabd\nHoussam Bkiyar 7b.houssam@gmail.com\nabd\nBrahim Housni brahimhousni@yahoo.fr\nabcd\na Intensive Care Unit, Mohammed VI University Hospital Center, Oujda, Morocco\nb Mohammed First University Oujda, Faculty of Medicine and Pharmacy, Oujda, Morocco\nc Mohammed First University Oujda, FMP Oujda, LAMCESM, Oujda, Morocco\nd Anesthesiology and Intensive Care Unit Department, Mohammed First University, Faculty of Medicine and Pharmacy, Oujda, Morocco\n∗ Corresponding author. Anesthesiology and Intensive Care Unit Department, Mohammed First University, Faculty of medicine and pharmacy, 60000, Oujda, Morocco. elaidounighizlane@gmail.com\n07 10 2021\n10 2021\n07 10 2021\n70 1029142 9 2021\n1 10 2021\n3 10 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nIntroduction\n\nAcute pancreatitis (AP) is considered one of the potentially rare complications of severe hypertriglyceridemia (HTG). Multiple treatment modalities have been suggested for patients with HTG-AP, such as permanent removal of TG by plasmapheresis, the use of insulin and heparin to enhance lipoprotein lipase activity and fibrate therapy, but the data remains limited.\n\nCase management\n\nwe reported a case of 33-year-old women admitted for HTG-induced PA (HTG-AP). The patient had hypertriglyceridemia for 7 years under fibrate therapy as a medical history. On admission to our intensive care unit, his triglyceride level was 1060 mg/dl and the lipase level was 298 IU/L. An abdominal CT scan revealed stage E AP. The patient was treated with a low dose insulin infusion (0.05 unit/kg/h) with heparin and 5-day course of plasmapheresis, Fibrate therapy was maintained. His triglycerides went down to 130.9 mg/dl and she was discharged.\n\nConclusion\n\nEarly recognition of severe HTG can prevent progression to multiples diseases such as acute pancreatitis, can facilitate appropriate or even aggressive treatment to minimize complications of this.\n\nHighlights\n\n• Hypertriglyceridemia is the third most common cause of acute pancreatitis.\n\n• It is necessary to have a TG level greater than 1000 mg/dl (or 20 mmol/l) to induce acute pancreatitis.\n\n• Treatment of this acute pancreatitis due to hypertriglyceridemia involves lowering lipid levels through the use of plasmapheresis, heparin and insulin infusions and/or fibrate therapy.\n\nKeywords\n\nAcute pancreatitis\nHypertriglyceridemia\nLipid metabolism\nInsulin injection\nLipase\nPlasmapheresis\n==== Body\npmc1 Introduction\n\nHypertriglyceridemia is the third most common cause of acute pancreatitis. it is relatively rare and the diagnosis can be very difficult. However, this requires a high level of clinical suspicion with a good history as well as the presence of high levels of triglycerides (TG) [1].\n\nTreatment of this acute pancreatitis due to hypertriglyceridemia involves lowering lipid levels through the use of plasmapheresis, heparin and insulin infusions to enhance lipoprotein lipase activity, and/or fibrate therapy [2].\n\nThis paper presented a case of 33-year-old- women admitted with HTG-induced PA (HTG-AP).\n\n2 Case management\n\nA 33-year-old women admitted to our intensive care unit for HTG-induced PA (HTG-AP). The patient had hypertriglyceridemia for 7 years under fibrate therapy as a medical history. She was referred after 7 days of abdominal pain (epigastric pain) radiating posteriorly with notions of vomiting and deterioration of general condition. The patient reports the notion of having eaten a hearty meal rich in fat and carbohydrate (fatty food) while forgetting her diet. Clinical examination showed an abdominal tenderness elicited on palpation, normal hemodynamic state with tachycardia 109 pulse/minute, normal respiratory state with SpO2 98% on room air.\n\nThe complete blood count showed: high level of triglyceride with 1060 mg/dl and lipase level was 298 IU/L, high C-reactive protein with 320 mg/L, normal white blood cells 6390/mm3 and normal kidney function. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were normal. Total cholesterol was 372.9 mg/dl, high-density lipoprotein (HDL), 13.8 mg/dl and Low-density lipoprotein (LDL) was not recorded. HbA1c was 7.9% and glycaemia level was 2.1 g/L. Her venous blood gas showed a pH of 7.51 and HCO3 of 22 mmol/L.\n\nAn abdominal CT scan revealed stage E of acute pancreatitis. Then she was diagnosed with HTG-AP.\n\nOn day 1 of stay, the patient was kept nil per mouth and started on a continuous infusion of normal saline at 135 ml/hr for 24 hours, she was treated with a low dose insulin infusion (0.05 unit/kg/h) by the endocrinologist with heparin. Besides, atorvastatin (40 mg once daily (OD)), fenofibrate (145 mg OD), and aspirin (100 mg OD) were given. On day 3, the patient showed no improvement leading to initiating plasma exchange (PLEX) therapy: for 5 sessions with exchange of 3 L of plasma each session.\n\nOn day 7, her lipase level reduced to normal (40 IU/L), and TG level came down to 130.9 mg/dl. Throughout her stay in the intensive care unit, oral nutrition was maintained, as was social interaction face-to-face with loved ones. Indeed, she was informed daily of his health state and she was discharged after 8 days of her stay in intensive care unit.\n\nThis case reports follows scare guidelines [3].\n\n3 Discussion\n\nWhile AP has multiple etiologies, hypertriglyceridemia is considered the third most common cause after gallstones and alcohol. it is the underlying cause of pancreatitis in 7% of the population [4,5]. Hypertriglyceridemia can lead to acute pancreatitis as a precipitating agent of pancreatitis or as an epiphenomenon [6].\n\nThe secondary causes of hypertriglyceridemia are generally not sufficient to cause an elevated level of TG to cause pancreatitis, thus necessitating the need for a pre-existing defect. Indeed, it is necessary to have a TG level greater than 1000 mg/dl (or 20 mmol/l) to induce acute pancreatitis [6,7].\n\nYoshifumi and all showed in his paper that the ingestion of fatty foods in the two cases studied had an acute abdomen with a high level of inflammation parameters accompanied by hypertriglyceridemia and lipasemia [8]. As in our case, our patient had an acute abdomen following the ingestion of fatty foods with a high rate of hypertriglyceridemia, lipasemia and C-reactive protein.\n\nOn imaging, abdominal ultrasound could not detect acute pancreatitis, abdominal CT remains the exam of choice for confirmation of this pathology. As indicated in our case.\n\nTreatment of hypertriglyceridemia-induced pancreatitis involves early management of acute pancreatitis and prevention of any of his complications. In the study by Tsuang and al; plasmapheresis has been used to facilitate the removal of chylomicrons from the bloodstream and to improve insulin sensitivity and glycemic control [9]. As our case report shows, our patient had benefited from 5 plasma exchange sessions with a clear improvement. However, several studies showed conflicting results regarding the effectiveness of the use of plasmapheresis, hence different studies are needed in this context [9]. Another effective therapy has been used to reduce TG in Jennifer study is the use of insulin and heparin infusions, either in combination or in monotherapy, as well as aggressive rehydration [10]. our patient was treated in the same way with a marked improvement in her clinical condition.\n\nOur patient was satisfied from our medical care.\n\nThe early measurement of serum triglyceride levels and pancreatic enzymes such as lipasemia, as well as the identification of chylomicrons could aid in the development of the treatment regimen and the prevention of the progression of complications due to this pathology.\n\n4 Conclusion\n\nHTG-AP is a serious disease requiring prompt diagnosis and treatment. In our case, HTG-AP was managed with an infusion of low dose insulin, heparin and the use of a 5-day course of plasmapheresis which prevented the progression of complications from pancreatitis. Several investigations are necessary to understand the efficacy of low dose insulin in the management of HTG-AP as well as the indication of plasmapheresis.\n\nEthical approval\n\nThe ethical committee approval was not required give the article type (case report). However, the written consent to publish the clinical data of the patients was given and is available to check by the handling editor if needed.\n\nSources of funding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nAuthor contribution\n\nEL AIDOUNI Ghizlane: Corresponding author, study concept, Data collection, data analysis, writing review & editing. MERBOUH Manal: Contributor. Taouihar Salma: Contributor. El Kaouini Abderrahim: Contributor. Maarad Mohammed: Contributor. Zaid Ikram: Contributor. Aftiss Fatem-Zahra: Contributor. El Mezzioui Sanae: Contributor. BKIYAR Houssam: Supervision and data validation. HOUSNI Brahim: Supervision and data validation.\n\nRegistration of research studies\n\nThis is not an original research project involving human participants in an interventional or an observational study but a case report. This registration is was not required.\n\nGuarantor\n\nEL AIDOUNI Ghizlane.\n\nConsent\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nProvenance and peer review\n\nNot commissioned, externally peer-reviewed.\n\nDeclaration of competing interest\n\nThe authors state that they have no conflicts of interest for this report.\n\nAppendix A Supplementary data\n\nThe following is the Supplementary data to this article:Multimedia component 1\n\nMultimedia component 1\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2021.102914.\n==== Refs\nReferences\n\n1 Weston Natasha Fernando Upul Baskar Varadarajan Hypertriglyceridaemia-induced pancreatitis BMJ Case Rep. 2013 2013 10.1136/bcr-2013-008722 bcr2013008722\n2 Garg R. Rustagi T. Management of hypertriglyceridemia induced acute pancreatitis BioMed Res. Int. 2018 2018 4721357 30148167\n3 Agha R.A. Franchi T. Sohrabi C. Mathew G. for the SCARE Group The SCARE 2020 guideline: updating consensus surgical CAse REport (SCARE) guidelines Int. J. Surg. 84 2020 226 230 33181358\n4 Gan S.I. Edwards A.L. Symonds C.J. Hypertriglyceridemia-induced pancreatitis: a case-based review World J. Gastroenterol. 12 2006 7197 7202 17131487\n5 Kota S.K. Kota S.K. Jammula S. Hypertriglyceridemia-induced recurrent acute pancreatitis: a case-based review Indian J Endocrinol Metab 16 2012 141 143 22276267\n6 Yadav D. Pitchumoni C.S. Issues in hyperlipidemic pancreatitis J. Clin. Gastroenterol. 36 2003 54 62 12488710\n7 Sandhu S. Al-Sarraf A. Taraboanta C. Incidence of pancreatitis, secondary causes, and treatment of patients referred to a speciality lipid clinic with severe hypertriglyceridemia: a retrospective cohort study Lipids Health Dis. 10 2011 157 21906399\n8 Okura Yoshifumi Hayashi Kozo Shingu Tetsuji Kajiyama Goro Nakashima Yoshiyuki Saku Keijiro Diagnostic evaluation of acute pancreatitis in two patients with hypertriglyceridemia World J. Gastroenterol. 10 24 2004 Dec 15 3691 3695 10.3748/wjg.v10.i24.3691 15534935\n9 Tsuang W. Navaneethan U. Ruiz L. Hypertriglyceridemic pancreatitis: presentation and management Am. J. Gastroenterol. 104 2009 984 991 19293788\n10 Jennifer D. Mancell T. Mancell J. Hypertriglyceridemia-induced acute pancreatitis treated with insulin and heparin Am. J. Health Syst. Pharm. 69 2012 213 216 22261942\n\n",
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"title": "Hypertriglyceridemia revealing acute pancreatitis: A case report.",
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"abstract": "Stent thrombosis is a life-threatening sequela of drug-eluting stent implantation. Dual antiplatelet therapy with aspirin and thienopyridine is typically used to prevent this catastrophic event. In terms of stent thrombosis, the major concern is the variable response of patients to clopidogrel, and this has raised interest in new antiplatelet agents. We present the case of a 64-year-old woman whom we successfully treated with prasugrel after she had repeated episodes of stent thrombosis caused by a poor response to clopidogrel. This case highlights the potential role of new antiplatelet agents for patients who are undergoing drug-eluting stent implantation.",
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"authors": "Kim|Yi-Sik|YS|;Lee|Sang-Rok|SR|",
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"medline_ta": "Tex Heart Inst J",
"mesh_terms": "D001241:Aspirin; D000077144:Clopidogrel; D017023:Coronary Angiography; D003324:Coronary Artery Disease; D003328:Coronary Thrombosis; D004351:Drug Resistance; D057915:Drug Substitution; D004359:Drug Therapy, Combination; D054855:Drug-Eluting Stents; D006801:Humans; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D010975:Platelet Aggregation Inhibitors; D010979:Platelet Function Tests; D000068799:Prasugrel Hydrochloride; D011474:Prosthesis Design; D012008:Recurrence; D013988:Ticlopidine; D013997:Time Factors; D016896:Treatment Outcome",
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"title": "Successful Prasugrel Therapy for Recurrent Left Main Stent Thrombosis in a Clopidogrel Hyporesponder.",
"title_normalized": "successful prasugrel therapy for recurrent left main stent thrombosis in a clopidogrel hyporesponder"
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"abstract": "With the increasing prevalence of type 2 diabetes mellitus (T2DM) in women of childbearing age, prescribing antidiabetic medications in first-trimester pregnancy is becoming more common. Metformin treatment during this time is usually avoided in countries with well-resourced healthcare. This is based on historical concerns about safety to the foetus and the widespread availability of insulin. However, there is now increasing interest in the potential benefits of metformin in pregnant women with T2DM. In this commentary, the main evidence supporting metformin safety in pregnancy is summarized, with an emphasis on the first trimester. Based on a structured literature search, the recent randomized controlled trials comparing metformin and insulin are reviewed. We then show that prescribing advice for metformin in pregnancy is inconsistent and product information/package inserts (PI) are universally out of date. This causes confusion and pushes some women and their clinicians to change from metformin to insulin. The potential advantages of metformin in pregnant women with T2DM are then discussed, including oral dosing and improved acceptability, lower resource utilization and cost, decreased insulin requirements, less maternal weight gain and less risk of maternal and neonatal hypoglycaemia. The conclusion is that metformin is a cheap and efficacious antidiabetic medication for many pregnant women with T2DM, with reasonable evidence for safety. Drug information resources should be updated so that metformin can be considered more broadly in women with T2DM who present for antenatal care.",
"affiliations": "Department of Clinical Pharmacology, Flinders University School of Medicine and Flinders Medical Centre, Bedford Park, South Australia 5042, Australia d3 Medicine, A Certara Company, Parkville, Victoria, 3052, Australia.;Department of Medicine, University of Otago, Dunedin, New Zealand Christchurch Hospital, Canterbury District Health Board, Christchurch, New Zealand.;Department of Clinical Pharmacology, Flinders University School of Medicine and Flinders Medical Centre, Bedford Park, South Australia, Australia.",
"authors": "Polasek|Thomas M|TM|https://orcid.org/0000-0003-1008-5223;Doogue|Matthew P|MP|;Thynne|Tilenka R J|TRJ|",
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"issue": "9(6)",
"journal": "Therapeutic advances in drug safety",
"keywords": "birth defects; metformin; pregnancy; safety; type 2 diabetes mellitus",
"medline_ta": "Ther Adv Drug Saf",
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"title": "Metformin treatment of type 2 diabetes mellitus in pregnancy: update on safety and efficacy.",
"title_normalized": "metformin treatment of type 2 diabetes mellitus in pregnancy update on safety and efficacy"
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"abstract": "In a phase 3 multicenter, randomized, double-blinded, placebo-controlled study of 298 patients with non-Hodgkin lymphoma (NHL), granulocyte colony-stimulating factor (G-CSF) plus plerixafor increased the proportion of patients who mobilized >or=5 x 10(6) CD34(+) hematopoietic stem cells (HSCs)/kg compared with placebo plus G-CSF (P < .001). Patients in either study arm who failed mobilization (< 0.8 x 10(6) CD34(+) cells/kg in 2 collections or <2 x 10(6) CD34(+) cells/kg in 4 collections) were eligible to enter the opened-label rescue protocol. Following a 7-day minimum rest period, these patients received G-CSF (10 microg/kg/day) for 4 days, followed by daily plerixafor (0.24 mg/kg) plus G-CSF and apheresis for up to 4 days. Of the 68 patients failing initial mobilization (plerixafor, n = 11; placebo, n = 57), 62 patients (91%) entered the rescue procedure (plerixafor, n = 10; placebo, n = 52). Four of 10 patients (40%) from the plerixafor group and 33 of 52 (63%) from the placebo group mobilized sufficient CD34(+) cells (>or= 2 x 10(6) cells/kg) for transplantation from the rescue mobilization alone (P = .11). Engraftment of neutrophils (11 days) and platelets (20 days) was similar to that in patients who did not fail initial mobilization, and all patients had durable grafts at the 12-month follow-up. Common plerixafor-related adverse events (AEs) included mild gastrointestinal (GI) effects and injection site reactions. There were no drug-related serious AEs. These data support that plerixafor plus G-CSF can safely and effectively remobilize patients with NHL who have failed previous mobilization.",
"affiliations": "Mayo Clinic, Department of Internal Medicine, Division of Hematology Rochester, Minnesota, USA. Micallef.Ivana@mayo.edu",
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"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
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"title": "Successful stem cell remobilization using plerixafor (mozobil) plus granulocyte colony-stimulating factor in patients with non-hodgkin lymphoma: results from the plerixafor NHL phase 3 study rescue protocol.",
"title_normalized": "successful stem cell remobilization using plerixafor mozobil plus granulocyte colony stimulating factor in patients with non hodgkin lymphoma results from the plerixafor nhl phase 3 study rescue protocol"
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"abstract": "Primary systemic therapy in resectable pancreatic cancer is currently under investigation. FOLFIRINOX has been shown to be effective in both the adjuvant and metastatic settings and is increasingly being used on and off study in the neoadjuvant setting. The objective pathologic response elicited by this regimen in truly resectable disease has not as yet been widely reported.\n\n\n\nThis analysis focuses on 14 patients with resectable pancreatic cancer who were treated in a pilot study of primary systemic therapy, using 4 cycles of neoadjuvant FOLFIRINOX before surgery. A dedicated pancreatic pathologist reviewed all of the subsequent surgical specimens to assess the degree of tumor regression elicited by this approach, according to the scoring system proposed by Evans.\n\n\n\nFour patients (28.6%) had Evans grade I, 4 (28.6%) Evans grade IIa, 2 (14.2%) Evans grade IIb, and 4 (28.6%) Evans grade III response to the primary systemic therapy. There were no Evans grade IV responses.\n\n\n\nThe results are intriguing with 28% of the specimens showing destruction of <10% of tumor cells, and only 28% achieving >90% destruction of tumor cells. The significant variation in response once again confirms the known heterogeneity in the biology of this cancer and clearly FOLFIRINOX is not equally effective in all patients. Future studies evaluating primary systemic therapy in pancreatic cancer should examine the optimal duration of therapy before surgery and should include a standardized pathologic grading scheme to better enable comparison of results.",
"affiliations": "NorthShore University HealthSystem.",
"authors": "Polish|Ariel|A|;Joseph|Nora E|NE|;Marsh|Robert de W|RW|",
"chemical_list": "C000627770:folfirinox; D000077150:Oxaliplatin; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1097/COC.0000000000000601",
"fulltext": null,
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"issn_linking": "0277-3732",
"issue": "42(10)",
"journal": "American journal of clinical oncology",
"keywords": null,
"medline_ta": "Am J Clin Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001707:Biopsy, Needle; D002423:Cause of Death; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil; D006785:Hospitals, University; D006801:Humans; D007150:Immunohistochemistry; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D000077150:Oxaliplatin; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms; D010865:Pilot Projects; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "8207754",
"other_id": null,
"pages": "761-766",
"pmc": null,
"pmid": "31569128",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pathologic Response to Primary Systemic Therapy With FOLFIRINOX in Patients With Resectable Pancreatic Cancer.",
"title_normalized": "pathologic response to primary systemic therapy with folfirinox in patients with resectable pancreatic cancer"
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"abstract": "Introduction: Malignant brain tumors in infants less than 12 months of age are extremely rare, and they have poor prognosis. We evaluated genetic characteristics and response rates of infants with congenital brain tumors subjected to high-dose chemotherapy and autologous stem cell transplant after gross total tumor resection. Materials and Methods: In total, 10 infants, aged less than 12 months, were enrolled in this study. The median age was 56 days (range: 1-279 days). Pathological examination demonstrated the following: four anaplastic astrocytomas, two glioblastomas, two central nervous system (CNS) embryonal tumors, not otherwise specified (NOS), and two atypical teratoid/rhabdoid tumors. Results: All patients were exposed to induction chemotherapy regimen, two high-dose chemotherapy courses, and autologous stem cell transplant after maximal surgery. At 1-3-5 years, the global overall survival (OS) was 90, 70, and 70% and the progression-free survival (PFS) was 80-60 and 60%. In all the patients, the copy number variants (CNVs) profile was analyzed using the SNP/CGH array approach. To investigate the clinical relevance of germline SMARCB1 mutation in AT/RT patients, we performed sequence analysis of the coding regions. The two patients with AT/RT were found to have germline SMARCB1 mutations. No BRAF mutations were found, and only NTRK gene fusion was present in one patient. We also have examined the association with OS and PFS and different histological subtypes of infant CNS proving that high-grade astrocytoma has better overall survival than other tumor types (p: 0.007 and p: 0.0590). Conclusion: High-dose chemotherapy regimen represents a valid therapeutic approach for congenital brain tumors with a high rate of response. The molecular analysis has to be analyzed in all infants' brain tumor types. High-grade gliomas are characterized by a better prognosis than other histologies of infant CNS.",
"affiliations": "Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children's Hospital, Florence, Italy.;Medical Genetics Unit, Meyer Children's Hospital, Florence, Italy.;Pathology Unit, Meyer Children's Hospital, Florence, Italy.;Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA, United States.;Neurosurgery Unit, Meyer Children's Hospital, Florence, Italy.;Clinical Trial Office, Meyer Children's Hospital, Florence, Italy.;Neurosurgery Unit, Meyer Children's Hospital, Florence, Italy.;Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children's Hospital, Florence, Italy.",
"authors": "Guidi|Milena|M|;Giunti|Laura|L|;Buccoliero|Anna Maria|AM|;Santi|Mariarita|M|;Spacca|Barbara|B|;De Masi|Salvatore|S|;Genitori|Lorenzo|L|;Sardi|Iacopo|I|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fped.2020.00135",
"fulltext": "\n==== Front\nFront Pediatr\nFront Pediatr\nFront. Pediatr.\nFrontiers in Pediatrics\n2296-2360 Frontiers Media S.A. \n\n10.3389/fped.2020.00135\nPediatrics\nOriginal Research\nUse of High-Dose Chemotherapy in Front-Line Therapy of Infants Aged Less Than 12 Months Treated for Aggressive Brain Tumors\nGuidi Milena 1 Giunti Laura 2 Buccoliero Anna Maria 3 Santi Mariarita 4 Spacca Barbara 5 De Masi Salvatore 6 Genitori Lorenzo 5 Sardi Iacopo 1* 1Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children's Hospital, Florence, Italy\n2Medical Genetics Unit, Meyer Children's Hospital, Florence, Italy\n3Pathology Unit, Meyer Children's Hospital, Florence, Italy\n4Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA, United States\n5Neurosurgery Unit, Meyer Children's Hospital, Florence, Italy\n6Clinical Trial Office, Meyer Children's Hospital, Florence, Italy\nEdited by: Anat Erdreich-Epstein, Children's Hospital of Los Angeles, United States\n\nReviewed by: Theodore Nicolaides, New York University, United States; Nathan John Robison, Children's Hospital of Los Angeles, United States\n\n*Correspondence: Iacopo Sardi iacopo.sardi@meyer.itThis article was submitted to Pediatric Oncology, a section of the journal Frontiers in Pediatrics\n\n\n09 4 2020 \n2020 \n8 13515 11 2019 10 3 2020 Copyright © 2020 Guidi, Giunti, Buccoliero, Santi, Spacca, De Masi, Genitori and Sardi.2020Guidi, Giunti, Buccoliero, Santi, Spacca, De Masi, Genitori and SardiThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Introduction: Malignant brain tumors in infants less than 12 months of age are extremely rare, and they have poor prognosis. We evaluated genetic characteristics and response rates of infants with congenital brain tumors subjected to high-dose chemotherapy and autologous stem cell transplant after gross total tumor resection.\n\nMaterials and Methods: In total, 10 infants, aged less than 12 months, were enrolled in this study. The median age was 56 days (range: 1–279 days). Pathological examination demonstrated the following: four anaplastic astrocytomas, two glioblastomas, two central nervous system (CNS) embryonal tumors, not otherwise specified (NOS), and two atypical teratoid/rhabdoid tumors.\n\nResults: All patients were exposed to induction chemotherapy regimen, two high-dose chemotherapy courses, and autologous stem cell transplant after maximal surgery. At 1–3–5 years, the global overall survival (OS) was 90, 70, and 70% and the progression-free survival (PFS) was 80–60 and 60%. In all the patients, the copy number variants (CNVs) profile was analyzed using the SNP/CGH array approach. To investigate the clinical relevance of germline SMARCB1 mutation in AT/RT patients, we performed sequence analysis of the coding regions. The two patients with AT/RT were found to have germline SMARCB1 mutations. No BRAF mutations were found, and only NTRK gene fusion was present in one patient. We also have examined the association with OS and PFS and different histological subtypes of infant CNS proving that high-grade astrocytoma has better overall survival than other tumor types (p: 0.007 and p: 0.0590).\n\nConclusion: High-dose chemotherapy regimen represents a valid therapeutic approach for congenital brain tumors with a high rate of response. The molecular analysis has to be analyzed in all infants' brain tumor types. High-grade gliomas are characterized by a better prognosis than other histologies of infant CNS.\n\ncongenital tumorchemotherapyglioblastomabrain tumornewborn\n==== Body\nIntroduction\nEarly childhood central nervous system (CNS) neoplasms are rare tumors, and they constitute only 2% of all pediatric brain tumors. The definition of “congenital brain tumor” has been submitted to continuous assessment; several years ago, Jellinger proposed the following: “definitely congenital—symptoms arise at birth or within the first 2 weeks of life; probably congenital—symptoms arise in the first year of life; and possibly congenital—symptoms arise beyond the first year of life” (1). Ellams suggested the following classification: congenital lesion up to 6 weeks from birth, probably congenital to 6 months, and possibly congenital—up to the end of the first year of life (2). The most common congenital neoplasia includes teratomas, astrocytomas (low and high grade), embryonal tumors [medulloblastoma, CNS embryonal tumor not otherwise specified (NOS), atypical teratoid rhabdoid tumors (AT/RT)], choroid plexus tumors, and craniopharyngiomas. Ependimomas and germinomas are less commonly encountered (3, 4). Most of these tumors have a very aggressive behavior, and patients are at a high risk for early mortality after diagnosis. For this reason, few patients are enrolled in clinical trials (5). Particularly, congenital AT/RTs have a fatal prognosis (6). Germline testing for constitutional gene mutations may provide a key information mainly on the AT/RT.\n\nThe main prognostic factors that characterize the prognosis of all infant brain tumors, in addition to the type of tumor, could be due to the massive size of these neoplasms at the time of diagnosis, the surgical difficulties in resecting large tumors, and the absence of consolidated therapeutic approaches. As with all brain tumors, surgery is the first fundamental therapeutic approach and the prognosis is highly dependent on the extent of the resection of the tumor. Being that radiotherapy is not recommended for very young patients, intensive chemotherapy regimens with high doses and autologous stem cell transplant (ASCT) after maximal possible surgery could seem to be a helpful adjuvant treatment. Strategically, a multidisciplinary team that includes pediatric neurosurgery and neuro-oncology experts is necessary to approach these complex children.\n\nIn this report, we present 10 infants aged less than 12 months with aggressive brain tumors. We evaluated the safety and the effectiveness of high-dose thiotepa and carboplatin/thiotepa followed by stem cell rescue.\n\nMaterials and Methods\nPatient Population\nAll infants less than 12 months of age with malignant brain tumors admitted between 2003 and 2016 to the Meyer Children's University Hospital of Florence were eligible for this study. Histological diagnosis was examined after admission for adjuvant treatment in all cases by two pathologists. After surgery, tumor specimens were routinely fixed in neutral buffered formol and embedded in paraffin.\n\nTreatment Protocol\nThe chemotherapy program was applied to all newly diagnosed patients, aged less than 12 months, at the time of diagnosis. No patient had radiation therapy as first line of treatment.\n\nA central line catheter was placed prior to starting standard chemotherapy and high-dose thiotepa and ASCT as previously reported (7). Doses were adjusted for weight. The four-course induction phase included the following: first, methotrexate 250 mg/kg plus vincristine 0.04 mg/kg; second, etoposide 80 mg/kg; third, cyclophosphamide 135 mg/kg plus vincristine 0.04 mg/kg; and finally carboplatin 25 mg/kg as the fourth cycle. Peripheral blood stem cells were collected for rescue therapy after the second course. Intensification and consolidation phases included two high-dose chemotherapy regimens: thiotepa at myeloablative doses (10 mg/kg/day for 3 days) followed by ASCT. The second conditioning regimen also included carboplatin (16 mg/kg/day for 2 days) with thiotepa to improve the response rate (8, 9) (Figure 1).\n\nFigure 1 Treatment protocol.\n\nGenetic Analysis\nTumor, peripheral blood, and buccal swab DNAs were pulled out using QIAamp Mini Kit (QIAGEN®, Hilden, Germany) according to manufacturers' instructions and quantified by NanoDROP 2000 Spectrophotometer (Thermo Scientific, Waltham, MA, USA).\n\nSequence analysis of the coding regions of INI1 gene was prepared with BigDye Terminator v1.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, CA) according to the manufacturer's protocol and sequenced on a 3130 Genetic Analyzer (Applied Biosystems). Primer sequences are available upon request. SNP/CGH array was performed using the Agilent Human Genome CGH Microarray Kit 180K (Agilent Technologies, Santa Clara, CA, USA). Labelling and hybridization were performed following the protocols provided by Agilent, and images of the arrays were acquired with the Agilent C Scanner (Agilent Technologies, Santa Clara, CA, USA) and processed using the Agilent Feature Extraction 10.5 software. The data were analyzed using the Genomic Workbench Standard Edition 5.0 software by the ADM-2 algorithm (breakpoint positions were reported according to Hg19, build 37). Chromosomal analysis was performed on phytohemagglutinin-stimulated peripheral lymphocyte cultures using standard cytogenetic methods (Chromosome Kit P Euro Clone), incubated 72 h at 37°C, and investigated by QFQ-banding analysis. BRAF V600E and NTRK gene fusions were analyzed by immunohistochemistry.\n\nStatistical Analysis\nThe main endpoint was the correlation between clinical and molecular factors and overall survival (OS), which included the time from diagnosis to death, whatever the cause. We also evaluated progression-free survival (PFS), which was calculated from the date of diagnosis to the date of relapse or to the date of death. Survival curves (OS and PFS) were estimated using the Kaplan–Meier method with 95% confidence intervals (95% CIs). P values are reported using the log-rank test. The model considered the variables associated with a P value < 0.05.\n\nResults\nTen infants aged less than 12 months with aggressive brain tumors were enrolled in the Neuro-Oncology Unit of Meyer Children's Hospital in Florence. In three cases, the diagnosis was prenatal. Patients with other diagnosis presented the disease from 52 days after birth to 279 days after birth, with a median of 114 days.\n\nTheir main clinical and molecular features are summarized in Table 1. Histological diagnoses and tumor grading were carried out based on the 2016 World Health Organization (WHO) criteria (10). The median age at diagnosis was 56 days (range: 1–279 days). Pathological diagnosis was available in all cases: four were AA (WHO-grade III), two GBM (WHO-grade IV), two CNS embryonal tumor NOS (WHO-grade IV), and two AT/RT (WHO-grade IV). The variables considered for each case were as follows: histological type, presence of mutations, localization of primary tumor, and surgery approach.\n\nTable 1 Clinical details of infants aged less than 12 months treated for aggressive brain tumors.\n\nPatient n\tAge at diagnosis (days)\tHistology\tResection R0 (gross total resection)\n\nR2 (partial resection)\tGenetic analysis\tOutcome\t\n1\t70\tAA\tR2\tNO\tAlive at 87 months\t\n2\t1\tGBM\tR0\tNO\tAlive at 67 months\t\n3\t176\tAA\tR0\tNTRK fusion\tAlive at 71 months\t\n4\t141\tAA\tR2\tNO\tAlive at 56 months\t\n5\t1\tAA\tR2\tSomatic trisomy 8 – mosaicism\tAlive at 36 months\t\n6\t1\tAT/RT\tR2\tGermline SMARCB1/INI1 mutation\tDOD at 18 months\t\n7\t279\tCNS embryonal tumor NOS\tR2\tNO\tAlive at 38 months\t\n8\t1\tCNS embryonal tumor NOS\tR2\tNO\tAlive at 16 months\t\n9\t60\tAT/RT\tR2\tGermline SMARCB1/INI1 mutation\tDOD at 6 months\t\n10\t52\tGBM\tR2\tNO\tDOD at 25 months\t\nAA, Anaplastic Astrocytoma; GBM, glioblastoma; AT/RT, Atypical Teratoid Rhabdoid Tumor; DOD, Dead of Disease, R0, gross total resection (a resection without visual residual enhancing tumor), R2, partial resection (a resection of only part of the tumor).\n\nIn our series, anaplastic astrocytoma was the more frequent histological type with 4 of the 10 cases, all with supratentorial localization. Two other supratentorial tumors were GBM, and the two posterior fossa tumors were AT/RT (in one of these, spinal and cerebrospinal fluid metastases were also present at the diagnosis). Finally, two CNS embryonal tumor NOSs were hemispheric lesions (Figure 2).\n\nFigure 2 Coronal Gd-enhanced T1-weighted MR scans of a CNS embryonal tumor NOS. (A) Preoperative images demonstrating the intraventricular tumor at the right caudate nucleus. (B) Postoperative scans after septostomy and biopsy of the lesion. (C) Complete response after high-dose chemotherapy and ASCT. (D) Last MR follow-up.\n\nThe global OS at 1–3–5 years were 90, 70, and 70%, (CI, 47–99, 32–89, and 32–89%, respectively), and the PFS were 80–60 and 60% at 1–3–5 years (CI, 41–95, 25–83, and 25–83%, respectively) (Figure 3). The gold standard treatment for these aggressive tumors is, when possible, maximal surgery (11). In our study, only two patients had GTR. All other patients had only partial resection.\n\nFigure 3 Overall survival (A) and progression free survival (B) in patients with congenital brain tumors.\n\nGermline SMARCB1 mutations were noted in both patients with AT/RT. One patient with AT/RT had a c.618G>A (p.Trp206*) mutation in exon 5 of the SMARCB1 gene (Figure 4). This variant, already described in rhabdoid tumors, produced a premature stop codon of SMARCB1 (12). No mutation was identified in the peripheral blood of the father, and unfortunately, the patient was the result of an oocyte donation. The genetic analysis of other patients showed heterozygous c.175C>T mutation in exon 2 of SMARCB1 in the tumor's DNA.\n\nFigure 4 Histological study of an AT/RT with a c.618G>A (p.Trp206*) mutation in exon 5 of SMARCB1 gene. (A) Markedly enlarged atypical epithelioid cells with prominent nucleoli and abundant cytoplasm. Hematoxylin and eosin staining, x60X. (B) Results of immunohistochemical staining indicating the loss of SMARCB1 (INI1/hSNF5) expression in neoplastic cells (IHC, ×60).\n\nA genetic rearrangement was found in an AA patient: a duplication of the entire chromosome 8 with a dosage suggestive of genetic mosaics of 15–20% (log2 ratio of +0.3). The supernumerary chromosome 8 was of maternal origin. No mosaicism of supernumerary chromosome 8 was identified in the blood, buccal swab of the patient, and parents' DNA. Chromosome examination on 100 metaphases of the peripheral blood of this patient provided normal results suggesting a plausible somatic trisomy 8 and so excluding a constitutional chromosome 8 mosaicism. No BRAF mutations were found, and only NTRK gene fusion was present in one patient with AA.\n\nWe also examined the different histologies of infant CNS tumors showing that high-grade gliomas have better prognosis than others; AT/RT has shown a worse prognosis (p: 0.007 and p: 0.0590; Figure 5).\n\nFigure 5 Statistical correlation with OS and PFS with the histology (p: 0.007 and p: 0.0590).\n\nDiscussion\nThe incidence of early childhood brain tumors is 1.1–3.6 per 100,000 newborns, and they cause 0.04–0.18% of deaths in infants aged less than 12 months (1, 13).\n\nMalignant congenital brain tumors are rare diseases, and their therapy management is difficult because of the patients' young age. Therefore, there are still no consolidated treatments widely accepted internationally.\n\nThe main prognostic factors of CNS tumors are macroscopic disease residual tumor volume after surgery, histology, and presence of metastatic disease. In children younger than 12 months, the main therapeutic approaches are surgery and chemotherapy in order to delay radiotherapy as much as possible. The exposure of immature CNS to radiotherapy can induce early and severe cognitive deficits and severe leukoencephalopathy. Thus, when possible, the best approach for infants remains to be adjuvant chemotherapy after maximal surgery (3, 14).\n\nOne-third of all congenital astrocytic tumors are GBM, which mostly grow from the cerebral hemispheres and basal nuclei. These tumors have a high risk of intracranial bleeding and therefore the intralesion hemorrhage may be the first sign of the disease at initial imaging (15). Due to the lack of effective treatments for newborns with malignant astrocytoma, the OS rate remains disheartening. Recently, Guerreiro et al., studying infant gliomas under 1 year of age by genetic analysis, found three subgroups with different outcomes. Group 1 tumors showed ALK/ROS1/NTRK/MET fusions and had a good OS in comparison to older children with HGG. Group 2 hemispheric RAS/MAPK tumors had a very good outcome requiring only a “wait and see” strategy after a safe surgery. Group 3 represented midline LGG characterized by RAS/MAPK alterations. Contrary to what happens in older children, infants with BRAF fused tumors have a dismal outcome. They concluded that an early genetic analysis allows infants with BRAF-fused midline tumors to be included in upfront clinical trials with targeted inhibitors (16).\n\nAT/RT is an extremely aggressive tumor of the CNS, and its biology and histology are similar to the rhabdoid tumor of the kidney, soft tissues, and other sites (17, 18). AT/RT often arises in the posterior fossa, especially in the cerebellum but can grow also in cerebral hemispheres and the brainstem (19).\n\nGermline mutation of the SMARCB1 gene results in a phenotype known as the “rhabdoid predisposition syndrome,” which increases the risk of developing renal and extrarenal rhabdoid tumors (20).\n\nIt is noteworthy that there is a strong correlation between congenital brain tumors and several genetic syndromes (21–25).\n\nThe treatment of early childhood brain tumors has always been the subject of wide discussion. The introduction of the prolonged postoperative chemotherapy improved the survival, and it has enabled us to avoid or defer the radiotherapy until relapse.\n\nDuring the last decades, several therapeutic approaches succeeded obtaining a different survival rate, probably because the same treatment was used for different tumor histologies.\n\nSome studies reported data of congenital brain tumors treated with both chemotherapy and radiotherapy. The 5-year OS in patients subjected to radiotherapy was approximately between 30 and 40%. The morbidity was high irrespective of radiotherapy and most of the patients developed a moderate or severe disability (26, 27).\n\nDi Rocco et al. reported a meta-analysis on 886 children showing minimal side effects in around 50% of patients with congenital brain tumors, whereas more long-term deficits were in infants receiving whole brain irradiation (28).\n\nThe “baby brain” study of the Pediatric Oncology Group (POG) analyzed the effect of dose-intensified chemotherapy for infant MB. They utilized cyclophosphamide and vincristine alternating with cisplatin and etoposide. The radiotherapy was done only in patients older than 2 years. Survival utility was not evidenced with this approach compared to other experiences (PFS was 31.8 and OS 39.7% at 5 years). In 1992, they directed the first multicenter trial using adjuvant chemotherapy for children less than 36 months old with malignant brain tumors, deferring the radiotherapy until the age of 3 years. The 5-year OS and PFS rates reached 39.4% and 30%, respectively. The highest proportion of progressive or relapse disease was observed in the first 6 months of chemotherapy (29).\n\nThe Children's Cancer Group (CCG) 945 protocol obtained a 3-year PFS and OS of 36 and 50%, respectively, in glioma patients treated with “8 drugs-in-1 day” (vincristine, carmustine, procarbazine, hydroxyurea, cisplatin, cytarabine, dacarbazine, and prednisone) (17).\n\nThe CCG with CCG-9921 proposed two more intensive treatment regimes in patients with MB (regimen A: cisplatin, cyclophosphamide, etoposide, and vincristine; regimen B: vincristine, carboplatin, ifosfamide, and etoposide). A 5-year event free-survival (EFS) for regimen A was 38 vs. 26% for regimen B. In patients with CNS embryonal tumor NOS, the rate was low; 5-year OS was 30%. The same results were obtained in AT/RT patients (5-year OS: 29%). In ependymoma patients, 5-year OS was around 58%, and the rate in malignant gliomas was similarly unsatisfactory; the 3-year OS was 42% (30).\n\nThe French Society of Pediatric Oncology Baby Brain Protocol (BB-SFOP) adopted the strategy by treating patients with low risk with standard chemotherapy (cycle of carboplatin, procarbazine, etoposide, cisplatin, vincristine, and cyclophosphamide), reserving RT and combined high-dose chemotherapy with ASCT for patients with tumor progression or recurrence. The 3-year OS was 70% for patients with low risk. For patients with high risk, the protocol provided also myeloablative busulfan and thiotepa combining with ASCT and posterior fossa irradiation (TD: 50 Gy). In these patients, neurologic deficits were described, with 5-year OS of 65% in locally relapsed patients (31).\n\nInstead, for children between 2.5 and 3.0 years of age at diagnosis with high-risk tumors, HIT-SKK'87” protocol of the German Society of Pediatric Oncology and Hematology (GPOH) provided the same protocol of patients with low risk. It was expected that after surgery, two cycles of a post-operative induction chemotherapy would be performed. Following the primary treatment, they recommended the maintenance chemotherapy. The radiotherapy was administered at 3 years of age. Radiotherapy was administered immediately in cases of progression or tumor recurrence.\n\nThe subsequent HIT-SKK'92 study for children under the age of 3 was aimed at avoiding radiation therapy. The infants were treated with intensive postoperative systemic chemotherapy (cyclophosphamide, methotrexate, vincristine, carboplatin, and etoposide) and intraventricular therapy (2 mg intraventricular methotrexate in single doses via Ommaya reservoir). Craniospinal radiotherapy was done in patients older than 18 months who weren't in remission.\n\nThe results obtained for low-risk medulloblastoma were 5-year PFS of 82 ± 9% and OS of 93 ± 6%. The rates obtained for patients with residual disease were 5-year PFS of 50 ± 13% and OS of 56 ± 14%, and for patients with macroscopic metastasis, the outcome was poor with 5-year PFS of 33 ± 14% and OS of 38 ± 15%. Although the study reported a high rate of asymptomatic leukoencephalopathy linked to the intensive use of intrathecal methotrexate, the strategy to postpone craniospinal radiotherapy using postoperative chemotherapy has shown considerable efficacy for controlling tumor growth and survival (32–34).\n\nThe role of high-dose, marrow-ablative chemotherapy and ASCT in young patients with MB was investigated by the “Head Start” regimen. In this study, the 5-year OS rate for infant MB was 52% (35). A limitation to this highly toxic approach was the mortality rate of 19%. In Head Start II, high-dose methotrexate was added only in patients with metastatic MB, showing a mortality rate of 5.4% and a 4-year EFS of 51% (36).\n\nFinally, the HIT 2000 trial for MB in children less than 4 years of age considered longer but less dose-intensive induction chemotherapy and a shorter dose-intensive chemotherapy. They planned a tandem high-dose chemotherapy with ASCT for good responders. Radiotherapy was applied to all patients with poor response to induction phase or residual disease after HDCT, whereas it was at the clinician's discretion for patients with residual disease before HDCT. The 5-year EFS and OS rates for the 17 patients were 24 ± 10% and 40 ± 12%, respectively (37, 38).\n\nIn 2012, Macy et al. reported a study of five congenital GBM patients who were successfully treated with surgery (one gross total resection, three subtotal resections, and one biopsy only) and a moderately intense chemotherapy regimen (carboplatin and etoposide every 21 days for a range of 6–10 cycles). They obtained good results: four patients were alive in complete remission, showing a disease-free survival range of 30–110 months (median: 36 months). They question the real need for high-dose chemotherapy in light of the obvious clinical progression even in infants treated with aggressive regimens. In their series, they also add that patients with GBM subjected to subtotal resection or biopsy did well, suggesting that aggressive surgery is not necessary because there is a high risk of bleeding causing more morbidity in this fragile population (39).\n\nAll our patients were subject to adjuvant chemotherapy after surgery and two cycles consisting of high-dose thiotepa and thiotepa/carboplatin with ASCT, using radiotherapy only in one patient as the second-line treatment. We observed a long-term survival for 5 out of 6 (83%) children. PFS and OS at 5 years were 60 and 70%, respectively. The second-line therapy was used in two patients with GBM. Only one is still alive after radiotherapy treatment at recurrence.\n\nThe statistical correlation found with OS and PFS and histology stresses that high-grade astrocytoma has better overall survival than other tumor histology. El-Ayadi et al. have reported a summary of the different studies in infants with primary high-grade gliomas. As confirmed by a previous study (40), they not only added that very young children with AA seem to have better overall survival but also reported important clinicobiological uniqueness of infant AA compared to older patients (41).\n\nMost important complications of chemotherapy are fever with high grade 3–4 neutropenia, moderate and severe anemia, and mucositis. All our patients show delay of growth (> or = 2 SD beyond the mean). The dynamic and evolving aspect of weight and growth is very important; therefore, a careful endocrinological follow-up must be done, considering GH therapy in the future. Treatment for infant brain tumors can reduce the cognitive function. Neurocognitive impairment in survivors is correlated with negative consequents for adulthood, such as unemployment, lower educational achievement, and lower likelihood of marrying. However, it is essential that the tests are submitted to a proper age to assess the actual long-term damage.\n\nIn conclusion, congenital brain tumors remain an oncological challenge due to the genetic profile and therapeutic approach. It seems difficult to consolidate the appropriate treatment for malignant congenital brain tumors, given the heterogeneity of histologies. The results extrapolated from international studies show that these complex tumors must be treated by a multidisciplinary neuro-oncology team specialized in the management of newborns/infants in collaboration with pediatric neurosurgery. Given these findings, we believe that future works should focus on multicentric studies to better understand which approach is the most correct.\n\nDespite having a small population, according to our experience, currently HDCT and ASCT represent a valid approach for these very delicate patients.\n\nData Availability Statement\nThe datasets generated for this study are available on request to the corresponding author.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by Comitato Etico Istituzionale - Meyer Children's Hospital. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.\n\nAuthor Contributions\nMG: literature search, study design, data collection, analysis, interpretation, figures, and writing. LGi: genetic analysis. SD: statistics and data analysis. AB and MS: data collection and pathological analysis. BS and LGe: data collection and writing. IS: idea, data analysis, interpretation, and writing. All authors contributed to manuscript critical revision, read, and approved the submitted version.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nWe would like to express deep gratitude to Drs. Maurizio Lucchesi and Ludovica Facchini for their valuable and constructive support during the development of this article. The article was supported by Fondazione Anna Meyer—Firenze.\n\nAbbreviations\nAAanaplastic astrocytoma\n\nASCTautologous stem cell transplant\n\nAT/RTatypical teratoid/rhabdoid tumor\n\nCCGChildren's Cancer Group\n\nCNScentral nervous system\n\nGBMglioblastoma\n\nGTRgross total resection\n\nHDCThigh-dose chemotherapy\n\nHGGHigh grade gliomas\n\nMBmedulloblastoma\n\nOSOverall survival\n\nPFSProgression-free survival\n\nPOGPediatric Oncology Group.\n==== Refs\nReferences\n1. Jellinger K Sunder-Plassmann M . Connatal intracranial tumours\n. Neuropaediatrie. (1973 ) 4 :46 –63\n. 10.1055/s-0028-1091727 4739778 \n2. Ellams ID Neuhauser G Agnoli AL . Congenital intracranial neoplasms\n. Childs Nerv Syst. (1986 ) 2 :165 –8\n. 10.1007/BF00706804 3779676 \n3. Campbell AN Chan HS O'Brien A Smith CR Becker LE \nMalignant tumors in the neonate\n. Arch Dis Child. (1987 ) 62 :19 –23\n. 10.1136/adc.62.1.19 3813632 \n4. Hwang SW Su JM Jea A . 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(2009 ) 16 :21 –8\n. 10.3747/co.v16i6.435 20016743 \n35. Mason WP Grovas A Halpern S . Intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors\n. J Clin Oncol. (1998 ) 16 :210 –21\n. 10.1200/JCO.1998.16.1.210 9440745 \n36. Chi SN Gardner SL Levy AS Knopp EA Miller DC Wisoff JH \nNewly diagnosed high-risk malignant brain tumors with leptomeningeal dissemination in young children: a final update on head start iI regimen a2 intensified with high-dose methotrexate\n. J Clin Oncol. (2004 ) 22 :4881 –7\n. 10.1200/jco.2007.25.18 15611503 \n37. Dhall G Grodman H Ji L Sands S Gardner S Dunkel IJ . Outcome of children less than three years old at diagnosis with non-metastatic medulloblastoma treated with chemotherapy on the “Head start” i and iI protocols\n. Pediatr Blood Cancer. (2008 ) 50 :1169 –75\n. 10.1002/pbc.21525 18293379 \n38. von Bueren AO von Hoff K Pietsch T Gerber NU Warmuth-Metz M Deinlein F . 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"fulltext_license": "CC BY",
"issn_linking": "2296-2360",
"issue": "8()",
"journal": "Frontiers in pediatrics",
"keywords": "brain tumor; chemotherapy; congenital tumor; glioblastoma; newborn",
"medline_ta": "Front Pediatr",
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"pubdate": "2020",
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"title": "Use of High-Dose Chemotherapy in Front-Line Therapy of Infants Aged Less Than 12 Months Treated for Aggressive Brain Tumors.",
"title_normalized": "use of high dose chemotherapy in front line therapy of infants aged less than 12 months treated for aggressive brain tumors"
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"abstract": "Therapy-related acute lymphoblastic leukaemia (t-ALL) is a poorly defined entity and is not featured in the World Health Organization classification as a distinct clinical entity from acute lymphoblastic leukaemia (ALL), thus differing from therapy-related acute myeloid leukaemia and myelodysplasia. We present a case of t-ALL occurring 18 months after treatment for metastatic endometrial cancer with a regimen of carboplatin, paclitaxel and radiotherapy. The patient presented with severe pancytopenia and diagnosed with common-B ALL, and the cytogenetic analysis showed a previously unreported deletion in chromosome 19 (q13.1) in 100% of the blast cells. The patient declined further therapy and died 1 month later. This rare but serious side effect of chemo-radiotherapy should be considered when deciding on treatment options for gynaecological cancers.",
"affiliations": "Consultant Haematologist, Department of Medicine, Hospital de Carabineros de Chile, Simón Bolívar 2200, Ñuñoa, Santiago, 7770199, Chile.;Physician General Medicine, Department of Medicine, Hospital de Carabineros de Chile, Simón Bolívar 2200, Ñuñoa, Santiago, 7770199, Chile.;Physician General Medicine, Department of Medicine, Hospital de Carabineros de Chile, Simón Bolívar 2200, Ñuñoa, Santiago, 7770199, Chile.;Tutor, Faculty of Medicine, University Mayor, Renato Sánchez 4369, Las Condes, Santiago, 27550224, Chile.;Physician General Medicine, Department of Medicine, Hospital de Carabineros de Chile, Simón Bolívar 2200, Ñuñoa, Santiago, 7770199, Chile.",
"authors": "Murray|Nigel P|NP|;Orrego|Shenda|S|;López|Marco Antonio|MA|;Munoz|Lorena|L|;Minzer|Simona|S|",
"chemical_list": null,
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"doi": "10.3332/ecancer.2019.972",
"fulltext": "\n==== Front\nEcancermedicalscienceEcancermedicalscienceecancermedicalscienceecancermedicalscience1754-6605Cancer Intelligence 10.3332/ecancer.2019.972can-13-972Case ReportCommon B-cell acute lymphoblastic leukaemia in a 70-year-old woman presenting 2 years after carboplatin-taxane radiotherapy for endometrial cancer Murray Nigel P 12Orrego Shenda 34López Marco Antonio 34Munoz Lorena 45Minzer Simona 3\n1 Consultant Haematologist, Department of Medicine, Hospital de Carabineros de Chile, Simón Bolívar 2200, Ñuñoa, Santiago, 7770199, Chile\n2 Professor Haematology, Faculty of Medicine, University Finis Terrae, Av Pedro de Valdivia 1509, Providencia, Santiago\n3 Physician General Medicine, Department of Medicine, Hospital de Carabineros de Chile, Simón Bolívar 2200, Ñuñoa, Santiago, 7770199, Chile\n4 Tutor, Faculty of Medicine, University Mayor, Renato Sánchez 4369, Las Condes, Santiago, 27550224, Chile\n5 Consultant Internal Medicine, Department of Medicine, Hospital de Carabineros de Chile, Simón Bolívar 2200, Ñuñoa, Santiago, 7770199, ChileCorrespondence to: Nigel P Murray nigelpetermurray@gmail.com2019 29 10 2019 13 97227 6 2019 © the authors; licensee ecancermedicalscience.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Therapy-related acute lymphoblastic leukaemia (t-ALL) is a poorly defined entity and is not featured in the World Health Organization classification as a distinct clinical entity from acute lymphoblastic leukaemia (ALL), thus differing from therapy-related acute myeloid leukaemia and myelodysplasia. We present a case of t-ALL occurring 18 months after treatment for metastatic endometrial cancer with a regimen of carboplatin, paclitaxel and radiotherapy. The patient presented with severe pancytopenia and diagnosed with common-B ALL, and the cytogenetic analysis showed a previously unreported deletion in chromosome 19 (q13.1) in 100% of the blast cells. The patient declined further therapy and died 1 month later. This rare but serious side effect of chemo-radiotherapy should be considered when deciding on treatment options for gynaecological cancers.\n\ntherapy-related acute lymphoblastic leukaemiaendometrial cancercarboplatinpaclitaxel\n==== Body\nIntroduction\nTherapy-related leukaemia is a long-term side effect of chemotherapy and/or radiotherapy in patients who have been treated for a previous cancer. Therapy-related myelodysplasia and acute myeloid leukaemia (AML) are an established category of the World Health Organization classification of myeloid neoplasms [1]. However, therapy-related acute lymphoblastic leukaemia (t-ALL) is a poorly defined entity and typically is not considered as a treatment-related complication due to a lack of large data sets that recognise the defining characteristics of this cancer [2]. Only a few relatively small series have been reported [3–9] and have included cases with a previous history of cancer but without cytotoxic or radiation exposure. Additional limitations of these studies have included a lack of cytogenetic analysis and specific details of previous treatments. We have used the definition that restricts t-ALL to those patients treated with chemotherapy and/or radiotherapy.\n\nt-ALL is infrequent representing 2%–9% of all acute lymphoblastic leukaemia (ALL) cases [3–5] and 10%–15% of all therapy-related leukaemia’s [3–5]. Rosenberg et al [4] analysed 14,470 patients with ALL using the California Cancer Registry data from 1988 to 2016; of this population of ALL patients, 3% of cases had been treated for a previous malignancy. A more recent analysis of 4,851,222 first cancer patients reported that 849 (0.02%) patients developed ALL as a second cancer. In comparison with the general population, the relative risk of developing ALL in the first 10 years after completing treatment was 1.59 for patients treated with only radiotherapy; 3.47 for those treated with chemotherapy and 3.22 for those treated with combined therapy. Patients’ not receiving chemotherapy or radiotherapy for their first cancer had no increased risk for ALL [2].\n\nWe present the case of a 70-year-old woman who presented with a pancytopenia 2 years after receiving chemo-radiotherapy for endometrial cancer. We discuss the treatment options and cytogenetic findings.\n\nClinical case\nA 70-year-old woman presented to the emergency service with a 1-month history of progressive dyspnoea and tachycardia with minimal activity. A full blood count revealed a haemoglobin level of 4.3 gr/dL, platelet count 7,000/mm3 and a white cell count of 7,200/mm3 with an absolute neutrophil count of 360/mm3. The total serum lactate dehydrogenase was 427 U/L (normal range 0–223), serum uric acid was 7.0 mg/dL (normal range 2.3–6.1) and a serum total alkaline phosphatase of 111 U/L (normal range 0–105).\n\nAnalysis of the blood smear showed small- and medium-sized lymphocytes, some with a nucleolus.\n\nThree years earlier, the patient had presented to the gynaecologist with pelvic pain without haemorrhage. A pelvic ultrasound revealed a uterine tumour and an endometrial biopsy confirmed an endometrial adenocarcinoma grade 2 with a focus of serous carcinoma. Immunohistochemistry showed positivity for vimentin, 80% of tumour cells were positive for the oestrogen receptor and negative for the expression of carcinoembryonic antigen. P53 expression was weakly positive in the adenocarcinoma component and strongly positive in 90% of the serous carcinoma component.\n\nThe patient was operated in September 2015, undergoing a total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, pelvic lymphadenectomy and samples for peritoneal cytology were taken. An intra-operative biopsy showed that the left obturator lymph node was 1.5 cm in diameter and infiltrated with adenocarcinoma. The uterus weighed 162 g with the uterine cavity occupied by tumour that was haemorrhagic in nature. It partially infiltrated the myometrium and extended distally to occupy the upper third of the cervix. Both ovaries and fallopian tubes were free of tumour. The omentum was free of tumour and peritoneal cytology was negative for tumour cells. The cancer comprised an exo-phytic growth of 4 cm × 2 cm × 2.5 cm with infiltration of the lymphovascular structures and up to 50% of the myometrium. There was a superficial invasion of the upper third of the cervix and metastasis in the left obturator and left hypogastric lymph nodes. In 17 other lymph nodes examined, there was no evidence of metastasis.\n\nThe patient’s recovery was complicated by a pulmonary embolus and was treated for 6 months with rivaroxaban.\n\nAfter surgery, the patient underwent six cycles of carboplatin-paclitaxel chemotherapy, which was completed in February 2016 and without dose reduction. In May 2016, she underwent two treatments of brachytherapy of 11 Gy to the vaginal vault and in June 2016 treated with external beam six-field conformational radiotherapy, with a dose of 45 Gy in 25 fractions. There was no evidence of metastatic spread on imaging studies at this time.\n\nHowever, in October 2016, a routine CT scan of the lungs showed a solid nodule irregular in the outline of 28 mm in the right inferior lobe, one of 18 mm in the right superior lobe and one of 15 mm in the left superior lobe of the lung. There was no evidence of relapse in the abdomen or pelvis. She underwent eight further cycles of carboplatin-paclitaxel, finishing treatment in March 2017.\n\nThe patient was hospitalised in December 2018, with a severe pancytopenia and the presence of blasts in the blood smear. Repeat CT scan did not show any pulmonary nodules or evidence of metastatic disease in the abdomen or pelvis.\n\nShe was treated initially with transfusions of filtered packed red cells and platelets, and a working diagnosis of acute secondary leukaemia with or without a previous phase of myelodysplasia.\n\nBone marrow aspiration of the right posterior superior iliac crest resulted in a ‘dry tap’ and a bone marrow biopsy showed an infiltration of 95% blasts morphologically lymphoid in nature (Figures 1 and 2). A sternal bone marrow aspirate was obtained for immunophenotyping and cytogenetic studies.\n\nFlow cytometry showed an infiltration of 98% blasts, which were positive for the B-cell markers CD19 (99% positive), human leukocyte antigen-DR (HLA-DR) (99%), CD10 (53%) and negative for CD20. The blasts were negative for the T-cell markers CD2, CD3 and CD7 and for the myeloid markers CD14, CD15, CD33, CD11c, CD64 and CD117.\n\n79% of the blasts were positive for cytoplasmic CD79a and 51% for CD34 and were negative for cytoplasmic CD3, myeloperoxidase, IgM and lysozyme.\n\nUsing the reverse transcriptase polymerase chain reaction, the blasts were negative for the t [9, 21] p190 and p210 variants of the BCR-ABL1 fusion genes and for the t [4, 10] fusion gene MLL-AF4. Cytogenetic analysis of G-banded chromosomes showed a karyotype 46, XX, deletion chromosome 19 (q13.1) in 100% of the blast cells (Figure 3).\n\nA diagnosis of treatment-related acute B-cell common type lymphoblastic leukaemia was made. The patient declined chemotherapy, was treated with transfusions as required and died 1 month later.\n\nDiscussion\nt-ALL has been divided into two major types; firstly, in those patients who had received alkylating agents and/or radiotherapy, the mean latency period between treatment and the presentation of acute leukaemia is between 5 and 7 years. The most commonly used alkylating agents being cyclophosphamide, melphalan and nitrosourea. The platinum containing derivatives, cisplatin and carboplatin are carcinogenic in vitro and in laboratory animals producing intra-strand and inter-strand DNA cross links in a manner similar to that of bi-functional alkylating agents. The relative risk of developing leukaemia after receiving a median dose of 3,300 mg of carboplatin has been reported as 6.5 times that of age-matched control patients [10]. The combined use of radiotherapy with carboplatin increased this relative risk to 8.1 [10]. Carboplatin has been reported to be associated with treatment-related myelodysplasia and AML [10]. These treatment-related leukaemias are associated with complex karyotype abnormalities and monosomy 5 or 7 [10, 11]. Monosomy or deletion of the long arm of chromosomes 5 and 7 is more common in t-ALL than de novo ALL, 16% versus 8%, respectively [4]. Radiation to the pelvis, which affects approximately 50% of the active bone marrow in adults, is associated with a three-fold increase in leukaemia [12]. It has been reported that for every 10,000 patients treated with radiotherapy at a dose of 25Gy for testicular cancer, an excess of nine leukaemia cases will be seen after 15 years of follow-up. As such the number of cases of t-ALL following radiotherapy is small in comparison with the potential benefits [12]. This has to be put in context with the survival advantage of treatment. Similarly, in patients treated with radiotherapy for cancer of the cervix, an increased risk of secondary leukaemia has been reported [13].\n\nThe second type of t-ALL is seen in patients treated with DNA topoisomerase II inhibitors; in these patients, there is a short latency period of 1–3 years between cancer treatment and development of t-ALL, typically in these patients, a myelodysplastic phase is not detected. In this type of t-ALL, there is an association with a chromosomal translocation involving the 11q23, mixed-lineage leukaemia (MLL) gene locus, although cases without this translocation have been described [14, 15]. MLL rearrangements have been described for both AML and ALL representing approximately 5% of therapy-related acute leukaemia. This rearrangement is more frequently found in t-ALL compared to t-AML and is associated with CD20 negative pro-B-cell acute lymphoblastic leukaemia (ALL) [16, 17]. Differing from treatment-related AML, in t-ALL, the 11q23 translocation appears to occur in patients treated with or without DNA topoisomerase II inhibitors [18] and is more frequently detected in t-ALL than in de novo ALL (17% versus 4%, respectively) [4]. With respect to prior treatment with taxanes, case reports of both paclitaxel [19] and docetaxel [20] have been associated with 11q23 t-AML.\n\nThe most common chromosomal abnormality reported in t-ALL is the 11q23 MLL translocation; followed by the BCL-ABL translocation. The presence of the BCL-ABL translocation in t-ALL has been associated with previous radiotherapy [16, 18]. The third commonest karyotype seen in t-ALL is a normal karyotype. However, it must be remembered that obtaining good quality metaphase cells in ALL is often suboptimal and cryptic aberrations may not be identified in all patient samples [14].\n\nThe chromosomal abnormality del (19) (q13.1) as the only cytogenetic abnormality has not been previously reported in t-ALL. Abnormalities involving chromosome 19 in patients with t-ALL have been previously reported; t (1:19) (q23: p13.1) involving the MLL1/ELL genes, t (1:19) (q23: p13.1) involving the MLL1/ENL genes, t (1:19) (q23:p13) involving the E2A/PBX genes and t (17:19) (q22:p13) involving the E2A/HLF genes [21]. The French Cytogenetics in Haematology Group in a study of 443 karyotypes did not report the del (19) (q13.1) as an abnormal karyotype found in ALL [22]. A pooled analysis of cytogenetic features in treatment-related myelodysplasia did not report the del (19) (q13.1) abnormality [23]. In a further report of 1,522 patients and cytogenetic analysis, the del (19) (q 13.1) was not reported [24], while one case of monosomy 19 was reported in 881 cases [25].\n\nWhy some patients develop t-ALL years after receiving radio-chemotherapy and others do not is unknown. In vitro studies to determine the chromosomal instability have used peripheral blood lymphocytes as a marker for the dysfunction of DNA reparation genes have suggested that patients with increased chromosomal instability have an increased risk of second cancers when exposed to chemotherapy or radiotherapy [26]. Thus, it may be that patients with higher chromosomal instability have a higher risk of developing t-ALL.\n\nTreatment options depend on patient age and co-morbidities, with older patients having a worse outcome. Where possible, a bone marrow transplant is recommended for younger patients with suitable donors. It is associated with a lower rate of relapse but there is increased transplant-related mortality with no overall increase in survival [27]. In those not eligible for transplant, the outcome to standard treatment is poorer than in de novo ALL [28]. There are no large-scale trails of t-ALL treatment; various chemotherapy protocols have been used, commonly with reduced dose in the more elderly patients and as such, there is no consensus on treatment. Relapse rates after standard treatment are relatively high and survival is low, which is likely related to the high frequency of adverse cytogenetic abnormalities.\n\nIn those patients positive for BCL-ABL1, the use of tyrosine kinase inhibitors has been used in combination with chemotherapy, although with the small number of cases, the effect of prognosis is not known [29, 30].\n\nIn summary with the increased use of combined chemo-radiotherapy in patients with gynaecological or urological cancers, as adjuvant therapy or for the treatment of metastasis, the number of patients presenting with t-ALL may increase. We presented a case of treatment-related acute B-cell lymphoblastic leukaemia with a previously unreported chromosomal abnormality. Although the patient did not have evidence of metastasis 2 years after combined chemo-radiotherapy, the patient decided against treatment for the t-ALL. Oncologists should be aware of this rare but significantly severe adverse effect and it should be kept in consideration when deciding on treatment options for these patients, especially concerning patient age and co-morbidities. Due to the paucity of cases and lack of consensus on treatment, multicentre studies or registers are warranted to accumulate evidence of treatment options and outcomes.\n\nConflicts of interest\nThe authors declare that they have no conflicts of interest.\n\nFunding declaration\nNo financial support was received for this case report.\n\nEthical approval\nThe case study was approved by the local ethics committee and in complete conformity with the Declaration of Helsinki and the Chilean law on patient’s rights.\n\nAcknowledgments\nThe authors wish to thank Mrs Ana Maria Palazuelos for her help in the redaction of this manuscript.\n\nFigure 1. Low power magnification ‘touch preparation’ bone marrow biopsy showing dense infiltration with lymphoid type blasts.\nFigure 2. Magnification × 400 showing blasts with an undifferentiated appearance and some with vacuoles.\nFigure 3. Karyotype analysis showing del (19) (q13.1).\n==== Refs\nReferences\n1. Arber DA Orazi A Hasserjian R The 2016 revision to the World Health Organization classifications of myeloid neoplasms and acute leukemia Blood 2016 127 2391 2405 10.1182/blood-2016-03-643544 27069254 \n2. Molenaar RJ Radivoyevitch T Gerds AT Is there an increased risk of ALL in patients with first cancers treated with radiotherapy and/or chemotherapy? Blood 2018 132 900 10.1182/blood-2018-99-118207 \n3. Aldoss I Stiller T Tsai NC Therapy related acute lymphoblastic leukemia has distinct clinical and cytogenetic features compared with de novo acute lymphoblastic leukemia, but outcomes are comparable in transplanted patients Haematologica 2018 103 1662 1668 10.3324/haematol.2018.193599 29903756 \n4. Rosenberg AS Brunson A Paulus JK Secondary acute lymphoblastic leukemia is a distinct clinical entity with prognostic significance Blood Cancer J 2017 7 e605 10.1038/bcj.2017.81 28885611 \n5. Swaika A Frank RD Yang D Secondary primary acute lymphoblastic leukemia in adults: a SEER analysis of incidence and outcomes Cancer Medicine 2018 7 499 507 10.1002/cam4.1266 29282894 \n6. Toft N Schmieglow K Klausen TW Adult ALL in Denmark. A national population based retrospective study on ALL in Denmark 1998–2008 Br J Haematol 2012 157 97 104 10.1111/j.1365-2141.2011.09020.x 22233128 \n7. Kelleher N Gallardo D Gonzalez-Campos J Incidence, clinical and biological characteristics and outcome of secondary acute lymphoblastic leukemia after solid organ or hematologic malignancy Leuk Lymphoma 2016 57 86 91 10.3109/10428194.2015.1040013 25860236 \n8. Shivakumar R Tan W Wilding GE Biological features and treatment outcome of secondary acute lymphoblastic leukemia-a review of 101 cases Annals Oncol 2008 19 1634 1638 10.1093/annonc/mdn182 \n9. Pagano L Pulsoni A Tosti ME Clinical and biological features of acute myeloid leukaemia occurring as second malignancy: GIMEMA archive of adult acute leukaemia Br J Haematol 2001 112 109 117 10.1046/j.1365-2141.2001.02527.x 11225603 \n10. Travis LB Holowaty EJ Bergfeldt K Risk of leukemia after platinum-based chemotherapy for ovarian cancer N Eng J Med 1999 340 351 357 10.1056/NEJM199902043400504 \n11. Smith SM LeBeau MM Huo D Clinical-cytogenetic associations in 306 patients with therapy related myelodysplasia and myeloid leukemia: the University of Chicago series Blood 2003 102 43 52 10.1182/blood-2002-11-3343 12623843 \n12. Travis LB Andersson M Gospodarowicz M Treatment associated leukemia following testicular cancer J Natl Cancer Inst 2000 92 1165 1171 10.1093/jnci/92.14.1165 10904090 \n13. Boice JD Jr Biettner M Kleinerman RA Radiation dose and leukemia risk in patients treated for cancer of the cérvix J Natl Cancer Inst 1987 79 1295 1311 3480381 \n14. Shivakumar R Tan W Wilding GE Biologic features and treatment outcome of secondary acute lymphoblastic leukemia-a review of 101 cases Annals Oncol 2008 19 1634 1638 10.1093/annonc/mdn182 \n15. Chen W Wang E Lu Y Therapy related acute lymphoblastic leukemia without 11q23 abnormality Am J Clin Pathol 2010 133 75 82 10.1309/AJCPYWC6AQC7BAVJ 20023261 \n16. Pagano L Pulsoni A Mele L Clinical and epidemiological features of acute lymphoblastic leukemia following a previous malignancy Leuk Lymphoma 2000 39 465 475 10.3109/10428190009113377 11342330 \n17. Ishizawa S Slovak ML Popplewell L High frequency of pro-B acute lymphoblastic leukemia in adults with secondary leukemia with 11q23 abnormalities Leukemia 2003 17 1091 1095 10.1038/sj.leu.2402918 12764373 \n18. Abdulwahab A Sykes J Kamel-Reid S Therapy related acute lymphoblastic leukemia is more frequent than previously recognized and has a poor prognosis Cancer 2012 118 1962 3967 10.1002/cncr.26735 22009259 \n19. Saito M Mori A Irie T Therapy related acute myeloid leukemia with 11q23 abnormality due to paclitaxel coexisting with bone marrow metástasis of breast cancer Rinsho Ketsueki 2009 50 192 196 19352087 \n20. Numakura K Tsichiya N Habuchi T Therapy related leukemia with 11q23 abnormality induced by chemotherapy consisted of docetaxel for advanced prostatic carcinoma: case report Nihon Hinyokika Gakkai Zasshi 2009 100 580 585 19663246 \n21. Choi HJ Kim HR Shin MG Spectra of chromosomal aberrations in 325 leukemia patients and implications for the development of new molecular detection systems J Korean Med Sci 2011 26 886 892 10.3346/jkms.2011.26.7.886 21738341 \n22. Groupe Francais de Cytogenetique Hematologique Cytogenetic abnormalities in adult acute lymphoblastic leukemia: correlations with hematologic findings and outcome. A collaborative study of the Group Francais de Cytogenetique Hematolgique Blood 1996 87 3135 3142 8605327 \n23. Mauritzson N Albin M Rylander L Pooled analysis of clinical and cytogenetic features in treatment related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976-1993 and on 5098 unselected cases reported in the literature 1974-2001 Leukemia 2002 16 2366 2378 10.1038/sj.leu.2402713 12454741 \n24. Moorman AV Harrison CJ Buck GAN Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trail Blood 2007 109 3189 3197 10.1182/blood-2006-10-051912 17170120 \n25. Motilo C Ribera JM Morgades M Prognostic significance of complex karyotype and monosomal karyotype in adult patients with acute lymphoblastic leukemia treated with risk adapted protocols Cancer 2014 120 3958 3964 10.1002/cncr.28950 25116331 \n26. Nesina IP Iurchenko NP Nespryadko SV The study of chromosomal instability in patients with endometrial cancer Exp Oncol 2014 36 202 206 25265355 \n27. Ferraro F Gao F Stockerl-Goldstein K Secondary acute lymphoblastic leukemia, a retrospective analysis from Washington University and meta-analysis of published data Leuk Res 2018 72 86 91 10.1016/j.leukres.2018.07.024 30114560 \n28. Giri S Chi M Johnson B Secondary acute lymphoblastic leukemia is an independent predictor of poor prognosis Leuk Res 2015 39 1342 1346 10.1016/j.leukres.2015.09.011 26427729 \n29. Aldoss I Stiller T Song J Philadelphia chromosome as a recurrent event among therapy related leukemia Am J Hematol 2017 92 18 19 10.1002/ajh.24604 27673280 \n30. Abou Dalle J Jabbour E Short NJ Treatment of Philadelphia chromosome positive acute lymphoblastic leukemia Curr Treat Options Oncol 2019 20 10.1007/s11864-019-0603-z\n\n",
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"keywords": "carboplatin; endometrial cancer; paclitaxel; therapy-related acute lymphoblastic leukaemia",
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"title": "Common B-cell acute lymphoblastic leukaemia in a 70-year-old woman presenting 2 years after carboplatin-taxane radiotherapy for endometrial cancer.",
"title_normalized": "common b cell acute lymphoblastic leukaemia in a 70 year old woman presenting 2 years after carboplatin taxane radiotherapy for endometrial cancer"
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"abstract": "Platinum-based drugs (cisplatin, carboplatin and oxaliplatin) are widely used in cancer treatment. They are administered intravenously, thus accidental extravasations of infusions can occur. This may cause severe complications for the patient as the toxic platinum compounds likely persist in subcutaneous tissue. At high concentrations, platinum toxicity in combination with local thrombosis may result in tissue necrosis, eventually requiring surgical intervention. To describe tissue distribution at the anatomic level, we quantified drug extravasation in cryosections of various tissues (muscle, nerve tissue, connective tissue, fat tissue) by means of quantitative laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) and compared the resulting data with bulk analysis of microwave-assisted digestion of tissue samples followed by ICP-MS analysis. Samples of three patients receiving systemic chemotherapy either via peripheral venous access or central access via port-a-cath® were analyzed. Pt was enriched up to 50-times in connective tissue when compared with muscle tissue or drain samples collected over five days. The large areas of subcutaneous fat tissue showed areactive necrosis and average Pt concentrations (determined upon sample digestion) ranged from 0.2 μg g(-1) (therapy with 25 mg m(-2) cisplatin, four weeks after peripheral extravasation) to 10 μg g(-1) (therapy with 50 mg m(-2) oxaliplatin: four weeks after port-a-cath® extravasation). A peripheral nerve subjected to bioimaging by LA-ICP-MS showed a 5-times lower Pt concentration (0.2 μg g(-1)) than the surrounding connective tissue (1.0 μg g(-1)). This is in accordance with the patient showing no signs of neurotoxicity during recovery from extravasation side-effects. Thus, bioimaging of cutaneous nerve tissue may contribute to understand the risk of peripheral neurotoxic events.",
"affiliations": "ADSI - Austrian Drug Screening Institute GmbH, Innsbruck, Austria.",
"authors": "Egger|Alexander E|AE|;Kornauth|Christoph|C|;Haslik|Werner|W|;Hann|Stephan|S|;Theiner|Sarah|S|;Bayer|Günther|G|;Hartinger|Christian G|CG|;Keppler|Bernhard K|BK|;Pluschnig|Ursula|U|;Mader|Robert M|RM|",
"chemical_list": "D000970:Antineoplastic Agents; D010984:Platinum",
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"issue": "7(3)",
"journal": "Metallomics : integrated biometal science",
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"medline_ta": "Metallomics",
"mesh_terms": "D000970:Antineoplastic Agents; D057785:Catheters; D003952:Diagnostic Imaging; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005260:Female; D006801:Humans; D007430:Intraoperative Care; D007700:Kinetics; D053685:Laser Therapy; D008297:Male; D009336:Necrosis; D010984:Platinum; D015203:Reproducibility of Results; D013054:Spectrophotometry, Atomic; D040521:Subcutaneous Tissue; D014018:Tissue Distribution",
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"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Extravasation of Pt-based chemotherapeutics - bioimaging of their distribution in resectates using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS).",
"title_normalized": "extravasation of pt based chemotherapeutics bioimaging of their distribution in resectates using laser ablation inductively coupled plasma mass spectrometry la icp ms"
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"abstract": "Patients with Nijmegen breakage syndrome (NBS) can develop life-threatening immunodeficiency, which should be treated with hematopoietic stem cell transplantation (HSCT). We report the case of a 14-year-old girl with NBS who due to an increasing number of severe complications was referred for HSCT from a matched unrelated donor. After reduced-intensity conditioning and transplantation of peripheral blood hematopoietic cells, during the early post-transplant period (days 0-30), the girl suffered from severe mucositis, fever episodes, mild acute renal injury and facial vasculitis. All these complications were managed successfully. During the intermediate post-transplant period (days 30-100) a number of hepatic and gastrointestinal complications occurred, including cholecystitis, cholelithiasis with choledocholithiasis, pancreatitis as well as acute bleeding from the lower gastrointestinal tract caused by rectal and recto-sigmoid junction ulcers. All the obstacles were obviously attributable both to the primary congenital disease, its complications, and transplantation itself. We overcame these complications and treated the patient with the best possible and safe methods. The multidisciplinary approach based on combined surgical, endoscopic and conservative management of multiple post-transplant complications was successful for the patient.",
"affiliations": "Department of General and Oncological Surgery for Children and Adolescents, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Antoni Jurasz University Hospital No. 1, Bydgoszcz, Poland.;Department of Paediatrics, Haematology and Oncology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Antoni Jurasz University Hospital No. 1, Bydgoszcz, Poland.;Department of Paediatric Endoscopy and Gastrointestinal Function Testing, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Antoni Jurasz University Hospital No. 1, Bydgoszcz, Poland.;Department of Paediatrics, Haematology and Oncology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Antoni Jurasz University Hospital No. 1, Bydgoszcz, Poland.;Department of Paediatrics, Haematology and Oncology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Antoni Jurasz University Hospital No. 1, Bydgoszcz, Poland.;Department of Paediatrics, Haematology and Oncology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Antoni Jurasz University Hospital No. 1, Bydgoszcz, Poland.",
"authors": "Gałązka|Przemysław|P|;Czyżewski|Krzysztof|K|;Szaflarska-Popławska|Anna|A|;Dębski|Robert|R|;Krenska|Anna|A|;Styczyński|Jan|J|",
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"doi": "10.5114/ceji.2019.89612",
"fulltext": "\n==== Front\nCent Eur J ImmunolCent Eur J ImmunolCEJICentral-European Journal of Immunology1426-39121644-4124Polish Society of Experimental and Clinical Immunology 318714228961210.5114/ceji.2019.89612Case ReportComplex profile of multiple hepatobiliary and gastrointestinal complications after hematopoietic stem cell transplantation in a child with Nijmegen breakage syndrome Gałązka Przemysław 1§Czyżewski Krzysztof 2§Szaflarska-Popławska Anna 3Dębski Robert 2Krenska Anna 2Styczyński Jan 21 Department of General and Oncological Surgery for Children and Adolescents, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Antoni Jurasz University Hospital No. 1, Bydgoszcz, Poland2 Department of Paediatrics, Haematology and Oncology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Antoni Jurasz University Hospital No. 1, Bydgoszcz, Poland3 Department of Paediatric Endoscopy and Gastrointestinal Function Testing, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Antoni Jurasz University Hospital No. 1, Bydgoszcz, PolandCorrespondence: Prof. Jan Styczyński, Department of Paediatrics, Haematology and Oncology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Antoni Jurasz University Hospital No. 1, 9 Marii Skłodowskiej-Curie St., 85-094 Bydgoszcz, Poland. e-mail: jstyczynski@cm.umk.pl* These authors contributed equally to this study.\n\n30 9 2019 2019 44 3 327 331 18 4 2018 24 5 2018 Copyright: © 2019 Polish Society of Experimental and Clinical Immunology2019This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.Patients with Nijmegen breakage syndrome (NBS) can develop life-threatening immunodeficiency, which should be treated with hematopoietic stem cell transplantation (HSCT). We report the case of a 14-year-old girl with NBS who due to an increasing number of severe complications was referred for HSCT from a matched unrelated donor. After reduced-intensity conditioning and transplantation of peripheral blood hematopoietic cells, during the early post-transplant period (days 0-30), the girl suffered from severe mucositis, fever episodes, mild acute renal injury and facial vasculitis. All these complications were managed successfully. During the intermediate post-transplant period (days 30-100) a number of hepatic and gastrointestinal complications occurred, including cholecystitis, cholelithiasis with choledocholithiasis, pancreatitis as well as acute bleeding from the lower gastrointestinal tract caused by rectal and recto-sigmoid junction ulcers. All the obstacles were obviously attributable both to the primary congenital disease, its complications, and transplantation itself. We overcame these complications and treated the patient with the best possible and safe methods. The multidisciplinary approach based on combined surgical, endoscopic and conservative management of multiple post-transplant complications was successful for the patient.\n\nhematopoietic cell transplantationcholecystitischolelithiasischoledocholithiasispancreatitisgut ulcer\n==== Body\nIntroduction\nNijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal instability disorder. Majority of patients affected are of Slavic origin and share the same founder mutation of 657del5 within the NBN gene encoding protein involved in DNA double-strand breaks repair. Clinically, this is characterized by a microcephaly, immunodeficiency and a high incidence of pediatric malignancies, mostly lymphomas and leukemias [1]. Recurrent episodes of pneumonia may result in respiratory failure and early death [2]. The major therapeutic issue in NBS patients is a prophylaxis of infections based on intravenous immunoglobulin supplementation together with administration of antifungal and antibacterial agents. In severe cases of immunodeficiency, hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning (RIC) should be considered, however current transplant experience in patients with NBS is very small [3].\n\nCase report\nA 14-year-old girl with NBS presented with a typical phenotype and genotype (homozygotic NBN gene mutation 657del5) has suffered since early childhood from acute and chronic infections of the respiratory tract, paranasal sinuses, cryptococcal meningoencephalitis, chronic bronchitis, chronic pneumonia, symptomatic Epstein-Barr virus (EBV) reactivation, hepatitis of unknown etiology with cholestasis, and skin infections including disseminated actinomycosis and non-tuberculosis granulomas. She has also been diagnosed and treated for secondary hemophagocytic lymphohistiocytosis (HLH), complicated with facial vasculitis, hypertension and cardiomyopathy. Additionally, she had a tri-lineage hematological insufficiency and hypogammaglobulinemia (IgA < 10 mg/dl, IgG 85 mg/dl). Absolute numbers of lymphocytes showed combined B- and T-cell immunodeficiency: 0.266 G/l for CD3; 0.084 G/l for CD4; 0.140 G/l for CD8 and 0.077 G/l for CD19.\n\nDue to an increasing number of life-threatening infectious complications, confirmed progressing immunodeficiency and marrow hypocellularity, she was referred for HSCT from a matched unrelated donor. On admission, she was in overall poor clinical condition, with Lansky performance score of 80, infection of the skin, symptoms of chronic pulmonary disease with various pulmonary rhonchi, oxygen saturation of 94%, and abnormal liver function tests.\n\nThe preparative RIC regimen included fludarabine (30 mg/m2/day; days from –9 to –5), cyclophosphamide (5 mg/kg bw/day; days from –5 to –2) and antithymocyte globulin (total 8 mg/kg bw divided between three consecutive days from –3 to –1). Due to previous infections, she was on continuous therapy with antibiotics. Other anti-infective prophylaxis included posaconazole and acyclovir. She received also prophylaxis against veno-occlusive disease with defibrotide. The graft included peripheral blood stem cells from HLA-matched, AB0/Rh-matched woman (11.6 × 108 NMC/kg bw; 7.8 × 106 CD34+ cells/kg bw). Prophylaxis against graft-versus-host disease (GVHD) included cyclosporine A and mycophenolate mofetil, however due to deterioration of parameters of the renal function, cyclosporine was converted to sirolimus, which in turn was converted to methylprednisolone, due to facial vasculitis (Fig. 1). Additionally, at day +5 rituximab was administered prophylactically against EBV reactivation and development of post-transplant lymphoproliferative disorder (EBV-PTLD).\n\nFig. 1 Facial vasculitis and symptoms of Cushing syndrome in the NBS patient at days: +19, +20 and +26 after transplantation\n\nDuring an early post-transplant period she was in otherwise good condition, however she suffered from severe mucositis, fever episodes, and necessity of total parenteral nutrition (TPN). Hematological and platelet recovery occurred at days +12 and +25, respectively. She was discharged from the transplant ward at day +28 with 49% donor chimerism, normal hematopoiesis in bone marrow, and no CMV or EBV viremia.\n\nAt day +35 she complained of acute abdominal pain accompanied by significant elevation of gamma glutamyl transpeptidase (3673 U/l), alkaline phosphatase activity (643 U/l) and a total and conjugated bilirubin level (5.17 mg/dl and 4.15 mg/dl, respectively). On magnetic resonance (MRI) cholangiopancreatography, the common bile duct (CBD) was widened with a diameter of 6 mm and in the distal part of CBD there were bile deposits of 5 × 3 mm size. She was qualified to urgent endoscopic retrograde cholangiopancreatography (ERCP). After sphincterotomy, removal of bile deposits was carried on with endoscopic basket. Additionally a 5 cm 7F prosthesis was inserted into the distal CBD (Fig. 2).\n\nFig. 2 ERCP showing a common bile duct (day +35): A) mildly dilated duct with biliary stone (black arrow) before extraction, B) with no signs of dilation after stone extraction (6 weeks later)\n\nShe was initially planned for early (within 7 days) CBD prosthesis removal, however this approach was postponed because of post-ERCP pancreatitis development with elevation of serum and urine amylase activity (2701 U/l and 3803 U/l, respectively). In the subsequent MRI examination, signs of pancreatic edema and irregularity of pancreatic borders were noted. Despite the presence of peripancreatic fluid collections, stranding fat densities and temporary signs of paralytic ileus she was successfully treated with TPN, fluid resuscitation and broad-spectrum antibiotics. She was qualified to elective laparoscopic cholecystectomy, which was performed 6 weeks after ERCP. On laparoscopy a thickened, callous wall of the gall bladder was revealed. Liver surface appeared to be nodular with increased consistency. Due to the problems with clear delineation of gall bladder bed, the lack of possibility of proper identification of hepatic hilum structures and bleeding, the procedure was converted to the open cholecystectomy. After gallbladder and biliary stent removal, a careful hemostasis of gallbladder fossa was performed using argon beam coagulation and 4DryField starch powder. In the early postoperative course an increased amount of drained fluid was observed but drainage was removed on the third postoperative day and spontaneous biliary flow without any complications was obtained. Due to subsequent transient elevation of serum amylase and poor wound healing she was successfully managed conservatively with vancomycin and ceftriaxone. Further postoperative course was uneventful.\n\nTwo weeks later she was admitted to hospital with mild acute lower gastrointestinal bleeding. Stool samples were tested negative for rotavirus, adenovirus and norovirus, but positive for Campylobacter jejuni and Clostridium difficile. Blood CMV and EBV reactivation were also ruled out. The ileocolonoscopy revealed a 3-4 cm crater-like ulcer located 2-3 cm from the anal margin, which was covered by yellowish slough surrounded by reactive mucosa. Another ulcer was found at the recto-sigmoid junction (Fig. 3). Microscopically, lymphocytic and neutrophilic mucosa infiltrate that focally infiltrated crypt epithelium with mild crypt distortion and signs of regeneration were present in the entire colon. Based on histopathology, CMV infection and GVHD in the colon were excluded. The girl was treated with intravenous azithromycin and orally budesonide and mesalamine. A clinical and endoscopic improvement was noted at the second endoscopy performed four weeks later.\n\nFig. 3 Endoscopic picture showing deep 2 cm in diameter crater-like ulcer located at the recto-sigmoid junction covered by yellowish slough with inflamed surrounding mucosa (day +104)\n\nThree month later no complaints were reported (Table 1). There were symptoms of immunological recovery, and the girl presented an increasing donor chimerism (63%).\n\nTable 1 Complications before and after hematopoietic stem cell transplantation\n\nAge/time\tComplications\t\n3-13 years\tChronic bronchitis, chronic pneumonia, chronic sinusitis, disseminated skin actinomycosis, skin granulomas, liver insufficiency with cholestasis\t\n13 years\tCNS cryptococcosis (treatment in Intensive Care Unit), secondary hemophagocytic lymphohistiocytosis, vasculitis, bone marrow hypocellularity\t\n14 years\tCombined B/T-cell immunodeficiency, bone marrow failure, skin dermatofibroma\t\nHSCT (day 0)\t\nDay +10\tSevere mucositis\t\nDay +19\tDeterioration of renal function, facial vasculitis\t\nDay +35\tSymptomatic choledocholithiasis\t\nDay +42\tPancreatitis\t\nDay +77\tRecurrent cholelithiasis with cholecystitis\t\nDay +91\tAcute skin graft-versus-host disease II°\t\nDay +99\tAcute bleeding from the lower gastrointestinal tract: rectal and recto-sigmoid junction ulcers\t\nDay +200\tNo complaints; overall good condition\t\nHSCT – hematopoietic stem cell transplantation, CNS – central nervous system\n\nDiscussion\nThe first report on treatment with HSCT in children with NBS was reported in 2010 [4], and up to 2017 data on a total number of 19 patients were published, including only three without underlying malignancy [3-6]. Recently, two analyses with data on 26 and 35 patients, respectively, were reported [7, 8]. In NBS patients without malignancy, the crucial pre-transplant problem includes development of severe immunodeficiency followed by infections. This was the case of our patient, who over the years developed symptomatic severe combined immunodeficiency syndrome.\n\nThe peritransplant period was typical, with manageable complications including myelosuppression, severe mucositis, facial vasculitis, mild acute kidney injury and neutropenic fever. Nevertheless, she was discharged from the transplant unit at day +28 in overall good condition. However, after day +30, a number of severe complications have developed including choledocholithiasis and recto-sigmoid ulcers.\n\nData on cholelithiasis after HSCT in the early post-transplant period are very scanty [9], and there is no report on cholelithiasis in patients with NBS after HSCT. The well-known risk factors associated with gallstones in pediatric population include autologous transplant, unrelated donor, grade 3 to 4 acute GVHD, chronic GVHD, second transplant, diabetes, and estrogen therapy [10]. Hemolysis is another possible risk factor [11]. None of these risk factors was present in our patient at day +35. Importantly, our patient was diagnosed for cholestasis after hepatitis of unknown etiology, already before HSCT. Non-malignant disease, mucositis, neutropenic fever and the necessity of TPN were additional risk factors. Clinical data show that children who underwent HSCT for malignancy showed a significantly lower risk of cholelithiasis compared with those treated for bone marrow failure (7.4% <i>vs</i> 27%) [12].\n\nIn the late post-transplant period, most children (85%) with gallstones after HSCT usually did not require surgical intervention, and strategy of non-operative management for asymptomatic cholelithiasis in this highly selected group of patients is supported [12]. According to other authors, surgical exploration and cholecystectomy still remain an important approach even in the case of acalculous acute cholecystitis [13].\n\nThe main difficulties in the management of our patient was the necessity of invasive diagnosis and treatment in the early post-transplant period, gastric endoscopy, ileocolonoscopy, endoscopic retrograde cholangiopancreatography, and open cholecystectomy. We had to answer the questions on selection of either conservative or surgical treatment of cholelithiasis, and either one or two interventions. The approach of two surgical interventions was successful for the patient. We decided to perform “delayed cholecystectomy” about 6 weeks after an episode of acute cholecystitis, obstructive jaundice and post-ECPW pancreatitis. This was a sufficient approach for the improvement in the general status of the patient and local conditions. We believe that an invasive strategy, consisting of close monitoring and early laparotomy combined with vigorous supportive therapy, should be used when dealing with suspected gastrointestinal complications in patients with hematological malignancies. Our patient presented acute symptoms and complications of cholelithiasis. In our opinion, the clinical picture of cholecystitis in our patient was progressive. This is why despite poor general condition of the patient, cholecystectomy should be performed in case of urgent indications regardless of anemia, granulocytopenia and thrombocytopenia, which should be corrected as much as possible.\n\nEndoscopic sphincterotomy after biliary pancreatitis may suffice for early treatment in lieu of cholecystectomy to prevent recurrent symptoms before delayed cholecystectomy: patients who underwent ERCP with sphincterotomy decreased their risk of readmission from 24% to 10% and their risk of developing recurrent biliary pancreatitis from 9% to 1% [14, 15].\n\nRelated acute abdominal complications often need emergency surgical treatment with a high rate of mortality. In these patients the surgical strategy is complex and hard to schematize. When deciding on the surgical strategy in treating of acute abdominal complications in the patient at early phase after HSCT, the surgeon must consider that surgical intervention is indicated only after unsuccessful medical treatment. Proper cooperation of a multi-disciplinary team plays a crucial role in the preparation and stabilization of patients’ general status. Obviously, post-transplant neutropenia, thrombocytopenia, immune suppression or positive blood cultures are adverse prognostic factors.\n\nConclusions\nIn conclusion, the key issue for our patient in the intermediate post-transplant period between days +30 and +100 were hepatic and pancreatic complications. All the obstacles were obviously attributable both to the primary congenital disease, its complications, and transplantation itself. We overcame these complications and treated the patient with the best possible and safe approach. Finally, we solved also the nature of recto-sigmoid ulcers, which ex iuvantibus has proven to be an unspecific inflammation of the gastrointestinal tract. In the meantime we excluded gastrointestinal GVHD, CMV infection, and late toxicity. This multidisciplinary approach based on combined surgical, endoscopic and conservative management of multiple post-transplant complications was successful for the patient.\n\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1 Pastorczak A Szczepanski T Mlynarski W Clinical course and therapeutic implications for lymphoid malignancies in Nijmegen breakage syndrome Eur J Med Genet 2016 59 126 132 26826318 \n2 Varon R Demuth I Chrzanowska KH Adam MP Ardinger HH Pagon RA Nijmegen Breakage Syndrome Gene Reviews 2017 Seattle 1993 University of Washington updated 2017 \n3 Wolska-Kusnierz B Gregorek H Chrzanowska K Nijmegen Breakage Syndrome: clinical and immunological features, long-term outcome and treatment options – a retrospective analysis J Clin Immunol 2015 35 538 549 26271390 \n4 Albert MH Gennery AR Greil J Successful SCT for Nijmegen Breakage Syndrome Bone Marrow Transplant 2010 45 622 626 19684627 \n5 Stajner T Vasiljevic Z Vujic D Atypical strain of Toxoplasma gondii causing fatal reactivation after hematopoietic stem cell transplantion in a patient with an underlying immunological deficiency J Clin Microbiol 2013 51 2686 2690 23761151 \n6 Wozniak M Krzywon M Holda MK Reduced-intensity conditioning umbilical cord blood transplantation in Nijmegen Breakage Syndrome Pediatr Transplant 2015 19 E51 55 25523867 \n7 Slack J Albert MH Balashov D Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders J Allergy Clin Immunol 2018 141 322 328 e10 28392333 \n8 Deripapa E Balashov D Rodina Y Prospective study of a cohort of Russian Nijmegen Breakage Syndrome patients demonstrating predictive value of low kappa-deleting recombination excision circle (KREC) numbers and beneficial effect of hematopoietic stem cell transplantation (HSCT) Front Immunol 2017 8 807 28791007 \n9 Alnusair MM DeMagalhaes-Silverman M Silverman WB The role of ERCP in patients with pancreatico-biliary problems in the setting of hematopoietic stem cell transplant Gastrointest Endosc 2006 63 655 659 16564868 \n10 Hoffmeister PA Storer BE McDonald GB Gallstones in pediatric hematopoietic cell transplant survivors with up to 40 years of follow-up J Pediatr Hematol Oncol 2014 36 484 490 25036277 \n11 Andoh A Hodohara K Inoue T ALL complicated by obstructive jaundice due to choledocholithiasis after unrelated bone marrow transplantation Rinsho Ketsueki 2000 41 612 614 11020987 \n12 Safford SD Safford KM Martin P Management of cholelithiasis in pediatric patients who undergo bone marrow transplantation J Pediatr Surg 2001 36 86 90 11150443 \n13 Kobbe G Heyll A Zodler T Acute acalculous cholecystitis complicating oral recontamination after allogeneic bone marrow transplantation Oncol Rep 1997 4 823 824 21590149 \n14 van Baal MC Besselink MG Bakker OJ Timing of cholecystectomy after mild biliary pancreatitis: a systematic review Ann Surg 2012 255 860 866 22470079 \n15 Eachempati SR Cocanour CS Dultz LA Acute cholecystitis in the sick patient Curr Probl Surg 2014 51 441 466 25497405\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1426-3912",
"issue": "44(3)",
"journal": "Central-European journal of immunology",
"keywords": "cholecystitis; choledocholithiasis; cholelithiasis; gut ulcer; hematopoietic cell transplantation; pancreatitis",
"medline_ta": "Cent Eur J Immunol",
"mesh_terms": null,
"nlm_unique_id": "9702239",
"other_id": null,
"pages": "327-331",
"pmc": null,
"pmid": "31871422",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "11020987;25497405;26826318;22470079;25036277;11150443;19684627;21590149;28392333;23761151;25523867;26271390;28791007;16564868",
"title": "Complex profile of multiple hepatobiliary and gastrointestinal complications after hematopoietic stem cell transplantation in a child with Nijmegen breakage syndrome.",
"title_normalized": "complex profile of multiple hepatobiliary and gastrointestinal complications after hematopoietic stem cell transplantation in a child with nijmegen breakage syndrome"
} | [
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"companynumb": "PL-MYLANLABS-2020M1027191",
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"activesubstancename": "FLUDARABINE PHOSPHATE"
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"abstract": "Atypical femoral fractures (AFFs) occur in osteoporosis patients receiving long-term bisphosphonate. Atypical femoral fractures also occur in cancer patients receiving long-term bisphosphonate or denosumab, but the prevalence is low. We describe a 53-year-old woman with a history of medullary thyroid cancer and skull metastasis who was prescribed bisphosphonate for 6 years and denosumab for 1.5 years, consecutively. Bone scintigraphy performed because of spontaneous groin pain showed uptake in the lateral aspect of the left femur, which was confirmed as impending AFF. In oncological patients receiving long-term bisphosphonate or denosumab, AFF should be included as a differential diagnosis with focal femoral findings.",
"affiliations": "From the Departments of *Nuclear Medicine, †Orthopedic Surgery, and ‡Head and Neck Surgery, Cancer Institute Hospital, Tokyo, Japan.",
"authors": "Koizumi|Mitsuru|M|;Gokita|Tabu|T|;Toda|Kazuhisa|K|",
"chemical_list": "D004164:Diphosphonates; D000069448:Denosumab",
"country": "United States",
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"doi": "10.1097/RLU.0000000000001592",
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"issn_linking": "0363-9762",
"issue": "42(6)",
"journal": "Clinical nuclear medicine",
"keywords": null,
"medline_ta": "Clin Nucl Med",
"mesh_terms": "D001859:Bone Neoplasms; D018278:Carcinoma, Neuroendocrine; D000069448:Denosumab; D004164:Diphosphonates; D005260:Female; D005264:Femoral Fractures; D006801:Humans; D008875:Middle Aged; D012307:Risk Factors; D013964:Thyroid Neoplasms; D013997:Time Factors",
"nlm_unique_id": "7611109",
"other_id": null,
"pages": "463-464",
"pmc": null,
"pmid": "28240655",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Impending Atypical Femoral Fracture in Patients With Medullary Thyroid Cancer With Skeletal Metastasis Treated With Long-term Bisphosphonate and Denosumab.",
"title_normalized": "impending atypical femoral fracture in patients with medullary thyroid cancer with skeletal metastasis treated with long term bisphosphonate and denosumab"
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"companynumb": "PHHY2017JP186672",
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"abstract": "Pelvic ring fractures are common in the elderly population and are usually a result of low-energy trauma, such as falls from standing. In most cases, low-energy pelvic ring injuries can be treated with appropriate analgesia and early mobilization. Arterial injury resulting in hemodynamic instability from a low-energy pelvic ring injury is rare but, given the poor compliance of vessels in the elderly population, possible. These patients must be carefully monitored after the initial injury. The purpose of this report is to describe an elderly patient who sustained a superior pubic ramus fracture and arterial injury following a low-energy fall from standing that required angiographic intervention. Elderly patients who sustain low-energy or pelvic insufficiency fractures are unlike the younger population with high-energy pelvic fractures and hemodynamic collapse. Elderly patients can have a delayed presentation of arterial injury and require careful physical examination and close monitoring. Additionally, the authors provide a review of the literature for low-energy pelvic fractures. [Orthopedics. 2017; 40(3):e546-e548.].",
"affiliations": null,
"authors": "Solarz|Mark K|MK|;Kistler|Justin M|JM|;Rehman|Saqib|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.3928/01477447-20161229-03",
"fulltext": null,
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"issn_linking": "0147-7447",
"issue": "40(3)",
"journal": "Orthopedics",
"keywords": null,
"medline_ta": "Orthopedics",
"mesh_terms": "D000058:Accidental Falls; D000368:Aged; D000792:Angiography; D001158:Arteries; D050723:Fractures, Bone; D015775:Fractures, Stress; D006470:Hemorrhage; D006801:Humans; D010384:Pelvic Bones; D010388:Pelvis; D011630:Pubic Bone; D016103:Spinal Fractures; D057772:Vascular System Injuries",
"nlm_unique_id": "7806107",
"other_id": null,
"pages": "e546-e548",
"pmc": null,
"pmid": "28056159",
"pubdate": "2017-05-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Obturator Artery Injury Resulting in Massive Hemorrhage From a Low-Energy Pubic Ramus Fracture.",
"title_normalized": "obturator artery injury resulting in massive hemorrhage from a low energy pubic ramus fracture"
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"companynumb": "US-BAYER-2017-121878",
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"abstract": "Cytokine release syndrome (CRS) has been reported after immunologic manipulations, most often through therapeutic monoclonal antibodies. To our knowledge, CRS after radiation therapy (RT) for cancer has not been reported before. The development of unusual clinical signs and symptoms after RT led us to investigate the possibility of CRS after RT and review the medical literature on this topic.\n\n\n\nA 65 year-old man with untreated chronic lymphocytic leukemia and recurrent, metastatic Merkel cell carcinoma undergoing anti-programmed death 1 (PD1) immunotherapy was referred for palliative RT to sites of progressing metastases. Within hours of each weekly dose of RT, he experienced fever, tachycardia, hypotension, rash, dyspnea, and rigors. Based on clinical suspicion for CRS, blood cytokine measurements were performed 1 h after the second and third dose of RT and demonstrated tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) levels approximately ten-fold higher than normal. These were near normal immediately prior to the third dose of RT, and resolved to normal levels 3 weeks after RT. He experienced rapid regression of irradiated tumors, with development of new sites of metastases soon thereafter. A literature review revealed no clinical cases of CRS after RT for cancer.\n\n\n\nRT during anti-PD1 immunotherapy in a patient with underlying immune dysfunction appeared to be the putative mediator of an immune process which yielded significant increases in pro-inflammatory cytokines, and produced the clinical symptoms meeting the definition of grade 3 CRS. This case demonstrates the capability of RT to elicit immune-related adverse events.",
"affiliations": "Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. barkerc@mskcc.org.;Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.;Immunology, Memorial Sloan Kettering Cancer Center, New York, USA.;Information Systems and Library, Memorial Sloan Kettering Cancer Center, New York, USA.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA.",
"authors": "Barker|Christopher A|CA|;Kim|Samuel K|SK|;Budhu|Sadna|S|;Matsoukas|Konstantina|K|;Daniyan|Anthony F|AF|;D'Angelo|Sandra P|SP|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D016207:Cytokines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor",
"country": "England",
"delete": false,
"doi": "10.1186/s40425-017-0311-9",
"fulltext": "\n==== Front\nJ Immunother CancerJ Immunother CancerJournal for Immunotherapy of Cancer2051-1426BioMed Central London 31110.1186/s40425-017-0311-9Case ReportCytokine release syndrome after radiation therapy: case report and review of the literature Barker Christopher A. 212-639-8168barkerc@mskcc.org 1Kim Samuel K. kims8@mskcc.org 1Budhu Sadna budhus@mskcc.org 2Matsoukas Konstantina matsoukk@mskcc.org 3Daniyan Anthony F. daniyana@mskcc.org 4D’Angelo Sandra P. dangelos@mskcc.org 41 0000 0001 2171 9952grid.51462.34Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 USA 2 0000 0001 2171 9952grid.51462.34Immunology, Memorial Sloan Kettering Cancer Center, New York, USA 3 0000 0001 2171 9952grid.51462.34Information Systems and Library, Memorial Sloan Kettering Cancer Center, New York, USA 4 0000 0001 2171 9952grid.51462.34Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA 3 1 2018 3 1 2018 2018 6 15 6 2017 18 12 2017 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nCytokine release syndrome (CRS) has been reported after immunologic manipulations, most often through therapeutic monoclonal antibodies. To our knowledge, CRS after radiation therapy (RT) for cancer has not been reported before. The development of unusual clinical signs and symptoms after RT led us to investigate the possibility of CRS after RT and review the medical literature on this topic.\n\nCase presentation\nA 65 year-old man with untreated chronic lymphocytic leukemia and recurrent, metastatic Merkel cell carcinoma undergoing anti-programmed death 1 (PD1) immunotherapy was referred for palliative RT to sites of progressing metastases. Within hours of each weekly dose of RT, he experienced fever, tachycardia, hypotension, rash, dyspnea, and rigors. Based on clinical suspicion for CRS, blood cytokine measurements were performed 1 h after the second and third dose of RT and demonstrated tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) levels approximately ten-fold higher than normal. These were near normal immediately prior to the third dose of RT, and resolved to normal levels 3 weeks after RT. He experienced rapid regression of irradiated tumors, with development of new sites of metastases soon thereafter. A literature review revealed no clinical cases of CRS after RT for cancer.\n\nConclusions\nRT during anti-PD1 immunotherapy in a patient with underlying immune dysfunction appeared to be the putative mediator of an immune process which yielded significant increases in pro-inflammatory cytokines, and produced the clinical symptoms meeting the definition of grade 3 CRS. This case demonstrates the capability of RT to elicit immune-related adverse events.\n\nKeywords\nCytokine release syndromeRadiation therapyRadiotherapySystemic inflammatory response syndromeCytokineTumor necrosis factorMerkel cell carcinomaChronic lymphocytic leukemiaImmunotherapyProgrammed death 1 (PD1)Cancer Center Support GrantP30-CA008748Barker Christopher A. issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nCytokine release syndrome (CRS) is defined by the Common Terminology Criteria for Adverse Events (CTCAE, version 4.03) as “a disorder characterized by nausea, headache, tachycardia, hypotension, rash, and dyspnea, and is caused by the release of cytokines by cells” [1]. More specific criteria for CRS are ill-defined, but the condition most likely represents a variant of the Systemic Inflammatory Response Syndrome (SIRS), which is not part of the CTCAE, but was defined by the American College of Chest Physicians and Critical Care Medicine Consensus Conference (ACCP/CCM CC) as the presence of more than one of the following clinical findings: body temperature > 38 °C or <36 °C; heart rate > 90 min−1; hyperventilation evidenced by respiratory rate > 20 min−1 or PaCO2 of <32 mmHg; and a white blood cell count of >12,000 cells mcL−1 or <4000 cells mcL−1 [2]. Clinical manifestations and laboratory studies (cytokine measurements) can be used to confirm the diagnosis of CRS. Management is often supportive, but patients at risk may benefit from prophylactic antihistamines and corticosteroids. Although a specific mechanistic understanding of CRS and SIRS is unclear, these entities have most often been attributed to immunologic manipulation (in the form of monoclonal antibodies) or insult (in the form of infection), respectively.\n\nTo our knowledge, CRS after radiation therapy (RT) has not been described before. Nevertheless, on the basis that RT can modulate the immune system, CRS after RT seems plausible. We recently cared for a patient who developed CRS after RT. For this reason, we report his case in detail and reviewed available literature on CRS and SIRS after RT.\n\nCase presentation\nA 65 year old man presented elsewhere with a 3 cm subcutaneous mass in the right buttock. His past medical history was notable for untreated chronic lymphocytic leukemia (CLL), diagnosed 7 years prior to presentation. He also had coronary artery disease, hypertension, hypothyroidism, and dyslipidemia, all well controlled on medications. Imaging suggested a malignant tumor, and subsequent positron emission tomography (PET) demonstrated 18-fluorodeoxyglucose (FDG) uptake in the right buttock mass, as well as the right inguinofemoral and external iliac lymphatics. Biopsy of the right buttock mass and a right inguinal lymph node demonstrated Merkel cell carcinoma (MCC). Immunohistochemical staining with CM2B4 indicated Merkel cell polyoma virus association with the tumor. Flow cytometric analysis of the lymph node demonstrated a clonal B cell population, consistent with the patient’s known CLL. After diagnosis, his MCC was staged cT2N2M1 and unresectable. He was treated elsewhere with 6 cycles of carboplatin and etoposide chemotherapy. Four weeks after chemotherapy, he was noted to have progression in the in-transit lymphatic metastases, which were biopsied and again revealed MCC.\n\nHe subsequently presented to our center for evaluation and treatment recommendations. Anti-programmed death 1 (PD1) immunotherapy was recommended, and he received 3 doses of this over 9 weeks at an outside facility without any treatment-related adverse events, including CRS. His in-transit metastases progressed during immunotherapy, and for this reason, he was referred to discuss RT. Physical examination revealed extensive in-transit metastases extending from the right buttock around the upper leg to the anterior leg and groin area, with associated malignant lymphadenopathy and right lower extremity lymphedema. PET/CT corroborated the clinical findings, and also demonstrated metastatic lymphadenopathy involving the right inguinofemoral, external iliac, common iliac and para-aortic lymphatics (see Fig. 1a). Palliative RT was recommended to all sites of grossly evident disease to a total dose of 24 Gy in 3 fractions given once weekly. This radiotherapy regimen has been proven to be safe and effective in a prospective phase II trial [3], and in our experience leads to response in a high proportion of patients with Merkel cell carcinoma [4]. Anti-PD1 therapy was continued during RT.Fig. 1 Computed tomography at the level of the pelvis and maximum intensity profile of 18-fluorodeoxyglucose positron emission tomography demonstrates the primary Merkel cell carcinoma tumor of the right buttock (red circle), as well as in-transit metastases and lymphatic metastases (yellow arrow) before (a) and after (b) radiotherapy. A partial response was noted in the irradiated tumors, with progression of metastases elsewhere\n\n\n\nApproximately 1-2 h after his first dose of RT, he developed nausea, vomiting, rigors and dizziness. He presented to another institution and was found to be febrile (temperature 39.1 °C) and tachycardic (heart rate 116 min−1). Leukocyte differential is presented in Fig. 2, and demonstrated a dramatic decrease in circulating lymphocytes (Fig. 2b). Blood cultures were obtained and demonstrated no evidence of infection. No signs of organ failure or tumor lysis were detected. He was admitted to another institution for observation and supportive care and discharged <24 h after admission without a specific diagnosis to explain his condition.Fig. 2 Absolute number of leukocytes (a), lymphocytes (b), monocytes (c), neutrophils (d), basophils (e), and eosinophils (f) before, during, and after radiotherapy and anti-PD1 immunotherapy demonstrate changes in cell counts after each fraction of radiotherapy. Shaded box represents normal range for each cell type\n\n\n\nDuring the 1 week interval between RT treatments, he noted low grade fever, fatigue and a faint maculopapular rash on the trunk. Additional evaluations for infection were unremarkable. He received another dose of anti-PD1 therapy, and this precipitated a low grade fever within hours of infusion. On presentation for his second fraction of RT, it was noted that the in-transit metastases were smaller in size. Given the limited effective alternative treatments available for his MCC, he elected to proceed with the second fraction of RT. Prophylactic antiemetic (ondansetron) and antipyretic (acetaminophen) medications were administered 1 h prior to RT. After RT he was closely observed. One hour after RT he developed violent rigors. He became tachycardic, dyspneic, and hypotensive. CRS was suspected, and laboratory studies (cytokine levels) were requested (Fig. 3). He was admitted to our hospital for <24 h of observation and supportive care. He was again found to have no evidence of infection, organ failure or tumor lysis.Fig. 3 Tumor necrosis factor-α (a), interleukin-6 (b), interleukin-10 (c), and interleukin-1β (d) before and after radiotherapy demonstrate increases in cytokines immediately after radiotherapy while the patient was experiencing fever, tachycardia, dyspnea and rigors. Relatively normal levels of cytokines were noted immediately before radiotherapy and 3 weeks after. Dashed lines represent the upper limit of normal for each cytokine\n\n\n\nOne week later, he presented for his third fraction of RT, and the potential risks, benefits and alternatives to continuing RT were again discussed. He was offered prophylactic immunosuppressants (corticosteroids) as a strategy to prevent CRS. Based on concerns that corticosteroids would abrogate his response to RT, he declined this intervention. Prior to RT, laboratory studies were performed (see Figs. 2 and 3). Approximately 1 h after RT, he again developed rigors, tachycardia, dyspnea, and hypotension. Laboratory tests were repeated, and he was monitored, given supportive care and discharged 6 h later in good condition.\n\nThree weeks after completing RT and receiving no further immunotherapy, he presented to report 2 new skin tumors on the contralateral leg. He had grade 2 radiation dermatitis, grade 1 fatigue, and resolution of his low grade fevers. He reported no other adverse events, including cystitis, enteritis, nausea, vomiting, or diarrhea. PET/CT revealed partial response of the irradiated MCC, with small volume metastatic progression at several new sites (Fig. 1b). Laboratory evaluations were repeated (Figs. 2 and 3). Peripheral blood flow cytometry revealed a clonal B cell population consistent with CLL which represented 4.8% of the peripheral WBCs. The absolute number of CLL cells did not meet diagnostic criteria for the presence of CLL.\n\nDiscussion\nAs part of the ACCP/CCM consensus definitions statement, it was noted that SIRS “is seen in association with a large number of clinical conditions. Besides the infectious insults that may produce systemic inflammatory response syndrome, noninfectious pathologic causes may include pancreatitis, ischemia, multitrauma and tissue injury, hemorrhagic shock, immune-mediated organ injury, and the exogenous administration of such putative mediators of the inflammatory process as tumor necrosis factor or other cytokines” [2]. In this patient’s case, RT was the putative mediator of the inflammatory process, which elicited increases in tumor necrosis factor-α (TNF-α) and other cytokines, and produced the clinical symptoms and signs observed, which in aggregate met the CTCAE definition of grade 3 CRS as well as SIRS.\n\nIt is noteworthy that each fraction of RT precipitated the clinical symptoms and signs of CRS. An assessment of cytokines was performed after the second fraction of RT when CRS was clinically suspected. Moreover, cytokine levels were assessed immediately before and after the third fraction of RT and were found to increase to abnormal levels approximately 1 h after RT, in concert with the development of clinical symptoms. Notably, prophylactic antiemetics (ondansetron) and antipyretics (acetaminophen) were able to prevent the nausea, vomiting and fever observed after the first fraction of RT; however, rigors, tachycardia and dyspnea associated with CRS were not mitigated. In monoclonal antibody therapy, prophylactic corticosteroids and antihistamines are administered to patients at high risk of CRS [5]. Our patient declined this prophylactic intervention. An antibody against TNF-α, such as infliximab, might have mitigated the CRS experienced by this patient.\n\nIn our comprehensive review of the published literature, we found no reports of CRS or SIRS after RT for cancer. In a prior phase II trial of the described radiotherapy regimen, CRS was not reported, and grade 3 adverse events occurred in 2 of 18 patients (neuritis, gastrointestinal hemorrhage) [6]. However, prospective studies of patients undergoing total body irradiation prior to bone marrow transplantation have reported some of the clinical manifestations of CRS and SIRS, but neither of these studies formally documented abnormal cytokine levels [7, 8]. A case series of patients with lung cancer reported cytokine levels before and after a protracted course of several weeks of RT, but found no significant changes in cytokine levels; moreover, symptom assessments of CRS or SIRS were not included in that analysis [9]. CRS has been reported after anti-PD1 immunotherapy in case reports [10–12], but does not seem to be common. In our patient anti-PD1 immunotherapy was not temporally associated with CRS.\n\nThe mechanism through which RT could cause CRS is unclear. RT likely produced tumor or tissue injury, releasing molecules that express damage-associated molecular patterns causing activated macrophages to release the proinflammatory cytokines, which cause endothelial expression of adhesion molecules and leukocyte extravasation from the periphery at the site of RT. There was no detectable increase in interleukin-1β, which is typically elaborated by activated macrophages in conjunction with TNF-α and interleukin-6. Moreover, the increase in interleukin-10 in conjunction with interleukin-6 suggests these cytokines were functioning in an anti-inflammatory capacity [13]. This patient experienced a precipitous decrease in WBCs and lymphocytes after the first dose of RT (Fig. 2a and b), and the flow cytometric analysis of peripheral lymphocytes 3 weeks after RT revealed minimal residual CLL. However, smaller changes in the WBC or lymphocyte count were observed after fractions 2 and 3 of RT, when CRS was clearly documented (Fig. 2a and b). Moreover, there was no laboratory evidence of tumor lysis syndrome (hyperkalemia, uric acidemia, etc) after fractions 2 or 3 of RT (data not shown). Therefore, it is unlikely that lymphocyte lysis was the primary cause for CRS, as we initially suspected.\n\nA prior study demonstrated that CRS after anti-CD20 monoclonal antibody therapy was most common and severe among patients with CLL that had lymphocyte counts >50 × 109 /L [14]. CRS in these patients was also associated with increases in TNF-α and interleukin-6, with a peak 90 min after infusion. A significant decrease in lymphocyte and platelet counts, and a significant increase in lactate dehydrogenase, liver enzymes and coagulation factors were also noted. However, subsequent doses of antibody therapy were not associated with adverse events. Our case is inconsistent with these results, as our patient’s lymphocyte counts were 13 × 109 /L, yet he developed grade 3 CRS nonetheless. Therefore, pretreatment lymphocyte count may not be a reliable method to predict CRS among patients undergoing RT. In CLL, lymphocyte counts >50 × 109 /L represent a significant volume of malignant cells; in our patient’s case, the large volume of MCC may have been the risk factor for CRS. We suspect that when large volumes of malignant cells are killed by effective cancer therapies, the risk of CRS is greatest.\n\nThe underlying immune dysfunction caused by CLL, and the ongoing immunotherapy with anti-PD1 therapy may have exacerbated what may typically be a subtle immunologically mediated response to cancer RT, although this is speculation requiring further investigation. Previous work has suggested that proinflammatory cytokine release by T cells is enhanced with PD-1 axis blockade [15]. Moreover, patients with untreated CLL and MCC are known to have an expanded myeloid derived suppressor cell (MDSC) compartment [16] and MDSC compartment at the tumor microenvironment interface [17], respectively. RT may have rapidly depleted MDSCs and allowed for unchecked elaboration of pro-inflammatory cytokines [18]. The pervasive innervation of the anatomic region of RT in this case (abdomen and pelvis) by the vagus nerve may also be a contributor to the autonomic physiologic response observed during CRS [19]. Finally, it is possible the advanced age of the patient (65 years) may have contributed to the observation of an atypical immune response to cancer therapy [20]. Because CRS after RT has never been reported before, it is possible that the unusual combination of circumstances (untreated CLL, antiPD1 immunotherapy, large volume MCC, advanced patient age) may have contributed to the development of CRS after RT.\n\nThe observation of rapid response of irradiated metastases and the development of new metastases after CRS is also of interest. Several studies have suggested the prometastatic and proinvasive effects of RT, and this may be mediated in part by PI3K/Akt-signaling pathway and NF-kB activation and induction of inflammatory cytokines such as TNF-α and interleukin-6 [21–24]. Furthermore, studies have also noted differences in disease prognosis based on the expression levels of various cytokines in numerous cancers, where higher levels of interleukin-6 and interleukin-10 were associated with poorer outcomes [25–27]. Further study of the acute cytokine release after RT with or without immunotherapy as well as the associated molecular pathways may help clarify the mechanisms of metastasis response and resistance to therapy.\n\nWhile CRS is most often attributed to immunomodulatory monoclonal antibodies, it is possible that other immunomodulatory cancer therapies (such as RT) could produce this effect [28]. While some regard RT as an immunosuppressant, we interpret the observations of this patient’s case as evidence that RT is best described as an immune-modulator, not with exclusive suppressive functions. Consistent with this, the immunomodulatory effects of RT have been associated with differences in the radiation dose delivered during treatment [29]. In an era of increasing interest in combining RT and immunotherapy for cancer, careful monitoring for immune-related adverse events not typically observed with RT or immunotherapy alone will probably be of great importance [30]. Clinicians and investigators alike are encouraged to consider how these agents may interact in both positive and negative ways to further our understanding of this promising therapeutic combination.\n\nConclusions\nTo our knowledge, we are the first to report CRS after the receipt of RT. RT in a patient with underlying immune dysfunction who was concurrently receiving anti-PD1 immunotherapy appeared to have been the likely mediator of this immune process. This immune process, in turn, generated significant increases in pro-inflammatory cytokines and produced the clinical symptoms meeting the definition of grade 3 CRS. Thus, this case demonstrates the capability of RT to elicit immune-related adverse events and allows us to gain greater insight into the therapeutic combination of RT and immunotherapy.\n\nAcknowledgements\nThe authors acknowledge the skilled nursing staff in the Department of Radiation Oncology for the attentive supportive care provided to this patient during an unusual adverse event.\n\nFunding\nThis study was conducted through generous support from the Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center, P30-CA008748 (PI: Craig Thompson). The funding body was not involved in the design of the study, data collection or analysis, interpretation of the data, or writing of the manuscript.\n\nAvailability of data and materials\nAll data generated and analyzed during this study are included in this published article.\n\nAuthors’ contributions\nCB provided patient care, designed the analysis, interpreted the data and drafted the manuscript. SK interpreted the data and drafted the manuscript. KM conducted the medical literature search. SD provided patient care, interpreted the data and drafted the manuscript. AD interpreted the data and drafted the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThis research study was conducted as part of a Memorial Sloan Kettering Cancer Center Institutional Review Board-approved retrospective research protocol, 16-934. All necessary consent from the patient involved in the study was obtained, including consent to participate in the study where appropriate.\n\nConsent for publication\nConsent to publish this case report was obtained. Written informed consent was obtained from the patient for publication of their individual details and accompanying images in this manuscript. The consent form is in the patients’ clinical notes and is available for review by the Editor-in-Chief.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 NCI, N., DHHS. May 29, 2009 NIH publication # 09–7473.\n2. Bone RC, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM consensus conference committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644–55.\n3. Salama JK, Chmura SJ, Mehta N, Yenice KM, Stadler WM, Vokes EE, Haraf DJ, Hellman S, Weichselbaum RR. An initial report of a radiation dose-escalation trial in patients with one to five sites of metastatic disease. Clin Cancer Res. 2008;14(16):5255–9.\n4. Cimbak N Barker CA Short-course radiation therapy for Merkel cell carcinoma: relative effectiveness in a \"radiosensitive\" tumor International Journal of Radiation Oncology Biology Physics 2016 96 2 S160 10.1016/j.ijrobp.2016.06.387 \n5. Breslin S Cytokine-release syndrome: overview and nursing implications Clin J Oncol Nurs 2007 11 1 Suppl 37 42 10.1188/07.CJON.S1.37-42 17471824 \n6. Salama JK Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Cancer 2012 118 11 2962 2970 10.1002/cncr.26611 22020702 \n7. Buchali A Immediate toxicity during fractionated total body irradiation as conditioning for bone marrow transplantation Radiother Oncol 2000 54 2 157 162 10.1016/S0167-8140(99)00178-4 10699479 \n8. Chaillet MP Prospective study of the clinical symptoms of therapeutic whole body irradiation Health Phys 1993 64 4 370 4 10.1097/00004032-199304000-00003 8449718 \n9. Trovo M Stereotactic body radiation therapy and intensity modulated radiation therapy induce different plasmatic cytokine changes in non-small cell lung cancer patients: a pilot study Clin Transl Oncol 2016 18 10 1003 10 10.1007/s12094-015-1473-x 26687367 \n10. Foran AE Nivolumab in the treatment of refractory pediatric Hodgkin lymphoma J Pediatr Hematol Oncol 2017 39 5 e263 e266 10.1097/MPH.0000000000000703 27841828 \n11. Rotz SJ Severe cytokine release syndrome in a patient receiving PD-1-directed therapy 2017 \n12. Rassy EE Diffuse edema suggestive of cytokine release syndrome in a metastatic lung carcinoma patient treated with pembrolizumab Immunotherapy 2017 9 4 309 311 10.2217/imt-2016-0134 28303768 \n13. Schaue D Kachikwu EL McBride WH Cytokines in radiobiological responses: a review Radiat Res 2012 178 6 505 523 10.1667/RR3031.1 23106210 \n14. Winkler U Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8) Blood 1999 94 7 2217 2224 10498591 \n15. Dirks J Blockade of programmed death receptor-1 signaling restores expression of mostly proinflammatory cytokines in anergic cytomegalovirus-specific T cells Transpl Infect Dis 2013 15 1 79 89 10.1111/tid.12025 23176118 \n16. Jitschin R CLL-cells induce IDOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs Blood 2014 124 5 750 760 10.1182/blood-2013-12-546416 24850760 \n17. Mitteldorf C PD-1 and PD-L1 in neoplastic cells and the tumor microenvironment of Merkel cell carcinoma J Cutan Pathol 2017 44 9 740 746 10.1111/cup.12973 28569410 \n18. Postow MA Immunologic correlates of the abscopal effect in a patient with melanoma N Engl J Med 2012 366 10 925 931 10.1056/NEJMoa1112824 22397654 \n19. Tracey KJ Physiology and immunology of the cholinergic antiinflammatory pathway J Clin Invest 2007 117 2 289 296 10.1172/JCI30555 17273548 \n20. Saavedra D Garcia B Lage A T cell subpopulations in healthy elderly and lung cancer patients: insights from Cuban studies Front Immunol 2017 8 146 28261208 \n21. Su WH Radiation-induced increase in cell migration and metastatic potential of cervical cancer cells operates via the K-Ras pathway Am J Pathol 2012 180 2 862 871 10.1016/j.ajpath.2011.10.018 22138581 \n22. Qian LW Radiation-induced increase in invasive potential of human pancreatic cancer cells and its blockade by a matrix metalloproteinase inhibitor, CGS27023 Clin Cancer Res 2002 8 4 1223 1227 11948136 \n23. Cheng JC Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-kappaB signal transduction pathway Oncogene 2006 25 53 7009 7018 10.1038/sj.onc.1209706 16732316 \n24. Wild-Bode C Sublethal irradiation promotes migration and invasiveness of glioma cells: implications for radiotherapy of human glioblastoma Cancer Res 2001 61 6 2744 2750 11289157 \n25. Voorzanger N Interleukin (IL)-10 and IL-6 are produced in vivo by non-Hodgkin's lymphoma cells and act as cooperative growth factors Cancer Res 1996 56 23 5499 5505 8968107 \n26. Suzuki S IL-6 and IFN-gamma regulation of IL-10 production by human colon carcinoma cells Int J Oncol 2001 18 3 581 586 11179490 \n27. Bien E Pre-treatment serum levels of interleukin-10, interleukin-12 and their ratio predict response to therapy and probability of event-free and overall survival in childhood soft tissue sarcomas, Hodgkin's lymphomas and acute lymphoblastic leukemias Clin Biochem 2009 42 10-11 1144 1157 10.1016/j.clinbiochem.2009.04.004 19376105 \n28. Suntharalingam G Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412 N Engl J Med 2006 355 10 1018 1028 10.1056/NEJMoa063842 16908486 \n29. Janiak MK Cancer immunotherapy: how low-level ionizing radiation can play a key role 2017 \n30. Escorcia FE Postow MA Barker CA Radiotherapy and immune checkpoint blockade for melanoma: a promising combinatorial strategy in need of further investigation Cancer J 2017 23 1 32 39 10.1097/PPO.0000000000000236 28114252\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2051-1426",
"issue": "6(1)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "Chronic lymphocytic leukemia; Cytokine; Cytokine release syndrome; Immunotherapy; Merkel cell carcinoma; Programmed death 1 (PD1); Radiation therapy; Radiotherapy; Systemic inflammatory response syndrome; Tumor necrosis factor",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D015266:Carcinoma, Merkel Cell; D003131:Combined Modality Therapy; D016207:Cytokines; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D061026:Programmed Cell Death 1 Receptor; D012878:Skin Neoplasms",
"nlm_unique_id": "101620585",
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"pages": "1",
"pmc": null,
"pmid": "29298730",
"pubdate": "2018-01-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "22138581;27841828;17273548;10699479;22020702;24850760;19376105;28261208;16908486;8968107;10498591;18698045;28569410;17471824;26687367;28303768;23176118;1303622;8449718;11289157;23106210;28361232;11948136;11179490;22397654;28114252;16732316;28544595",
"title": "Cytokine release syndrome after radiation therapy: case report and review of the literature.",
"title_normalized": "cytokine release syndrome after radiation therapy case report and review of the literature"
} | [
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"companynumb": "US-CIPLA LTD.-2018US12143",
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"abstract": "BACKGROUND\nThe aim of this study was to estimate the incidence of and risk factors for Pneumocystis pneumonia (PCP) infection in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP).\n\n\nMETHODS\nThe medical records of 739 DLBCL patients who received R-CHOP between May 2004 and January 2019 were retrospectively evaluated. Patients were divided into two groups: those who received primary PCP prophylaxis (prophylaxis group) and those who did not (control group). The incidence rate of PCP in each group was calculated, and risk factors for PCP were evaluated in the control group.\n\n\nRESULTS\nBaseline characteristics were significantly different between the two groups. Compared to the 602 patients who did not receive prophylaxis, the prophylaxis group (n = 137) had poor prognostic factors of older age, high lactate dehydrogenase (LDH) levels, advanced Ann Arbour stage, and high International Prognostic Index (IPI) risk scores. None of the patients receiving PCP prophylaxis developed PCP, while the incidence of PCP in the control group was 8.1% (definite cases 5.5% and probable cases 2.7%). Out of the 49 patients who developed PCP, 10 patients (20.4%) were admitted to the intensive care unit, and the PCP-related death rate was 16.3% (8/49).\n\n\nCONCLUSIONS\nThis study showed that PCP prophylaxis is highly effective against PCP infection and may help guide prevention of PCP during R-CHOP treatment in DLBCL patients.",
"affiliations": "Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.;Division of Infectious Diseases, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.;Division of Infectious Diseases, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.;Division of Infectious Diseases, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.",
"authors": "Lee|Ji Yun|JY|https://orcid.org/0000-0002-5835-7219;Kang|Minsu|M|https://orcid.org/0000-0001-6491-2277;Suh|Koung Jin|KJ|https://orcid.org/0000-0002-1881-8738;Kim|Ji-Won|JW|https://orcid.org/0000-0001-6426-9074;Kim|Se Hyun|SH|https://orcid.org/0000-0002-2292-906X;Kim|Jin Won|JW|https://orcid.org/0000-0002-1357-7015;Kim|Yu Jung|YJ|http://orcid.org/0000-0002-5037-0523;Song|Kyoung-Ho|KH|https://orcid.org/0000-0002-4517-3840;Kim|Eu Suk|ES|https://orcid.org/0000-0001-7132-0157;Kim|Hong Bin|HB|https://orcid.org/0000-0001-6262-372X;Lee|Keun-Wook|KW|https://orcid.org/0000-0002-8491-703X;Kim|Jee Hyun|JH|https://orcid.org/0000-0003-1336-3620;Bang|Soo-Mee|SM|http://orcid.org/0000-0002-0938-3007;Lee|Jong-Seok|JS|http://orcid.org/0000-0002-7336-7124;Lee|Jeong-Ok|JO|http://orcid.org/0000-0001-9402-6372",
"chemical_list": "C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Germany",
"delete": false,
"doi": "10.1111/myc.13184",
"fulltext": null,
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"issue": "64(1)",
"journal": "Mycoses",
"keywords": "Pneumocystis pneumonia; R-CHOP; incidence; lymphoma; mortality; prophylaxis; risk factors; trimethoprim-sulfamethoxazole",
"medline_ta": "Mycoses",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D011241:Prednisone; D012189:Retrospective Studies; D012307:Risk Factors; D000069283:Rituximab; D014750:Vincristine",
"nlm_unique_id": "8805008",
"other_id": null,
"pages": "60-65",
"pmc": null,
"pmid": "32970331",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pneumocystis jirovecii pneumonia in diffuse large B-cell Lymphoma treated with R-CHOP.",
"title_normalized": "pneumocystis jirovecii pneumonia in diffuse large b cell lymphoma treated with r chop"
} | [
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"companynumb": "KR-CELLTRION INC.-2020KR028400",
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"abstract": "OBJECTIVE\nDiffuse isolated liver metastases are the dominant mode of tumor progression in a number of cancers and present a major treatment challenge for oncologists. An experimental treatment, percutaneous hepatic perfusion (PHP), utilizes partial venovenous cardiopulmonary bypass to allow administration of high-dose chemotherapy directly and solely to the liver with filtration of chemotherapeutic agents from the blood prior to its return to the systemic circulation, thereby minimizing toxic systemic effects. The following case series describes the management of 5 patients with metastatic melanoma undergoing serial PHPs.\n\n\nMETHODS\nA single-center experience from a national multi-center random-assignment trial comparing PHP to best alternative care (BAC) in patients with diffuse melanoma liver metastases.\n\n\nMETHODS\nA tertiary care hospital.\n\n\nMETHODS\nFive patients with metastatic melanoma to the liver.\n\n\nMETHODS\nFive patients underwent a total of fifteen PHPs using a venovenous bypass circuit with hemofiltration, receiving hepatic intra-arterial melphalan, 3 mg/kg of ideal body weight, for 30 minutes with a total of 60 minutes of hemofiltration.\n\n\nRESULTS\nFive patients tolerated the procedure well with transient hemodynamic and metabolic changes.\n\n\nCONCLUSIONS\nIn patients with diffuse isolated liver metastases, PHP is a safe and well-tolerated procedure that can be performed more than once and is associated with marked anti-tumor activity in some patients.",
"affiliations": "Division of Cardiothoracic Anesthesiology, University of Maryland School of Medicine, Baltimore, MD.;Department of Surgical Oncology, University of Maryland School of Medicine, Baltimore, MD.;Division of Cardiothoracic Anesthesiology, University of Maryland School of Medicine, Baltimore, MD.;Clinical Quality Management, Clinical Services, and Clinical Anesthesia Services, University of Maryland School of Medicine, Baltimore, MD.;Division of Perioperative Services, University of Maryland School of Medicine, Baltimore, MD.;Division of Cardiothoracic Anesthesiology, University of Maryland School of Medicine, Baltimore, MD. Electronic address: agrigore@anes.umm.edu.",
"authors": "Fitzpatrick|Molly|M|;Richard Alexander|H|H|;Deshpande|Seema P|SP|;Martz|Douglas G|DG|;McCormick|Brian|B|;Grigore|Alina M|AM|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D008558:Melphalan",
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"issue": "28(3)",
"journal": "Journal of cardiothoracic and vascular anesthesia",
"keywords": "liver metastases; percutaneous hepatic perfusion; venovenous cardiopulmonary bypass",
"medline_ta": "J Cardiothorac Vasc Anesth",
"mesh_terms": "D018906:Antineoplastic Agents, Alkylating; D001831:Body Temperature; D002315:Cardiopulmonary Bypass; D002404:Catheterization; D005260:Female; D006440:Hemofiltration; D006801:Humans; D008102:Liver Circulation; D008113:Liver Neoplasms; D008297:Male; D008545:Melanoma; D008558:Melphalan; D008875:Middle Aged; D010477:Perfusion",
"nlm_unique_id": "9110208",
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"references": null,
"title": "Use of partial venovenous cardiopulmonary bypass in percutaneous hepatic perfusion for patients with diffuse, isolated liver metastases: a case series.",
"title_normalized": "use of partial venovenous cardiopulmonary bypass in percutaneous hepatic perfusion for patients with diffuse isolated liver metastases a case series"
} | [
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"abstract": "Concentrations of lidocaine and MEGX were determined in a variety of tissues and other samples collected at autopsy. In 13 of the cases examined in which lidocaine was associated with death, tissue concentrations were greater than 15 mg/kg. Tissue concentrations in other patients treated with lidocaine were significantly lower.",
"affiliations": null,
"authors": "Peat|M A|MA|;Deyman|M E|ME|;Crouch|D J|DJ|;Margot|P|P|;Finkle|B S|BS|",
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"country": "United States",
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"issn_linking": "0022-1198",
"issue": "30(4)",
"journal": "Journal of forensic sciences",
"keywords": null,
"medline_ta": "J Forensic Sci",
"mesh_terms": "D001344:Autopsy; D006801:Humans; D008012:Lidocaine; D014018:Tissue Distribution",
"nlm_unique_id": "0375370",
"other_id": null,
"pages": "1048-57",
"pmc": null,
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"pubdate": "1985-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Concentrations of lidocaine and monoethylglycylxylidide (MEGX) in lidocaine associated deaths.",
"title_normalized": "concentrations of lidocaine and monoethylglycylxylidide megx in lidocaine associated deaths"
} | [
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"companynumb": "US-PFIZER INC-2020392044",
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"activesubstancename": "LIDOCAINE HYDROCHLORIDE"
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"abstract": "Skin rashes, proteinuria, systemic lupus erythematosus, polymyositis and myasthenia gravis have all been recorded as complications of penicillamine therapy in patients with rheumatoid arthritis. A patient who had developed all 5 is now described. The skin lesion resembled elastosis perforans serpiginosa, which has been reported as a rare side effect in patients with Wilson's disease but not in patients with rheumatoid arthritis treated with penicillamine.",
"affiliations": null,
"authors": "Essigman|W K|WK|",
"chemical_list": "D010396:Penicillamine",
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"delete": false,
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"keywords": null,
"medline_ta": "Ann Rheum Dis",
"mesh_terms": "D000328:Adult; D001172:Arthritis, Rheumatoid; D003875:Drug Eruptions; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D008297:Male; D009157:Myasthenia Gravis; D009220:Myositis; D010396:Penicillamine; D011507:Proteinuria",
"nlm_unique_id": "0372355",
"other_id": null,
"pages": "617-20",
"pmc": null,
"pmid": "6216862",
"pubdate": "1982-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "4100034;4750215;1125624;984614;1085099",
"title": "Multiple side effects of penicillamine therapy in one patient with rheumatoid arthritis.",
"title_normalized": "multiple side effects of penicillamine therapy in one patient with rheumatoid arthritis"
} | [
{
"companynumb": "GB-BAUSCH-BL-2019-003129",
"fulfillexpeditecriteria": "2",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PENICILLAMINE"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nThe introduction of BEACOPP(escalated) (escalated-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) has significantly improved tumor control and overall survival in patients with advanced-stage Hodgkin lymphoma. However, this regimen has also been associated with higher treatment-related mortality (TRM). Thus, we analyzed clinical course and risk factors associated with TRM during treatment with BEACOPP(escalated).\n\n\nMETHODS\nIn this retrospective analysis, we investigated incidence, clinical features, and risk factors for BEACOPP(escalated)-associated TRM in the German Hodgkin Study Group trials HD9, HD12, and HD15.\n\n\nRESULTS\nAmong a total of 3,402 patients, TRM of 1.9% (64 of 3,402) was mainly related to neutropenic infections (n = 56; 87.5%). Twenty of 64 events occurred during the first course of BEACOPP(escalated) (31.3%). Higher risk of TRM was seen in patients age ≥ 40 years with poor performance status (PS) and in patients age ≥ 50 years. PS and age were then used to construct a new risk score; those with a score ≥ 2 had TRM of 7.1%, whereas patients who scored 0 or 1 had TRM of 0.9%.\n\n\nCONCLUSIONS\nThe individual risk of TRM associated with BEACOPP(escalated) can be predicted by a simple algorithm based on age and PS. High-risk patients should receive special clinical attention.",
"affiliations": "University Hospital of Cologne, Cologne, Germany.",
"authors": "Wongso|Diana|D|;Fuchs|Michael|M|;Plütschow|Annette|A|;Klimm|Beate|B|;Sasse|Stephanie|S|;Hertenstein|Bernd|B|;Maschmeyer|Georg|G|;Vieler|Tom|T|;Dührsen|Ulrich|U|;Lindemann|Walter|W|;Aulitzky|Walter|W|;Diehl|Volker|V|;Borchmann|Peter|P|;Engert|Andreas|A|",
"chemical_list": "D001761:Bleomycin; D011344:Procarbazine; D014750:Vincristine; D014747:Vinblastine; D005047:Etoposide; D003606:Dacarbazine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2012.47.9774",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "31(22)",
"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; D001761:Bleomycin; D015992:Body Mass Index; D003520:Cyclophosphamide; D003606:Dacarbazine; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011241:Prednisone; D011344:Procarbazine; D012189:Retrospective Studies; D012307:Risk Factors; D014747:Vinblastine; D014750:Vincristine",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "2819-24",
"pmc": null,
"pmid": "23796987",
"pubdate": "2013-08-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Treatment-related mortality in patients with advanced-stage hodgkin lymphoma: an analysis of the german hodgkin study group.",
"title_normalized": "treatment related mortality in patients with advanced stage hodgkin lymphoma an analysis of the german hodgkin study group"
} | [
{
"companynumb": "DE-JNJFOC-20170805931",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BLEOMYCIN SULFATE"
},
"drugadditional": null,
... |
{
"abstract": "Corrected QT interval (QTc) prolongation is long considered as a predisposing factor for the occurrence of torsade de pointes (TdP) and sudden cardiac arrest in methadone maintenance treatment. We aimed to elucidate the correlation between QTc prolongation and in-hospital death, respiratory arrest, and endotracheal intubation in acute methadone-intoxicated patients presenting to the emergency department and to assess the value of QTc in predicting these outcomes. A prospective cross-sectional study with a convenience sample of patients with acute methadone overdose was done. Participants were 152 patients aged 15-65 with negative urinary dipstick test for cyclic antidepressants, no history of other QTc-prolonging conditions and co-ingestions, no severe comorbidities affecting the outcomes, and positive urinary dipstick results for methadone. QTc intervals were measured and calculated in triage-time electrocardiogram (ECG). Death was correlated with QTc (P = 0.014) and length of ICU admission (P < 0.001). In multivariable analysis, death was independently associated only with length of ICU admission [odds ratio (OR) 95 % confidence intervals (95 % CI) 1.36 (1.14-1.61)]. Intubation and respiratory arrest were independently associated with QTc interval [OR (95 % CI) 1.03 (1.02-1.04) and 1.02 (1.01-1.03), respectively]. The receiver operating characteristics curves drawn to show the ability of QTc to predict death, intubation, and respiratory arrest showed thresholds of 470, 447.5, and 450 ms with sensitivity (95 % CI) and specificity (95 % CI) of 87.5 (47.3-99.7), 86.8 (74.7-94.5), and 77.3 (62.2-88.5), respectively. Our study showed that QTc is a potential predictor for adverse outcomes related to acute methadone intoxication. The correlations shown in this study between triage-time QTc and in-hospital respiratory arrest or intubation in methadone overdose may be of clinical value, whether these outcomes are hypothesized to be a reflection of background TdP or intoxication severity.",
"affiliations": "Department of Emergency Medicine, Iran University of Medical Sciences, Tehran, Iran.",
"authors": "Farsi|Davood|D|;Mirafzal|Amirhossein|A|;Hassanian-Moghaddam|Hossein|H|;Azizi|Zahra|Z|;Jamshidnejad|Nyoosha|N|;Zehtabchi|Shahriar|S|",
"chemical_list": "D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1007/s12012-014-9259-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-7905",
"issue": "14(4)",
"journal": "Cardiovascular toxicology",
"keywords": null,
"medline_ta": "Cardiovasc Toxicol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D003430:Cross-Sectional Studies; D062787:Drug Overdose; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007442:Intubation, Intratracheal; D008133:Long QT Syndrome; D008297:Male; D008691:Methadone; D008875:Middle Aged; D012119:Respiration; D016171:Torsades de Pointes; D055815:Young Adult",
"nlm_unique_id": "101135818",
"other_id": null,
"pages": "358-67",
"pmc": null,
"pmid": "24811951",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The correlation between prolonged corrected QT interval with the frequency of respiratory arrest, endotracheal intubation, and mortality in acute methadone overdose.",
"title_normalized": "the correlation between prolonged corrected qt interval with the frequency of respiratory arrest endotracheal intubation and mortality in acute methadone overdose"
} | [
{
"companynumb": "IR-ROXANE LABORATORIES, INC.-2014-RO-01153RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
... |
{
"abstract": "Obesity increases the risk of opioid-related morbidity. Lidocaine patches have been shown to reduce postoperative pain after noncesarean surgeries.\n\n\n\nThis study aimed to determine whether the application of lidocaine patches around the cesarean incision in women with obesity reduces the total dose of opioids administered in the first 24 hours after cesarean delivery.\n\n\n\nThis was a pilot single-blind randomized controlled trial of 61 women with obesity undergoing cesarean delivery at a community tertiary referral hospital staffed by academic physicians. After cesarean delivery, the allocated patches (either 5% lidocaine patches or placebo patches) were applied superior and lateral to the incision dressing and remained in place for 12 hours. The average cumulative opioid dose received within the first 24 hours after cesarean delivery was measured in morphine milligram equivalents. We also assessed pain and patient satisfaction. A sample size of 60 (30 per group) was determined to be adequate to inform a future appropriately powered randomized controlled trial. The primary outcome of morphine milligram equivalents was compared using the Student t test, and pain scores were compared using the Wilcoxon rank sum test.\n\n\n\nOf the 146 women screened between February 2019 and September 2019, 61 consented and were analyzed: 30 women were allocated to lidocaine patch and 31 were allocated to placebo (hydrocolloid patch). Women who were allocated to the lidocaine patch used an average of 87.0 (standard deviation, 35.8) morphine milligram equivalents of opioids in the first 24 hours compared with an average of 83.9 (standard deviation, 27.5) morphine milligram equivalents among women who were allocated to the placebo patch (P=.702). Women who were allocated to the lidocaine vs placebo patches reported median pain scores of 3.0 (interquartile range, 2.1-4.9) and 3.5 (interquartile range, 2.5-5.0), respectively (P=.217). The time to the first dose of opioids, total number of opioid doses, and total morphine milligram equivalents in 48 hours and for the entire hospital stay did not differ. Patient satisfaction with both patches was high and not statistically different.\n\n\n\nThis pilot suggests that 5% lidocaine patches applied superior and lateral to the cesarean incision are not effective at reducing the average total dose of morphine milligram equivalents administered in the first 24 hours after cesarean delivery among women with obesity, and they did not seem to improve median pain scores. An appropriately powered randomized trial would not be expected to demonstrate reduction in opioid use or pain.",
"affiliations": "Division of Maternal-Fetal Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI. Electronic address: kantony@wisc.edu.;Division of Maternal-Fetal Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI.;Division of Academic Specialists in Obstetrics and Gynecology, University of Wisconsin School of Medicine and Public Health, Madison, WI.;Department of Obstetrics and Gynecology, and Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI.;Department of Obstetrics and Gynecology, and Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI.;Department of Pharmacy, UnityPoint Health - Meriter Hospital, Madison, WI.;Division of Hematology and Oncology, Department of Medicine, Wisconsin Institutes for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI; University of Wisconsin Carbone Cancer Center, Madison, WI.",
"authors": "Antony|Kathleen M|KM|;Adams|Jacquelyn H|JH|;Jacques|Laura|L|;Hetzel|Scott|S|;Chappell|Richard J|RJ|;Gnadt|Sarah E|SE|;Tevaarwerk|Amye J|AJ|",
"chemical_list": "D008012:Lidocaine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajogmf.2020.100281",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2589-9333",
"issue": "3(1)",
"journal": "American journal of obstetrics & gynecology MFM",
"keywords": "cesarean; local anesthetic patches; multimodal analgesia; obesity; obstetrics; opioid-sparing analgesia; pain; postcesarean pain; postoperative; pregnancy",
"medline_ta": "Am J Obstet Gynecol MFM",
"mesh_terms": "D005260:Female; D006801:Humans; D008012:Lidocaine; D009765:Obesity; D010147:Pain Measurement; D010149:Pain, Postoperative; D010865:Pilot Projects; D011247:Pregnancy; D016037:Single-Blind Method",
"nlm_unique_id": "101746609",
"other_id": null,
"pages": "100281",
"pmc": null,
"pmid": "33451596",
"pubdate": "2021-01",
"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": null,
"title": "Lidocaine patches for postcesarean pain control in obese women: a pilot randomized controlled trial.",
"title_normalized": "lidocaine patches for postcesarean pain control in obese women a pilot randomized controlled trial"
} | [
{
"companynumb": "US-DENTSPLY PHARMACEUTICAL-2021SCDP000038",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditiona... |
{
"abstract": "The aim of this study was to examine cancer and bleeding in atrial fibrillation patients administered with dabigatran.\n\n\n\nThis study enrolled 509 consecutive nonvalvular atrial fibrillation patients who received dabigatran. The mean administration period was 14.8 ± 15.7 months. We investigated the prevalence and new development of cancers. Further, the relation between cancer and adverse events was evaluated.\n\n\n\nIn the 509 patients, major bleeding occurred in 2.6% and dyspepsia in 8.4%. Further, 16.9% patients had a history of cancer and 3.9% developed new cancers. These adverse events developed in 45% patients who developed new cancers. The cancer (hazard ratio: 6.30; p = 0.003) was a significant predictor of major bleeding.\n\n\n\nBleeding was associated with the presence of cancer.",
"affiliations": "Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, Tokyo, Japan.;Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, Tokyo, Japan.;Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, Tokyo, Japan.;Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, Tokyo, Japan.;Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, Tokyo, Japan.;Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, Tokyo, Japan.;Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, Tokyo, Japan.;Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, Tokyo, Japan.;Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, Tokyo, Japan.",
"authors": "Koike|Hideki|H|;Fujino|Tadashi|T|;Koike|Makiko|M|;Yao|Shintaro|S|;Akitsu|Katsuya|K|;Shinohara|Masaya|M|;Yuzawa|Hitomi|H|;Suzuki|Takeya|T|;Ikeda|Takanori|T|",
"chemical_list": "D000991:Antithrombins; D000069604:Dabigatran",
"country": "England",
"delete": false,
"doi": "10.2217/fca-2017-0063",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1479-6678",
"issue": "14(1)",
"journal": "Future cardiology",
"keywords": "bleeding; dabigatran; direct oral anticoagulant; gastrointestinal cancers; atrial fibrillation",
"medline_ta": "Future Cardiol",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000991:Antithrombins; D001281:Atrial Fibrillation; D000069604:Dabigatran; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006471:Gastrointestinal Hemorrhage; D005770:Gastrointestinal Neoplasms; D006801:Humans; D015994:Incidence; D007564:Japan; D008297:Male; D008875:Middle Aged; D009382:Neoplasms, Unknown Primary; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors; D020521:Stroke; D015996:Survival Rate",
"nlm_unique_id": "101239345",
"other_id": null,
"pages": "27-36",
"pmc": null,
"pmid": "29199852",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Bleeding with oral anticoagulant dabigatran is highly associated with occult cancers in atrial fibrillation patients.",
"title_normalized": "bleeding with oral anticoagulant dabigatran is highly associated with occult cancers in atrial fibrillation patients"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-NB-001921",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "Continuation maintenance therapy with pemetrexed (PEM) and bevacizumab (BEV) following induction therapy with cisplatin (CDDP), PEM, and BEV is beneficial in advanced non-squamous non-small-cell lung cancer (NS-NSCLC), but the survival benefit of addition of BEV to CDDP/PEM as induction therapy is still unclear. The aim of this phase II study was to evaluate the feasibility and safety of a CDDP/PEM/BEV regimen in Japanese patients with EGFR wild-type NS-NSCLC.\nThis study included 25 patients who receive intravenous CDDP, PEM, and BEV (15 mg/kg) from August 2010 to February 2013. The primary endpoint of this study was the response rate (RR) and the secondary endpoint was progression free survival (PFS), overall survival (OS), and safety.\nThe median cycles of induction chemotherapy were four (range 1-6). RR was 64%. Most patients (64%) transitioned to maintenance therapy. The median PFS was 9.7 months. Median OS was 21.6 months. Haematological adverse events reaching grade 3 to 4 were neutropenia (8%) without febrile neutropenia, thrombocytopenia (4%), and anemia (4%). BEV-related non-haematological toxicities of grade 3/4 were hypertension (16%), thrombosis (4%), and gastrointestinal perforation (4%). Each adverse events was controllable, and there were no treatment-related deaths.\nCDDP/PEM/BEV regimen is effective and tolerable in patients with EGFR wild-type advanced NS-NSCLC, but should be paid attention to some BEV-related toxicities.",
"affiliations": "Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan.;Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan.;Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan.;Department of Internal Medicine, Kanagawa Prefectual Ashigarakami Hospital, Ashigarakami-gun, Japan.;Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan.",
"authors": "Murakami|Shuji|S|;Saito|Haruhiro|H|;Kondo|Tetsuro|T|;Oshita|Fumihiro|F|;Yamada|Kouzo|K|",
"chemical_list": "D000068437:Pemetrexed; D000068258:Bevacizumab; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1359-4117",
"issue": "13(2)",
"journal": "Journal of experimental therapeutics & oncology",
"keywords": "Cisplatin; bevacizumab; non-small-cell lung cancer; non-squamous; pemetrexed",
"medline_ta": "J Exp Ther Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002289:Carcinoma, Non-Small-Cell Lung; D002945:Cisplatin; D066246:ErbB Receptors; D006801:Humans; D008175:Lung Neoplasms; D009367:Neoplasm Staging; D000068437:Pemetrexed; D016896:Treatment Outcome",
"nlm_unique_id": "9604933",
"other_id": null,
"pages": "131-138",
"pmc": null,
"pmid": "31881129",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Phase II study of bevacizumab, cisplatin, and pemetrexed in advanced non-squamous non-small cell lung cancer (NS-NSCLC) with EGFR wild-type.",
"title_normalized": "phase ii study of bevacizumab cisplatin and pemetrexed in advanced non squamous non small cell lung cancer ns nsclc with egfr wild type"
} | [
{
"companynumb": "JP-ROCHE-1442160",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PEMETREXED"
},
"drugadditional": null,
"drug... |
{
"abstract": "BACKGROUND\nPremature infants are considered high-risk subgroup for neonatal sepsis due to yet defective immune system, interventions practised and synergy of factors favoring multiple resistance of Gram-positive and Gram-negative pathogens to antimicrobial agents.\n\n\nMETHODS\nWe present a case of late-onset neonatal sepsis in a premature infant caused by an uncommon pathogen; a premature infant of extremely low birth weight had in his 4th week of life severe clinical deterioration with lethargy, fever, pallor, mottling, abdominal distention, tachycardia, and worsening respiratory impairment. Full septic screen was performed, broad-spectrum antibiotic therapy was initiated and supportive care per needs was provided. Blood cultures (endotracheal tube tip cultures) isolated meropenem- and gentamicin-resistant strain of rare pathogen Ralstonia mannitolilytica. Ralstonia spp. are aerobic, Gram-negative, lactose non-fermenting, oxidaseand catalase-positive bacilli, thriving in water and soil. Ralstonia spp. are identified only sporadically as causative agents of neonatal sepsis; to our knowledge, this is the second report of neonatal sepsis due to R. mannitolilytica in the literature so far. Our patient was eventually treated (per sensitivity pattern) with intravenous ciprofloxacin and recovered well from the infection.\n\n\nCONCLUSIONS\nWe intend to raise awareness among neonatologists with regard to early detection of unusual pathogens, the emergence of antibiotic resistance patterns, and the obligation for adherence to infection control policies.",
"affiliations": "Department of Pediatrics and Neonatology, University General Hospital of Patras, Patras, Greece.;Department of Pediatrics and Neonatology, University General Hospital of Patras, Patras, Greece.;Department of Pediatrics and Neonatology, University General Hospital of Patras, Patras, Greece.;Department of Microbiology, University General Hospital of Patras, Patras, Greece.;Department of Pediatrics and Neonatology, University General Hospital of Patras, Patras, Greece.;Department of Microbiology, University General Hospital of Patras, Patras, Greece.;Department of Pediatrics and Neonatology, University General Hospital of Patras, Patras, Greece.",
"authors": "Lampropoulos|Panagiotis|P|;Gkentzi|Despoina|D|;Tzifas|Sotirios|S|;Kapnisi|Georgia|G|;Karatza|Ageliki|A|;Kolonitsiou|Fevronia|F|;Dimitriou|Gabriel|G|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1871526520666200330163504",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1871-5265",
"issue": "21(2)",
"journal": "Infectious disorders drug targets",
"keywords": "Ralstonia spp.; Sepsis; bacteraemia; gram-negative; neonate; resistance.",
"medline_ta": "Infect Disord Drug Targets",
"mesh_terms": "D000900:Anti-Bacterial Agents; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D000071074:Neonatal Sepsis; D043367:Ralstonia; D018805:Sepsis",
"nlm_unique_id": "101269158",
"other_id": null,
"pages": "168-172",
"pmc": null,
"pmid": "32223739",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Ralstonia Mannitolilytica, an Unusual Pathogen in the Neonatal Intensive Care Unit: A Case of Neonatal Sepsis and Literature Review.",
"title_normalized": "ralstonia mannitolilytica an unusual pathogen in the neonatal intensive care unit a case of neonatal sepsis and literature review"
} | [
{
"companynumb": "GR-PFIZER INC-2021248211",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional": "3",
... |
{
"abstract": "Vancomycin is a glycopeptide antibiotic commonly used in the management of methicillin-resistant Staphylococcus aureus infection. The recent increase in prevalence of methicillin-resistant Staphylococcus aureus with reduced susceptibility to vancomycin has prompted experts to advocate for higher target trough serum concentrations. This study aimed to evaluate the potential consequences of more aggressive vancomycin therapy, by examining the association between higher serum concentrations and acute kidney injury (AKI) in a population of critically ill patients. We collected data for all patients who received vancomycin over a five-year period and evaluated the prevalence of new-onset AKI using the Risk, Injury, Failure, Loss and End-stage (RIFLE) kidney disease criteria. One-hundred and fifty-nine patients provided complete data, with 8.8% manifesting new onset AKI while receiving vancomycin. The median age was 57 (44 to 68) years, while the median trough serum concentration was 16 (10 to 19) mg/l. Multivariate logistic regression analysis identified mean trough concentration (OR=1.174, P=0.024), APACHE II score (OR=1.141, P=0.012) and simultaneous aminoglycoside prescription (OR=18.896, P=0.002) as significant predictors of AKI. These data suggest higher trough vancomycin serum concentrations are associated with greater odds of AKI in the critically ill.",
"affiliations": "Co-First Author, Resident Medical Officer, Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital and Burns Trauma and Critical Care Research Centre, School of Medicine, The University of Queensland, Brisbane, Queensland.;Co-First Author, Registrar, Department of Intensive Care Medicine, The Royal Brisbane and Women's Hospital, Brisbane, Queensland.;Resident Medical Officer, Department of Intensive Care Medicine, The Royal Brisbane and Women's Hospital and Burns Trauma and Critical Care Research Centre, School of Medicine, The University of Queensland, Brisbane, Queensland.;Medical Student, Department of Intensive Care Medicine, The Royal Brisbane and Women's Hospital, Brisbane, Queensland.;Director and Consultant Intensivist, Department of Intensive Care Medicine, The Royal Brisbane and Women's Hospital and Burns Trauma and Critical Care Research Centre, School of Medicine, The University of Queensland, Brisbane, Queensland.;Consultant Pharmacist, Department of Intensive Care Medicine, The Royal Brisbane and Women's Hospital and Burns Trauma and Critical Care Research Centre, School of Medicine, The University of Queensland, Brisbane, Queensland.;Consultant Intensivist, Department of Intensive Care and Hyperbaric Medicine, The Alfred Hospital, Melbourne, Victoria.",
"authors": "Hanrahan|T P|TP|;Kotapati|C|C|;Roberts|M J|MJ|;Rowland|J|J|;Lipman|J|J|;Roberts|J A|JA|;Udy|A|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin",
"country": "United States",
"delete": false,
"doi": "10.1177/0310057X1504300507",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0310-057X",
"issue": "43(5)",
"journal": "Anaesthesia and intensive care",
"keywords": "acute kidney injury; glycopeptide; infection; intensive care unit; sepsis; vancomycin",
"medline_ta": "Anaesth Intensive Care",
"mesh_terms": "D018806:APACHE; D058186:Acute Kidney Injury; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D016638:Critical Illness; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D014640:Vancomycin",
"nlm_unique_id": "0342017",
"other_id": null,
"pages": "594-9",
"pmc": null,
"pmid": "26310409",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Factors associated with vancomycin nephrotoxicity in the critically ill.",
"title_normalized": "factors associated with vancomycin nephrotoxicity in the critically ill"
} | [
{
"companynumb": "AU-PFIZER INC-2020422941",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VANCOMYCIN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "OBJECTIVE\nThe objective was to determine the safety of ocrelizumab (OCR) in patients with rheumatoid arthritis (RA).\n\n\nMETHODS\nThis was an analysis of the double-blind, placebo-controlled periods and long-term follow-up of 4 OCR phase III trials in RA (SCRIPT, STAGE, FILM and FEATURE). Safety data per study and the results of a meta-analysis of serious infectious events (SIEs) are presented.\n\n\nRESULTS\nOverall, 868 patients received placebo, 1064 patients OCR 200 mg×2 (or 400 mg×1) (OCR200), and 827 patients OCR 500 mg×2 (OCR500) plus background methotrexate (MTX) at baseline and 24 weeks. During the double-blind, placebo-controlled periods, the incidence of adverse events and serious adverse events was comparable between the OCR+MTX and placebo +MTX groups. Infusion-related reactions were more common with OCR+MTX and decreased in frequency with subsequent infusions. Serious infusion-related reactions were rare (0.1%). Serious infections occurred more frequently with OCR500+MTX. In the meta-analysis, a statistically significant difference from placebo +MTX in incidence of SIEs per 100 patient-years of 2.4 (95% CI, 0.3-4.5) was observed with OCR500+MTX, but not with OCR200+MTX (0.6; 95% CI, -1.3 to 2.4). Patients recruited in Asia exhibited a higher risk of serious infections (hazard ratio, 1.78; 95% CI, 1.03-3.06). The incidence of human anti-human antibodies was <5%. Long-term follow-up indicated no differences in malignancy rates between the treatment groups. There was no apparent difference in time to B-cell repletion between the OCR dose groups.\n\n\nCONCLUSIONS\nIn placebo-controlled clinical trials of RA, OCR500+MTX was associated with a higher risk of serious infections compared with placebo +MTX. The safety profile of OCR 200+MTX was comparable with placebo+MTX.\n\n\nBACKGROUND\nSTAGE ClinicalTrials.gov NCT00406419 SCRIPT ClinicalTrials.gov NCT00476996 FILM ClinicalTrials.gov NCT00485589 FEATURE ClinicalTrials.gov NCT00673920.",
"affiliations": "Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom ; NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.;The Geisel School of Medicine at Darthmouth, Lebanon, New Hampshire, United States of America.;Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.;Charité University Hospitals and DRFZ, Berlin, Germany.;University of Nevada School of Medicine, Las Vegas, Nevada, United States of America.;Roche Products, Ltd, Welwyn Garden City, United Kingdom.;Roche Products, Ltd, Welwyn Garden City, United Kingdom.;Roche Products, Ltd, Welwyn Garden City, United Kingdom.;Roche Products, Ltd, Welwyn Garden City, United Kingdom.",
"authors": "Emery|Paul|P|;Rigby|William|W|;Tak|Paul P|PP|;Dörner|Thomas|T|;Olech|Ewa|E|;Martin|Carmen|C|;Millar|Laurie|L|;Travers|Helen|H|;Fisheleva|Elena|E|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; C533411:ocrelizumab; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0087379",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, USA 24498318PONE-D-13-3177410.1371/journal.pone.0087379Research ArticleBiologyImmunologyImmunityImmunotherapyMedicineClinical ImmunologyAutoimmune DiseasesRheumatoid ArthritisImmune CellsB CellsImmunityImmunotherapyClinical research designClinical trialsPhase IIIMeta-AnalysesDrugs and DevicesDrug InformationRheumatologyRheumatoid ArthritisSafety with Ocrelizumab in Rheumatoid Arthritis: Results from the Ocrelizumab Phase III Program Ocrelizumab Safety in Rheumatoid ArthritisEmery Paul \n1\n\n2\n\n*\nRigby William \n3\nTak Paul P. \n4\n\n¤\nDörner Thomas \n5\nOlech Ewa \n6\nMartin Carmen \n7\nMillar Laurie \n7\nTravers Helen \n7\nFisheleva Elena \n7\n\n1 \nLeeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom\n\n2 \nNIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom\n\n3 \nThe Geisel School of Medicine at Darthmouth, Lebanon, New Hampshire, United States of America\n\n4 \nAcademic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands\n\n5 \nCharité University Hospitals and DRFZ, Berlin, Germany\n\n6 \nUniversity of Nevada School of Medicine, Las Vegas, Nevada, United States of America\n\n7 \nRoche Products, Ltd, Welwyn Garden City, United Kingdom\nSchooling C. Mary Editor\nCUNY, United States of America\n* E-mail: p.emery@leeds.ac.ukCompeting Interests: This study was funded by F. Hoffmann-La Roche, the employer of Carmen Martin, Laurie Millar, Helen Travers, and Elena Fisheleva. Helen Travers holds stock in Roche. PE has provided expert advice and undertaken clinical trials for Pfizer, Merck Sharpe Dome, Abbvie, UCB, Roche, BMS and Novartis. WR has served as a consultant for Roche. PPT has served as a consultant for Roche/Genentech and became an employee of GlaxoSmithKline after completion of this work. TD has served as a consultant for Roche and has received speakers' bureau honoraria from Roche. EO has received research funding from Abbvie, Genentech, Pfizer, UCB and Vertex, consultancy fees from Abbvie, Crescendo, Genentech, Janssen, Pfizer and UCB, and speakers' bureau honoraria from Abbvie, Crescendo and UCB. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.\n\nConceived and designed the experiments: PE WR PPT CM LM HT EF. Performed the experiments: PE WR CM LM EF. Analyzed the data: PE WR CM LM HT EF. Contributed reagents/materials/analysis tools: PE WR PPT TD EO. Wrote the paper: PE WR PPT TD EO CM LM HT EF.\n\n¤ Current address: GlaxoSmithKline, Stevenage, United Kingdom\n\n2014 3 2 2014 9 2 e8737931 7 2013 17 12 2013 © 2014 Emery et al2014Emery et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Objective\nThe objective was to determine the safety of ocrelizumab (OCR) in patients with rheumatoid arthritis (RA).\n\nMethods\nThis was an analysis of the double-blind, placebo-controlled periods and long-term follow-up of 4 OCR phase III trials in RA (SCRIPT, STAGE, FILM and FEATURE). Safety data per study and the results of a meta-analysis of serious infectious events (SIEs) are presented.\n\nResults\nOverall, 868 patients received placebo, 1064 patients OCR 200 mg×2 (or 400 mg×1) (OCR200), and 827 patients OCR 500 mg×2 (OCR500) plus background methotrexate (MTX) at baseline and 24 weeks. During the double-blind, placebo-controlled periods, the incidence of adverse events and serious adverse events was comparable between the OCR+MTX and placebo +MTX groups. Infusion-related reactions were more common with OCR+MTX and decreased in frequency with subsequent infusions. Serious infusion-related reactions were rare (0.1%). Serious infections occurred more frequently with OCR500+MTX. In the meta-analysis, a statistically significant difference from placebo +MTX in incidence of SIEs per 100 patient-years of 2.4 (95% CI, 0.3–4.5) was observed with OCR500+MTX, but not with OCR200+MTX (0.6; 95% CI, −1.3 to 2.4). Patients recruited in Asia exhibited a higher risk of serious infections (hazard ratio, 1.78; 95% CI, 1.03–3.06). The incidence of human anti-human antibodies was <5%. Long-term follow-up indicated no differences in malignancy rates between the treatment groups. There was no apparent difference in time to B-cell repletion between the OCR dose groups.\n\nConclusions\nIn placebo-controlled clinical trials of RA, OCR500+MTX was associated with a higher risk of serious infections compared with placebo +MTX. The safety profile of OCR 200+MTX was comparable with placebo+MTX.\n\nTrial Registration\nSTAGE Clinical Trials.gov NCT00406419\n\n\nSCRIPT Clinical Trials.gov NCT00476996\n\n\nFILM Clinical Trials.gov NCT00485589\n\n\nFEATURE Clinical Trials.gov NCT00673920\n\n\nThis study was funded by F. Hoffmann-La Roche, the employer of Carmen Martin, Laurie Millar, Helen Travers, and Elena Fisheleva. EO has received research funding from Abbvie, Genentech, Pfizer, UCB and Vertex. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n==== Body\nIntroduction\nAlthough the immunopathogenesis of rheumatoid arthritis (RA) is not fully understood, accumulating evidence suggests that B cells have multiple potential roles through both antibody-dependent and antibody-independent pathways [1], [2]. Rituximab is a chimeric mouse-human monoclonal antibody that depletes CD20+ B cells and has been shown to be an effective therapy in patients with RA [3]–[7]. Pooled analysis of long-term safety data from patients receiving rituximab within a global clinical trial program indicated that rituximab is well tolerated over time and during multiple courses of treatment [8], [9]. However, as with all chimeric antibodies, immunogenicity may be a potential concern. A safety analysis showed that 11% of patients with RA developed a titer positive for human anti-chimeric antibody (HACA) on at least one occasion during treatment with rituximab [8]. The presence of HACAs was not associated with the development of infusion-related reactions (IRRs) or loss of efficacy on retreatment. Thus, the clinical impact of HACA directed at rituximab remains unclear.\n\nOcrelizumab (rhuMAb 2H7, [OCR]) is a humanized anti-CD20 monoclonal antibody. In vitro characterization of OCR demonstrated enhanced antibody-dependent cell-mediated cytotoxicity and reduced complement-dependent cytotoxicity compared with rituximab (unpublished data), although the clinical implications of these differences remain unclear. The efficacy and safety of OCR in RA has been evaluated in a robust phase III clinical trial program in a broad spectrum of patients [10]–[13]. In May 2010, OCR development in RA was terminated as a result of the overall risk-benefit assessment from the 2 pivotal phase III studies STAGE and SCRIPT. The efficacy and safety profiles of the OCR 200 mg (OCR200) and OCR 500 mg (OCR500) dosing regimens led the sponsors to conclude that OCR did not demonstrate an additional benefit over existing therapies, including rituximab for patients with RA, and that an application for regulatory approval of OCR in RA was not warranted. This paper presents the key safety outcomes of the 4 phase III OCR trials in RA to provide an overview of the safety of OCR in patients with RA and background methotrexate (MTX) treatment.\n\nPatients and Methods\nThe CONSORT checklist is available as supporting information; see Checklist S1.\n\nEthics Statement\nThese studies were conducted at 686 sites across more than 20 different countries in accordance with the ethical principles of the Declaration of Helsinki. Ethical approval from the local institutional review board at each study center was obtained before the start of each study and all patients provided written informed consent. All studies included were previously registered with ClinicalTrials.gov (registration nos. NCT00406419, NCT00476996, NCT00485589 and NCT00673920).\n\nPatients\nPatients included in the analyses were participants in 1 of 4 OCR phase III trials [10]–[13]. The analysis population represented a broad spectrum of patients, ranging from patients with early RA who were MTX-naive (FILM [12], registration no. NCT00485589) to patients with advanced RA disease who were refractory to disease-modifying antirheumatic drugs (DMARDs) (FEATURE [13], registration no. NCT00673920 and STAGE [10], registration no. NCT00406419) and/or anti-TNFs (SCRIPT [11], registration no. NCT00476996). The overwhelming majority of patients received background MTX; leflunomide could also be used instead of MTX in SCRIPT.\n\nStudy Designs\nAll 4 trials were phase III international, randomized, and double-blind, placebo-controlled (DBPC); STAGE was conducted at 209 centers in 24 countries, SCRIPT was conducted at 227 centers in 25 countries, FEATURE was conducted at 96 centers in 14 countries and FILM was conducted at 154 centers in 21 countries. The study designs and numbers of patients randomized were reported previously [10]–[13] and are summarized in Table 1. During the DBPC period of STAGE, SCRIPT and FILM, patients received treatment on Days 1 and 15 followed by a retreatment course at Weeks 24 and 26 (patients in FILM were eligible for 2 additional retreatment courses at Weeks 52 and 54, and Weeks 76 and 78). At the end of the DBPC period in FEATURE (Week 24), all patients were re-randomized to receive either OCR200 ×2+MTX or OCR 400 mg (OCR400) +MTX for a 24-week double-blind (but not placebo-controlled) treatment period. After completion of the double-blind period (48 weeks [SCRIPT, STAGE and FEATURE] and 104 weeks [FILM]), patients entered an open-label extension, where they were treated with OCR500 ×2+MTX (SCRIPT, STAGE and FILM) or OCR400+MTX (FEATURE) at the discretion of the investigator. At the time that FILM was terminated, all patients had completed 52 weeks of DBPC treatment and only a few had completed 104 weeks and entered the open-label extension. Therefore, analysis of the DBPC period for FILM included only the Week 52 data. At the time that FEATURE, SCRIPT and STAGE were terminated, all patients had completed the double-blind 48-week period. Upon withdrawal from treatment, all patients were required to continue in safety follow-up (SFU) for at least 48 weeks from the first infusion of their last course and until their CD19+ B-cell counts either returned to baseline level or the lower limit of normal (80 cells/µl), whichever was lower.\n\n10.1371/journal.pone.0087379.t001Table 1 Summary of 4 Phase III Studies of Ocrelizumab.\nTrial Name\tPatients Treated, n\tRA Characteristics\tTreatment Groups+MTXa\n\tDuration of PBO-Controlled Period, weeks\t\n\nSTAGE\n\t1006\tMTX-IR; 51% to 54% steroid use; Baseline DAS28 ≈6.4\tPBO (n = 320); OCR200 (n = 343); OCR500 (n = 343)\t48\t\n\nSCRIPT\n\t836\tTNF-IR; 56% to 62% steroid use; Baseline DAS28 ≈6.5\tPBO (n = 277); OCR200 (n = 277); OCR500 (n = 282)\t48\t\n\nFEATURE\n\t312\tMTX-IR/biological DMARD-IR; 52% to 59% steroid use; Baseline DAS28 ≈6.5\tPBO (n = 64); OCR200 (n = 131); OCR400 (n = 117)\t24\t\n\nFILM\n\t605\tMTX-naïve; 39% to 42% steroid use; Baseline DAS28 ≈7.0\tPBO (n = 207); OCR200 (n = 196); OCR500 (n = 202)\t104b\n\t\n Abbreviations: DAS28, disease activity score in 28 joints; DMARD, disease-modifying antirheumatic drug; IR, inadequate responder; MTX, methotrexate; OCR200, ocrelizumab 200 mg×2; OCR500, ocrelizumab 500 mg×2; PBO, placebo; RA, rheumatoid arthritis; TNF, tumor necrosis factor.\n\na All patients in all studies received background MTX 7.5 to 25 mg/week (7.5–20 mg/week in FILM), except for in SCRIPT, in which MTX or leflunomide was permitted. Treatment with corticosteroids (≤10 mg/day prednisolone or equivalent) was permitted in all studies provided the dose was stable 4 weeks prior to baseline.\n\nb Study terminated early. Safety evaluation conducted for 52-week data.\n\nSafety Assessments\nIn each trial, clinical adverse events (AEs) and serious AEs (SAEs) were recorded, and the intensity of AEs was graded using the National Cancer Institute Common Toxicity Criteria (version 3) and coded according to MedDRA (version 12.1). Malignancies were identified using the wide standard MedDRA query Malignant or Unspecified Tumors. Serious infectious events (SIEs) also included those requiring intravenous antibiotics. IRRs and symptoms were recorded on a specifically designed page of the case report form.\n\nImmunogenicity and Pharmacodynamics\nThe primary pharmacodynamic (PD) marker for OCR is the presence of CD20+ B cells in the blood. Because the presence of OCR in serum could confound assays of CD20+ cells, CD19 was used to measure the levels of peripheral B cells following treatment (limit of detection, 0.05×109 cells/l in conventional flow cytometry). In each trial, serum samples were collected at prespecified time points for the determination of human anti-human antibodies (HAHAs) and B-cell levels (CD19+ cells). A bridging format enzyme-linked immunosorbent assay was used to determine HAHA titers. All positive samples were further confirmed by competitive binding to anti-IgM, followed by implementation of an additional decision tree to confirm or reject true positivity.\n\nStatistical Analysis\nSafety and PD analyses were conducted on the safety population, which included all patients in each trial who were randomized, received any part of an infusion of study drug, and underwent at least one assessment of safety. Evaluation of the safety data for each study led to the conduct of a fixed-effects meta-analysis of SIEs. The incidence rate difference in SIEs from placebo (PBO)+MTX during the DBPC period, weighted by study size was calculated for both dose groups using data from all four studies (STAGE, SCRIPT, FEATURE and FILM). An exploratory, hypothesis-generating analysis of risk factors for SIEs was performed on STAGE, SCRIPT and FILM DBPC pooled data sets. The multivariate approach (COX regression models) investigated treatment group as a risk factor, with baseline covariates that included but were not limited to age, body mass index, body surface area, weight, race, region, previous use of biological and nonbiological DMARDs, MTX dose, corticosteroid use, RA disease duration, presence of selected comorbid conditions and study.\n\nAll available malignancy data from baseline to long-term SFU (up to 5 years of follow-up) in the 4 trials were pooled. Immunogenicity results included all data available for the DBPC periods.\n\nPD data were analyzed using Kaplan-Meier methodology and included all data available after each patient completed at least 72 weeks of SFU after the last dose in each study.\n\nIn all analyses in which the FEATURE study was included, patients who received OCR200 or OCR400+MTX were grouped together in the OCR200+MTX group.\n\nResults\nPatient Population\nThe safety analysis population comprised 2759 patients (868 patients treated with PBO+MTX, 1064 with OCR200+MTX and 827 with OCR500+MTX; Figure 1). The majority of patients were female and white and had a mean age ranging from approximately 49 to 55 years (Table 2). Disease duration varied because of the different patient populations. Patients in SCRIPT had long-standing RA, with a duration of approximately 11 to 12 years; patients in FILM had a considerably shorter disease duration of approximately 1.2 years. Corticosteroid (<10 mg/d) use varied from 39% to 42% in FILM to 56% to 62% in SCRIPT. In SCRIPT, leflunomide was received by 10.1%, 15.2% and 14.5% of the PBO+MTX, OCR200+MTX and OCR500+MTX groups, respectively, with mean doses of 19.6, 18.3 and 17.4 mg/d, respectively. All other patients in SCRIPT and all patients in the other trials received concomitant MTX.\n\n10.1371/journal.pone.0087379.g001Figure 1 Patient disposition flow diagram of pooled safety population.\n10.1371/journal.pone.0087379.t002Table 2 Baseline Patient Characteristics in Pooled Safety Populationsa.\nCharacteristic\tPBO+MTXb\n\tOCR200+MTXb\n\tOCR500+MTXb\n\t\n\t(n = 868)\t(n = 1064)\t(n = 827)\t\nFemale, %\t74.0 to 87.5\t77.3 to 82.5\t80.0 to 83.7\t\nWhite, %\t68.8 to 74.4\t65.9 to 73.0\t67.0 to 75.6\t\nMean age, years\t49.2 to 54.2\t50.8 to 54.5\t48.6 to 53.8\t\nMean RA disease duration, years\t1.2 to 11.8\t1.2 to 12.7\t1.2 to 12.3\t\nSerological status, %\t\t\t\t\n— RF+/ACPA+\t83.0 to 87.9\t80.2 to 87.8\t77.1 to 86.1\t\n— RF+/ACPA−\t4.8 to 8.5\t6.6 to 9.7\t4.5 to 8.5\t\n— RF–/ACPA+\t6.3 to 9.4\t5.1 to 11.2\tto 15.3\t\n— RF–/ACPA−\t0 to 1.6\t0 to 1.2\t0.7 to 1.5\t\nSJC (66 joints), mean\t16.6 to 21.1\t16.5 to 19.4\t17.1 to 19.5\t\nTJC (68 joints), mean\t26.0 to 31.6\t26.2 to 30.8\t26.4 to 30.0\t\nCRP (mg/dl), mean\t2.4 to 3.8\t1.8 to 3.5\t1.9 to 3.4\t\nESR (mm/h), mean\t46.7 to 60.0\t44.5 to 55.8\t45.5 to 58.1\t\nHAQ-DI, mean\t1.5 to 1.8\t1.5 to 1.8\t1.5 to 1.7\t\nDAS28-ESR, mean\t6.4 to 7.0\t6.4 to 7.0\t6.4 to 6.9\t\nOral corticosteroid use, %\t40 to 62\t39 to 58\t42 to 56\t\n Abbreviations: ACPA, anti-citrullinated peptide antibody; CRP, C-reactive protein; DAS28, disease activity score in 28 joints; ESR, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire Disease Index; MTX, methotrexate; OCR200, ocrelizumab 200 mg×2; OCR500, ocrelizumab 500 mg×2; PBO, placebo; RA, rheumatoid arthritis; RF, rheumatoid factor; SJC, swollen joint count; TJC, tender joint count.\n\na Data shown as ranges (minimum and maximum values) across the 4 trials.\n\nb All patients in all studies received background MTX 7.5 to 25 mg/week (7.5 to 20 mg/week in FILM), except for in SCRIPT, in which MTX or leflunomide was permitted.\n\nOverall Safety Profile\nIn all 4 trials, the incidence of all AEs during the DBPC periods was comparable in the PBO+MTX–treated and OCR+MTX–treated patients (Table 3). Grade 3 AEs were relatively infrequent, occurring in approximately 5% to 10% of patients across the treatment groups, with no clear differences between the PBO+MTX and OCR+MTX groups. The incidence of grade 4 AEs was 0% to 2.5%. AEs leading to patient withdrawal were infrequent; the most common in all 4 trials were IRRs and infections. Patients who received OCR500+MTX in FILM had a higher incidence of AEs leading to withdrawal than did patients who received PBO+MTX (5.9% vs 1.0%). Although the incidence of SAEs varied across the trials, there were no clear differences in general between the PBO+MTX and OCR+MTX groups or between the different dose groups (Table 3); the percentages of patients reporting ≥1 SAE were approximately 8% to 14% (OCR200+MTX) and 11% to 14% (OCR500+MTX), compared with 8% to 12% (PBO+MTX). The most common SAEs overall were infections and infestations. In STAGE and FEATURE, the occurrence of SAEs in other system organ classes was infrequent and comparable across treatment groups. In SCRIPT, serious musculoskeletal and connective tissue disorders were reported more frequently by patients in the PBO+MTX group (4.3%) compared with the OCR200+MTX (2.5%) and OCR500+MTX (2.5%) groups; this difference was mainly driven by an increased reporting of “exacerbation of RA.” The occurrence of SAEs in other system organ classes in SCRIPT was infrequent and comparable across treatment groups. In FILM, SAEs classified as respiratory, thoracic, and mediastinal disorders occurred more frequently with OCR500+MTX (2.5%) than with OCR200+MTX (0.5%) and PBO+MTX (0%); the most common SAE in this body system was interstitial lung disease, which was reported in 3 patients in the OCR500+MTX group. The occurrence of other body-system SAEs was infrequent and comparable across treatment groups.\n\n10.1371/journal.pone.0087379.t003Table 3 Summary of Safety During the Double-Blind, Placebo-Controlled Periodsa.\nSafety Profile\tPBO+MTXb\n\tOCR200+MTXb\n\tOCR500+MTXb\n\t\n\nSTAGE (MTX-IR)\n\t\t\t\t\nPatients, n\t320\t343\t343\t\nAny AE, n (%)\t254 (79.4)\t282 (82.2)\t287 (83.7)\t\n— Grade 3, n (%)\t25 (7.8)\t20 (5.8)\t25 (7.3)\t\n— Grade 4, n (%)\t2 (<1)\t2 (<1)\t2 (<1)\t\n— Serious, n (%)\t37 (11.6)\t26 (7.6)\t38 (11.1)\t\nAEs leading to withdrawal, n (%)\t5 (1.6)\t5 (1.5)\t6 (1.7)\t\nDeaths, n (%)\t1 (<1)\t0 (0.0)\t3 (<1)\t\nIRRs, n (%)\t31 (9.7)\t69 (20.1)\t80 (23.3)\t\n— Serious, n (%)\t0 (0.0)\t1 (<1)\t1 (<1)\t\nInfections, n (%)\t173 (54.1)\t188 (54.8)\t194 (56.6)\t\n— Serious, n (%)\t10 (3.1)\t11 (3.2)\t21 (6.1)\t\nMalignancies, n (%)\t6 (1.9)\t3 (<1)\t4 (1.2)\t\n\nSCRIPT (TNF-IR)\n\t\t\t\t\nPatients, n\t277\t277\t282\t\nAny AE, n (%)\t227 (81.9)\t232 (83.8)\t238 (84.4)\t\n— Grade 3, n (%)\t28 (10.1)\t25 (9.0)\t28 (9.9)\t\n— Grade 4, n (%)\t1 (<1)\t2 (<1)\t3 (1.1)\t\n— Serious, n (%)\t32 (11.6)\t40 (14.4)\t32 (11.3)\t\nAEs leading to withdrawal, n (%)\t10 (3.6)\t11 (4.0)\t7 (2.5)\t\nDeaths, n (%)\t1 (<1)\t0 (0.0)\t0 (0.0)\t\nIRRs, n (%)\t30 (10.8)\t53 (19.1)\t67 (23.8)\t\n— Serious, n (%)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\nInfections, n (%)\t143 (51.6)\t150 (54.2)\t164 (58.2)\t\n— Serious, n (%)\t7 (2.5)\t14 (5.1)\t12 (4.3)\t\nMalignancies, n (%)\t5 (1.8)\t7 (2.5)\t2 (<1)\t\n\nFEATURE (MTX-IR/biological DMARD-IR)\n\t\t\t\t\nPatients, n\t64\t248\tN/A\t\nAny AE, n (%)\t40 (62.5)\t162 (65.3)\t—\t\n— Grade 3, n (%)\t4 (6.3)\t8 (3.2)\t—\t\n— Grade 4, n (%)\t0 (0.0)\t0 (0.0)\t—\t\n— Serious, n (%)\t5 (7.8)\t5 (2.0)\t—\t\nAEs leading to withdrawal, n (%)\t2 (3.1)\t3 (1.2)\t—\t\nDeaths, n (%)\t0 (0.0)\t0 (0.0)\t—\t\nIRRs, n (%)\t7 (10.9)\t53 (21.4)\t—\t\n— Serious, n (%)\t0 (0.0)\t0 (0.0)\t—\t\nInfections, n (%)\t24 (37.5)\t90 (36.3)\t—\t\n— Serious, n (%)\t2 (3.1)\t5 (2.0)\t—\t\nMalignancies, n (%)\t0 (0.0)\t1 (<1)\t—\t\n\nFILM (MTX-naïve)\n\t\t\t\t\nPatients, n\t207\t196\t202\t\nAny AE, n (%)\t167 (80.7)\t171 (87.2)\t167 (82.7)\t\n— Grade 3, n (%)\t16 (7.7)\t18 (9.2)\t24 (11.9)\t\n— Grade 4, n (%)\t0 (0.0)\t1 (<1)\t5 (2.5)\t\n— Serious, n (%)\t21 (10.1)\t18 (9.2)\t28 (13.9)\t\nAEs leading to withdrawal, n (%)\t2 (1.0)\t3 (1.5)\t12 (5.9)\t\nDeaths, n (%)\t2 (1.0)\t2 (1.0)\t1 (<1)\t\nIRRs, n (%)\t18 (8.7)\t52 (26.5)\t54 (26.7)\t\n— Serious, n (%)\t0 (0.0)\t0 (0.0)\t1 (<1)\t\nInfections, n (%)\t106 (51.2)\t101 (51.5)\t105 (52.0)\t\n— Serious, n (%)\t6 (2.9)\t5 (2.6)\t10 (5.0)\t\nMalignancies, n (%)\t2 (1.0)\t0 (0.0)\t1 (<1)\t\n Abbreviations: AE, adverse event; DMARD, disease-modifying antirheumatic drug; IR, inadequate responder; IRR, infusion-related reaction; MTX, methotrexate; OCR200, ocrelizumab 200 mg×2; OCR500, ocrelizumab 500 mg×2; PBO, placebo; TNF, tumor necrosis factor.\n\na Multiple events in individual patients were only counted once. Serious infections were defined as those requiring intravenous antibiotics and/or hospitalization or classified as serious by the investigator. Any opportunistic infection was classified as a serious infection.\n\nb All patients in all studies received background MTX 7.5 to 25 mg/week (7.5 to 20 mg/week in FILM), except for in SCRIPT, in which MTX or leflunomide was permitted.\n\nInfusion-Related Reactions\nThe most common AEs overall were IRRs. The incidence of IRRs was approximately 2 to 3 times higher in the OCR+MTX group relative to the PBO+MTX group (Table 3). The highest incidence of IRRs occurred during and following the first infusion of the first course; the second infusion was tolerated better, and IRRs became less frequent with subsequent infusions. The most common symptoms were pruritus, pyrexia, flushing, laryngeal/throat irritation, headache, nausea, rash, chills/rigors, hypertension, urticaria and dizziness. IRRs were reported slightly more frequently with OCR500+MTX than with OCR200+MTX in both STAGE and SCRIPT but at a similar frequency with both OCR+MTX doses in FILM. Only 2 patients in STAGE and 1 patient in FILM reported a serious IRR. The 2 serious IRRs that occurred in STAGE were recorded for 1 patient in each of the 2 OCR+MTX groups. Both occurred during the first infusion of the first course and resolved following symptomatic treatment. In addition, 1 patient (OCR500+MTX) had an anaphylactoid reaction that began 45 min after the start of the first infusion of the first course. The reaction resolved without sequelae following symptomatic treatment. One patient in the OCR500+MTX group of FILM reported a serious IRR, which occurred approximately 12 hours after the second infusion of the second course. This patient experienced weakness, headache, elevated blood pressure and increased heart rate. Following hospitalization, the patient received antihypertensive medication and the elevated blood pressure resolved within 24 hours; the results of an electrocardiogram were normal.\n\nHuman Anti-Human Antibodies\nAt baseline, pre-infusion, 0.6% of all patients were HAHA-positive—a result that was expected given the specificity and sensitivity of the assay used. In all 4 trials, the proportion of patients who developed HAHAs during the DBPC periods was low and comparable between the OCR+MTX and PBO+MTX groups. In FILM, the incidence of HAHAs over 52 weeks was 4/202 (2.0%), 2/194 (1.0%), and 8/201 (4.0%) in the PBO+MTX, OCR200+MTX and OCR500+MTX groups, respectively. The corresponding HAHA incidences in SCRIPT over 48 weeks were 5/274 (1.8%), 8/273 (2.9%) and 7/277 (2.5%), respectively, and in STAGE were 9/318 (2.8%), 16/338 (4.7%) and 7/339 (2.1%), respectively. In FEATURE, the HAHA incidence ranged from 0% in patients who received PBO followed by OCR 200 mg×2 to 10.7% (3/28) in patients who received PBO followed by OCR 400 mg×1. Among all patients who were HAHA-positive post-baseline, there was no apparent association between HAHA positivity and corresponding CD19 counts or DAS28 scores in any of the treatment groups across the 4 trials. Of the 3 patients who experienced a serious IRR, none was HAHA-positive at any time point tested; of the patients who were HAHA-positive, 4 experienced IRRs—all grade 1 or 2.\n\nSerious Infections\nIn the DBPC periods of FILM, SCRIPT and STAGE, the rates of SIEs (events per 100 patient-years) were higher in the OCR500+MTX group than in the PBO+MTX group (Figure 2). SIE rates were comparable between the OCR200+MTX and PBO+MTX groups in these trials, with the exception of SCRIPT. In SCRIPT, there was also a numerically higher rate of SIEs with OCR200+MTX. The most common types of SIEs in all trials were respiratory tract infections (most frequently pneumonia), cellulitis and urinary tract infections.\n\n10.1371/journal.pone.0087379.g002Figure 2 Rates of serious infectious events (SIEs) in the double-blind, placebo-controlled periods.\nMultiple occurrences of the same event in one individual were counted multiple times. MTX, methotrexate; OCR200, ocrelizumab 200 mg×2; OCR500, ocrelizumab 500 mg×2; PBO, placebo; pt-yrs, patient-years.\n\nA meta-analysis of SIEs was conducted. Following pooling of data by treatment group, the weighted difference in incidence rate per 100 patient-years from PBO in patients with SIEs was significantly higher with OCR500+MTX (2.4; 95% CI, 0.3–4.5) but not with OCR200+MTX (0.6; 95% CI, −1.3 to 2.4) (Figure 3, A and B).\n\n10.1371/journal.pone.0087379.g003Figure 3 Fixed-effects meta-analysis of incidence rate differences in serious infectious events (SIEs).\n(A) OCR200+MTX; (B) OCR500+MTX. The pooled rate difference accounts for study and is weighted according to the inverse of the estimated variance. These analyses are based on patients with at least one event (does not count all events). Zero indicates no difference, and a positive value indicates that ocrelizumab (OCR) is worse. MTX, methotrexate; OCR200, ocrelizumab 200 mg×2; OCR500, ocrelizumab 500 mg×2; PBO, placebo.\n\nSIE rates by region for the individual studies (Asia versus Rest of World) showed that SIE rates were particularly high in patients recruited in Asia treated with OCR500+MTX (Figure 4). To explore this further, individual patient data from the larger studies was pooled (STAGE, SCRIPT and FILM) and an exploratory COX regression analysis of risk factors for SIEs was performed. After adjustment for all risk factors in the final model, the following results were found: prior cardiac disease (hazard ratio [HR], 2.29; 95% CI, 1.37–3.83; p = 0.002); use of oral corticosteroids at baseline (HR, 1.69; 95% CI, 1.08–2.65; p = 0.022); history of diabetes (HR, 1.77; 95% CI, 1.02–3.05; p = 0.041); treatment group (relative to PBO+MTX; OCR200+MTX [HR, 1.30; 95% CI, 0.76–2.24; p = 0.341] and OCR500+MTX [HR, 1.87; 95% CI, 1.13–3.11; p = 0.016]); and body weight (≤47.5 kg [5th percentile] relative to >47.5 kg; HR, 2.02; 95% CI, 1.00–4.67; p = 0.049). In addition, after adjustment for these risk factors, patients recruited in Asia appeared to have a higher risk of SIEs compared with those recruited outside of Asia (HR [Asia vs non-Asia] 1.78; 95% CI, 1.03–3.06; p = 0.039). It was not possible to determine whether this effect was driven by race or region because an overwhelming majority of Asian patients were recruited from the Asian region. Study was not significant in the model after adjustment for the risk factors specified. In the exploratory model analyses, there were no statistically significant treatment interactions, including a nonsignificant interaction between Asia and treatment.\n\n10.1371/journal.pone.0087379.g004Figure 4 Rates of serious infectious events (SIEs) by region.\n(A) STAGE; (B) SCRIPT; (C) FILM. MTX, methotrexate; OCR200, ocrelizumab 200 mg×2; OCR500, ocrelizumab 500 mg×2; PBO, placebo. “Asia” includes China, Hong Kong, Indonesia, Malaysia, Philippines, Republic of Korea, Singapore, Taiwan, Thailand and Japan; “Other” includes North and South America, Europe and South Africa.\n\nData from the long-term SFU of patients during B-cell depletion post-OCR treatment indicated that the incidence of SIEs decreased over time, and the previously identified imbalance in SIEs in the pivotal studies (STAGE and SCRIPT) in the OCR500+MTX group disappeared. Rates of SIEs in Asian countries also decreased over the long-term follow-up, although it should be noted that the Asian groups consisted of small numbers of patients, and the CIs were wide and overlapped with those of the non-Asian population.\n\nOpportunistic Infections\nA total of 10 opportunistic infections were recorded during the DBPC period. One occurred in the PBO+MTX group (Mycobacterium abscessus on the thigh in a patient from Thailand), 5 in the OCR200+MTX group (de novo pulmonary tuberculosis [n = 2; Mexico], hepatitis B reactivation [Japan], Mycobacterium kansasii infection [Germany] and histoplasmosis [United States]) and 4 in the OCR500+MTX group (Pneumocystis jiroveci [Japan], esophageal candidiasis [France], Varicella pneumonia [South Korea] and systemic Candida infection [South Korea]). No cases of progressive multifocal leukoencephalopathy were recorded, and no fatal outcomes resulted from opportunistic infection. The patient with hepatitis B virus reactivation tested negative for hepatitis B surface antigen, positive for hepatitis B core antibody and negative for hepatitis B virus DNA at the time of enrollment. Approximately 300 patients with this serologic status for hepatitis B virus were enrolled in the RA program, and no other cases of hepatitis B reactivation were observed.\n\nMalignancies\nPooled long-term follow-up data (of up to 5 years) from the four studies showed that the rate of malignancies per 100 patient-years was 1.18 (95% CI, 0.61–2.06) in the PBO+MTX group (n = 865; 1018 patient-years), 1.51 (95% CI, 0.99–2.19) in the OCR200+MTX group (n = 1121; 1792 patient-years) and 1.41 (95% CI, 1.07–1.83) in the OCR 500+MTX group (n = 1849; 4034 patient-years). The rate of all active treatments combined (n = 2434; 5826 patient-years) was 1.44 (95% CI, 1.15–1.78). In summary, these pooled analyses revealed no differences in the rate of malignancies between treatment groups.\n\nDeaths\nOverall, 10 deaths occurred during the DBPC periods (Table 3). The 4 deaths in the PBO+MTX groups were due to acute myocardial infarction (n = 2), congestive cardiac failure (n = 1) and rheumatoid vasculitis (n = 1). Of the 6 fatalities among OCR+MTX-treated patients, 4 occurred in patients receiving the OCR500 dose (1 each due to respiratory failure, sepsis, acute myocardial infarction and ischemic stroke) and 2 in patients receiving the OCR200 dose (1 each due to hemorrhagic stroke and acute respiratory failure).\n\nPharmacodynamics\nIn all 4 trials, following the initiation of OCR treatment, a rapid depletion of CD19+ B cells was observed in the OCR200+MTX and OCR500+MTX groups as early as the first post-dose evaluation time point at week 2, in contrast with the PBO+MTX groups. Kaplan-Meier curves of times to B-cell repletion (return of CD19+ levels to baseline or ≥80 cells/µl, whichever was lower) in each of the 4 studies are shown in Figure 5. Data from FILM allowed evaluation of the potential dose effect (after 2–4 courses) on B-cell repletion. No clinically meaningful difference was observed in the median time to B-cell repletion from the first dose of the last course between the OCR200+MTX (63.6 weeks; 95% CI, 53–72) and OCR500+MTX (66.1 weeks; 95% CI, 60–73) groups. In addition, the median times to B-cell repletion were similar between the OCR200+MTX and OCR500+MTX groups in the DBPC period of FILM and between the OCR200/OL OCR500+MTX and OCR500/OL OCR500+MTX groups in the open-label extension of STAGE, respectively, suggesting that a greater number of OCR re-treatments were not associated with a longer repletion time. A slightly more prolonged B-cell repletion profile was observed in SCRIPT when compared with the other studies; this may be related to this patient population having more severe, long-term disease with multiple previous treatments. There was no indication that the time to B-cell repletion in patients recruited in Asia was different from that in patients recruited outside Asia.\n\n10.1371/journal.pone.0087379.g005Figure 5 Cumulative probability of B-cell repletion in each clinical trial.\n(A) STAGE; (B) SCRIPT; (C) FEATURE and (D) FILM. B-cell repletion was defined as a return of CD19+ levels to baseline or 80 cells/µL, whichever was lower. Data summarized under the PBO/OL OCR500+MTX, OCR200/OL OCR500+MTX and OCR500/OL OCR500+MTX treatment groups are OL data only. The x-axis represents the number of weeks since the first infusion of the last course of OCR. MTX, methotrexate; OCR200, ocrelizumab 200 mg×2; OCR500, ocrelizumab 500 mg×2; OL, open-label; PBO, placebo.\n\nDiscussion\nThis report summarizes the safety results from the 4 phase III trials conducted with OCR in patients with RA. The majority of the population studied included patients with long-standing RA, who had been using numerous immunosuppressive treatments in the past and at least one immunosuppressive agent in combination with OCR during participation in the studies. Approximately one-third of the population studied previously received biological DMARDs and more than one-half of the patients were concomitantly receiving systemic corticosteroids. These factors have to be taken into consideration when interpreting safety data from the OCR clinical trial program in RA.\n\nAlthough the overall safety profiles were generally comparable between the PBO+MTX and both OCR+MTX dose groups, an imbalance in the incidence of SIEs during the DBPC periods was observed in the OCR500+MTX group. A meta-analysis of SIEs in the DBPC treatment periods indicated a significantly higher rate of SIEs among patients who were treated with OCR500+MTX when compared with PBO+MTX. This was not observed with the lower dose studied. Other factors associated with risk of SIEs were prior cardiac disease, use of oral corticosteroids at baseline, and history of diabetes. Patients recruited in Asia were also at a higher risk of SIEs than were those recruited outside of Asia. Because nearly all Asian patients were recruited in the Asian region, we were unable to distinguish between geographic effects and ethnicity. In addition, the low number of SIEs in the DBPC period meant that we had limited statistical power in the analyses of interactions of risk factors, such as Asian region with treatment.\n\nConfounding factors may have contributed to the higher incidence of opportunistic infections (9 cases across the OCR+MTX groups: 5 cases in the OCR200+MTX group and 4 cases in the OCR500+MTX group compared with a single case in the PBO group) such as endemic areas for histoplasmosis in the United States, tuberculosis in Mexico, and hepatitis B in Japan. In addition, the patient with Candida infections was receiving high-dose steroid treatment for concurrent medical conditions.\n\nThe clinical development of OCR was initiated in part with the aim of evaluating the potential safety advantage of a humanized molecule over chimeric antibodies. Humanization may be expected to reduce the incidence of anti-drug antibody responses. The incidence of HAHAs was low across the 4 trials (<5%) and, in general, comparable between the pooled OCR+MTX and PBO+MTX groups. There was no association between IRRs and development of HAHAs. In addition, there were no clear differences in the incidence of HAHAs when single-infusion and dual-infusion OCR were compared, although, because the patient numbers in FEATURE were small, the question of whether a difference exists between single- and dual-infusion OCR remains open. In a previous pooled analysis of approximately 2500 patients in the rituximab RA clinical trial program, 11% of those treated with rituximab developed human anti-chimeric antibodies [8].\n\nAs expected, both doses of OCR rapidly depleted B cells shortly after infusion. The question was whether the higher rates of serious infections seen in patients treated with OCR500+MTX could have been explained, in part, by differences in B-cell depletion/repletion profiles between the higher and lower doses. It should be noted that evaluation of B-cell levels in clinical trials is limited by measurement of peripheral CD19 counts only; however, the analyses suggested that there was no difference in time to peripheral B-cell repletion between the OCR500 and OCR200 doses. Moreover, the number of repeat treatment courses also did not seem to have a clinically meaningful effect on time to B-cell repletion.\n\nThe conclusion that the two doses of OCR, in combination with MTX tested in the RA clinical trials did not demonstrate a superior benefit-risk profile compared with available treatments led to the termination of the clinical development program of OCR in RA. OCR500+MTX demonstrated clinical benefit by improving signs and symptoms of RA and radiographic outcomes [10]–[13]; however this dose was associated with an increased incidence of SIEs. OCR200+MTX did not show superior efficacy compared with existing therapies, but was safe and well-tolerated.\n\nThe clinical development of OCR is continuing in multiple sclerosis, for which there remains an unmet need for more effective therapies and background immunosuppressant therapy is not used. A phase II study in multiple sclerosis reported good efficacy and safety data, with no imbalance in serious infections between PBO and OCR (maximum dose up to 1000 mg×2 for 24 weeks) [14]. Phase III studies are continuing and, because of the low prevalence of multiple sclerosis in Asia, no investigational sites in that region have been included.\n\nSupporting Information\nChecklist S1 \nCONSORT Checklist.\n\n\n(DOC)\n\nClick here for additional data file.\n\n The authors and sponsors thank all patients and investigators for their contributions to the ocrelizumab RA clinical trials. Support for third party writing assistance was provided by F. Hoffmann-La Roche.\n==== Refs\nReferences\n1 \nDörner T , Kinnman N , Tak PP (2010 ) Targeting B cells in immune-mediated inflammatory disease: a comprehensive review of mechanisms of action and identification of biomarkers . Pharmacol Ther \n125 : 464 –475 .20097226 \n2 \nSilverman GJ , Carson DA (2003 ) Roles of B cells in rheumatoid arthritis . Arthritis Res Ther \n5 : S1 –6 .\n3 \nCohen SB , Emery P , Greenwald MW , Dougados M , Furie RA , et al (2006 ) Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks . Arthritis Rheum \n54 : 2793 –2806 .16947627 \n4 \nEdwards JC , Szczepanski L , Szechinski J , Filipowicz-Sosnowska A , Emery P , et al (2004 ) Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis . N Engl J Med \n350 : 2572 –2581 .15201414 \n5 \nEmery P , Fleischmann R , Filipowicz-Sosnowska A , Schechtman J , Szczepanski L , et al (2006 ) The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: Results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial . Arthritis Rheum \n54 : 1390 –1400 .16649186 \n6 \nEmery P , Deodhar A , Rigby WF , Isaacs JD , Combe B , et al (2010 ) Efficacy and safety of different doses and retreatment of rituximab: A randomised, placebo-controlled trial in patients who are biologic naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE)) . Ann Rheum Dis \n69 : 1629 –1635 .20488885 \n7 \nRubbert-Roth A , Tak PP , Zerbini C , Tremblay JL , Carreño L , et al (2010 ) Efficacy and safety of various repeat treatment dosing regimens of rituximab in patients with active rheumatoid arthritis: Results of a Phase III randomized study (MIRROR) . Rheumatology (Oxford) \n49 : 1683 –1693 .20463186 \n8 \nvan Vollenhoven RF , Emery P , Bingham CO III, Keystone EC , Fleischmann R , et al (2010 ) Long term safety of patients receiving rituximab in rheumatoid arthritis clinical trials . J Rheumatol \n37 : 558 –567 .20110520 \n9 van Vollenhoven RF, Emery P, Bingham CO III, Keystone E, Fleischmann R, et al.. (2012) Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with focus on adverse events of interest in RA patients. Ann Rheum Dis [Epub ahead of print].\n10 \nRigby W , Tony HP , Oelke K , Combe B , Laster A , et al (2012 ) Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: Results of a forty-eight-week randomized, double-blind, placebo-controlled, parallel-group phase III trial . Arthritis Rheum \n64 : 350 –359 .21905001 \n11 \nTak PP , Mease PJ , Genovese MC , Kremer J , Haraoui B , et al (2012 ) Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to at least one tumor necrosis factor inhibitor: Results of a forty-eight-week randomized, double-blind, placebo-controlled, parallel-group phase III trial . Arthritis Rheum \n64 : 360 –370 .22389919 \n12 \nStohl W , Gomez-Reino J , Olech E , Dudler J , Fleischmann RM , et al (2012 ) Safety and efficacy of ocrelizumab in combination with methotrexate in MTX-naive subjects with rheumatoid arthritis: The phase III FILM trial . Ann Rheum Dis \n71 : 1289 –1296 .22307942 \n13 \nHuffstutter JE , Taylor J , Schechtman J , Leszczynski P , Brzosko M , et al (2011 ) Single versus dual infusion of B cell depleting antibody ocrelizumab (humanized aCD20) in rheumatoid arthritis: Results from the Phase III FEATURE trial . Int J Clin Rheumatol \n6 : 689 –696 .\n14 \nKappos L , Li D , Calabresi PA , O'Connor P , Bar-Or A , et al (2011 ) Ocrelizumab in relapsing-remitting multiple sclerosis: A phase 2, randomised, placebo-controlled, multicentre trial . Lancet \n378 : 1779 –1787 .22047971\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "9(2)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D017326:Clinical Trials, Phase III as Topic; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007239:Infections; D008297:Male; D015201:Meta-Analysis as Topic; D008727:Methotrexate; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009369:Neoplasms; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e87379",
"pmc": null,
"pmid": "24498318",
"pubdate": "2014",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "20110520;21905001;22389919;23136242;20488885;22307942;20097226;15201414;22047971;16947627;16649186;20463186;15180890",
"title": "Safety with ocrelizumab in rheumatoid arthritis: results from the ocrelizumab phase III program.",
"title_normalized": "safety with ocrelizumab in rheumatoid arthritis results from the ocrelizumab phase iii program"
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"abstract": "BACKGROUND\nSecondary lymphoblastic leukemia has been rarely reported in patients with multiple myeloma.\n\n\nMETHODS\nWe report 3 cases of secondary lymphoblastic leukemia in multiple myeloma patients. They shared a similar phenotype of myeloma cells and secondary lymphoblasts. The chemotherapy treatments in the 3 patients were complex due to various factors.\n\n\nCONCLUSIONS\nMultiple immune defects caused by exposure to a variety of agents can play an important role in the development of secondary lymphoblastic leukemia. Microscopic morphology and flow cytometry are important means to detect secondary malignancies in multiple myeloma. Further clinical, experimental and genetic studies of secondary malignancies in multiple myeloma will be necessary in the future.",
"affiliations": "Department of Laboratory Science, First Affiliated Hospital of Sun Yatsen University, Guangzhou - China.;Department of Hematology, First Affiliated Hospital of Sun Yatsen University, Guangzhou - China.;Department of Hematology, First Affiliated Hospital of Sun Yatsen University, Guangzhou - China.;Department of Laboratory Science, First Affiliated Hospital of Sun Yatsen University, Guangzhou - China.;Department of Laboratory Science, First Affiliated Hospital of Sun Yatsen University, Guangzhou - China.;Department of Pediatrics, First Hospital of Baiyun District, Guangzhou - China.;Department of Laboratory Science, First Affiliated Hospital of Sun Yatsen University, Guangzhou - China.;Department of Laboratory Science, First Affiliated Hospital of Sun Yatsen University, Guangzhou - China.;Department of Laboratory Science, First Affiliated Hospital of Sun Yatsen University, Guangzhou - China.;Department of Laboratory Science, First Affiliated Hospital of Sun Yatsen University, Guangzhou - China.;Department of Hematology, First Affiliated Hospital of Sun Yatsen University, Guangzhou - China.",
"authors": "Junxun|Li|L|;Junru|Liu|L|;Meilan|Chen|C|;Chujia|Liang|L|;Shaoqian|Chen|C|;Jieyu|Zhan|Z|;Zhuangjian|Ye|Y|;Fan|Zhang|Z|;Juan|Ouyang|O|;Jing|Cheng|C|;Juan|Li|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5301/tj.5000377",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8916",
"issue": "102(Suppl. 2)",
"journal": "Tumori",
"keywords": null,
"medline_ta": "Tumori",
"mesh_terms": "D000130:Achondroplasia; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001853:Bone Marrow; D003131:Combined Modality Therapy; D005260:Female; D015322:Gene Rearrangement, B-Lymphocyte; D006801:Humans; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D009101:Multiple Myeloma; D016609:Neoplasms, Second Primary; D000072078:Positron Emission Tomography Computed Tomography; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D016896:Treatment Outcome",
"nlm_unique_id": "0111356",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26166219",
"pubdate": "2016-11-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Three patients with multiple myeloma developing secondary lymphoblastic leukemia: case reports and review of the literature.",
"title_normalized": "three patients with multiple myeloma developing secondary lymphoblastic leukemia case reports and review of the literature"
} | [
{
"companynumb": "CN-TAKEDA-2017MPI002385",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"drugadditional": null,... |
{
"abstract": "OBJECTIVE\nPatients with villous atrophy (VA) and negative celiac disease (CD) serologies pose a diagnostic and therapeutic dilemma. When a definitive etiology for VA is not determined, patients are characterized as having unclassified sprue (US), the optimal management of which is unknown.\n\n\nMETHODS\nWe studied adult patients with VA on biopsy and negative celiac serologies, evaluated at our tertiary referral center over a 10-year period. Testing for HLA DQ2/8 alleles, antienterocyte antibodies, giardia stool antigen, bacterial overgrowth, total serum immunoglobulins, and HIV was noted. Treatment, response, and repeat-biopsy findings were recorded.\n\n\nRESULTS\nThe most common diagnoses of the 72 patients were seronegative CD, medication-related villous atrophy, and US. Of those with US, the majority reported symptomatic improvement with immunosuppressive therapy. Some patients initially labeled as unclassified were found to have VA associated with olmesartan use.\n\n\nCONCLUSIONS\nThe role of medications in the development of VA and the optimal dose and length of immunosuppression for patients with US should be investigated further.",
"affiliations": "Celiac Disease Center, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA.",
"authors": "DeGaetani|Marisa|M|;Tennyson|Christina A|CA|;Lebwohl|Benjamin|B|;Lewis|Suzanne K|SK|;Abu Daya|Hussein|H|;Arguelles-Grande|Carolina|C|;Bhagat|Govind|G|;Green|Peter H R|PH|",
"chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D001323:Autoantibodies; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D007093:Imidazoles; D007136:Immunoglobulins; D007166:Immunosuppressive Agents; D013777:Tetrazoles; C437965:olmesartan",
"country": "United States",
"delete": false,
"doi": "10.1038/ajg.2013.45",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9270",
"issue": "108(5)",
"journal": "The American journal of gastroenterology",
"keywords": null,
"medline_ta": "Am J Gastroenterol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D047228:Angiotensin II Type 1 Receptor Blockers; D001284:Atrophy; D001323:Autoantibodies; D001706:Biopsy; D002446:Celiac Disease; D016208:Databases, Factual; D004386:Duodenum; D005260:Female; D006683:HLA-DQ Antigens; D006801:Humans; D007093:Imidazoles; D007136:Immunoglobulins; D007166:Immunosuppressive Agents; D007413:Intestinal Mucosa; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013777:Tetrazoles",
"nlm_unique_id": "0421030",
"other_id": null,
"pages": "647-53",
"pmc": null,
"pmid": "23644957",
"pubdate": "2013-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Villous atrophy and negative celiac serology: a diagnostic and therapeutic dilemma.",
"title_normalized": "villous atrophy and negative celiac serology a diagnostic and therapeutic dilemma"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201603225",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "This study aims to describe adherence rates to the 2014 American Academy of Pediatrics (AAP) Committee on Infectious Disease guidance document recommending which patients should receive palivizumab for prophylaxis against respiratory syncytial virus (RSV).\n\n\n\nA retrospective, single-center analysis of patients who received at least one dose of palivizumab between October 1, 2012, and March 1, 2017 was conducted. Data collected included demographics, medical history, palivizumab administration regimens, and incidence of RSV infection.\n\n\n\nData were collected on 457 patients who received palivizumab over five RSV seasons. Approximately half of the patients (45% and 55%, respectively) received palivizumab according to the AAP recommendations in place at the time (2012 or 2014 recommendations, respectively). One percent of patients had a breakthrough RSV infection after receiving at least one dose of palivizumab. There was no significant difference in the number of breakthrough infections before and after the 2014 recommendations were released (3 vs. 2).\n\n\n\nApproximately half of the patients received prophylaxis in accordance with the 2014 AAP recommendations and infrequently suffered from a breakthrough RSV infection.",
"affiliations": "Loma Linda University School of Pharmacy, Loma Linda, California, USA.;Rite-Aid Pharmacy, Rancho Cucamonga, California, USA.;Loma Linda University School of Pharmacy, Loma Linda, California, USA.;Loma Linda University School of Pharmacy, Loma Linda, California, USA.;Loma Linda University School of Pharmacy, Loma Linda, California, USA.;University of Maryland Medical Center, Baltimore, Maryland, USA.;Loma Linda University School of Pharmacy, Loma Linda, California, USA.;School of Pharmacy, University of Maryland, Baltimore, Maryland, USA.",
"authors": "Sierra|Caroline M|CM|0000-0002-9336-5644;Park|Alice|A|;Eum|Eunsi|E|;Garcia|Giselle|G|;Lopez|Mireya|M|;Daniel|Shawnée N|SN|;Bahjri|Khaled|K|;Parbuoni|Kristine A|KA|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000998:Antiviral Agents; D000069455:Palivizumab",
"country": "United States",
"delete": false,
"doi": "10.1002/ppul.25225",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1099-0496",
"issue": "56(5)",
"journal": "Pediatric pulmonology",
"keywords": "antiviral; palivizumab; pediatrics; respiratory syncytial virus",
"medline_ta": "Pediatr Pulmonol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000998:Antiviral Agents; D002648:Child; D006760:Hospitalization; D006801:Humans; D007223:Infant; D000069455:Palivizumab; D010372:Pediatrics; D018357:Respiratory Syncytial Virus Infections; D018113:Respiratory Syncytial Virus, Human; D012189:Retrospective Studies; D014481:United States",
"nlm_unique_id": "8510590",
"other_id": null,
"pages": "1121-1126",
"pmc": null,
"pmid": "33314771",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Adherence to the 2014 American Academy of Pediatrics palivizumab prophylaxis recommendations.",
"title_normalized": "adherence to the 2014 american academy of pediatrics palivizumab prophylaxis recommendations"
} | [
{
"companynumb": "US-BIOVITRUM-2021US1718",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PALIVIZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "A 45-year-old man presented with acute onset ataxia for last 1 week. On examination he had signs of left-sided cerebellar involement. MRI brain revealed asymmetric altered signal intensities in bilateral cerebellar hemispheres suggesting demyelinating lesions. ELISA for Human Immune Deficiency virus-1 was positive. CSF JC virus DNA PCR was positive. A diagnosis of Progressive Multifocal Leukoencephalopathy (PML) was made on the basis of clinico-radiological picture and JC virus DNA PCR presence in CSF. PML is unknown and under diagnosed CNS infection seen in HIV patients mostly seen with advanced disease. We present an unusual case report where isolated cerebellar involvement occurred as the first AIDS defining event in the absence of appreciable immunodeficiency in a patient with previously undiagnosed HIV infection.",
"affiliations": "Department of General Medicine, Regional Institute of Medical Sciences, Imphal, Manipur, India.;Department of General Medicine, Regional Institute of Medical Sciences, Imphal, Manipur, India.",
"authors": "Singh|Th Suraj|TS|;Singh|Kuldeep|K|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0028-3886.325348",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3886",
"issue": "69(4)",
"journal": "Neurology India",
"keywords": "Cerebellar ataxia; HIV; JC virus; progressive multifocal encephalopathy",
"medline_ta": "Neurol India",
"mesh_terms": "D002524:Cerebellar Ataxia; D015658:HIV Infections; D006801:Humans; D007968:Leukoencephalopathy, Progressive Multifocal; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging",
"nlm_unique_id": "0042005",
"other_id": null,
"pages": "1018-1020",
"pmc": null,
"pmid": "34507433",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Acute Cerebellar Ataxia as the Presenting Symptom of Progressive Multifocal Leukoencephalopathy with HIV - A Case Report.",
"title_normalized": "acute cerebellar ataxia as the presenting symptom of progressive multifocal leukoencephalopathy with hiv a case report"
} | [
{
"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2021-24083",
"fulfillexpeditecriteria": "2",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugad... |
{
"abstract": "We report on a former 28-week gestation neonate with persistent methicillin-resistant Staphylococcus aureus (MRSA) endocarditis, with a heterozygous Factor V Leiden mutation. The neonate became clinically ill after 1 week of life, with positive blood cultures for MRSA. Echocardiography revealed large thrombi in the inferior vena cava and right atrium. Bacteremia persisted despite removal of umbilical arterial and venous catheters and empiric administration of therapeutic doses of vancomycin (minimum inhibitory concentration [MIC] 2 mg/L) and ceftazidime. To narrow therapy, ceftazidime was discontinued, while gentamicin and rifampin were added. Cultures remained positive and, therefore, linezolid was added, and subsequent blood cultures became negative. Since prolonged linezolid use of 2 weeks or longer carries potential adverse effects, antibiotics were changed to daptomycin, which is bactericidal and recommended for treatment of invasive MRSA infections when vancomycin MICs are ≥2 mg/L to minimize vancomycin treatment failure. Enoxaparin was initiated, with anti-Xa assay monitoring. A workup for thrombophilia revealed heterozygous Factor V Leiden mutation. Serial echocardiograms demonstrated decreasing size of the thrombi, which were no longer visualized at 2 months of age. Creatinine kinase remained normal. The infant had no seizures on daptomycin. The management of persistent MRSA bacteremia in neonates associated with a large thrombus poses a unique challenge due to the long duration of treatment. To our knowledge, this is the first case of prolonged and safe daptomycin and enoxaparin use in a preterm neonate. Daptomycin may be considered in cases of clinical failure with vancomycin when a lengthy treatment course is contemplated.",
"affiliations": null,
"authors": "Chan|Joshua I|JI|;Noor|Asif|A|;Clauss|Christie|C|;Aggarwal|Renu|R|;Nayak|Amrita|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5863/1551-6776-25.1.68",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1551-6776",
"issue": "25(1)",
"journal": "The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG",
"keywords": "MRSA; daptomycin; endovascular infection; enoxaparin; neonate",
"medline_ta": "J Pediatr Pharmacol Ther",
"mesh_terms": null,
"nlm_unique_id": "101089851",
"other_id": null,
"pages": "68-74",
"pmc": null,
"pmid": "31897079",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "26910590;27870104;17235512;18977985;25564402;11772150;15342842;21694874;28895694;22315277;22271402;24616358;27820879;20515969;28471867;25859172;28521068;20013573;20420500;21217178;16882797;18309318;21281885;21127158;22627869;23478571;19131899;11420328",
"title": "Methicillin-Resistant Staphylococcus aureus Endovascular Infection in a Neonate: Prolonged, Safe, and Effective Use of Daptomycin and Enoxaparin.",
"title_normalized": "methicillin resistant staphylococcus aureus endovascular infection in a neonate prolonged safe and effective use of daptomycin and enoxaparin"
} | [
{
"companynumb": "US-EMCURE PHARMACEUTICALS LTD-2020-EPL-0028",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VANCOMYCIN HYDROCHLORIDE"
},
... |
{
"abstract": "BACKGROUND\nPeripartum cardiomyopathy (PPCM) is a rare and sometimes fatal systolic heart failure that affects women during late pregnancy or the early postpartum period. Heart failure symptoms can mimic the physiological changes of normal pregnancy, and the diagnosis is based on echocardiography.\nA 38-year-old multiparous woman with a history of cervical incompetence underwent cervical cerclage and received tocolysis for 100 days.\nShe delivered vaginally at 37 weeks of gestation but developed postpartum decompensated acute heart failure with low left ventricular ejection fraction (LVEF: 34%) and was diagnosed with PPCM.\n\n\nMETHODS\nShe received standard therapy for acute heart failure.\n\n\nRESULTS\nThe patient's pulmonary edema cleared, and she was fully ambulatory 6 days after admission. A follow-up echocardiogram 3 months later demonstrated recovery of LVEF to 66%.\n\n\nCONCLUSIONS\nProlonged tocolysis may contribute to cardiomyopathy and should be used with caution. PPCM management requires standard treatments for acute heart failure with modifications for fetal safety.",
"affiliations": "Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.;Division of Cardiology, Department of Internal Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.;Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.",
"authors": "Li|Pei-Chen|PC|;Chang|Huai-Ren|HR|;Kao|Sheng-Po|SP|0000-0002-1174-6962",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000027080",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\nMD-D-21-04096\n10.1097/MD.0000000000027080\n27080\n5600\nResearch Article\nClinical Case Report\nPeripartum cardiomyopathy and acute heart failure associated with prolonged tocolytic therapy in pregnancy\nA case report\nLi Pei-Chen MD a\nChang Huai-Ren MD, PhD b\nKao Sheng-Po MD a ∗\nSaranathan. Maya\na Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan\nb Division of Cardiology, Department of Internal Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.\n∗ Correspondence: Sheng-Po Kao, Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan (e-mail: kaoshengpo@gmail.com).\n27 8 2021\n27 8 2021\n100 34 e2708011 6 2021\n28 7 2021\n12 8 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\nPeripartum cardiomyopathy (PPCM) is a rare and sometimes fatal systolic heart failure that affects women during late pregnancy or the early postpartum period. Heart failure symptoms can mimic the physiological changes of normal pregnancy, and the diagnosis is based on echocardiography.\n\nPatient concerns:\n\nA 38-year-old multiparous woman with a history of cervical incompetence underwent cervical cerclage and received tocolysis for 100 days.\n\nDiagnoses:\n\nShe delivered vaginally at 37 weeks of gestation but developed postpartum decompensated acute heart failure with low left ventricular ejection fraction (LVEF: 34%) and was diagnosed with PPCM.\n\nInterventions:\n\nShe received standard therapy for acute heart failure.\n\nOutcomes:\n\nThe patient's pulmonary edema cleared, and she was fully ambulatory 6 days after admission. A follow-up echocardiogram 3 months later demonstrated recovery of LVEF to 66%.\n\nLessons:\n\nProlonged tocolysis may contribute to cardiomyopathy and should be used with caution. PPCM management requires standard treatments for acute heart failure with modifications for fetal safety.\n\nKeywords\n\nacute heart failure\ncervical insufficiency\nperipartum cardiomyopathy\ntocolysis\nOPEN-ACCESSTRUE\n==== Body\n1 Introduction\n\nPeripartum cardiomyopathy (PPCM) is a rare, life-threatening form of dilated cardiomyopathy defined as systolic cardiac heart failure in the last month of pregnancy or the first 5 months after delivery.[1] The incidence of PPCM has increased in the past decade and ranges from one in 1000 to 4000 live births in the United States.[2] Risk factors include pre-eclampsia, advanced maternal age, multiparity, multifetal gestation, long-term tocolysis with beta-agonists, and African American ethnicity.[3] Delayed diagnosis and treatment may result in irreversible cardiac dysfunction or mortality.[2]\n\nMid-trimester loss or premature birth can be caused by cervical insufficiency or a short and dilated cervix. Cerclage should be considered if the cervical length is ≤25 mm at less than 24 weeks.[4]\n\nTocolytics are frequent adjunctive therapy for patients who undergo cervical cerclage.[5] However, adverse side effects can be caused by beta-2 adrenergic agonists, which are widely used tocolytic agents, including maternal pulmonary edema[6] and vasodilatation, which leads to a compensatory increase in heart rate, stroke volume, cardiac output, and systolic blood pressure.[7] Cardiovascular decompensation may occur after prolonged use of beta-2 adrenergic agonists. The direct effects of beta-2 adrenergic agonists on cardiovascular function have not been fully investigated.\n\nWe report the case of a woman who received tocolytic therapy for 3.5 months after cervical cerclage and presented with acute symptoms and signs of decompensated heart failure 3 days after delivery. The patient provided informed consent for the publication of the case.\n\n2 Case report\n\nA 38-year-old postpartum woman, gravida 3, para 2, ab 1, with no history of diabetes, hypertension, or cardiovascular disease was admitted to the hospital for acute dyspnea and leg edema.\n\nThe patient had a preterm delivery at 36 weeks of gestation in her first pregnancy 12 years ago, which did not require cervical cerclage or tocolysis. Her father had hypertension. She presented to the obstetric department at 21 weeks of gestation and underwent cerclage after her cervical length was found to be <19 mm. She was given tocolytic therapy with ritodrine, nifedipine, and diclofenac, which continued for 100 days until her delivery. The patient remained healthy until the last week of pregnancy when she developed mild dyspnea and increased leg swelling. She had a vaginal birth at 37 weeks of gestation.\n\nThree days after delivery, the patient presented to the emergency department with progressive dyspnea, orthopnea, and significant bilateral leg swelling. Her blood pressure was 161/110 mmHg, respiratory rate 30/min, and tachycardia 118/min. Laboratory data showed her troponin T level at 0.13 ug/l and N-terminal pro-brain natriuretic peptide level at 5,430 pg/ml. Chest imaging revealed pulmonary edema and bilateral pleural effusion (Fig. 1). A computed tomography pulmonary angiogram was negative for pulmonary emboli and electrocardiography revealed sinus tachycardia (Fig. 2). An echocardiogram showed generalized hypokinesia of left ventricular (LV) wall motion and a low ejection fraction of 34% (Fig. 3).\n\nFigure 1 Chest x-ray showing cardiomegaly and pulmonary edema.\n\nFigure 2 Twelve lead electrocardiograms showing sinus tachycardia at a rate of 111 beats per min with a QRS duration of 64 ms.\n\nFigure 3 M-mode echocardiography demonstrating low left ventricular ejection fraction.\n\nThe patient was diagnosed with PPCM and given standard therapy for acute heart failure, including inotrope, vasodilators, ACE-inhibitors, beta-blockers, and diuretics; she improved clinically and the pulmonary edema cleared by the fifth day of hospitalization. The patient was fully ambulatory and was discharged 6 days after admission. A follow-up echocardiogram at 3 months and 12 months showed normalization of her ejection fraction to 64% and 80%, respectively. The patient showed complete recovery from PPCM and remained asymptomatic.\n\n3 Discussion\n\nWe describe a multiparous female patient with cervical incompetence treated with a cervical cerclage and long-term tocolysis. Three days after delivery, she developed decompensated acute heart failure and was diagnosed with PPCM, which is a rare and sometimes fatal disease of unknown etiology. The 2010 Heart Failure Association of the European Society of Cardiology(ESC) Working Group defined PPCM as idiopathic cardiomyopathy with heart failure secondary to LV systolic dysfunction with a left ventricular ejection fraction (LVEF) of <45% during the last month of pregnancy or within 5 months following delivery. Their study finds no identifiable cause for heart failure but they speculate that it could be due to ventricular dilatation.[8]\n\nThe proposed pathogenesis of PPCM includes viral vasculitis,[9] endothelial dysfunction,[10] selenium deficiency,[11] increased levels of prolactin,[12] oxidative stresses from the vascular hormone soluble fms-like tyrosine kinase receptor 1,[13] autoimmune response,[14,15] or genetic predisposition.[16,17] Previous studies have shown advanced age, black race, pre-eclampsia, hypertension, multiple gestations, anemia, and prolonged tocolysis to be risk factors for PPCM.[18] Long-term use of tocolytic agents may contribute to cardiovascular dysfunction. A previous case series by Witlin et al reported PPCM in 2 patients out of 28 who had been administered tocolysis, including magnesium sulfate, ritodrine, terbutaline, and indomethacin.[19] Lampert et al retrospectively reviewed 15 patients who had PPCM and found that 4 had undergone prolonged tocolytic therapy for 4 to 11 weeks, with a mean duration of treatment of 6.7 weeks.[20]\n\nCardiovascular events have been associated with ritodrine use in pregnancy, including chest pain, pulmonary edema, cardiac arrhythmias, and peripheral vasodilatation.[21,22] Studies also found that ritodrine decreased cardiac baroreflex sensitivity, resulting in dysregulation of the vagal heart rate and increased blood pressure variability.[7] Following a rise in heart rate, decompensated heart failure may occur because of reduced time for left atrial emptying, diastolic ventricular filling, and systolic ejection.[6] On the other hand, β-adrenergic regulation also affects the balance between cardio-protection and cardiotoxicity.[7,23] Cardiomyopathy may be triggered by beta-stimulation.\n\nThere is a high prevalence of pre-eclampsia in women with PPCM, and the 2 may share the same pathophysiology.[24] Recent data suggest that antiangiogenic factor sFlt-1 from the placenta antagonizes circulating vascular endothelial growth factor and placental growth factor, leading to hypertension and endothelial dysfunction in pre-eclampsia. Higher serum soluble fms-like tyrosine kinase receptor 1 levels have also been found in women with PPCM, which correlates with poor myocardial recovery.[13] However, our patient was treated with a calcium channel blocker to inhibit preterm labor, possibly concealing and delaying a pregnancy-induced hypertension diagnosis. Early detection of pre-eclampsia may help to enhance alertness and recognition of PPCM.\n\nThe management of PPCM requires a multidisciplinary team involving obstetricians, cardiologists, and anesthesiologists. The treatment goals are similar to non-pregnant acute heart failure with special consideration for fetal safety. Treatments for heart failure that are compatible with pregnancy status and breastfeeding include sodium restriction, loop diuretics, β blockers, hydralazine, nitrates, digoxin, and heparin. However, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are contraindicated during pregnancy due to fetotoxicity. According to ESC[25] and American Heart Association[26] guidelines, an urgent cesarean delivery should be considered in women presenting with acute heart failure and hemodynamic instability. In hemodynamically stable patients, vaginal delivery is preferable with epidural analgesia.\n\nThe reported mortality rate ranges from 2.0% to 12.6%[25]; however, recent evidence suggests that the LVEF recovers to a normal range within the first 3 to 6 months in 50% to 80% of women with PPCM.[27] However, an LVEF of <30% at the time of diagnosis indicates lower recovery rates and increased adverse events.[3] In addition, approximately 50% of recovered patients could experience recurrent PPCM and deterioration of LV function in subsequent pregnancies.[28,29] Therefore, both the ESC and American Heart Association guidelines recommend contraception to PPCM patients without normalized LVEF.[25,26]\n\nPPCM is a significant cause of maternal morbidity and mortality worldwide. The rising incidence of PPCM may be related to the higher prevalence of predisposing disorders such as advanced maternal age, hypertension, diabetes, and multifetal pregnancies, and possibly to increased recognition of the disease. A major challenge is distinguishing the physiologic peripartum changes in healthy women from the pathological symptoms of PPCM. Diagnosis of PPCM is difficult and requires close attention to heart failure signs and symptoms, especially in late pregnancy and the puerperium.\n\nThe present case was that of a multiparous woman of advanced maternal age, who did not have a history of hypertensive disease. Long-term intravenous tocolytic therapy not only results in fluid overload but also dysregulation of heart rate and blood pressure. Hemodynamic stress results in decompensated heart failure. As a result, tocolytic agents, especially β agonists, should be used with considerable caution in pregnant women with underlying cardiovascular disorders. The best prognosis can be achieved with early attention to cardiac failure symptoms in women who receive tocolysis and medical treatment.\n\nAuthor contributions\n\nWriting – original draft: Pei-Chen Li.\n\nWriting – review & editing: Huai-Ren Chang, Sheng-Po Kao.\n\nAbbreviations: ESC = European Society of Cardiology, LV = left ventricular, LVEF = left ventricular ejection fraction, PPCM = peripartum cardiomyopathy.\n\nHow to cite this article: Li PC, Chang HR, Kao SP. Peripartum cardiomyopathy and acute heart failure associated with prolonged tocolytic therapy in pregnancy: a case report. Medicine. 2021;100:34(e27080).\n\nThe authors received approval by the Research Ethical Committee of Buddhist Tzu Chi General Hospital to use the clinical material in this manuscript (CR109-09). Informed written consent was obtained from the patient for publication of this case report and accompanying images.\n\nThe authors have no conflicts of interests to disclose.\n\nAll data generated or analyzed during this study are included in this published article [and its supplementary information files].\n==== Refs\nReferences\n\n[1] Pearson GD Veille JC Rahimtoola S . Peripartum cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review. JAMA 2000;283 :1183–8.10703781\n[2] Gunderson EP Croen LA Chiang V Yoshida CK Walton D Go AS . Epidemiology of peripartum cardiomyopathy: incidence, predictors, and outcomes. Obstet Gynecol 2011;118 :583–91.21860287\n[3] Honigberg MC Givertz MM . Peripartum cardiomyopathy. BMJ 2019;364 :k5287.30700415\n[4] Brown R Gagnon R Delisle M-F . No. 373-Cervical insufficiency and cervical cerclage. J Obstet Gynaecol Can 2019;41 :233–47.30638557\n[5] Smith J DeFranco EA . Tocolytics used as adjunctive therapy at the time of cerclage placement: a systematic review. J Perinatol 2015;35 :561–5.25905689\n[6] Lamont RF . The pathophysiology of pulmonary oedema with the use of beta-agonists. BJOG 2000;107 :439–44.10759259\n[7] Vesalainen RK Ekholm EM Jartti TT Tahvanainen KU Kaila TJ Erkkola RU . Effects of tocolytic treatment with ritodrine on cardiovascular autonomic regulation. Br J Obstet Gynaecol 1999;106 :238–43.10426643\n[8] Sliwa K Hilfiker-Kleiner D Petrie MC . Current state of knowledge on aetiology, diagnosis, management, and therapy of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Working Group on peripartum cardiomyopathy. Eur J Heart Fail 2010;12 :767–78.20675664\n[9] Fett JD . Viral infection as a possible trigger for the development of peripartum cardiomyopathy. Int J Gynaecol Obstet 2007;97 :149–50.17368646\n[10] Patten IS Rana S Shahul S . Cardiac angiogenic imbalance leads to peripartum cardiomyopathy. Nature 2012;485 :333–8.22596155\n[11] Fett JD Ansari AA Sundstrom JB Combs GF . Peripartum cardiomyopathy: a selenium disconnection and an autoimmune connection. Int J Cardiol 2002;86 :311–6.12419571\n[12] Hilfiker-Kleiner D Kaminski K Podewski E . A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 2007;128 :589–600.17289576\n[13] Damp J Givertz MM Semigran M . Relaxin-2 and soluble Flt1 levels in peripartum cardiomyopathy: results of the multicenter IPAC study. JACC Heart Fail 2016;4 :380–8.26970832\n[14] Haghikia A Kaya Z Schwab J . Evidence of autoantibodies against cardiac troponin I and sarcomeric myosin in peripartum cardiomyopathy. Basic Res Cardiol 2015;110 :60.26519371\n[15] Vilela EM Bettencourt-Silva R da Costa JT . Anti-cardiac troponin antibodies in clinical human disease: a systematic review. Ann Transl Med 2017;5 :307.28856147\n[16] Canpolat U Çetin EH Yayla Ç Aras D . Familial occurrence of peripartum cardiomyopathy: genetic origin, unrecognized dilated cardiomyopathy or chance effect? J Cardiol Cases 2015;12 :101–3.30546567\n[17] Ware JS Seidman JG Arany Z . Shared genetic predisposition in peripartum and dilated cardiomyopathies. N Engl J Med 2016;374 :2601–2.\n[18] Lee S Cho GJ Park GU . Incidence, risk factors, and clinical characteristics of peripartum cardiomyopathy in South Korea. Circ Heart Fail 2018;11 :e004134.29626099\n[19] Witlin AG Mabie WC Sibai BM . Peripartum cardiomyopathy: an ominous diagnosis. Am J Obstet Gynecol 1997;176 :182–8.9024111\n[20] Lampert MB Hibbard J Weinert L Briller J Lindheimer M Lang RM . Peripartum heart failure associated with prolonged tocolytic therapy. Am J Obstet Gynecol 1993;168 :493–5.8438916\n[21] Neilson JP West HM Dowswell T . Betamimetics for inhibiting preterm labour. Cochrane Database Syst Rev 2014;CD004352.24500892\n[22] Benedetti TJ . Maternal complications of parenteral beta-sympathomimetic therapy for premature labor. Am J Obstet Gynecol 1983;145 :01–6.\n[23] Fabry IG De Paepe P Kips JG Van Bortel LM . The influence of tocolytic drugs on cardiac function, large arteries, and resistance vessels. Eur J Clin Pharmacol 2011;67 :573–80.21494767\n[24] Bello N Rendon ISH Arany Z . The relationship between pre-eclampsia and peripartum cardiomyopathy: a systematic review and meta-analysis. J Am Coll Cardiol 2013;62 :1715–23.24013055\n[25] Regitz-Zagrosek V Roos-Hesselink JW Bauersachs J . 2018 ESC guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J 2018;39 :3165–241.30165544\n[26] Canobbio MM Warnes CA Aboulhosn J . Management of pregnancy in patients with complex congenital heart disease: a scientific statement for healthcare professionals from the American Heart Association. Circulation 2017;135 :e50–87.28082385\n[27] McNamara DM Elkayam U Alharethi R . Clinical outcomes for peripartum cardiomyopathy in North America: results of the IPAC Study (investigations of pregnancy-associated cardiomyopathy). J Am Coll Cardiol 2015;66 :905–14.26293760\n[28] Elkayam U . Risk of subsequent pregnancy in women with a history of peripartum cardiomyopathy. J Am Coll Cardiol 2014;64 :1629–36.25301468\n[29] Hilfiker-Kleiner D Haghikia A Masuko D . Outcome of subsequent pregnancies in patients with a history of peripartum cardiomyopathy. Eur J Heart Fail 2017;19 :1723–8.28345302\n\n",
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"mesh_terms": "D000328:Adult; D009202:Cardiomyopathies; D004452:Echocardiography; D005260:Female; D006801:Humans; D058725:Peripartum Period; D011247:Pregnancy; D015145:Tocolysis",
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"title": "Peripartum cardiomyopathy and acute heart failure associated with prolonged tocolytic therapy in pregnancy: A case report.",
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"abstract": "Renal cell carcinoma (RCC) comprises 4.2% of all new cancer cases in the United States and 30% of cases are metastatic (mRCC) at diagnosis. Brain metastatic RCC historically has poor prognosis, but the development of immune checkpoint inhibitors has revolutionized their care and may be successfully combined with SBRT to improve prognosis. Here, we present a case of a patient with mRCC who had brain metastases treated with concurrent immune checkpoint inhibitors and SBRT. He continues to survive with good functional status years following his initial diagnosis. We discuss the relevant history regarding treatment approach in patients with brain metastatic RCC, ongoing trials focusing on the combination of immunotherapy and radiation, and the potential and promise of the abscopal effect.",
"affiliations": "Barbara Ann Karmanos Cancer Institute, Detroit, MI, United States.;Washington University School of Medicine, St. Louis, MO, United States.;Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States.;Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States.;Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States.;Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States.;Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States.",
"authors": "Levitin|Maria|M|;Ofori|Joel|J|;Shin|Woo Jae|WJ|;Huang|Jiayi|J|;Daly|Mackenzie|M|;Cao|Dengfeng|D|;Pachynski|Russell|R|",
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"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.566070\nOncology\nCase Report\nRadiation and Checkpoint Inhibitor Immunotherapy Lead to Long Term Disease Control in a Metastatic RCC patient With Brain Metastases\nLevitin Maria 1 Ofori Joel 2 Shin Woo Jae 3 Huang Jiayi 4 Daly Mackenzie 4 Cao Dengfeng 5 Pachynski Russell 36* 1Barbara Ann Karmanos Cancer Institute, Detroit, MI, United States\n2Washington University School of Medicine, St. Louis, MO, United States\n3Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States\n4Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States\n5Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States\n6Bursky Center for Human Immunology and Immunotherapy Programs (CHiiPs), Washington University School of Medicine, St. Louis, MO, United States\nEdited by: Ugo De Giorgi, Romagnolo Scientific Institute for the Study and Treatment of Tumors (IRCCS), Italy\n\nReviewed by: Jaleh Fallah, Cleveland Clinic, United States; Takeshi Yuasa, Japanese Foundation for Cancer Research, Japan\n\n*Correspondence: Russell Pachynski rkpachynski@wustl.eduThis article was submitted to Genitourinary Oncology, a section of the journal Frontiers in Oncology\n\n\n23 9 2020 \n2020 \n10 56607027 5 2020 13 8 2020 Copyright © 2020 Levitin, Ofori, Shin, Huang, Daly, Cao and Pachynski.2020Levitin, Ofori, Shin, Huang, Daly, Cao and PachynskiThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Renal cell carcinoma (RCC) comprises 4.2% of all new cancer cases in the United States and 30% of cases are metastatic (mRCC) at diagnosis. Brain metastatic RCC historically has poor prognosis, but the development of immune checkpoint inhibitors has revolutionized their care and may be successfully combined with SBRT to improve prognosis. Here, we present a case of a patient with mRCC who had brain metastases treated with concurrent immune checkpoint inhibitors and SBRT. He continues to survive with good functional status years following his initial diagnosis. We discuss the relevant history regarding treatment approach in patients with brain metastatic RCC, ongoing trials focusing on the combination of immunotherapy and radiation, and the potential and promise of the abscopal effect.\n\nrenal cell carcinoma (RCC)brain metastases (BMs)immunotherapySBRT (stereotactic body radiation therapy)abscopal\n==== Body\nIntroduction\nRenal cell carcinoma (RCC) comprises 4.2% of all new cancer cases in the United States, with an estimated 73,820 diagnoses in 2019 (1, 2). Thirty percent of cases are metastatic at the time of diagnosis (3) and the incidence of brain metastasis over the course of 5 years is 9.8% (4). Prognosis without treatment is poor, with median survival of about 3 to 4 months (5). Prior to the use of targeted agents, mRCC was treated with interferon and the possible addition of surgery, whole brain radiotherapy, or radiosurgery for brain metastases. The prognosis for patients with brain metastases stagnated at around 3–7 months (5, 6). The development of targeted agents represented the first appreciable increase in life expectancy to a median overall survival (OS) of 9.2 months (7, 8). The management of mRCC has been revolutionized with the development of immune checkpoint inhibitors. Nivolumab is an immunoglobulin (Ig) G4 antibody against human programmed death (PD) 1 that blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2. This helps limit the downregulation of immunostimulatory cytokines and exhaustion that occur during T cell receptor stimulation, mediated in part by the PD-1 receptor (9). The CheckMate 025 trial was an open label, randomized phase 3 study of patients with mRCC previously treated with antiangiogenic therapy which showed that second line treatment with nivolumab improved OS to 25.0 months compared to 19.6 months with the mTOR inhibitor everolimus (10). This led to the FDA approval of nivolumab in RCC and established it as the standard of care for mRCC in the second line setting. Several other checkpoint inhibitors including ipilimumab (anti-CTLA4; in combination with nivolumab), pembrolizumab (anti-PD1; in combination with axitinib), and avelumab (anti-PD-L1; in combination with axitinib) have been approved for the treatment of advanced RCC, with several others currently under investigation (11).\n\nRCC has traditionally considered radioresistant (12). This is based on trials from the 1970's and 80's that utilized outdated radiation techniques and in vitro data describing methods of RCC resistance to radiation (13, 14). Newer data suggest that modern stereotactic ablative radiotherapy can bypass the resistance mechanism and can be an effective therapy both in the primary setting and in treating metastatic disease (14). More recently, there has been interest in interactions between radiation and immunotherapy. Here, we present a patient with mRCC with brain metastases who received checkpoint inhibitors and radiotherapy, with near complete response. We highlight relevant aspects of the case and discuss the current status of combining radiotherapy and immunotherapy in mRCC.\n\nCase Vignette\nAn 83-year-old male presented in March 2016 with progressive shortness of breath (Figure 1). CT angiogram (CTA) revealed multiple bilateral lung nodules, pleural effusion, and a large left kidney mass measuring 9.1 × 7.5 cm concerning for malignancy. Biopsy of a right pleural based mass demonstrated RCC, clear cell histology. Bone scan and plain-radiograph showed a single site of bone involvement, with a lytic lesion measuring 3.4 × 2.3 cm in the left femoral diaphysis. The patient was started on systemic therapy with pazopanib until he developed liver toxicity 2 months later. Shortly following cessation of the medication in June 2016, he again complained of dyspnea and new right foot drop. Imaging showed progression of metastatic disease with bilateral increase in size of pulmonary nodules, mediastinal lymphadenopathy, an additional osseous lesion in the pelvis, and growth of the primary lesion (Figure 2B). MRI of the brain and spinal axis revealed no cord compression, but two brain metastases in the left pre-central gyrus and left corona radiata were identified (Figure 2A). Second line therapy with nivolumab was initiated at that time. The CNS lesions, as well as two new 2 mm brain lesions in the right frontal pole and cerebellum identified at the time of treatment, were treated with gamma knife radiosurgery 20 Gy to the 50% isodose line in July 2016, after initiation of nivolumab.\n\nFigure 1 Timeline.\n\nFigure 2 (A) Pre-treatment MRI, coronal, and axial views, (B) post-SRS and immunotherapy MRI, (C) pre-treatment CT, coronal view, and (D) post-treatment CT.\n\nFour months later in October 2016, the patient had a fall and brain MRI revealed a new 5 mm left posterior parietal lesion and a small subdural hematoma. He was initially planned for further radiosurgery, however, he became symptomatic with right arm weakness, and repeat imaging revealed hematoma expansion causing mass effect on the right ventricle and midline shift, increased size of a left post-central gyrus lesion and improvement in the left posterior parietal lesion. The patient underwent surgical evacuation of the hematoma in November 2016 without local therapy for the metastases. All neurologic deficits resolved, and the patient was asymptomatic from his disease.\n\nBrain imaging in March 2017 discovered two new metastatic lesions measuring 6 mm in the left temporal lobe and 3 mm in the right frontal lobe. Due to his excellent functional status, the patient declined further radiosurgery in favor of continued immunotherapy with close monitoring. His next brain MRI in May 2017 revealed complete resolution of the two lesions (Figure 2). Therapy with nivolumab was generally well-tolerated, however, the patient did develop a grade 3 immune-mediated rash (confirmed by biopsy) in July 2017 after ~1 year on nivolumab therapy. He was treated with a prolonged steroid course, with eventual complete resolution of his rash.\n\nIn January 2018, after extensive discussion regarding the potential risks and benefits, he was re-started on nivolumab. The patient demonstrated stable disease with interval decrease in the size of the primary lesion. However, in consultation with Radiation Oncology, the decision was made to administer SBRT to the primary site. He was treated to 40 Gy in five fractions in March 2018. Nivolumab was continued until May 2018 but held at that time due to fatigue. The patient completed a total of 34 cycles of nivolumab in May 2018 and has not received additional therapy since then. The patient's most recent imaging in May 2020 showed a stable 4.6 cm left renal lesion with stable small pulmonary lesions and no other evidence of disease (Figures 2C,D).\n\nDiscussion\nPatients with mRCC have benefited from the paradigm shift brought about with the use of immune checkpoint inhibitors. However, patients with brain metastases are often excluded from these trials unless they have stable or treated disease (10, 15, 16). A subgroup analysis of patients from the phase 3 Checkmate 025 trial who continued nivolumab after progression of disease showed median OS of 22.5 months, compared to 12.3 months in subjects who were not treated beyond progression of disease (17). Although not the focus of the analysis, this cohort included patients who progressed due to brain involvement. The French expanded access trial, GETUG-AFU 26 (Nivoren), is a prospective phase II trial evaluating the efficacy and safety of nivolumab in patients with mRCC. Those with brain metastases (with or without previous focal treatment, not requiring steroids; ECOG at least 2) were followed prospectively for intracranial response rate. Seventy six (10.4%) subjects had brain metastases, 39 had not received focal treatment (cohort A), 34 had prior focal treatment (cohort B), and 3 did not undergo treatment due to performance status. Median follow up was 23.6 (95% CI = 18.1–24.6) months and 20.2 (95% CI = 16.3–22.9) months and median duration of treatment was 4.9 (range: 0.5–24.2) months and 4.5 (range 0.5–22.3) months for cohort A and B, respectively. Median intracranial PFS was 2.7 months (95% CI = 2.3–4.6) in cohort A and 4.8 months (95% CI = 3.0–8.0) in cohort B. Prior focal brain therapy, as in cohort B, decreased the risk of intracranial progression at a hazard ratio of 0.49 (95% CI = 0.26–0.92). This study highlights the role of focal treatment of brain metastases and notes that only four patients in cohort A achieved objective intracranial response. Despite the favorable intracranial PFS and lower incidence of symptoms due to brain metastases among cohort B (32% in cohort B, 49% in cohort A, there was no significant difference in 12-month overall survival (66.7% [CI = 49.6–79.1) cohort A and 58.8% [CI = 40.6–73.2] cohort B) (18, 19). The Italian expanded-access study consisted of patients who were treated with Nivolumab for a median of 7.2 months and included 32 (8.2%) patients with brain metastases that did not require steroids or radiotherapy. The median PFS was 4.4 months (95% CI = 3.7–6.2), ORR was 23.1 and 36.2% of patients had progressive disease. Overall survival at 6 and 12 months was 87 and 66.8% respectively, with median OS not reached at the time of analysis. Treatment-related adverse events were similar between the brain-metastatic patients and the overall population, but grade 3–4 toxicities were more common among those with brain metastases (12 vs. 7%) (20). These trials suggest improved outcome for brain metastatic patients with acceptable toxicity profiles. Indeed, the checkpoint 025 trial reported greater adverse events for patients treated with everolimus than with nivolumab (88%, compared with 79%) (10).\n\nRCC has historically been considered a radioresistant tumor and the role of radiation has been limited to the palliative setting (21). Radioresistance was demonstrated in vitro in a 1995 meta-analysis in which RCC was found to have the highest survival among 694 human cell lines after irradiation to a dose of 2 Gy (13). The mechanism of resistance was proposed in 2005 and highlighted the role of the HIF-1 pathway (22). A feature of RCC is its loss of function mutation/methylation in the von Hippel-Lindau (VHL) tumor suppressor gene. This results in high levels of HIF-1α expression and upregulation of VEGF and downstream proangiogenic factors that protect epithelial cells and induce radioresistance. Clinical data seemed to uphold this concept. Two prospective studies in the 1970s investigated neoadjuvant RT followed by nephrectomy vs. nephrectomy alone in the non-metastatic setting failed to improve in 5-year survival (23, 24). Studies of adjuvant RT by Kjaer et al. (25) and Finney (26) similarly failed to improve survival and in fact, the 1973 study was concerning for a significant number of patient deaths (19.6%), in part due to radiation-induced liver damage. In contrast, data from Haimovitz-Friedman et al. (27) indicated that fractions larger than 8 Gy overcame the HIF-1 mediated resistance mechanism. These higher doses activate the cell surface sphingomyelin pathway to produce ceramide and induce apoptosis, providing an alternative pathway of cell death. This was first supported in human data by a Phase I dose-escalation study by Greco et al. (28) and a retrospective analysis by Vogelbaum et al. (29) both demonstrating good locoregional control and a dose-response (14).\n\nResults from the first prospective trial to investigate the combination of multi-site SBRT in combination with pembrolizumab was reported at the 2018 ASCO-SITC Clinical Immuno-Oncology Symposium. This is a Phase I clinical trial studying the safety of SBRT and pembrolizumab in adults with advanced solid tumors who have progressed on standard of care treatment. Patients with active metastatic CNS disease were excluded from the trial. Seventy-six subjects underwent SBRT to up to four sites followed by pembrolizumab within 7 days of the final radiation treatment. Most patients (94.5%) received SBRT to two sites. Of the 76 subjects studied, only 1 case of RCC was included. Median follow up was 5.5 months. Six grade 3 toxicities were observed, including three cases of pneumonitis, two cases of colitis, and one case of hepatic failure. The ORR was 13.2%, significantly greater in irradiated than non-irradiated lesions (mean tumor diameter change 21.7% vs. 1.7%). Abscopal effect, which is immune-mediated tumor response outside of the radiation field, was observed in 13.5% of patients and was defined as a 30% reduction in the aggregate sum of nonirradiated lesions. A similar reduction in any single nonirradiated site was observed in 26.9% of patients (30). Two phase II trials evaluating the combination of immunotherapy and SBRT in mRCC were presented at the 2020 ASCO Genitourinary Cancers Symposium. The NIVES trial recruited 69 immunotherapy-naive patients with disease progression following at least two lines of anti-angiogenic therapy. Patients received SBRT 7 days following the first infusion of nivolumab and were continued on immunotherapy until disease progression or toxicity. The most common sites of SBRT were lung (37.7%), lymph nodes (11.6%), and bone (11.6%). At median follow up of 15 months, ORR was 17.4%, CR 1.4%, and disease control rate of 58%. Progression-free survival was 4.1 months, median OS was 22.07 months, and 1-year PFS and OS rates were 32.6 and 73.4%, respectively. Grade 3–4 toxicities were observed in 24.6% of patients and none of these occurred within the radiation field (31). RADVAX RCC evaluated the combination of nivolumab and ipilimumab with SBRT, with most patients having previously undergone nephrectomy (68%). The most common site for SBRT was lung (56%). Twenty-five participants were recruited and underwent SBRT to 1–2 sites between the first and second cycles of nivolumab-ipilimumab. Median follow up was 24 months. ORR was 56%, median PFS 8.21 months, and 1-year PFS rate 36%. The median OS and duration of response had not been reached. Grade 3–4 toxicities were reported in 36% of subjects (32). These two trials differed not only in single vs. dual immunotherapy regimens, but also in the radiation regimen. The RADVAX trial treated with SBRT to a dose of 50 Gy in five fractions, while the NIVES trial treated to a dose of 10 Gy in three fractions. It is not clear whether the favorable results from the RADVAX trial are due to the combination of nivolumab and ipilimumab, or more optimal dosing of SBRT. An interim analysis of CheckMate 920 features safety and efficacy results for the cohort of patients with brain metastases. Subjects who were previously untreated, had asymptomatic brain metastases not requiring steroids or radiation, and had a Karnofsky performance score of at least 70% were treated with nivolumab (3 mg/kg) and ipilumumab (1 mg/kg) every 3 weeks for four doses followed by nivolumab 480 mg every 4 weeks until disease progression or unacceptable toxicity for up to 2 years. Twenty-eight patients were enrolled with a median follow up of 6.47 months and analyzed for the primary endpoint of high-grade immune-mediated adverse events and secondary endpoints of progression free survival and objective response rate, with exploratory endpoints of safety analysis and overall survival. ORR was 28.6% (95% CI = 13.2–48.7), median PFS 9 months (CI = 2.9 – not estimable), and median OS had not been reached. There were six cases of grade 3–4 immune-mediated adverse events within 100 days of the last dose of immunotherapy. These data suggest that there may be a beneficial effect of SBRT which was reflected in results from the RADVAX trial; however, long term follow up and randomized data are required.\n\nFurther study is warranted, and future trials are underway. The CYTOSHRINK trial is a Phase II randomized trial that will include patients with advanced RCC who decline or are unsuitable for cytoreductive nephrectomy. Subjects will be randomized 2:1 to received ipilimumab or nivolumab plus SBRT (30–40 Gy in five fractions) to the primary kidney lesion vs. immunotherapy alone. The primary endpoint is the hazard ratio for PFS, and secondary endpoints are safety, OS, ORR, and health-related quality of life (NCT04090710) (33). There are several more ongoing phase I/II trials testing the use of stereotactic radiotherapy in combination with immunotherapy: NCT02864615 (SBRT in mRCC treated with targeted or immunotherapy), NCT02599779 (pembrolizumab + SBRT in TKI-refractory mRCC), NCT02781506 (nivolumab + SAbR in mRCC) (14) whose results will provide more insight into the effectiveness of such regimens for patients with RCC.\n\nThe combination of immune checkpoint inhibitors and radiation therapy may offer a pathway for achieving durable clinical response through the abscopal effect. Physiologic mechanisms responsible for the abscopal effect have been proposed primarily utilizing non-small-cell-lung-cancer (NSCLC) and melanoma as models. Twyman-Saint Victor et al. (9) utilized a B16-F10 melanoma mouse model with bilateral flank tumors and treated them with radiation to one tumor, anti-CTLA4 antibodies, or both treatments concurrently. The response rate in the concurrent treatment arm was 17%, consistent with a human phase I clinical trial in patients with metastatic melanoma, as reported by the same group. The top predictor of resistance was the CD8+/Treg ratio, which failed to increase in resistant tumors but did increase in sensitive tumors. The mechanism of resistance was not mediated by factors contributing to radiation resistance, but rather factors that blunt the expansion of CD8 T cells. Among these, the most prevalent upregulated genes in resistant tumors were PD-L1 and interferon-stimulated genes. Elimination of PD-L1 using CRISPR restored response to radiation and CTLA-4 blockade and increased survival from 0 to 60%. Elevated levels of PD-L1 have been found to contribute to T-cell exhaustion. The addition of PD-1 or PD-L1 blockade to radiation and anti-CTLA4 in the mouse models increased complete response rates to 80% and was strongly correlated with reversal of exhaustion of CD8 T cells as well as an increase in the CD8/Treg ratio. Additionally, assessment of T-cell receptors (TCR) revealed that irradiated tumors displayed increased diversity of TCR clonotypes compared to unirradiated tumors. TCR clonotype expansion was demonstrated in humans with NSCLC in a prospective study of the combination of radiation and CTLA-4 blockade (34). The study included patients who progressed after at least one prior treatment. Forty-one percent of patients on this trial had pre-existing brain metastases controlled by surgery or radiation. Patients received radiation to one metastasis and were treated with concurrent ipilimumab. The objective response rate was 33% in evaluable patients, with two patients achieving complete response. In contrast to the melanoma mouse model, in this study of human NSCLC neither PD-1 expression in pretreatment tumor nor CD8 T cell infiltration was associated with response. In addition, there was no evidence that PD-1+ T cell exhaustion was a factor in response. Instead, EGFR mutation, which is associated with poor response to PD-1/PD-L1 blockade (35), was significantly higher in patients with progressive disease than those with stable disease or partial/complete response. Similar to the melanoma mouse model, peripheral blood TCR clonotype diversity was associated with response, and had the highest predictive value. Ongoing clinical trials studying the abscopal effect in RCC include NCT02334709 (SBRT + TKI in mRCC) and NCT03469713 (NIVES trial).\n\nHere, we have presented a case of RCC with brain metastases treated successfully with radiation and immunotherapy. The patient continues to follow in clinic with stable imaging and remains off treatment for over 2 years. His survival currently exceeds expectations based on the available data and historical averages. While anecdotal, this case is impressive and shows long term control of brain metastatic RCC, as this patient has remained off treatment, suggesting a robust treatment-induced immune response. While limited in the tissue correlatives, given the patient refused subsequent biopsies, his clinical course compared to patients treated with immunotherapy alone perhaps suggests some contribution of radiation. As mentioned, additional formal clinical study of the abscopal effect in mRCC is ongoing. Future avenues for research may investigate the optimal sequencing of immunotherapy and SBRT in patients with mRCC, the appropriate combinations and duration of treatment with immunotherapeutic agents, and broader inclusion of patients with CNS disease.\n\nData Availability Statement\nThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by IRB protocol #20141135 Institutional Review Board of Washington University School of Medicine, St. Louis, MO. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nML drafted the manuscript. JO collected patient data and organized relevant radiology images. WS and DC produced radiology and histology figures. RP conceived of the idea, contributed to manuscript writing, and oversaw the project. JH and MD treated patients and provided radiation treatment data. All authors reviewed and approved the manuscript.\n\nConflict of Interest\nRP reports consulting or advisory role for EMD Serono, Bristol-Myers Squibb, Pfizer/EMD Serono, Sanofi, Jounce Therapeutics, Dendreon, Bayer, and Genomic Health; speakers' bureau for Dendreon, Merck, Genentech/Roche, AstraZeneca, Sanofi, and Genomic Health; travel, accommodations, expenses from Genentech/Roche, DAVA Oncology; and research funding from Janssen Oncology. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nWe would like to thank the patients who agreed to participate in this study.\n==== Refs\nReferences\n1. Ferlay J Soerjomataram I Dikshit R Eser S Mathers C Rebelo M . Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN\n (2012 ). Int J Cancer. (2015 ) 136 :E359 –86\n. 10.1002/ijc.29210 25220842 \n2. Howlader N Noone AM Krapcho M Miller D Brest A Yu M \nSEER Cancer Statistics Review, 1975-2016 . Bethesda, MD : National Cancer Institute (2018 ). Available online at: https://seer.cancer.gov/csr/1975_2016/\n3. Motzer RJ Bander NH Nanus DM . Renal-cell carcinoma\n. New Engl J Med. (1996 ) 335 :865 –75\n. 10.1056/NEJM199609193351207 8778606 \n4. Schouten LJ Rutten J Huveneers HAM Twijnstra A . Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma\n. Cancer. (2002 ) 94 :2698 –705\n. 10.1002/cncr.10541 12173339 \n5. Decker D Decker V Herskovic A Cummings G . Brain metastases in patients with renal cell carcinoma: prognosis and treatment\n. J Clin Oncol. (1984 ) 2 :169 –73\n. 10.1200/JCO.1984.2.3.169 6699668 \n6. Sun M Velasco GD Brastianos PK Aizer AA Martin A Moreira R . The development of brain metastases in patients with renal cell carcinoma: epidemiologic trends, survival, and clinical risk factors using a population-based cohort\n. Eur Urol Focus. (2018 ) 5 :474 –81\n. 10.1016/j.euf.2017.12.007 29311016 \n7. Stadler WM Figlin RA McDermott DF Dutcher JP Knox JJ Miller WH . Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America\n. Cancer. (2010 ) 116 :1272 –80\n. 10.1002/cncr.24864 20082451 \n8. Gore ME Hariharan S Porta C Bracarda S Hawkins R Bjarnason GA . Sunitinib in metastatic renal cell carcinoma patients with brain metastases\n. Cancer. (2011 ) 117 :501 –9\n. 10.1002/cncr.25452 20862748 \n9. Twyman-Saint Victor C Rech AJ Maity A Rengan R Pauken KE Stelekati E . Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer\n. Nature. (2015 ) 520 :373 –7\n. 10.1038/nature14292 25754329 \n10. Motzer RJ Escudier B McDermott DF George S Hammers HJ Srinivas S . Nivolumab versus everolimus in advanced renal-cell carcinoma\n. N Engl J Med. (2015 ) 373 :1803 –13\n. 10.1056/NEJMoa1510665 26406148 \n11. Hanna KS . A review of checkpoint inhibitors in the management of renal cell carcinoma\n. J Oncol Pharm Pract. (2019 ) 26 :445 –58\n. 10.1177/1078155219881178 31631812 \n12. Motzer RJ Jonasch E Agarwal N Bhayani S Bro WP Chang SS . Kidney Cancer, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology\n. J National Compr Cancer Netw Jnccn. (2017 ) 15 :804 –34\n. 10.6004/jnccn.2017.0100 28596261 \n13. Deschavanne PJ Fertil B . A review of human cell radiosensitivity in vitro\n. Int J Radiat Oncol Biol Phys. (1996 ) 34 :251 –66\n. 10.1016/0360-3016(95)02029-2 12118559 \n14. Felice FD Tombolini V . Radiation therapy in renal cell carcinoma\n. Crit Rev Oncol Hemat. (2018 ) 128 :82 –7\n. 10.1016/j.critrevonc.2018.06.002 29958634 \n15. Motzer RJ Tannir NM McDermott DF Frontera O Melichar B Choueiri TK . Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma\n. N Engl J Med. (2018 ) 378 :1277 –90\n. 10.1056/NEJMoa1712126 29562145 \n16. Motzer RJ Rini BI McDermott DF Redman BG Kuzel TM Harrison MR . Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial\n. J Clin Oncol. (2014 ) 33 :1430 –7\n. 10.1200/JCO.2014.59.0703 25452452 \n17. George S Motzer RJ Hammers HJ Redman BG Kuzel TM Tykodi SS . Safety and efficacy of nivolumab in patients with metastatic renal cell carcinoma treated beyond progression: a subgroup analysis of a randomized clinical trial\n. JAMA Oncol. (2016 ) 2 :1179 . 10.1001/jamaoncol.2016.0775 27243803 \n18. Flippot R Dalban C Laguerre B Borchiellini D Gravis G Négrier S . Safety and efficacy of nivolumab in brain metastases from renal cell carcinoma: results of the GETUG-AFU 26 NIVOREN multicenter phase II study\n. J Clin Oncol. (2019 ) 37 :2008 –16\n. 10.1200/JCO.18.02218 31194611 \n19. Escudier BJ Motzer RJ Sharma P Wagstaff J Plimack ER Hammers HJ \nTreatment beyond progression with nivolumab (nivo) in patients (pts) with advanced renal cell carcinoma (aRCC) in the phase III CheckMate 025 study\n. J Clin Oncol. (2016 ) 34 :4509 \n10.1200/JCO.2016.34.15_suppl.4509 \n20. Giorgi UD Cartenì G Giannarelli D Basso U Galli L Cortesi E . Safety and efficacy of nivolumab for metastatic renal cell carcinoma: real-world results from an expanded access programme\n. BJU Int. (2019 ) 123 :98 –105\n. 10.1111/bju.14461 29956884 \n21. Motzer RJ Jonasch E Michaelson MD Nandagopal L Gore JL George S \nNCCN guidelines insights: kidney cancer, Version 2\n.2020. J National Compr Cancer Netw. (2019 ) 17 :1278 –85\n. 10.6004/jnccn.2019.0054 \n22. Moeller BJ Cao Y Li CY Dewhirst MW . Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors role of reoxygenation, free radicals, and stress granules\n. Cancer Cell. (2004 ) 5 :429 –41\n. 10.1016/S1535-6108(04)00115-1 15144951 \n23. van der Werf-Messing B . Carcinoma of the kidney\n. Cancer . (1973 ) 32 :1056 –61\n. 10.1002/1097-0142(197311)32:5<1056::AID-CNCR2820320505>3.0.CO;2-M 4757899 \n24. Juusela H Malmio K Alfthan O Oravisto KJ . Preoperative irradiation in the treatment of renal adenocarcinoma\n. Scand J Urol Nephrol. (2010 ) 11 :277 –81\n. 10.3109/00365597709179965 594674 \n25. Kjaer M Iversen P Hvidt V Bruun E Skaarup P Hansen JB . A randomized trial of postoperative radiotherapy versus observation in stage II and III renal adenocarcinoma\n. Scand J Urol Nephrol. (1987 ) 21 :285 –9\n. 10.3109/00365598709180784 3445125 \n26. Finney R . The value of radiotherapy in the treatment of hypernephroma-a clinical trial\n. Br J Urol. (1973 ) 45 :258 –69\n. 10.1111/j.1464-410X.1973.tb12152.x 4712834 \n27. Haimovitz-Friedman A Kan CC Ehleiter D Persaud RS McLoughlin M Fuks Z . Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis\n. J Exp Med. (1994 ) 180 :525 –35\n. 10.1084/jem.180.2.525 8046331 \n28. Greco C Zelefsky MJ Lovelock M Fuks Z Hunt M Rosenzweig K . Predictors of local control after single-dose stereotactic image-guided intensity-modulated radiotherapy for extracranial metastases\n. Int J Radiat Oncol Biology Phys . (2011 ) 79 :1151 –7\n. 10.1016/j.ijrobp.2009.12.038 20510537 \n29. Vogelbaum MA Angelov L Lee S-Y Li L Barnett GH Suh JH . Local control of brain metastases by stereotactic radiosurgery in relation to dose to the tumor margin\n. J Neurosurg . (2006 ) 104 :907 –12\n. 10.3171/jns.2006.104.6.907 16776334 \n30. Luke JJ Lemons JM Karrison TG Pitroda SP Melotek JM Zha Y . Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors\n. J Clin Oncol. (2018 ) 36 :1611 –8\n. 10.1200/JCO.2017.76.2229 29437535 \n31. Masini C MD \nNivolumab (NIVO) in combination with stereotactic body radiotherapy (SBRT) in pretreated patients (pts) with metastatic renal cell carcinoma (mRCC): first results of phase II NIVES study\n. In: 2020 Genitourinary Cancers Symposium . (2020 ). Available online at: https://meetinglibrary.asco.org/record/183202/abstract (cited February 24, 2020).\n32. Hammers HJ \nCombination of dual immune checkpoint inhibition (ICI) with stereotactic radiation (SBRT) in metastatic renal cell carcinoma (mRCC) (RADVAX RCC)\n. In: 2020 Genitourinary Cancers Symposium (2020 ). Available online at: https://meetinglibrary.asco.org/record/183203/abstract (cited Feb 24, 2020).\n33. Lalani A-KA Swaminath A Pond GR Kapoor A Chu W Bramson JL \nPhase II trial of cytoreductive stereotactic hypofractionated radiotherapy with combination ipilimumab/nivolumab for metastatic kidney cancer (CYTOSHRINK)\n. In: San Francisco, CA (2020 ). Available online at: https://meetinglibrary.asco.org/record/183756/abstract\n10.1200/JCO.2020.38.6_suppl.TPS761 \n34. Formenti SC Rudqvist N-P Golden E Cooper B Wennerberg E Lhuillier C . Radiotherapy induces responses of lung cancer to CTLA-4 blockade\n. Nat Med. (2018 ) 24 :1845 –51\n. 10.1038/s41591-018-0232-2 30397353 \n35. Gainor JF Shaw AT Sequist LV Fu X Azzoli CG Piotrowska Z . EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis\n. Clin Cancer Res. (2016 ) 22 :4585 –93\n. 10.1158/1078-0432.CCR-15-3101 27225694\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "10()",
"journal": "Frontiers in oncology",
"keywords": "SBRT (stereotactic body radiation therapy); abscopal; brain metastases (BMs); immunotherapy; renal cell carcinoma (RCC)",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "566070",
"pmc": null,
"pmid": "33072598",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "26406148;27225694;25220842;31631812;12173339;29958634;30397353;29437535;20082451;31693980;6699668;20862748;29311016;31194611;4757899;8778606;20510537;29562145;3445125;27243803;29956884;12118559;4712834;25452452;25754329;15144951;28596261;8046331;594674;16776334",
"title": "Radiation and Checkpoint Inhibitor Immunotherapy Lead to Long Term Disease Control in a Metastatic RCC patient With Brain Metastases.",
"title_normalized": "radiation and checkpoint inhibitor immunotherapy lead to long term disease control in a metastatic rcc patient with brain metastases"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-046752",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "BACKGROUND\nPosterior fossa (PF) ependymomas (EPNs) in infants less than 1 year of age (iEPN-PF) have a poorer clinical outcome than EPNs in older children. While radiation therapy is the standard of care for the latter, it is withheld in infants to avoid neurotoxicity to immature brain. It is unknown whether the adverse outcome in iEPN-PFs is due to treatment differences or aggressive biology. We examined this question using molecular profiling.\n\n\nMETHODS\nSix anaplastic iEPN-PFs were subjected to transcriptomic analysis and FISH for p16 loss and gains of 1q, and compared with anaplastic PF EPNs from older children. Results were validated by immunohistochemistry (IHC).\n\n\nRESULTS\nAll six iEPN-PFs were grouped within EPN PF subgroup A (PFA). E2F targets and G2M checkpoint were identified as the most enriched gene sets in iEPN-PF, which was validated in a larger independent cohort. Accordingly, MIB-1 IHC demonstrated a higher mitotic rate in iEPN-PFs than noninfant anaplastic EPN PFA. Genetic and protein analyses demonstrated that p16 loss and low p16 protein expression is a hallmark of iEPN-PF, and that none harbored 1q gains. Kaplan-Meier analysis confirmed the poorer clinical outcome of the iEPN-PF cohort.\n\n\nCONCLUSIONS\nBiological differences, characterized by loss of p16 expression without gains of 1q in iEPN-PFs, as well as deregulated E2F target gene transcription, are indicative of deregulated p16-CDK4/6-pRB-E2F pathway activity. This may underlie the poor clinical outcome seen in this group of iEPN-PFs, rather than the withholding of radiation therapy. Results suggest a potential actionable therapy for iEPN-PF, namely cyclin-dependent kinase 4/6 (CDK4/6) inhibitors.",
"affiliations": "Department of Pathology, The University of Colorado School of Medicine, Aurora, Colorado.;Children's Hospital Colorado, Aurora, Colorado.;Department of Pediatrics, The University of Colorado School of Medicine, Aurora, Colorado.;Department of Pediatrics, The University of Colorado School of Medicine, Aurora, Colorado.;Children's Hospital Colorado, Aurora, Colorado.;Children's Hospital Colorado, Aurora, Colorado.;Department of Pathology, The University of Colorado School of Medicine, Aurora, Colorado.",
"authors": "Lummus|Seth C|SC|;Donson|Andrew M|AM|;Gowan|Katherine|K|;Jones|Kenneth L|KL|;Vibhakar|Rajeev|R|;Foreman|Nicholas K|NK|;Kleinschmidt-DeMasters|B K|BK|http://orcid.org/0000-0002-4471-1678",
"chemical_list": "D050684:E2F Transcription Factors",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.26656",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "64(12)",
"journal": "Pediatric blood & cancer",
"keywords": "E2F; ependymoma; infant; mitosis; p16",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000367:Age Factors; D002453:Cell Cycle; D016543:Central Nervous System Neoplasms; D002675:Child, Preschool; D050684:E2F Transcription Factors; D004806:Ependymoma; D005260:Female; D020869:Gene Expression Profiling; D019942:Genes, p16; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28548702",
"pubdate": "2017-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "22322993;21840481;21654818;25968456;22338015;11943886;26971296;10550587;24314616;18084249;16609018;21636552;25398846;9888153;26649278;20516456;27397505;14631364;16575538;19531565;16874765;11752295;22711607;20951942;25965575;8633069;25563815;21278246;25586788;25417786;21627842",
"title": "p16 Loss and E2F/cell cycle deregulation in infant posterior fossa ependymoma.",
"title_normalized": "p16 loss and e2f cell cycle deregulation in infant posterior fossa ependymoma"
} | [
{
"companynumb": "PHHY2017US079525",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LAPATINIB"
},
"drugadditional": null,
"druga... |
{
"abstract": "OBJECTIVE\nTo understand the clinical features of osteonecrosis of the jaw after bisphosphonates use for therapy of breast cancer patients with bone metastasis.\n\n\nMETHODS\nThe cases diagnosed as bisphosphonates-related osteonecrosis of the jaws (BRONJ) were retrospectively analyzed from January 2011 to August 2015 in the Peking University School and Hospital of Stomatology, and those breast cancer patients with bone metastasis were selected. The clinical symptoms, imaging characteristics and treatment results were summarized.\n\n\nRESULTS\nA total of 14 cases of breast cancer patients with bone metastasis were selected, with an average age of 60.21 years. The average time of suffering from breast cancer was 9.77 years, and the average time of bone metastasis and bisphosphonates drugs use was 5.67 and 3.29 years individually. There was no patient with systemic application history of hormone therapy, and no history of diabetes. There were 9 patients with tooth extractions history, and the mean time of bone necrosis symptoms was 8.58 months. There were 10 cases with bone necrosis occurring on mandible, 3 cases on maxilla, and one case with both upper and lower jaws involved. Among the 10 patients with surgical treatment, there were 3 cases cured, and 6 cases improved. However, the clinical symptoms of 2 cases with conservative treatment were significantly aggravated.\n\n\nCONCLUSIONS\nThe medication time between the bisphosphonates use beginning and the occurrence of BRONJ is relatively long. The history of diabetes and long-time hormone use did not exist in this group. Tooth extraction itself does not determine the severity of BRONJ. Mandible is the most common site involved by BRONJ. Surgical treatment can alleviate the clinical symptoms of BRONJ with breast cancer to some extent.",
"affiliations": "Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China.;Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China.;Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China.;Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China.;Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China.;Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China.",
"authors": "Guo|Yu-xing|YX|;Wang|Dian-can|DC|;Wang|Yang|Y|;Peng|Xin|X|;Mao|Chi|C|;Guo|Chuan-bin|CB|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1671-167X",
"issue": "48(1)",
"journal": "Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences",
"keywords": null,
"medline_ta": "Beijing Da Xue Xue Bao Yi Xue Ban",
"mesh_terms": "D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D001859:Bone Neoplasms; D001943:Breast Neoplasms; D003920:Diabetes Mellitus; D004164:Diphosphonates; D005260:Female; D006801:Humans; D008334:Mandible; D008437:Maxilla; D008875:Middle Aged; D012189:Retrospective Studies; D014081:Tooth Extraction; D016896:Treatment Outcome",
"nlm_unique_id": "101125284",
"other_id": null,
"pages": "80-3",
"pmc": null,
"pmid": "26885913",
"pubdate": "2016-02-18",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Clinical features of osteonecrosis of jaws after bisphosphonates therapy for bone metastasis of breast cancer.",
"title_normalized": "clinical features of osteonecrosis of jaws after bisphosphonates therapy for bone metastasis of breast cancer"
} | [
{
"companynumb": "PHHY2016CN033059",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PAMIDRONATE DISODIUM"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThiopurine-induced leukopenia is a relatively common adverse event related to thiopurine medication in Korean pediatric Crohn's disease. In addition to the mutations of TPMT gene, the NUDT15 c.415C>T variant was recently identified to have a strong association with thiopurine-induced early leukopenia. We conducted this study to define the incidence of azathioprine (AZA)-related leukopenia and to determine the incidence and characteristics of their genetic variants in Korean pediatric Crohn's disease patients.\n\n\nMETHODS\nPatients diagnosed with pediatric Crohn's disease who had used AZA for more than 3 months were recruited. The dose and duration of medication and data regarding adverse events including leukopenia were collected. TPMT and NUDT15 gene sequencing was performed for patients who had experienced AZA-induced leukopenia.\n\n\nRESULTS\nA total of 81 patients had used AZA as a maintenance therapy of Crohn's disease. The mean dose of AZA was 1.88±0.39 mg/kg/day. Nine patients (11.1%) experienced AZA-induced leukopenia, and eight patients (9.9%) experienced AZA-induced early leukopenia. Among the eight early leukopenia patients, six patients (75.0%) harbored the NUDT15 c.415C>T variant and one patient (12.5%) had the TPMT c.719A>G (TPMT*3C) variant. All the three patients with NUDT15 c.415C>T homozygous variant suffered from alopecia totalis, and two of them experienced severe systemic infection. Three patients with the NUDT15 heterozygous variant are currently treated with AZA at a dose of 0.76 mg/kg/day.\n\n\nCONCLUSIONS\nMutations of the NUDT15 and TPMT gene accounted for ∼88% of cases with thiopurine-induced early leukopenia. Extensive hair loss was a recognizable early symptom in patients with the homozygous NUDT15 c.415C>T variant. Sequencing of the NUDT15 genes can guide the clinicians before thiopurine medication. An alternative immunosuppressive medication is recommended for patients with homozygous NUDT15 c.415C>T variant. For those with the heterozygous variant, half the usual dose of AZA can achieve efficacy comparable to that for wild-type patients.",
"affiliations": "aDepartment of Pediatrics, Pusan National University Children's Hospital, Pusan National University School of Medicine bDepartment of Neurology cLaboratory of Molecular Neurology, Pusan National University Yangsan Hospital, Yangsan dDepartment of Neurology, University of Ulsan, College of Medicine, Ulsan, Korea.",
"authors": "Lee|Yeoun Joo|YJ|;Hwang|Eun Ha|EH|;Park|Jae Hong|JH|;Shin|Jin-Hong|JH|;Kang|Boram|B|;Kim|Sun-Young|SY|",
"chemical_list": "D005765:Gastrointestinal Agents; D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; C543721:NUDT15 protein, human; D011755:Pyrophosphatases; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.1097/MEG.0000000000000564",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-691X",
"issue": "28(4)",
"journal": "European journal of gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Eur J Gastroenterol Hepatol",
"mesh_terms": "D000367:Age Factors; D000505:Alopecia; D044466:Asians; D001379:Azathioprine; D003424:Crohn Disease; D005260:Female; D005765:Gastrointestinal Agents; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007166:Immunosuppressive Agents; D015994:Incidence; D007970:Leukopenia; D008297:Male; D008780:Methyltransferases; D010641:Phenotype; D011110:Polymorphism, Genetic; D011755:Pyrophosphatases; D056910:Republic of Korea; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "9000874",
"other_id": null,
"pages": "475-8",
"pmc": null,
"pmid": "26735160",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "NUDT15 variant is the most common variant associated with thiopurine-induced early leukopenia and alopecia in Korean pediatric patients with Crohn's disease.",
"title_normalized": "nudt15 variant is the most common variant associated with thiopurine induced early leukopenia and alopecia in korean pediatric patients with crohn s disease"
} | [
{
"companynumb": "KR-MYLANLABS-2016M1017576",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nIn this study we report our experience in the management of Splenic Artery Aneurysm (SAA), diagnosed during pregnancy.\n\n\nMETHODS\nThe current manuscript describes three different events, treated in out our department, involving SAAs diagnosed during pregnancy. Each case presents an unusual course and a unique clinical challenge.\n\n\nRESULTS\nThe first case is of a 25 week's gestation twin pregnancy with ruptured SAA ending in maternal and fetal death. Another case of SAA rupture presented at 27 week's gestation with consequent emergency cesarean section and splenectomy. In the last case, two SAAs were incidentally diagnosed at 25 weeks' singleton gestation. The patient was managed conservatively and delivered by an elective cesarean section at 34 weeks followed by postpartum angiographic embolization of the aneurysms.\n\n\nCONCLUSIONS\nHealth care providers and especially obstetricians should be aware of the diagnosis of ruptured SAA in a pregnant woman with abdominal discomfort and hemodynamic deterioration. In addition, once an asymptomatic pregnant patient is diagnosed with a SAA, conservative surveillance may be allowed.",
"affiliations": "Departments of Obstetrics and Gynecology, The Yitzhak Shamir Medical Center (formerly Assaf Harofeh Medical Center), Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Zerifin, 70300, Israel. Electronic address: wiener_yi@mac.org.il.;Departments of Obstetrics and Gynecology, The Yitzhak Shamir Medical Center (formerly Assaf Harofeh Medical Center), Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Zerifin, 70300, Israel.;Departments of Obstetrics and Gynecology, The Yitzhak Shamir Medical Center (formerly Assaf Harofeh Medical Center), Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Zerifin, 70300, Israel.;Department of Interventional Radiology, The Yitzhak Shamir Medical Center (formerly Assaf Harofeh Medical Center), Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Zerifin, 70300, Israel.;Department of Vascular Surgery, The Yitzhak Shamir Medical Center (formerly Assaf Harofeh Medical Center), Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Zerifin, 70300, Israel.;Departments of Obstetrics and Gynecology, The Yitzhak Shamir Medical Center (formerly Assaf Harofeh Medical Center), Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Zerifin, 70300, Israel.;Departments of Obstetrics and Gynecology, The Yitzhak Shamir Medical Center (formerly Assaf Harofeh Medical Center), Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Zerifin, 70300, Israel.",
"authors": "Wiener|Yifat|Y|;Tomashev|Roni|R|;Neeman|Ortal|O|;Itzhakov|Zalman|Z|;Heldenberg|Eitan|E|;Melcer|Yaakov|Y|;Maymon|Ron|R|",
"chemical_list": null,
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.ejogrb.2019.04.029",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-2115",
"issue": "237()",
"journal": "European journal of obstetrics, gynecology, and reproductive biology",
"keywords": "Conservative management; Pregnancy; Splenic artery aneurysm; Ultrasound",
"medline_ta": "Eur J Obstet Gynecol Reprod Biol",
"mesh_terms": "D000783:Aneurysm; D004621:Embolization, Therapeutic; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D013156:Splenectomy; D013157:Splenic Artery",
"nlm_unique_id": "0375672",
"other_id": null,
"pages": "121-125",
"pmc": null,
"pmid": "31035119",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Splenic artery aneurysms during pregnancy: An obstetric nightmare.",
"title_normalized": "splenic artery aneurysms during pregnancy an obstetric nightmare"
} | [
{
"companynumb": "PHHY2019IL117831",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "INDOMETHACIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Cerebral toxoplasmosis is a rare, potentially fatal, complication of hematopoietic cell transplantation. Early definitive diagnosis is very difficult and it may be associated with a poor prognosis. Herein, we describe a 60-year-old woman who developed cerebral toxoplasmosis after cord blood transplantation for myelodysplastic syndrome. During treatment with tacrolimus and methylprednisolone for relapsed grade 2 acute gut GVHD, fever and disturbance of consciousness occurred on day 210. Brain MRI showed multiple ring-enhancing nodular lesions in the thalamus, basal ganglia, brainstem, and subcortical white matter. Cerebrospinal fluid (CSF) assessment revealed elevations of both anti-to-xoplasma IgM and IgG, which were also elevated in serum, but no evidence of other infections or malignancies. Notably, the IgM level was higher in the CSF than in serum. Thus, cerebral toxoplasmosis was diagnosed. Soon after administration of oral sulfamethoxazole/trimethoprim and intravenous clindamycin in combination with short-term dexamethasone for the cerebral edema, her symptoms and signs began to improve. On day 229, both IgM and IgG titers in CSF had clearly decreased but remained essentially constant in serum. She was discharged without clinically significant neurological disorders. This case suggests that CSF specific anti-toxoplasma IgM titers might be useful for early diagnosis of cerebral toxoplasmosis after transplantation.",
"affiliations": "Department of Hematology, Graduate School of Medicine, Osaka City University.",
"authors": "Inaba|Akiko|A|;Koh|Hideo|H|;Nakashima|Yasuhiro|Y|;Nishimoto|Mitsutaka|M|;Hayashi|Yoshiki|Y|;Okamura|Hiroshi|H|;Inoue|Atsushi|A|;Nanno|Satoru|S|;Nakane|Takahiko|T|;Shimono|Taro|T|;Nakamae|Hirohisa|H|;Hino|Masayuki|M|",
"chemical_list": "D000913:Antibodies, Protozoan; D015415:Biomarkers; D007075:Immunoglobulin M; D002981:Clindamycin; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D016559:Tacrolimus; D008775:Methylprednisolone",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "55(4)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": null,
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000913:Antibodies, Protozoan; D015415:Biomarkers; D002981:Clindamycin; D036101:Cord Blood Stem Cell Transplantation; D042241:Early Diagnosis; D005260:Female; D006086:Graft vs Host Disease; D006801:Humans; D016867:Immunocompromised Host; D007075:Immunoglobulin M; D008775:Methylprednisolone; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D016559:Tacrolimus; D014122:Toxoplasma; D016781:Toxoplasmosis, Cerebral; D016896:Treatment Outcome; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "456-60",
"pmc": null,
"pmid": "24850458",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cerebral toxoplasmosis after umbilical cord blood transplantation diagnosed by the detection of anti-toxoplasma specific IgM antibody in cerebrospinal fluid.",
"title_normalized": "cerebral toxoplasmosis after umbilical cord blood transplantation diagnosed by the detection of anti toxoplasma specific igm antibody in cerebrospinal fluid"
} | [
{
"companynumb": "JP-WATSON-2014-20240",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Tapentadol (TAP) is an analgesic agent indicated for the management of different types of pain. It has a novel mechanism of action in that it induces analgesia via both μ-opioid receptor agonism and norepinephrine reuptake inhibition. Although deaths associated with TAP use have been reported, there is a paucity of published literature regarding TAP concentrations in biological samples obtained from TAP-associated fatalities. We report a case of TAP toxicity resulting in death with postmortem peripheral and central blood concentrations, liver, vitreous, urine, and gastric contents. A 41-year-old female was found slumped over a sink at home following a welfare check by police. She was transported to a local hospital where she was pronounced dead despite all resuscitative measures. The autopsy was remarkable only for pulmonary edema and signs of aspiration pneumonia. Postmortem concentrations of TAP were confirmed in peripheral blood at 1.1mg/L, central blood 1.3mg/L, liver 9.9mg/kg, vitreous humor 0.94mg/L, urine 88mg/L, and the gastric contained 2mg. Also of note, oxycodone was found in the decedent's blood at a concentration of 0.58mg/L. We report a death related to an intentional ingestion of TAP and oxycodone-the cause and manner of death were determined to be mixed drug intoxication; suicide. We hope that the variety of TAP concentrations identified in this case provide valuable points of reference for future cases of TAP intoxication.",
"affiliations": "California Poison Control System, San Diego Division, Clinical Pharmacy, University of California, San Francisco, 200 W. Arbor Dr., San Diego, CA 92103-8925, USA. Electronic address: lcantrell@calpoison.org.;County of San Diego Medical Examiner's Department, 5570 Overland Ave., Suite 101, San Diego, CA 92123, USA.;County of San Diego Medical Examiner's Department, 5570 Overland Ave., Suite 101, San Diego, CA 92123, USA.;County of San Diego Medical Examiner's Department, 5570 Overland Ave., Suite 101, San Diego, CA 92123, USA.;County of San Diego Medical Examiner's Department, 5570 Overland Ave., Suite 101, San Diego, CA 92123, USA.",
"authors": "Cantrell|F Lee|FL|;Mallett|Phyllis|P|;Aldridge|Lenore|L|;Verilhac|Kimi|K|;McIntyre|Iain M|IM|",
"chemical_list": "D000701:Analgesics, Opioid; D010636:Phenols; D010098:Oxycodone; D000077432:Tapentadol",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2016.08.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "266()",
"journal": "Forensic science international",
"keywords": "Fatality; Liver; Postmortem blood; Postmortem redistribution; Tapentadol",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D005260:Female; D005766:Gastrointestinal Contents; D006801:Humans; D008099:Liver; D010098:Oxycodone; D010636:Phenols; D013405:Suicide; D000077432:Tapentadol; D014822:Vitreous Body",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "e1-e3",
"pmc": null,
"pmid": "27568082",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A tapentadol related fatality: Case report with postmortem concentrations.",
"title_normalized": "a tapentadol related fatality case report with postmortem concentrations"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-16-02302",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TAPENTADOL"
},
"... |
{
"abstract": "M. abscessus is a rapidly growing mycobacteria (RGM) and is the most common cause of pulmonary RGM infection. M. abscessus pleurisy is extremely rare. We herein report the case of a young patient with M. abscessus pleurisy without any lung lesions. A laboratory analysis of the pleural effusion revealed lymphocyte predominance and increased adenosine deaminase, similar to the findings observed in tuberculous pleurisy. The patient was initially treated for tuberculous pleurisy, which resulted in the partial improvement of the patient's symptoms and pleural effusion. M. abscessus pleurisy should be considered, especially in immunocompromised individuals, even in the absence of pulmonary involvement.",
"affiliations": "Department of Respiratory Medicine, Wakamatsu Hospital of the University of Occupational and Environmental Health, Japan.;The First Department of Internal Medicine, Wakamatsu Hospital of the University of Occupational and Environmental Health, Japan.;The First Department of Internal Medicine, Wakamatsu Hospital of the University of Occupational and Environmental Health, Japan.;Department of Respiratory Medicine, Wakamatsu Hospital of the University of Occupational and Environmental Health, Japan.;Department of Respiratory Medicine, Wakamatsu Hospital of the University of Occupational and Environmental Health, Japan.;The First Department of Internal Medicine, Wakamatsu Hospital of the University of Occupational and Environmental Health, Japan.;Department of Respiratory Medicine, Yamaguchi-ken Saiseikai Shimonoseki General Hospital, Japan.;Department of Respiratory Medicine, Wakamatsu Hospital of the University of Occupational and Environmental Health, Japan.;Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan.",
"authors": "Noguchi|Shingo|S|;Hanami|Kentaro|K|;Miyata|Hiroko|H|;Torii|Ryo|R|;Shimabukuro|Ikuko|I|;Kubo|Satoshi|S|;Obata|Hideto|H|;Yoshii|Chiharu|C|;Yatera|Kazuhiro|K|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D007136:Immunoglobulins",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.9537-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2926965810.2169/internalmedicine.9537-17Case ReportPleurisy Caused by Mycobacterium abscessus in a Young Patient with Dermatomyositis: A Case Report and Brief Review of the Literature Noguchi Shingo 1Hanami Kentaro 2Miyata Hiroko 2Torii Ryo 1Shimabukuro Ikuko 1Kubo Satoshi 2Obata Hideto 3Yoshii Chiharu 1Yatera Kazuhiro 4\n1 Department of Respiratory Medicine, Wakamatsu Hospital of the University of Occupational and Environmental Health, Japan\n2 The First Department of Internal Medicine, Wakamatsu Hospital of the University of Occupational and Environmental Health, Japan\n3 Department of Respiratory Medicine, Yamaguchi-ken Saiseikai Shimonoseki General Hospital, Japan\n4 Department of Respiratory Medicine, University of Occupational and Environmental Health, JapanCorrespondence to Dr. Shingo Noguchi, sn0920@med.uoeh-u.ac.jp\n\n21 12 2017 1 4 2018 57 7 997 1002 19 5 2017 7 8 2017 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article 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/).M. abscessus is a rapidly growing mycobacteria (RGM) and is the most common cause of pulmonary RGM infection. M. abscessus pleurisy is extremely rare. We herein report the case of a young patient with M. abscessus pleurisy without any lung lesions. A laboratory analysis of the pleural effusion revealed lymphocyte predominance and increased adenosine deaminase, similar to the findings observed in tuberculous pleurisy. The patient was initially treated for tuberculous pleurisy, which resulted in the partial improvement of the patient's symptoms and pleural effusion. M. abscessus pleurisy should be considered, especially in immunocompromised individuals, even in the absence of pulmonary involvement. \n\nMycobacterium abscessuspleurisydermatomyositis\n==== Body\nIntroduction\nThe rate of nontuberculous mycobacteria (NTM) infection has been increasing worldwide (1-3). The pulmonary diseases associated with NTM infection are commonly caused by Mycobacterium avium-intracellulare complex (MAC) and M. kansasii, which are slow-growing species (1).\n\nRecently, lung diseases caused by rapidly growing mycobacteria (RGM) have often been recognized in patients with NTM infection. M. abscessus (formerly M. chelonae subspecies abscessus) is the most common cause of pulmonary infection by RGM and has been increasingly commonly identified as a pathogen in both healthy and immunocompromised hosts (1, 4). Morimoto et al. reported that pulmonary M. abscessus disease accounted for 2.6% of the pulmonary infections caused by NTM and that the incidence of M. abscessus disease was highest in the Kyushu-Okinawa area in a large laboratory-based analysis of Japan (5).\n\nPleurisy caused by NTM is relatively rare. It is reported to account for only 5% of pulmonary NTM infections (1, 6). In cases of NTM pleurisy, the most frequently identified pathogen is MAC. Thus far, there have only been a few reported cases of RGM pleurisy, which is suggested to be extremely rare (7-11).\n\nWe herein report a case of pleurisy caused by M. abscessus without infectious lung lesions in a young patient who was undergoing corticosteroid treatment for dermatomyositis.\n\nCase Report\nA 28-year-old Japanese man was admitted to our hospital in November 2016 due to a high-grade fever of 38.0-40.0℃ that had persisted for 1 week. The patient had received prednisolone treatment for dermatomyositis at a starting dose of 50 mg since October 2014. The dose had been tapered to 10 mg in October 2016. He was a never-smoker, and he had no history of traumatic injury. In addition, he had no family history of chronic lung or collagen disease.\n\nOn admission, the patient's height and body weight were 167.0 cm and 66.1 kg, respectively. A physical examination revealed the following findings: body temperature, 37.6℃; heart rate, 80 beats/min; blood pressure, 117/64 mmHg; and oxygen saturation, 95% in room air. On auscultation, the respiratory sounds in the right lower lung field were weak. In addition, facial flushing, Gottron-like eruption, and Raynaud syndrome of the maniphalanx were observed; however, these findings were not obviously aggravated in comparison to the time in which he was afebrile, before the dose of prednisolone had been reduced (from 11 mg/day to 10 mg/day). The laboratory findings on admission (Table 1) demonstrated a normal white blood cell count (6,400 /μL) and creatinine kinase level (62 IU/L) but an elevated C-reactive protein level (CRP) (10.79 mg/dL). The patient was negative for anti-Jo-1 and anti-aminoacyl tRNA synthase antibodies. In addition, the results of an interferon-gamma releasing assay (IGRA) for M. tuberculosis (T-SPOTⓇ), anti-MAC antibodies, β-D glucan, and C7-horseradish peroxidase (HRP) were all within the normal ranges. Chest X-ray on admission showed right pleural effusion (Fig. 1), and chest computed tomography (CT) on admission also demonstrated right pleural effusion with no abnormal pulmonary or lymph node lesions (Fig. 2A, B and C). The right pleural effusion was a purulent pale yellow color. A laboratory analysis of the pleural effusion demonstrated lymphocyte predominance (54%) and a marked increase in the lactic acid dehydrogenase level (1,919 IU/L) (Table 2). In addition, no bacteria were detected in bacterial cultures or by Ziehl-Neelsen staining of the pleural effusion. At 1 week after admission, an analysis of the pleural effusion revealed that the adenosine deaminase (ADA) level was increased (132.7 U/L).\n\nTable 1. The Results of the Peripheral Blood Analysis on Admission.\n\n<Blood cell counts>\t<Blood chemistry>\t<Serology>\t<Infection>\t\nWBC\t6,400\t/μL\tTP\t7.2\tg/dL\tCRP\t10.79\tmg/dL\tIGRA\t(-)\t\t\nNeut\t84\t%\tAlb\t3.6\tg/dL\t\t\t\tAnti MAC antibody\t(-)\t\t\nLymph\t10\t%\tT-bil\t0.3\tmg/dL\tAnti-nuclear antibody\t<40\t\t\t\t\t\nEos\t1.0\t%\tAST\t26\tIU/L\tAnti ds-DNA antibody\t2.0\tIU/mL\tβ-D glucan\t<6.0\tpq/mL\t\nRBC\t413×104\t/μL\tALT\t28\tIU/L\tAnti Sm antibody\t1.3\tU/mL\tAspergillus antigen\t0.1\t\t\nHb\t12.5\tg/dL\tLDH\t247\tIU/L\tAnti Scl-70 antibody\t<1.0\tU/mL\tC7-HRP\t(-)\t\t\nHt\t36.7\t%\tALP\t298\tIU/L\tAnti Jo-1 antibody\t(-)\t\tHIV antibody\t(-)\t\t\nPlt\t20.9×104\t/μL\tγ-GTP\t69\tIU/L\tAnti centromere antibody\t<5.0\t\t\t\t\t\n\t\t\tBUN\t17\tmg/dL\tAnti RNP antibody\t<2.0\tU/mL\t\t\t\t\nESR\t74\tmm/h\tCre\t0.51\tmg/dL\tAnti ARS antibody\t(-)\t\t\t\t\t\n\t\t\tNa\t141\tmEq/L\tMPO-ANCA\t<10\t\t\t\t\t\n\t\t\tK\t4\tmEq/L\tPR3-ANCA\t<10\t\t\t\t\t\n\t\t\tCK\t62\tIU/L\t\t\t\t\t\t\t\nIGRA: interferon-gamma-releasing assay\n\nFigure 1. Chest X-ray obtained on admission showed right pleural effusion and no abnormal shadows in the bilateral lung fields.\n\nFigure 2. Chest computed tomography (CT) obtained on admission (November, 2016) (A, B and C) revealed right pleural effusion but no abnormal findings in the bilateral lung fields or lymph nodes. Chest CT performed at two months after the start of antimicrobial treatment (INH, RFP, EB, PZA) (January, 2017) (D, E and F) demonstrated a decrease in right pleural effusion and thickening of the right pleura.\n\nTable 2. The Results of the Right Pleural Effusion Analysis on Admission.\n\nColor\tYellow\t\t<Bacteriological examination>\t<Drug sensitivity for M.abscessus>\t\nCell count\t1,995\t/µlL\tBacterial culture\tNo growth\t\t\tMIC\t(S/R)\t\nNeut\t3\t%\t\t\tClarithromycin\tS\t2\t(8/32)\t\nLymph\t54\t%\tAcid-fast bacilli\t\tAmikacin\tS\t8\t(16/64)\t\nEos\t0\t%\tSmear\t(-)\tRifampicin\tR\t>32\t(0.5/2)\t\nTP\t5.5\tg/dL\tCulture (2w)\t(+)\tRifabutin\tR\t8\t(1/4)\t\nAlb\t3.1\tg/dL\tDDH\tM.abscessus\tEthambutol\tR\t4\t(4/8)\t\nLDH\t1,919\tIU/L\t\t\tStreptomycin\tR\t32\t(4/32)\t\nBS\t84\tmg/dL\t\t\tKanamycin\tI\t8\t(4/32)\t\nAnti-nuclear antibody\t<40\t\t\t\tLevofloxacin\tR\t4\t(1/4)\t\nADA\t132.7\tU/L\t\t\t\t\t\t\t\nDDH: nucleic acid identification of Mycobacterium group, MIC: minimum inhibitory concentration, S: sensitive, I: intermediate, R: resistant\n\nMeropenem (3.0 g/day) was initiated after admission to treat the right pleurisy. However, with the exception of right pleurisy, no other obvious infectious foci were seen. Despite the treatment, there was no obvious change in the patient's febrile condition. Although the IGRA for M. tuberculosis was negative, the elevated ADA level and the lymphocyte predominance of the right pleural effusion was suggestive of tuberculous pleurisy. Given the clinical and laboratory findings, isoniazid (INH) (300 mg/day), rifampicin (RFP) (450 mg/day), ethambutol (EB) (750 mg/day), and pyrazinamide (PZA) (1.2 g/day) were started on the ninth day after admission. He did not show symptoms of cough or sputum production at this time and sputum was not obtained. After the initiation of treatment with anti-tuberculosis agents (INH, RFP, EB, and PZA), the patient's high-grade fever and serum CRP level improved to around 37.0℃ and 3.0-4.0 mg/dL, respectively, on the 20th day after admission (11 days after starting treatment with INH, RFP, EB, and PZA). The patient was discharged from our hospital on the 29th day after admission (Fig. 3).\n\nAt two weeks after the examination of the right pleural effusion, a mycobacterial culture of the right pleural effusion was found to be positive. M. abscessus was finally identified on the 48th day, based on the nucleic acid identification of the Mycobacterium group.\n\nFigure 3. The clinical course of the patient.\n\nAfter discharge from our hospital, the patient started to feel bilateral femoral muscle pain, which was exacerbated with time. In addition, his low-grade fever (approximately 37.0℃) and increased serum CRP level (approximately 3.0-6.0 mg/dL) continued after discharge. He was therefore readmitted to our hospital in January 2017. On readmission, chest CT demonstrated an obvious decrease in the right pleural effusion (Fig. 2D, E and F). Based on the mycobacterial culture results, INH was switched to clarithromycin (CAM) (800 mg/day) and moxifloxacin (400 mg/day) in addition to RFP (450 mg/day) and EB (750 mg/day) to treat an M. abscessus infection. However, there was no obvious improvement in the patient's low-grade fever or in the increased CRP level. At the same time, recurrence of dermatomyositis was suspected. In February 2017, intravenous immunoglobulin treatment resulted in the improvement of the low-grade fever, bilateral femoral muscle pain, and serum CRP level (approximately 1.0 mg/dL).\n\nDiscussion\nPleurisy caused by M. abscessus was first reported in a lung transplant patient by Fairhurst et al., and a total of six case reports, including our own, have been published (Table 3) (3, 11-14). These cases are characterized by complication with pulmonary infectious lesions and comorbid diseases. In addition, only the case reported by Lai et al. and our patient showed no obvious pulmonary involvement. Therefore, physicians should consider M. abscessus pleurisy in patients with pleural effusion with comorbid disease, even if lung disease is absent.\n\nTable 3. Reported Cases of M. abscessus Pleurisy.\n\nReference\tAge (y)\tSex\tPresentation\tComorbidity\tCultured part of M. abscessus\tPleural effusion\tAntibiotics used for outcome\tOutcome\t\nPredominant cell type\tADA (U/L)\t\n12\t66\tM\tLung infection + empyema\tLung transplant recipient\tPleural effusion, BALF\tLymphocyte\t-\tCAM, CFX, CPFX\tDied\t\n11\t68\tF\tLung infection + empyema\tLiver cirrhosis\tPleural effusion, sputum\tNeutrophil\t101\tCAM, AMK, IPM/CS\tImproved\t\n13\t57\tM\tLung infection + empyema necessitatis\tOld tuberculosis\tPleural effusion, sputum\tNeutrophil\t-\tCAM, CFX, AMK, CPFX\tImproved\t\n14\t50\tF\tLung infection + pleural effusion\tOrganizing pneumonia\tSputum\tLymphocyte\t79.7\tCAM, AMK, IPM/CS\tPartially improved\t\n3\t44\tM\tEmpyema + bacteremia\tDiabetes mellitus, liver cirrhosis\tPleural effusion, blood\tNeutrophil\t-\tCAM, AMK, IPM/CS\tImproved\t\nPresent case\t28\tM\tPleurisy\tDermatomyositis\tPleural effusion\tLymphocyte\t132.7\tINH, RFP, EB, PZA\tPartially improved\t\nCAM: clarithromycin, CFX: cefoxitin, CPFX: ciprofloxacin, AMK: amikacin, IPM/CS: imipenem/cilastatin sodium, INH: isoniazid, RFP: rifampicin, EB: ethambutol, PZA: pyrazinamide\n\nIn diagnosing tuberculous pleurisy, an increased lymphocyte-to-neutrophil ratio (>0.75 lymphocytes/neutrophils) and an ADA level of >40 U/L (especially >70 U/L) are considered to be useful (15), and a meta-analysis revealed that the diagnostic odds ratio of an elevated ADA level was 110.08 (95% confidence interval: 69.96-173.20) (16). In comparison to tuberculous pleurisy, the characteristics of NTM-associated pleurisy are unknown (3, 14, 17, 18). In the five reported cases of M. abscessus pleurisy, the predominant cell types of pleural effusion were different. In addition, the ADA levels in the pleural effusion were only described in two patients, although both showed an increase in these levels (Table 3) (3, 11-14).\n\nThe combination of intravenous amikacin and cefoxitin or imipenem, in addition to CAM or azithromycin, was recommended for the treatment of M. abscessus infection in the 2007 American Thoracic Society (ATS)/Infectious Disease Society of America (IDSA) guidelines. However, no consensus treatment regimen has been established for extra-pulmonary NTM diseases (2), and poor outcomes of patients with M. abscessus disease have been reported (19). Similar to our patient, anti-tuberculosis regimens were often used initially in patients with NTM pleurisy including M. abscessus, but RGMs are reported to show no susceptibility to treatment with these first-line agents (10, 12). A few reports have shown the clinical effect of combined treatment with CAM, EB, and RFP on patients with pulmonary NTM infection (20, 21), and improvements in the pleural effusion and high-grade fever were achieved by treatment with first-line anti-tuberculosis medications in our case. M. abscessus is generally resistant to RFP and EB in vitro, but the in vitro susceptibility of agents do not always represent the in vivo clinical activity in patients with NTM (1). However, Hsieh et al. reported a case in which an incomplete response to anti-tuberculosis drugs in patients with pulmonary NTM infection caused empyema (7). The subsequent response to treatment should therefore be carefully monitored.\n\nAn apparent response to treatment with anti-tuberculosis drugs was recognizable after approximately two weeks in our patient. During this early stage of treatment, other possible causes of the patient's pleural effusion were considered, including comorbidities associated with dermatomyositis; however, pleural effusion due to dermatomyositis is thought to be extremely rare (22). In the present case, we made a diagnosis of M. abscessus pleurisy based on the results of mycobacterial culture, but tuberculous pleurisy could not be ruled out from the clinical course because M. tuberculosis is often uncultured in patients with tuberculous pleurisy, and M. tuberculosis can be missed in cases in which RGM is first cultured. In addition, the blood IGRA has been reported to not be very useful in identifying patients with tuberculous pleurisy (15); in a meta-analysis, the sensitivity and specificity of the blood IGRA for tuberculous pleurisy were 0.80 and 0.72, respectively (23). Therefore, physicians should take particular care in diagnosing M. abscessus pleurisy.\n\nOnly the pleural effusion obtained in the first thoracentesis procedure was positive for M. abscessus, and pleural mycobacterial cultures after starting anti-tuberculosis agents were negative. Shu et al. reported that the prognosis of NTM pleurisy patients with single and multiple positive results were not markedly different (2). Thus, the finding of more than one positive mycobacterial culture might be sufficient to start treatment for NTM pleurisy.\n\nThe precise pathogenetic mechanism of M. abscessus pleurisy is unknown; however, development from a lung parenchymal infection with M. abscessus and/or minor chest trauma is usually considered the pathway in patients with NTM pleurisy (17). Other mechanisms, such as the entrance of NTM into the pleural cavity through transient bacteremia or by contiguous spread from a small subpleural focus, have also been proposed (18).\n\nIn conclusion, we presented a case of M. abscessus pleurisy in a young patient complicated with dermatomyositis. Even in patients without preceding M. abscessus lung disease, M. abscessus pleurisy should be considered in the differential diagnosis of the cause of pleural effusion, especially in immunocompromised patients and aging individuals.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Lai CC , Hsueh PR \nDiseases caused by nontuberculous mycobacteria in Asia . Future Microbiol \n9 : 93 -106 , 2014 .24328383 \n2. Shu CC , Lee LN , Wang JT , et al \nNon-tuberculous mycobacterial pleurisy: an 8-year single-centre experience in Taiwan . Int J Tuberc Lung Dis \n14 : 635 -641 , 2010 .20392359 \n3. Lai CC , Chao CM , Gau SJ , Hsueh PR \nThoracic empyema and bacteremia due to Mycobacterium abscessus in a patient with liver cirrhosis . J Microbiol Immunol Infect \n46 : 482 -484 , 2013 .23831159 \n4. Benwill JL , Wallace RJ \nMycobacterium abscessus: challenges in diagnosis and treatment . Curr Opin Infect Dis \n27 : 506 -510 , 2014 .25268925 \n5. Morimoto K , Hasegawa N , Izumi K , et al \nA laboratory-based analysis of nontuberculous Mycobacterial lung disease in Japan from 2012 to 2013 . Ann Am Thorac Soc \n14 : 49 -56 , 2017 .27788025 \n6. Satyanarayana G , Heysell SK , Scully KW , Houpt ER \nMycobacterial infections in a large Virginia hospital, 2001-2009 . BMC Infect Dis \n11 : 113 , 2011 .21545738 \n7. Hsieh HC , Lu PL , Chen TC , Chang K , Chen YH \nMycobacterium chelonae empyema in an immunocompetent patient . J Med Microbiol \n57 : 664 -667 , 2008 .18436603 \n8. Fabbian F , De Giorgi A , Pala M , Fratti D , Contini C \nPleural effusion in an immunocompetent woman caused by Mycobacterium fortuitum . J Med Microbiol \n60 : 1375 -1378 , 2011 .21459911 \n9. Matsumoto T , Otsuka K , Tomii K \nMycobacterium fortuitum thoracic empyema: a case report and review of the literature . J Infect Chemother \n21 : 747 -750 , 2015 .26139179 \n10. Blair P , Moshgriz M , Siegel M \nMycobacterium fortuitum empyema associated with an indwelling pleural catheter: case report and review of the literature . J Infect Chemother \n23 : 177 -179 , 2017 .27890417 \n11. Orihashi T , Yatera K , Matsuo M , et al \nA case of successfully treated pulmonary Mycobacterium abscessus infection asociated with empyema thoracies . Nihon Kokyuki Gakkai Zasshi \n1 : 213 -218 , 2012 (in Japanese, Abstract in English).\n12. Fairhurst RM , Kubak BM , Shpiner RB , Levine MS , Pegues DA , Ardehali A \nMycobacterium abscessus empyema in a lung transplant recipient . J Heart Lung Transplant \n21 : 391 -394 , 2002 .11897529 \n13. Jo KW , Kim JW , Hong Y , Shim TS \nA case of empyema necessitatis caused by Mycobacterium abscessus . Respir Med Case Rep \n6 : 1 -4 , 2012 .26029591 \n14. Okazaki A , Takato H , Fujimura M , Ohkura N , Katayama N , Kasahara K \nSuccessful treatment with chemotherapy and corticosteroids of pulmonary Mycobacterium abscessus infection accompanied by pleural effusion . J Infect Chemother \n19 : 964 -968 , 2013 .23263189 \n15. Light RW \nUpdate on tuberculous pleural effusion . Respirology \n15 : 451 -458 , 2010 .20345583 \n16. Liang QL , Shi HZ , Wang K , Qin SM , Qin XJ \nDiagnostic accuracy of adenosine deaminase in tuberculous pleurisy: a meta-analysis . Respir Med \n102 : 744 -754 , 2008 .18222681 \n17. Park SU , Koh WJ , Kwon OJ , et al \nAcute pneumonia and empyema caused by Mycobacterium intracellulare . Intern Med \n45 : 1007 -1010 , 2006 .17016001 \n18. Kakugawa T , Mukae H , Kajiki S , et al \nMycobacterium avium pleuritis in a non-immunocompromised patient . Intern Med \n47 : 1727 -1731 , 2008 .18827425 \n19. Jarand J , Levin A , Zhang L , Huitt G , Mitchell JD , Daley CL \nClinical and microbiologic outcomes in patients receiving treatment for Mycobacterium abscessus pulmonary disease . Clin Infect Dis \n52 : 565 -571 , 2011 .21292659 \n20. Matsuzawa K , Tsukaguchi K , Okamura H , Kasahara R , Tamura M , Kimura H \n[A case of lung infection due to Mycobacterium abscessus (M. abscessus) complicated with primary macroamylasemia] . Nihon Kokyuki Gakkai Zasshi \n42 : 519 -522 , 2004 (in Japanese, Abstract in English).15228140 \n21. Nishizawa Y , Fujimura M , Tagami A , et al \n[Two cases of pulmonary infection by Mycobacterium abscessus in which drug susceptibility testing results conflicted with clinical courses] . Nihon Kokyuki Gakkai Zasshi \n43 : 241 -246 , 2005 (in Japanese, Abstract in English).15966372 \n22. Bouros D , Pneumatikos I , Tzouvelekis A \nPleural involvement in systemic autoimmune disorders . Respiration \n75 : 361 -371 , 2008 .18477860 \n23. Zhou Q , Chen YQ , Qin SM , Tao XN , Xin JB , Shi HZ \nDiagnostic accuracy of T-cell interferon-γ release assays in tuberculous pleurisy: a meta-analysis . Respirology \n16 : 473 -480 , 2011 .21299686\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(7)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Mycobacterium abscessus; dermatomyositis; pleurisy",
"medline_ta": "Intern Med",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D044466:Asians; D003882:Dermatomyositis; D006801:Humans; D007136:Immunoglobulins; D008297:Male; D009165:Mycobacterium Infections, Nontuberculous; D000073358:Mycobacterium abscessus; D010996:Pleural Effusion; D016896:Treatment Outcome; D014396:Tuberculosis, Pleural",
"nlm_unique_id": "9204241",
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"pmid": "29269658",
"pubdate": "2018-04-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "23831159;18222681;26029591;20392359;26139179;25268925;27788025;21459911;11897529;18436603;24328383;15228140;15966372;20345583;18477860;27890417;23263189;21545738;21292659;18827425;21299686;17016001",
"title": "Pleurisy Caused by Mycobacterium abscessus in a Young Patient with Dermatomyositis: A Case Report and Brief Review of the Literature.",
"title_normalized": "pleurisy caused by mycobacterium abscessus in a young patient with dermatomyositis a case report and brief review of the literature"
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"abstract": "OBJECTIVE\nChronic kidney disease (CKD) has become a critical problem due to immunosuppressant related nephrotoxicity in liver transplant (LTx) recipients, especially in patients with pre-transplant risk factors. LTx recipients with uraemia and diabetes have poor prognosis even when treated with dialysis and insulin. Simultaneous pancreas and kidney transplantation (SPK) has been proven to be an effective treatment for patients with diabetic uraemia, but rarely performed in patients after LTx. Two cases of SPK after LTx were performed in our centre and we present our experience here.\n\n\nMETHODS\nTwo patients received LTx because of HBV related liver cirrhosis; both of them had pre-transplant diabetes mellitus (DM), which worsened after the administration of immunosuppressive drugs. These two patients suffered from CKD and developed uraemia due to diabetic nephropathy and immunosuppressive drugs induced renal toxicity years after LTx. They relied on dialysis and insulin injection. SPK were performed years after LTx and the clinical data was retrospectively analyzed.\n\n\nRESULTS\nSPK was successfully performed in these two patients. Pancreatic fluid drainage was achieved via a side-to-side duodenojejunostomy into the proximal jejunum. No serious surgical complications, including pancreatitis or pancreatic fistula were observed postoperatively. In both cases, kidney and pancreatic grafts were functioning well as evidenced by euglycemia without the need for insulin injections and normal serum-creatinine level 7days after the operation. One of the patients presented with renal graft impairment 1week after the operation. FK506 was tapered and rapamycin was used when the renal graft biopsy indicated drug toxicity. The patient's kidney graft function recovered gradually after the adjustment. Both patients have good function of liver, kidney and pancreas grafts during a 60-month and 30-month period of follow up.\n\n\nCONCLUSIONS\nSPK could serve as an effective option for patients with diabetes and uremia after LTx. Perioperative management, especially the immunosuppressive strategy is crucial to improve the outcome of this procedure.",
"affiliations": "Organ Transplantation Center of the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Hepatobiliary surgery department, the University of Hong Kong, Shenzhen Hospital, Shenzhen, Guangdong, China.;Organ Transplantation Center of the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.;Organ Transplantation Center of the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.;Organ Transplantation Center of the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.;Organ Transplantation Center of the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.;Pathology Department, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.;Department of Clinical Laboratories, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.;Organ Transplantation Center of the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.;Organ Transplantation Center of the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.;Organ Transplantation Center of the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China. Electronic address: lw97002@163.com.;Organ Transplantation Center of the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China. Electronic address: gdtrc@163.com.",
"authors": "Tam|Ngalei|N|;Zhang|Chuanzhao|C|;Lin|Jianwei|J|;Wu|Chenglin|C|;Deng|Ronghai|R|;Liao|Bing|B|;Hu|Shuiqing|S|;Wang|Dongping|D|;Zhu|Xiaofeng|X|;Wu|Linwei|L|;He|Xiaoshun|X|",
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"issue": "39(3)",
"journal": "Clinics and research in hepatology and gastroenterology",
"keywords": null,
"medline_ta": "Clin Res Hepatol Gastroenterol",
"mesh_terms": "D003920:Diabetes Mellitus; D003928:Diabetic Nephropathies; D006801:Humans; D016030:Kidney Transplantation; D008103:Liver Cirrhosis; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D016035:Pancreas Transplantation; D051436:Renal Insufficiency, Chronic; D012189:Retrospective Studies; D014511:Uremia",
"nlm_unique_id": "101553659",
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"pages": "399-404",
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"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Simultaneous pancreas and kidney transplantation for liver transplant recipients with diabetes and uremia.",
"title_normalized": "simultaneous pancreas and kidney transplantation for liver transplant recipients with diabetes and uremia"
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"abstract": "BACKGROUND\nChronic granulomatous disease (CGD) characterized by recurrent and severe bacterial and fungal infections is most common in childhood.\n\n\nMETHODS\nWe reported a 24-d-old male infant who developed gastrointestinal symptoms as the first sign of CGD.\n\n\nCONCLUSIONS\nGastrointestinal symptoms representing the first sign of CGD are very rare, and prompt diagnosis and treatment with broad-spectrum antibiotics were of crucial importance.",
"affiliations": "Division of Neonatology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.;Chongqing Medical College, Chongqing 400016, China.;Division of Neonatology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.;Division of Neonatology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China. shanglihong10@163.com.",
"authors": "Meng|Er-Yan|EY|;Wang|Zi-Ming|ZM|;Lei|Bing|B|;Shang|Li-Hong|LH|",
"chemical_list": null,
"country": "United States",
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"doi": "10.12998/wjcc.v9.i32.9997",
"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960\nBaishideng Publishing Group Inc\n\njWJCC.v9.i32.pg9997\n10.12998/wjcc.v9.i32.9997\nCase Report\nGastrointestinal symptoms as the first sign of chronic granulomatous disease in a neonate: A case report\nMeng EY et al. Gastrointestinal involvement in neonatal CGD\nMeng Er-Yan Division of Neonatology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China\n\nWang Zi-Ming Chongqing Medical College, Chongqing 400016, China\n\nLei Bing Division of Neonatology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China\n\nShang Li-Hong Division of Neonatology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China. shanglihong10@163.com\n\nAuthor contributions: Meng EY and Shang LH conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript. Wang ZM and Lei B collected data, carried out the initial analyses, and reviewed the manuscript; all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\n\nCorresponding author: Li-Hong Shang, MD, Doctor, Division of Neonatology, The Third Affiliated Hospital of Zhengzhou University, No. 7 Kangfuqian Street, Zhengzhou 450052, Henan Province, China. shanglihong10@163.com\n\n16 11 2021\n16 11 2021\n9 32 999710005\n30 6 2021\n27 7 2021\n23 9 2021\n©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/\nBACKGROUND\n\nChronic granulomatous disease (CGD) characterized by recurrent and severe bacterial and fungal infections is most common in childhood.\n\nCASE SUMMARY\n\nWe reported a 24-d-old male infant who developed gastrointestinal symptoms as the first sign of CGD.\n\nCONCLUSION\n\nGastrointestinal symptoms representing the first sign of CGD are very rare, and prompt diagnosis and treatment with broad-spectrum antibiotics were of crucial importance.\n\nChronic granulomatous disease\nGastrointestinal symptoms\nInfant\nNeonate\nFever\nDiarrhea\n==== Body\npmc Core Tip: Most chronic granulomatous diseases (CGDs) present with life-threatening recurrent bacterial and fungal infections, usually diagnosed in childhood. We describe a newborn with CGD that initially showed gastrointestinal symptoms. CGD cases with gastrointestinal manifestations as the first sign are very rare. To the best of our knowledge, this might be the youngest case of confirmed CGD with gastrointestinal involvement.\n\nINTRODUCTION\n\nChronic granulomatous disease (CGD) is a rare inherited primary immunodeficiency of the phagocytic system that leads to recurrent and severe bacterial and fungal infections, with a high mortality rate[1,2]. Most patients initially have an infection, which affects the lymph nodes, lungs, liver, bones and skin[3]. Recent studies have shown the high prevalence of gastrointestinal complications in patients with CGD[4,5]. CGD episodes in the neonatal period have some uncommon features and can easily be ignored. Herein, we describe a 24-d-old male infant with newly diagnosed CGD who presented with prolonged fever of unknown origin, persistent diarrhea and elevated C-reactive protein (CRP).\n\nCASE PRESENTATION\n\nChief complaints\n\nA 24-d-old Chinese male baby with a history of fever for 8 d and diarrhea for 10 d attended the Neonatology Department in our hospital.\n\nHistory of present illness\n\nThe baby was treated with antibiotics at the local hospital, but he did not respond. He was fed with formula milk. The mother reported that the baby had increased fussiness, irritability, and unsatisfactory weight gain, while he continued to feed well and maintained good urine output. She denied any other symptoms or any medication use.\n\nHistory of past illness\n\nAfter birth, the infant received mechanical ventilation and piperacillin-tazobactam treatment in the Neonatal Intensive Care Unit due to meconium aspiration syndrome, and was discharged on the 10th day of life.\n\nPersonal and family history\n\nThe primipara gave birth to the baby via a simple cesarean section at 38 wk of gestation. The baby weighed 3350 g at birth, with an APGAR Score of 6 points at 1 min and 7 points at 5 min after birth. No family history of CGD was reported. The newborn was cared for by his parents.\n\nPhysical examination\n\nDuring the physical examination, the baby had a body temperature of 39.3°C, a heart rate of 152 bpm, respiratory rate of 40 breaths/min, weight of 3.92 kg, blood pressure of 65/36 mmHg, and an oxygen saturation of 95% in room air. The baby cried continuously and was not easily pacified. He was alert and appeared in distress. His abdomen was bulging, but there was no evident tenderness. The lung, heart, skin and nervous system examination results were all within the normal range.\n\nLaboratory examinations\n\nA complete blood count suggested mild anemia and leukocytosis. Renal function test results and the measured values of serum electrolytes, glucose, phosphorus, direct and total bilirubin were all within the normal range. Total protein and albumin concentrations were decreased, while alanine aminotransferase and aspartate aminotransferase concentrations were slightly elevated. A routine stool test was normal. Blood, urine, stool and cerebrospinal fluid cultures indicated the absence of pathogens. Serum galactomannan and (1,3)-β-D-glucan (two fungal tests were negative, revealing no fungal infection. Only CRP level was significantly increased.\n\nImaging examinations\n\nChest X-ray showed increased bilateral markings. Mild flatulence was evident on abdominal X-ray images. Ultrasound examinations of the baby’s abdomen and brain were performed, and the results were normal.\n\nFINAL DIAGNOSIS\n\nThe child was finally diagnosed with CGD with initial gastrointestinal symptoms.\n\nTREATMENT\n\nPiperacillin-tazobactam (300 mg/kg/d) was commenced under the diagnosis of sepsis. After 4 d of antibiotic treatment, fever and diarrhea did not improve, and the CRP level rose sharply to 239.45 mg/dL. This suggested that the newborn did not respond to piperacillin-tazobactam. Therefore, vancomycin and meropenem were intravenously injected 4 d after admission. X-ray was performed on the 6th day to check the lower gastrointestinal tract, and no abnormalities were observed (Figure 1). As inflammatory bowel disease (IBD) was highly suspected, a colonoscopy was conducted on day 9, revealing intestinal mucosal enteritis (Figure 2A). Histopathological examination of the intestinal tissue showed chronic mucosal inflammation without granulomas, fissures, or bowel wall thickening (Figure 2B). Therefore, the diagnosis of IBD was excluded.\n\nFigure 1 Positive and lateral view of lower digestive tract radiography. Dilatation of the rectum and distal colon was not observed.\n\nFigure 2 Colonoscopy and colonic biopsy showing chronic mucosal inflammation without granulomas, fissures, or bowel wall thickening. Hematoxylin and eosin stain, magnification: 20 ×.\n\nThe infant still had a high fever (Tmax 40ºC) every day, but no obvious infection site was found. A computed tomography (CT) scan of the thorax was performed on day 11, revealing diffuse, scattered nodules and bilateral consolidation areas (Figure 3A). Due to suspicion of aspergillosis, voriconazole (20 mg/kg/d) was injected intravenously.\n\nFigure 3 Computed tomography scan of the thorax. A: Bilateral diffuse, scattered nodules and consolidation areas in different lung areas; B: The reduction of nodules and consolidations in the lungs.\n\nAs primary immunodeficiencies were suspected, immunologic evaluations were performed. The neutrophil dihydrorhodamine (DHR) test revealed that the baby’s neutrophils lacked the ability to produce superoxide, and the ratio of activated neutrophils in his mother and father was 99.6% and 98.5%, respectively (Figure 4). The diagnosis of CGD was preliminarily confirmed, and subsequent genetic testing revealed a mutation in the CYBB gene (Figure 5).\n\nFigure 4 Histograms of the dihydrorhodamine assay of granulocytes from the male pediatric patient, his mother and father. Histograms of the dihydrorhodamine (DHR) assay of the patient’s granulocyte (A) revealed the absence of fluorescence upon granulocyte stimulation. The DHR assay of granulocytes from the patient’s mother (B) and father (C) showed that the ratio of activated neutrophils was 99.6% and 98.5%, respectively.\n\nFigure 5 Analysis of a CYBB gene exon of the patient and his parents. Chromatogram of a CYBB exon of the patient showed a missense mutation, c.997T>C (p.S333P). A: Patient; B: The patient’s mother; C: The patient’s father.\n\nOUTCOME AND FOLLOW-UP\n\nAfter four weeks of combined anti-infection therapy with meropenem, vancomycin and voriconazole, the baby’s condition improved, and chest CT revealed a reduction in nodules and consolidations (Figure 3B). He was discharged on day 30. Following discharge, as the baby had a history of recurrent perianal abscesses, he received prophylactic trimethoprim-sulfamethoxazole, linezolid and voriconazole treatment. During the one-and-half-year follow-up, the child was in good condition except for recurrent perianal abscesses and infection. He underwent hematopoietic stem cell transplantation (HSCT) at another medical institution. The clinical time course of the patient is shown in Figure 6, and sequential laboratory data are shown in Table 1.\n\nFigure 6 Clinical time course of the patient. CRP: C-reactive protein; CT: Computed tomography; DHR: Dihydrorhodamine; VRCZ: Voriconazole; PIPC/TAZ: Piperacillin/tazobactam.\n\nTable 1 Sequential laboratory data\n\n\tDay 1\tDay 3\tDay 5\tDay 10\tDay 14\tDay 17\tDay 22\tDay 28\t\nWhite blood cells [103/mL]\t15640\t13620\t4910\t9180\t10720\t10740\t8160\t9320\t\nHemoglobin [g/dL]\t11.2\t9.3\t8.3\t7.3\t9.9\t9.5\t9.5\t9\t\nPlatelets [107/mL]\t17.8\t19.5\t18.5\t11.5\t11.1\t24.1\t34.2\t28.2\t\nCRP [mg/dL]\t121.59\t239.45\t193.53\t124.33\t82.52\t52.3\t26.72\t5.8\t\nCSF white blood cells [103/mL]\t10\t\t33\t\t0\t\t\t\t\nCSF glucose [mmol/L]\t3.1\t\t2\t\t2.8\t\t\t\t\nCSF protein [mg/dL]\t7.9\t\t17.7\t\t9.6\t\t\t\t\nCRP: C-reactive protein; CSF: Colony stimulating factor.\n\nDISCUSSION\n\nAs stated in the United States and European cohorts[1,3], the prevalence of CGD has been reported to range between 1/200000-250000 live births. However, the actual incidence might be even higher as estimations also tend to depend on clinical expertise. To date, fewer cases have been reported in China, which reveals that the disease has not yet been widely recognized in China.\n\nDue to the inability to generate superoxide and to destroy certain infectious pathogens, CGD is one of the most common primary immunodeficiency diseases. The majority of patients are diagnosed before they are 5 years old[1,2]. Only 35 neonatal CGD cases have been reported in the English literature to date[6]. The main clinical features included pneumonia or pulmonary abscess or pleural effusion, diarrhea, perianal abscess, skin infection, aspergillus infection and tuberculosis infection. Pneumonia is the most common form of infection, although abscesses and lymphangitis are also frequently observed. Infections are mainly caused by five pathogens: Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia, Nocardia and Aspergillus[7,8]. Fungal infection is the leading cause of death in patients with CGD, and Aspergillus is the most common invasive fungal pathogen[9,10]. Granuloma formation is the most common complication of CGD, which can be seen even before diagnosis. Granulomatous inflammation can affect various organ systems. Nevertheless, it seems that the gastrointestinal system is more frequently involved[4]. Gastrointestinal lesions in CGD are discontinuous and may involve any part of the gastrointestinal tract from the mouth to the anus, with the colon being most often affected[11].\n\nApproximately half of CGD patients have IBD which may be indistinguishable from Crohn’s disease[5,12,13]. Inflammatory granulomatous colitis can also be accompanied by obstructive disease, diarrhea, malabsorption, perianal abscess, or other complications. The baby in this report first presented with fever, diarrhea and elevated CRP. Consequently, he was thought to be suffering from IBD, for which colonoscopy was performed, revealing no evidence of colitis or related complications. We did not consider CGD until a chest CT performed one week after admission revealed diffuse, scattered bilateral nodules and consolidation areas. Early diagnosis and prompt treatment for these conditions are crucial for optimal outcome in affected patients. It is important to recognize that CGD can present with gastrointestinal manifestations without any evidence of infection. Diarrhea in this baby was a specific symptom of CGD, but not the finding of concomitant infection.\n\nAs primary immunodeficiencies were suspected, immunologic evaluations were performed. Flow cytometry is currently the most widely used technique, as it is rapid, sensitive and multiparametric. DHR is the most effective indicator for reactive oxygen species (ROS) measurement by flow cytometry[14]. The DHR assay revealed that the superoxide-generating ability of neutrophils in this baby was absent, and his parents were healthy. Based on the above results, the baby was initially diagnosed with CGD. Further gene sequencing data confirmed the diagnosis. The DHR assay has become the main diagnostic method for CGD, which can be used to identify patients with mild disease and CGD-related gene carriers and may help differentiate the X-linked recessive (XR) and autosomal recessive (AR) inheritance[1].\n\nGenetic mutations of CGD occur in one of the six following genes: CYBB (encoding gp91), NCF1 (p47p hox), NCF2 (p67phox), CYBA (p22 phox), NCF4 (p40phox) and CYBC1 (EROS). XR-CGD is caused by mutation of the CYBB gene in 65% of all CGD patients. AR-CGD has been shown to be associated with mutations of NCF1, NCF2 and CYBA genes encoding p47phox, p67phox or P22phox[15]. Furthermore, the geographic context and social/cultural background, which influence the frequency of consanguineous marriage, change the balance between XR-CGD and AR-CGD and determine the relative distribution of the two inheritance forms in different countries. XR-CGD is the most common form in Europe, United States and Japan[3,16,17]. AR-CGD is the most predominant form in the Middle East, North Africa, and western, central, and southern Asia[18]. However, the study by Marks et al[5] suggested no significant difference in any demographic characteristics between the X-linked and autosomal groups. A large sample single-center study in China showed that XR-CGD accounted for 81.6% of all CGD[19].\n\nGastrointestinal manifestations in CGD have been reported to occur at greater rates in patients with X-linked disease[20]. The baby had a CYBB coding region hemizygous variant C. 997T > C, resulting in a serine to proline amino acid 333 substitution (p.S333P), which was a previously reported missense variant. Family validation analysis showed that there was no mutation in the paternal and maternal locus. The mutation was spontaneous and pathogenic. Clinicians have noted a milder clinical course for AR-CGD patients, leading to longer survival compared to X-linked CGD patients, although the exact cause was unclear[20]. The deficiency of gp91phox still appears to be one of the steady determinants of mortality[21]. Unfortunately, the baby had a hemizygous variant in the CYBB gene (encoding gp91), and the presentation in the neonatal period was related to the effect of the variant on ROS production. It was evident that this variant was associated with a marked decrease in ROS production, which might explain his early manifestations.\n\nAt present, HSCT is the only definitive treatment to cure CGD and reverse organ dysfunction[22]. Timing, donor selection and conditioning regimens remain the key points of this therapy. Furthermore, surviving CGD patients with gastrointestinal manifestations who received HSCT seem to thrive and have better outcomes. Colitis in CGD patients may be a consideration in favoring HSCT[23,24]. Our patient presented with gastrointestinal manifestations so he may achieve a good outcome through HSCT. Fortunately, the patient underwent HSCT recently, and the treatment effect was good.\n\nCONCLUSION\n\nThe diagnosis of CGD in the neonatal period tends to be delayed due to the heterogeneity of clinical manifestations. The male neonate in this report initially presented with CGD-associated IBD. His abnormal DHR test and the detection of CYBB gene mutation confirmed the diagnosis. This case highlights the importance of a thorough medical history review and complete laboratory examination in evaluating patients. To the best of our knowledge, this might be the youngest confirmed case of CGD with gastrointestinal involvement as the first sign.\n\nInformed consent statement: Informed consent was obtained from all individual participants included in the study.\n\nConflict-of-interest statement: The authors declare that they have no conflict of interest.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: June 30, 2021\n\nFirst decision: July 26, 2021\n\nArticle in press: September 30, 2021\n\nSpecialty type: Gastroenterology and Hepatology\n\nCountry/Territory of origin: China\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B, B, B\n\nGrade C (Good): 0\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Afzal MS, Crocé LS, Farhadi R S-Editor: Wu YXJ L-Editor: Webster JR P-Editor: Wu YXJ\n==== Refs\n1 Winkelstein JA Marino MC Johnston RB Jr Boyle J Curnutte J Gallin JI Malech HL Holland SM Ochs H Quie P Buckley RH Foster CB Chanock SJ Dickler H Chronic granulomatous disease. Report on a national registry of 368 patients Medicine (Baltimore) 2000 79 155 169 10844935\n2 Wolach B Gavrieli R de Boer M van Leeuwen K Berger-Achituv S Stauber T Ben Ari J Rottem M Schlesinger Y Grisaru-Soen G Abuzaitoun O Marcus N Zion Garty B Broides A Levy J Stepansky P Etzioni A Somech R Roos D Chronic granulomatous disease: Clinical, functional, molecular, and genetic studies. The Israeli experience with 84 patients Am J Hematol 2017 92 28 36 27701760\n3 van den Berg JM van Koppen E Ahlin A Belohradsky BH Bernatowska E Corbeel L Español T Fischer A Kurenko-Deptuch M Mouy R Petropoulou T Roesler J Seger R Stasia MJ Valerius NH Weening RS Wolach B Roos D Kuijpers TW Chronic granulomatous disease: the European experience PLoS One 2009 4 e5234 19381301\n4 Marciano BE Rosenzweig SD Kleiner DE Anderson VL Darnell DN Anaya-O'Brien S Hilligoss DM Malech HL Gallin JI Holland SM Gastrointestinal involvement in chronic granulomatous disease Pediatrics 2004 114 462 468 15286231\n5 Marks DJ Miyagi K Rahman FZ Novelli M Bloom SL Segal AW Inflammatory bowel disease in CGD reproduces the clinicopathological features of Crohn's disease Am J Gastroenterol 2009 104 117 124 19098859\n6 Ling W Xiao-wen C Yang-shan O Li T Wei Z Juan H A case report of neonatal-onset chronic granulomatosis disease with aspergillus infection and literature review Zhonghua Xinshengerke Zazhi 2019 34 42 46\n7 Davoodi P Wright SA Brown EV Perry JR Rare diagnosis in a neonate who presents with fever Clin Pediatr (Phila) 2015 54 91 93 25022948\n8 Greenberg DE Goldberg JB Stock F Murray PR Holland SM Lipuma JJ Recurrent Burkholderia infection in patients with chronic granulomatous disease: 11-year experience at a large referral center Clin Infect Dis 2009 48 1577 1579 19400745\n9 Blumental S Mouy R Mahlaoui N Bougnoux ME Debré M Beauté J Lortholary O Blanche S Fischer A Invasive mold infections in chronic granulomatous disease: a 25-year retrospective survey Clin Infect Dis 2011 53 e159 e169 22080130\n10 Dellepiane RM Tortorano AM Liotto N Laicini E Di Landro G Carnelli V Pietrogrande MC Invasive Aspergillus nidulans infection in a patient with chronic granulomatous disease Mycoses 2008 51 458 460 18783555\n11 Khangura SK Kamal N Ho N Quezado M Zhao X Marciano B Simpson J Zerbe C Uzel G Yao MD DeRavin SS Hadigan C Kuhns DB Gallin JI Malech HL Holland SM Heller T Gastrointestinal Features of Chronic Granulomatous Disease Found During Endoscopy Clin Gastroenterol Hepatol 2016 14 395 402.e5 26545803\n12 Ramanuja S Wolf KM Sadat MA Mahoney SJ Dinauer MC Nelson RP Jr Newly diagnosed chronic granulomatous disease in a 53-year-old woman with Crohn disease Ann Allergy Asthma Immunol 2005 95 204 209 16136772\n13 Metzger JC Kurz E von Spee-Mayer C Kolck G Bogumil A Galle PR Zimmermann T [Chronic granulomatous disease as a rare differential diagnosis of inflammatory bowel disease] Z Gastroenterol 2018 56 1507 1512 30466133\n14 Alvarez-Larrán A Toll T Rives S Estella J Assessment of neutrophil activation in whole blood by flow cytometry Clin Lab Haematol 2005 27 41 46 15686506\n15 Lekstrom-Himes JA Gallin JI Immunodeficiency diseases caused by defects in phagocytes N Engl J Med 2000 343 1703 1714 11106721\n16 Martire B Rondelli R Soresina A Pignata C Broccoletti T Finocchi A Rossi P Gattorno M Rabusin M Azzari C Dellepiane RM Pietrogrande MC Trizzino A Di Bartolomeo P Martino S Carpino L Cossu F Locatelli F Maccario R Pierani P Putti MC Stabile A Notarangelo LD Ugazio AG Plebani A De Mattia D IPINET Clinical features, long-term follow-up and outcome of a large cohort of patients with Chronic Granulomatous Disease: an Italian multicenter study Clin Immunol 2008 126 155 164 18037347\n17 Kobayashi S Murayama S Takanashi S Takahashi K Miyatsuka S Fujita T Ichinohe S Koike Y Kohagizawa T Mori H Deguchi Y Higuchi K Wakasugi H Sato T Wada Y Nagata M Okabe N Tatsuzawa O Clinical features and prognoses of 23 patients with chronic granulomatous disease followed for 21 years by a single hospital in Japan Eur J Pediatr 2008 167 1389 1394 18335239\n18 Köker MY Camcıoğlu Y van Leeuwen K Kılıç SŞ Barlan I Yılmaz M Metin A de Boer M Avcılar H Patıroğlu T Yıldıran A Yeğin O Tezcan I Sanal Ö Roos D Clinical, functional, and genetic characterization of chronic granulomatous disease in 89 Turkish patients J Allergy Clin Immunol 2013 132 1156 1163.e5 23910690\n19 Xu H Tian W Li SJ Zhang LY Liu W Zhao Y Zhang ZY Tang XM Wang M Wu DQ Shi JS Ding Y Zhao XD Yang XQ Jiang LP Clinical and molecular features of 38 children with chronic granulomatous disease in mainland china J Clin Immunol 2014 34 633 641 24943880\n20 Liese J Kloos S Jendrossek V Petropoulou T Wintergerst U Notheis G Gahr M Belohradsky BH Long-term follow-up and outcome of 39 patients with chronic granulomatous disease J Pediatr 2000 137 687 693 11060536\n21 Kuhns DB Alvord WG Heller T Feld JJ Pike KM Marciano BE Uzel G DeRavin SS Priel DA Soule BP Zarember KA Malech HL Holland SM Gallin JI Residual NADPH oxidase and survival in chronic granulomatous disease N Engl J Med 2010 363 2600 2610 21190454\n22 Cole T Pearce MS Cant AJ Cale CM Goldblatt D Gennery AR Clinical outcome in children with chronic granulomatous disease managed conservatively or with hematopoietic stem cell transplantation J Allergy Clin Immunol 2013 132 1150 1155 23870668\n23 Arnon Reem. M, R. B. Gastrointestinal Abnormalities among Patients with Chronic Granulomatous Disease J Clin Cell Immunol 2014 5 1 6\n24 Freudenberg F Wintergerst U Roesen-Wolff A Albert MH Prell C Strahm B Koletzko S Ehl S Roos D Tommasini A Ventura A Belohradsky BH Seger R Roesler J Güngör T Therapeutic strategy in p47-phox deficient chronic granulomatous disease presenting as inflammatory bowel disease J Allergy Clin Immunol 2010 125 943 946.e1 20371400\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2307-8960",
"issue": "9(32)",
"journal": "World journal of clinical cases",
"keywords": "Chronic granulomatous disease; Diarrhea; Fever; Gastrointestinal symptoms; Infant; Neonate",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "9997-10005",
"pmc": null,
"pmid": "34877342",
"pubdate": "2021-11-16",
"publication_types": "D002363:Case Reports",
"references": "19098859;30466133;16136772;25022948;24943880;23910690;19400745;11106721;19381301;15686506;20371400;27701760;18335239;11060536;21190454;18783555;18037347;10844935;22080130;23870668;26545803;15286231",
"title": "Gastrointestinal symptoms as the first sign of chronic granulomatous disease in a neonate: A case report.",
"title_normalized": "gastrointestinal symptoms as the first sign of chronic granulomatous disease in a neonate a case report"
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"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326923",
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"abstract": "Solid organ transplant (SOT) recipients are considered to be \"vulnerable\" to COVID-19 infection due to immunosuppression. To date, there are no studies that compared the disease severity of COVID-19 in SOT recipients with nontransplant patients.\n\n\n\nIn this case-control study, we compared the outcomes of COVID-19 between SOT recipients and their matched nontransplant controls. The cases were all adult SOT recipients (N = 41) from our academic health center who were diagnosed with COVID-19 between March 10, 2020 and May 15, 2020 using positive reverse transcriptase polymerase chain reaction for SARS-CoV2. The controls (N = 121) were matched on age (±5 y), race, and admission status (hospital or outpatient). The primary outcome was death and secondary outcomes were severe disease, intubation and renal replacement therapy (RRT).\n\n\n\nMedian age of SOT recipients (9 heart, 3 lung, 16 kidney, 8 liver, and 5 dual organ) was 60 y, 80% were male and 67% were Black. Severe disease adjusted risk of death was similar in both the groups (hazard ratio = 0.84 [0.32-2.20]). Severity of COVID-19 and intubation were similar, but the RRT use was higher in SOT (odds ratio = 5.32 [1.26, 22.42]) compared to non-SOT COVID-19 patients. Among SOT recipients, COVID-19-related treatment with hydroxychloroquine (HCQ) was associated with 10-fold higher hazard of death compared to without HCQ (hazard ratio = 10.62 [1.24-91.09]).\n\n\n\nAlthough African Americans constituted one-tenth of all SOT in our center, they represented two-thirds of COVID-19 cases. Despite high RRT use in SOT recipients, the severe disease and short-term death were similar in both groups. HCQ for the treatment of COVID-19 among SOT recipients was associated with high mortality and therefore, its role as a treatment modality requires further scrutiny.",
"affiliations": "Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI.;Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI.;Department of Emergency Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI.;Michigan Institute for Clinical and Health Research, University of Michigan, Ann Arbor, MI.;Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI.;Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI.;Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI.;Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI.;Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI.;Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI.;Department of Surgery, School of Public Health, Michigan Medicine, University of Michigan, Ann Arbor, MI.;Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI.;Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI.;Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI.",
"authors": "Sharma|Pratima|P|;Chen|Vincent|V|;Fung|Christopher M|CM|;Troost|Jonathan P|JP|;Patel|Vaiibhav N|VN|;Combs|Michael|M|;Norman|Silas|S|;Garg|Puneet|P|;Colvin|Monica|M|;Aaronson|Keith|K|;Sonnenday|Christopher J|CJ|;Golob|Jonathan L|JL|;Somers|Emily C|EC|;Doshi|Mona M|MM|",
"chemical_list": "D006886:Hydroxychloroquine",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0000000000003447",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "105(1)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000368:Aged; D000086382:COVID-19; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D017582:Renal Replacement Therapy; D012189:Retrospective Studies; D000086402:SARS-CoV-2; D066027:Transplant Recipients",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "128-137",
"pmc": null,
"pmid": "32890139",
"pubdate": "2021-01-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "COVID-19 Outcomes Among Solid Organ Transplant Recipients: A Case-control Study.",
"title_normalized": "covid 19 outcomes among solid organ transplant recipients a case control study"
} | [
{
"companynumb": "US-AMNEAL PHARMACEUTICALS-2020-AMRX-02957",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE SULFATE"
},
... |
{
"abstract": "RAS mutations predict lack of response to epidermal growth factor receptor monoclonal antibody therapy in patients with metastatic colorectal cancer (mCRC), but preclinical studies and retrospective clinical data suggest that patients with tumors harboring the exon 2 KRAS G13D mutation may benefit from cetuximab. We aimed to assess cetuximab monotherapy and cetuximab plus irinotecan in patients with molecularly selected (G13D mutation) chemotherapy-refractory mCRC in a randomized phase II trial of this rare molecular subtype.\n\n\n\nPatients with chemotherapy-refractory KRAS G13D mutation-positive mCRC who had progressed within 6 months of irinotecan therapy were randomly assigned to cetuximab 400 mg/m(2) loading dose and then 250 mg/m(2) once per week with or without irinotecan 180 mg/m(2) once every 2 weeks. The primary end point was 6-month progression-free survival; secondary end points were response rate, overall survival, quality of life, and toxicity.\n\n\n\nFifty-one of 53 patients recruited over 2 years were eligible. The 6-month progression-free survival rate was 10% (95% CI, 2% to 26%) for cetuximab versus 23% (95% CI, 9% to 40%) for cetuximab plus irinotecan with a hazard ratio of 0.74 (95% CI, 0.42 to 1.32). Response and stable disease rates were 0% and 58% for monotherapy versus 9% and 70% for combination treatment, respectively. Overall survival and quality of life were similar; toxicities were higher with combination therapy.\n\n\n\nIn patients with G13D-mutated chemotherapy-refractory mCRC, there was no statistically significant improvement in disease control at 6 months with either cetuximab monotherapy or cetuximab plus irinotecan. No responses were seen with single-agent cetuximab. The responses observed with the combination of cetuximab and irinotecan may reflect true drug synergy or persistent irinotecan sensitivity. The ICECREAM (Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation Among Patients with a G13D Mutation) study demonstrates the need to prospectively evaluate hypotheses that were previously supported by retrospective analyses and exemplifies the value of international collaboration in trials of rare molecular subtypes.",
"affiliations": "Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom. e.segelov@unsw.edu.au.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.;Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Università degli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London, United Kingdom.",
"authors": "Segelov|Eva|E|;Thavaneswaran|Subotheni|S|;Waring|Paul M|PM|;Desai|Jayesh|J|;Robledo|Kristy P|KP|;Gebski|Val J|VJ|;Elez|Elena|E|;Nott|Louise M|LM|;Karapetis|Christos S|CS|;Lunke|Sebastian|S|;Chantrill|Lorraine A|LA|;Pavlakis|Nick|N|;Khasraw|Mustafa|M|;Underhill|Craig|C|;Ciardiello|Fortunato|F|;Jefford|Michael|M|;Wasan|Harpreet|H|;Haydon|Andrew|A|;Price|Timothy J|TJ|;van Hazel|Guy|G|;Wilson|Kate|K|;Simes|John|J|;Shapiro|Jeremy D|JD|",
"chemical_list": "C117307:KRAS protein, human; D000077146:Irinotecan; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab; D002166:Camptothecin",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2015.65.6843",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "34(19)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D000068818:Cetuximab; D015179:Colorectal Neoplasms; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D016283:Proto-Oncogene Proteins p21(ras); D011788:Quality of Life",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "2258-64",
"pmc": null,
"pmid": "27114605",
"pubdate": "2016-07-01",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Response to Cetuximab With or Without Irinotecan in Patients With Refractory Metastatic Colorectal Cancer Harboring the KRAS G13D Mutation: Australasian Gastro-Intestinal Trials Group ICECREAM Study.",
"title_normalized": "response to cetuximab with or without irinotecan in patients with refractory metastatic colorectal cancer harboring the kras g13d mutation australasian gastro intestinal trials group icecream study"
} | [
{
"companynumb": "AU-CIPLA LTD.-2016AU09927",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": "3",
... |
{
"abstract": "We report a case of sinus tract development within a connective tissue nevus in a patient with velocardiofacial syndrome and describe our treatment of sinus tracts using surgical deroofing and trichloroacetic acid scarification.",
"affiliations": "Henry Ford Dermatology, Detroit, Michigan.;Henry Ford Dermatology, Detroit, Michigan.;Loyola University, Chicago Stritch School of Medicine, Chicago, Illinois.",
"authors": "Shwayder|Tor|T|;Rambhatla|Pranita|P|;Novice|Karlee|K|",
"chemical_list": "D002424:Caustics; D014238:Trichloroacetic Acid",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.12671",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "32(6)",
"journal": "Pediatric dermatology",
"keywords": null,
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000293:Adolescent; D002424:Caustics; D004062:DiGeorge Syndrome; D006801:Humans; D008297:Male; D009506:Nevus; D012878:Skin Neoplasms; D014238:Trichloroacetic Acid",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "e298-9",
"pmc": null,
"pmid": "26337925",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Development of Sinus Tracts within a Connective Tissue Nevus.",
"title_normalized": "development of sinus tracts within a connective tissue nevus"
} | [
{
"companynumb": "US-GALDERMA-US16007959",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ADAPALENE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo evaluate the efficacy of chemotherapy with itraconazole for advanced or recurrent gastric cancer.\n\n\nMETHODS\nPatients with human epidermal growth factor receptor 2 (HER2) negative unresectable gastric cancer referred to our hospital were included. The regimen comprised 160 mg/m2 nab-paclitaxel i.v. and 100 mg/m2 oxaliplatin i.v. on day 1, 60 mg/m2 S-1 orally on days 1-3, and 400 mg itraconazole orally on days -2 to 2, repeated every 2 weeks for 6-8 cycles.\n\n\nRESULTS\nTwenty-three patients aged 40-80 years (median age=68 years) were enrolled, of whom 21 had stomach cancer and two gastroesophageal junction cancer. Regarding stage, two, one, and 20 patients had stage IIIA, IIIB, and IV, respectively. Among patients with liver metastases, 2/10 had simultaneous lung metastases. Nine patients had peritoneal dissemination, and five patients with stage IV disease developed recurrence after primary surgery followed by adjuvant S-1. The other 18 patients had no history of surgery or chemotherapy. The response rate was 70% (complete response in two; partial response in 14). Among 12 patients (67%) who underwent conversion surgery, R0 resection was conducted in eight, and no residual tumour was observed in two. For the population overall, the median overall survival was 24 months (95% confidence intervaI=21 months-not reached) and the 1-year overall survival rate was 95% (95% confidence intervaI=67-98%). Grade 3/4 neutropenia and grade 2 peripheral sensory neuropathy occurred in five (22%) and six (26%) patients, respectively, while no patient developed grade 3/4 thrombocytopenia.\n\n\nCONCLUSIONS\nChemotherapy with itraconazole is promising for patients with unresectable gastric cancer.",
"affiliations": "Department of Medical Oncology, Meiwa Hospital, Nishinomiya, Japan.;Department of Medical Oncology, Meiwa Hospital, Nishinomiya, Japan tsuba@hyo-med.ac.jp.;Department of Surgery, Meiwa Hospital, Nishinomiya, Japan.;Department of Pathology, Meiwa Hospital, Nishinomiya, Japan.;Department of Medical Oncology, Meiwa Hospital, Nishinomiya, Japan.",
"authors": "Sawasaki|Miyuki|M|;Tsubamoto|Hiroshi|H|;Nakamoto|Yoshihiko|Y|;Kakuno|Ayako|A|;Sonoda|Takashi|T|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D004338:Drug Combinations; D000077150:Oxaliplatin; C079198:S 1 (combination); D005641:Tegafur; D017964:Itraconazole; D010094:Oxonic Acid; D017239:Paclitaxel",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.14033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "40(2)",
"journal": "Anticancer research",
"keywords": "Gastric cancer; conversion surgery; itraconazole; repurposing",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D004338:Drug Combinations; D005260:Female; D005774:Gastrostomy; D006801:Humans; D017964:Itraconazole; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D000077150:Oxaliplatin; D010094:Oxonic Acid; D017239:Paclitaxel; D013274:Stomach Neoplasms; D005641:Tegafur; D016896:Treatment Outcome",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "991-997",
"pmc": null,
"pmid": "32014944",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "S-1, Oxaliplatin, Nab-paclitaxel and Itraconazole for Conversion Surgery for Advanced or Recurrent Gastric Cancer.",
"title_normalized": "s 1 oxaliplatin nab paclitaxel and itraconazole for conversion surgery for advanced or recurrent gastric cancer"
} | [
{
"companynumb": "JP-JNJFOC-20181103109",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Frequent administration of gadolinium-based contrast agents in multiple sclerosis (MS) may increase signal intensity (SI) unenhanced T1-weighted imaging MRI throughout the brain. We evaluated the association between lifetime cumulative doses of gadodiamide administration and increased SI within the dentate nucleus (DN), globus pallidus (GP), and thalamus in patients with early MS.\n\n\n\nA total of 203 patients with MS (107 with baseline and follow-up MRI assessments) and 262 age- and sex-matched controls were included in this retrospective, longitudinal, 3T MRI-reader-blinded study. Patients with MS had disease duration <2 years at baseline and received exclusively gadodiamide at all MRI time points. SI ratio (SIR) to pons and CSF of lateral ventricle volume (CSF-LVV) were assessed. Analysis of covariance and correlation analyses, adjusted for age, sex, and region of interest volume, were used.\n\n\n\nThe mean follow-up time was 55.4 months, and the mean number of gadolinium-based contrast agents administrations was 9.2. At follow-up, 49.3% of patients with MS and no controls showed DN T1 hyperintensity (p < 0.001). The mean SIR of DN (p < 0.001) and of GP (p = 0.005) to pons and the mean SIR of DN, GP, and thalamus to CSF-LVV were higher in patients with MS compared to controls (p < 0.001). SIR of DN to pons was associated with number of gadodiamide doses (p < 0.001). No associations between SIR of DN, GP, and thalamus and clinical and MRI outcomes of disease severity were detected over the follow-up.\n\n\n\nDN, GP, and thalamus gadolinium deposition in early MS is associated with lifetime cumulative gadodiamide administration without clinical or radiologic correlates of more aggressive disease.",
"affiliations": "From the Buffalo Neuroimaging Analysis Center (R.Z., N.B., J.H., D.P.R.) and Jacobs Comprehensive MS Treatment and Research Center (C.K., B.W.-G., D.H.), Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, and Center for Biomedical Imaging at Clinical Translational Science Institute (R.Z., M.G.D., F.S.), University at Buffalo, State University of New York. rzivadinov@bnac.net.;From the Buffalo Neuroimaging Analysis Center (R.Z., N.B., J.H., D.P.R.) and Jacobs Comprehensive MS Treatment and Research Center (C.K., B.W.-G., D.H.), Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, and Center for Biomedical Imaging at Clinical Translational Science Institute (R.Z., M.G.D., F.S.), University at Buffalo, State University of New York.;From the Buffalo Neuroimaging Analysis Center (R.Z., N.B., J.H., D.P.R.) and Jacobs Comprehensive MS Treatment and Research Center (C.K., B.W.-G., D.H.), Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, and Center for Biomedical Imaging at Clinical Translational Science Institute (R.Z., M.G.D., F.S.), University at Buffalo, State University of New York.;From the Buffalo Neuroimaging Analysis Center (R.Z., N.B., J.H., D.P.R.) and Jacobs Comprehensive MS Treatment and Research Center (C.K., B.W.-G., D.H.), Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, and Center for Biomedical Imaging at Clinical Translational Science Institute (R.Z., M.G.D., F.S.), University at Buffalo, State University of New York.;From the Buffalo Neuroimaging Analysis Center (R.Z., N.B., J.H., D.P.R.) and Jacobs Comprehensive MS Treatment and Research Center (C.K., B.W.-G., D.H.), Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, and Center for Biomedical Imaging at Clinical Translational Science Institute (R.Z., M.G.D., F.S.), University at Buffalo, State University of New York.;From the Buffalo Neuroimaging Analysis Center (R.Z., N.B., J.H., D.P.R.) and Jacobs Comprehensive MS Treatment and Research Center (C.K., B.W.-G., D.H.), Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, and Center for Biomedical Imaging at Clinical Translational Science Institute (R.Z., M.G.D., F.S.), University at Buffalo, State University of New York.;From the Buffalo Neuroimaging Analysis Center (R.Z., N.B., J.H., D.P.R.) and Jacobs Comprehensive MS Treatment and Research Center (C.K., B.W.-G., D.H.), Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, and Center for Biomedical Imaging at Clinical Translational Science Institute (R.Z., M.G.D., F.S.), University at Buffalo, State University of New York.;From the Buffalo Neuroimaging Analysis Center (R.Z., N.B., J.H., D.P.R.) and Jacobs Comprehensive MS Treatment and Research Center (C.K., B.W.-G., D.H.), Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, and Center for Biomedical Imaging at Clinical Translational Science Institute (R.Z., M.G.D., F.S.), University at Buffalo, State University of New York.;From the Buffalo Neuroimaging Analysis Center (R.Z., N.B., J.H., D.P.R.) and Jacobs Comprehensive MS Treatment and Research Center (C.K., B.W.-G., D.H.), Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, and Center for Biomedical Imaging at Clinical Translational Science Institute (R.Z., M.G.D., F.S.), University at Buffalo, State University of New York.",
"authors": "Zivadinov|Robert|R|;Bergsland|Niels|N|;Hagemeier|Jesper|J|;Ramasamy|Deepa P|DP|;Dwyer|Michael G|MG|;Schweser|Ferdinand|F|;Kolb|Channa|C|;Weinstock-Guttman|Bianca|B|;Hojnacki|David|D|",
"chemical_list": "D003287:Contrast Media; C064925:gadodiamide; D005682:Gadolinium; D019786:Gadolinium DTPA",
"country": "United States",
"delete": false,
"doi": "10.1212/WNL.0000000000007892",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": "93(6)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000328:Adult; D001921:Brain; D003287:Contrast Media; D005260:Female; D005500:Follow-Up Studies; D005682:Gadolinium; D019786:Gadolinium DTPA; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis; D012189:Retrospective Studies",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "e611-e623",
"pmc": null,
"pmid": "31285398",
"pubdate": "2019-08-06",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "24475844;18344005;30015589;26079490;26105022;25633504;28569398;25742194;19401576;30617409;27684794;21820063;26523910;30630068;29097315;28289935;21387374;25942417;26564433;26149978;28495943;28653648;26905870;12482100;28952018;24872007;27585702;28956156;26608061;20378467;27513848;27679460;17659998;27211256;28005498;29319556;24333394;28367903;19195496;29237148;16904911;27054693;27664936",
"title": "Cumulative gadodiamide administration leads to brain gadolinium deposition in early MS.",
"title_normalized": "cumulative gadodiamide administration leads to brain gadolinium deposition in early ms"
} | [
{
"companynumb": "US-GE HEALTHCARE LIFE SCIENCES-2020CSU001809",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GADODIAMIDE"
},
"drugaddit... |
{
"abstract": "A 57-year-old woman with a sudden-onset seizure was hospitalized. Brain magnetic resonance imaging findings led to a suspicion of leptomeningeal carcinomatosis (LMC) without a brain parenchymal tumor, and abdominal computed tomography showed a tumor in the pancreatic tail. Endoscopic ultrasonography-guided fine needle aspiration of the pancreatic mass revealed adenocarcinoma. Therefore, LMC from pancreatic ductal adenocarcinoma was strongly suspected. She received three courses of nab-paclitaxel plus gemcitabine and whole-brain radiation. Shortly thereafter, she developed a severe consciousness impediment and died. A pathological autopsy showed adenocarcinoma in a wide area of the leptomeninges.",
"affiliations": "Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine Graduate School of Medicine, Japan.;Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine Graduate School of Medicine, Japan.;Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine Graduate School of Medicine, Japan.;Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine Graduate School of Medicine, Japan.;Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine Graduate School of Medicine, Japan.;Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine Graduate School of Medicine, Japan.;Division of Gastroenterology, Yokohama Chuo Hospital, Japan.;Division of Pathology, Nihon University School of Medicine Graduate School of Medicine, Japan.;Department of Gastroenterology, Narita Memorial Hospital, Japan.",
"authors": "Iwatsuka|Kunio|K|;Kikuta|Daiichiro|D|;Shibuya|Hitoshi|H|;Ogawa|Masahiro|M|;Gotoda|Takuji|T|;Moriyama|Mitsuhiko|M|;Nakagawara|Hiroshi|H|;Hemmi|Akihiro|A|;Yamao|Kenji|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.4456-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n34148945\n10.2169/internalmedicine.4456-20\nCase Report\nTreatment Outcome of Nab-paclitaxel Plus Gemcitabine for Leptomeningeal Carcinomatosis from Pancreatic Ductal Adenocarcinoma: An Autopsy Case Report\nIwatsuka Kunio 1\nKikuta Daiichiro 1\nShibuya Hitoshi 1\nOgawa Masahiro 1\nGotoda Takuji 1\nMoriyama Mitsuhiko 1\nNakagawara Hiroshi 2\nHemmi Akihiro 3\nYamao Kenji 4\n1 Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine Graduate School of Medicine, Japan\n2 Division of Gastroenterology, Yokohama Chuo Hospital, Japan\n3 Division of Pathology, Nihon University School of Medicine Graduate School of Medicine, Japan\n4 Department of Gastroenterology, Narita Memorial Hospital, Japan\nCorrespondence to Dr. Kunio Iwatsuka, knwtsk29@gmail.com\n\n19 6 2021\n1 12 2021\n60 23 37433748\n9 1 2020\n7 5 2021\nCopyright © 2021 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The 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/).\nA 57-year-old woman with a sudden-onset seizure was hospitalized. Brain magnetic resonance imaging findings led to a suspicion of leptomeningeal carcinomatosis (LMC) without a brain parenchymal tumor, and abdominal computed tomography showed a tumor in the pancreatic tail. Endoscopic ultrasonography-guided fine needle aspiration of the pancreatic mass revealed adenocarcinoma. Therefore, LMC from pancreatic ductal adenocarcinoma was strongly suspected. She received three courses of nab-paclitaxel plus gemcitabine and whole-brain radiation. Shortly thereafter, she developed a severe consciousness impediment and died. A pathological autopsy showed adenocarcinoma in a wide area of the leptomeninges.\n\nleptomeningeal carcinomatosis\npancreatic ductal adenocarcinoma\nchemotherapy\nradiation therapy\n==== Body\npmcIntroductiofn\n\nMetastatic leptomeningeal carcinomatosis (LMC) is defined as infiltration of the leptomeninges by malignant cells and it is a fatal complication of cancer (1-5). LMC is estimated to occur in from 3% to 8% of patients with solid cancers (6) and it is a devastating complication of such cancers; the median survival time is less than 2 months without treatment (7). In patients with pancreatic ductal adenocarcinoma (PDAC), metastasis to the central nervous system (CNS) is generally rare (occurring in approximately 0.3% of all cases) (8). In particular, the development of LMC metastasis is quite rare: only 17 cases of LMC from PDAC have been reported to date (9-25). LMC is a serious complication of PDAC with an extremely poor prognosis and limited treatment options. Few articles to date have described the treatment approach for LMC from PDAC (11,13-15,18,19,23,25). In this report, we present an autopsy case of LMC from PDAC in a patient who was treated with nab-paclitaxel plus gemcitabine (nab-PTX+GEM).\n\nCase Report\n\nA 57-year-old woman without any notable medical history was transferred to our hospital by ambulance because of a sudden-onset seizure. The seizure was stopped by the intravenous injection of diazepam. However, her severe consciousness impediment did not improve. Symptoms of meningeal irritation (stiff neck, Brudzinski's sign, and Kernig's sign) were not present. Magnetic resonance imaging (MRI) of the brain revealed edematous cerebral parenchyma of the right frontal lobe (Fig. 1A) and leptomeningeal enhancement around the right to left cerebral folia (Fig. 1B). Although leptomeningeal metastasis was suspected, a brain parenchymal tumorous lesion was noticeably absent. Abdominal computed tomography (CT) showed a tumor in the tail of the pancreas, and the tumor was invading the splenic artery and vein (Fig. 2). The tumor was hypovascular and poorly enhanced compared with the surrounding pancreatic parenchyma in the early phase of dynamic CT and it became gradually enhanced on delayed images. Distal metastasis was not detected on chest or abdominal CT. Laboratory blood tests revealed high levels of tumor markers: carbohydrate antigen 19-9, 518 U/mL (reference range, <30 U/mL); DUPAN-2, 2,500 U/mL (reference range, <150 U/mL); and SPan-1, 1,800 U/mL (reference range, <30 U/mL). The carcinoembryonic antigen level was within the reference range at 2.0 ng/mL (reference range, <5 ng/mL).\n\nFigure 1. Brain magnetic resonance imaging (MRI). (A) T2-weighted brain MRI revealed edematous cerebral parenchyma of the right frontal lobe (arrow). Parenchymal involvement was noticeably absent. (B) Contrast-enhanced brain MRI showed partial enhancement around the right to left cerebral leptomeninges (arrow).\n\nFigure 2. Contrast-enhanced computed tomography. Contrast-enhanced abdominal computed tomography showed a tumor in the tail of the pancreas. The tumor invaded the splenic artery and vein (arrow). Distal metastasis was not detected.\n\nBased on these findings, LMC from PDAC was suspected. Because the cause of the consciousness impediment was considered to be intracranial hypertension associated with LMC, an osmotic diuretic (600 mg of glycerol per day) and steroids (3.3 mg of dexamethasone per day) were administered as neurogenic symptomatic therapy. Her consciousness gradually improved: her Japan Coma Scale score on the first, second, and fourth days after admission was III-200, II-10, and I-1, respectively. Beside the consciousness impairment, headache, nausea, and limb numbness were seen. These neurogenic symptoms also suggested that LMC had caused intracranial hypertension.\n\nOn the 12th day after admission, endoscopic ultrasonography-guided fine needle aspiration of the pancreatic mass lesion was performed, and ductal adenocarcinoma was identified. As a result, the patient was clinically diagnosed with PDAC (cT3N1M1 Stage IV). In general, LMC is definitively diagnosed by cerebrospinal fluid (CSF) cytology via a lumbar puncture. However, multiple lumbar punctures are sometimes needed because of the low sensitivity of CSF cytology for malignant cells (26). The patient refused lumbar puncture because of the period of time required to achieve a definitive diagnosis and the possible complications of lumbar puncture. Therefore, we prioritized treatment for PDAC, and systemic chemotherapy was begun 19 days after admission.\n\nWe chose the combination of nab-PTX+GEM, which was the first-line regimen for unresectable PDAC at that time in Japan. The regimen comprised nab-PTX (125 mg/m2) followed by GEM (1,000 mg/m2) administered on days 1, 8, and 15 every 4 weeks (one cycle). Shortly after chemotherapy administration, the patient developed an exacerbation of her headache and a left hearing impairment associated with LMC. Thus, a total of 20 Gy of whole-brain radiation therapy (WBRT) was performed as symptomatic therapy, and her symptoms were gradually relieved. The patient then developed two episodes of neutropenia associated with chemotherapy. Therefore, the dosages of nab-PTX and GEM were reduced to 80% and 60%, respectively, from the second dose in the first cycle and first dose in the third cycle.\n\nAfter three courses of chemotherapy, abdominal CT showed a slightly reduced mass volume of the PDAC (Fig. 3). However, brain MRI revealed widespread LMC from the right to left cerebral folia (Fig. 4). The carbohydrate antigen 19-9 level after the first, second, and third course of chemotherapy was 1,080 U/mL, 623 U/mL, and 1,613 U/mL, respectively. After the third course, the patient developed a consciousness impediment and left hearing impairment (Japan Coma Scale score of I-3) and was readmitted on an emergency basis (108 days after the first visit). Although neurogenic symptomatic therapy was promptly administered, the patient's consciousness level worsened, and she finally died 161 days after the first visit. A pathological autopsy revealed well-differentiated adenocarcinoma throughout a wide area of the bilateral leptomeninges. Brain parenchymal involvement was not detected (Fig. 5). Cancer tissue was not detected in the spinal pia mater. Well-differentiated tubular adenocarcinoma measuring 4 cm in size was identified in the pancreatic tail (Fig. 6). Apparent damage of cancer cells or nests, which is regarded as a treatment effect, was not seen in either the primary PDAC lesion or leptomeninges. Additionally, several metastatic lymph nodules were detected, including the para-aorta lymph nodules, and a single liver metastasis with a diameter of 1 cm was detected in liver segment 4. Despite the inability to confirm the definitive diagnosis before treatment, LMC from PDAC was still suspected.\n\nFigure 3. Contrast-enhanced computed tomography (CT) before and after chemotherapy. (A) The maximum diameter of the pancreatic ductal carcinoma was 37 mm on contrast-enhanced CT before chemotherapy (arrow). (B) The maximum diameter of the pancreatic ductal carcinoma was 30 mm on contrast-enhanced CT after chemotherapy (arrow).\n\nFigure 4. Contrast-enhanced magnetic resonance imaging before and after chemotherapy. (A) Brain contrast-enhanced magnetic resonance imaging showed partial enhancement around the right cerebral leptomeninges before chemotherapy (arrow). (B) Widespread leptomeningeal carcinomatosis was observed from the right to left cerebral folia after chemotherapy (arrow).\n\nFigure 5. A histological examination of the brain. Well-differentiated tubular adenocarcinoma was seen throughout a wide area of the leptomeninges, but no brain parenchymal involvement was detected.\n\nFigure 6. A histological examination of the pancreas. Well-differentiated tubular adenocarcinoma similar to the cancer seen in the leptomeninges was identified in the pancreatic tail.\n\nDiscussion\n\nSymptoms of LMC may include generalized findings such as headache and nausea, or patients may exhibit focal neurologic deficits that reflect the location of the involved leptomeninges, cranial neuropathies, and focal motor deficits (7). Symptomatic therapy is occasionally required for patients with LMC, and WBRT is commonly used. WBRT promptly provides significant palliation for neurogenic symptoms associated with CNS metastasis (27) and it was also effective for the patient's neurogenic symptoms in the present case. However, long-term toxicity induced by WBRT may cause dementia when WBRT is performed with chemotherapy (28). Therefore, the indications for WBRT in patients with a long-term prognosis should be carefully considered.\n\nThe diagnosis of LMC is confirmed by neuropathological examination of contrast-enhanced brain MRI and CSF analysis. Brain MRI shows leptomeningeal contrast enhancement, subependymal deposits, nodular enhancement, and hydrocephalus; these findings support the diagnosis (7). The definitive diagnosis is difficult in most patients because it requires the detection of malignant cells on CSF cytology obtained via lumbar puncture. Malignant cells are detected in the initial CSF sample in only 50% of patients with LMC (26). Thus, multiple lumbar punctures are sometimes required. Occasionally, the diagnosis must be confirmed comprehensively (e.g., MRI findings, existence of advanced cancer, and elevated tumor markers) if malignant cells are not detected.\n\nSystemic chemotherapy is a common treatment for unresectable PDAC but it is generally regarded as ineffective for LMC because only a limited number of anticancer drugs have shown good intracerebral fluid transferability (29). Although the effectiveness of intrathecal chemotherapy for brain metastasis has been reported, the evidence level remains insufficient: only small case series have so far been published (30). Thus, systemic chemotherapy with good intracerebral fluid transferability is reasonable for the treatment of LMC from PDAC in daily clinical practice. Nevertheless, most patients with PDAC have already undergone several treatment regimens when LMC develops, and the available regimens are generally limited.\n\nThe combination of nab-PTX+GEM is widely used as the first-line regimen for unresectable PDAC (31). However, only one report has focused on the treatment outcomes for LMC from PDAC. In this report, Ceccon et al. (25) described a 51-year-old man with LMC from PDAC that responded to nab-PTX+GEM in terms of elimination of tumor cells from the CSF and concurrent long-term clinical improvement (3 months after diagnosis of LMC). The patient finally developed neurogenic disorders associated with LMC progression (palsies of cranial nerves, gait disorder, and severe consciousness impediment) and soon died.\n\nIn our case, the primary PDAC lesion decreased in size as it responded to nab-PTX+GEM. However, the LMC lesion spread widely throughout the cerebral folia. Although the patient finally died of LMC progression, her survival time exceeded that of most patients with LMC described to date (Table). This result might indicate that nab-PTX+GEM can provide a longer survival period than other regimens (e.g., thiotepa+methotrexate+cytarabine, methotrexate+cytarabine+gemcitabine, and pelareorep+carboplatin+paclitaxel) (11,15,19). However, nab-PTX+GEM seems to be insufficient to suppress LMC progression because our patient eventually died of LMC progression, as did the patient described by Ceccon et al. (25). A possible reason for these outcomes might be the poor intracerebral fluid transferability of nab-PTX+GEM.\n\nTable. Reported Cases of Leptomeningeal Carcinomatosis from Pancreatic Ductal Adenocarcinoma.\n\nReference\t\tAge (y)/Sex\t\tChemotherapy\t\tRadiotherapy\t\tSurvival\t\n9\t\tN.R./N.R.\t\tN.R.\t\tN.R.\t\tN.R.\t\n10\t\t36/Male\t\tNo\t\tNo\t\tFew weeks, not specified\t\n11\t\t49/Male\t\tThiotepa, methotrexate, cytarabine\t\tNo\t\t8 weeks\t\n12\t\t55/Male\t\tNo\t\tNo\t\t7 weeks\t\n13\t\t64/Male\t\tGemcitabine\t\tYes\t\t168 weeks\t\n14\t\t44/Female\t\tMethotrexate and intrathecal 125IUdR\t\tNo\t\t24 weeks\t\n15\t\t59/Male\t\tMethotrexate, cytarabine, gemcitabine\t\tNo\t\t6 weeks\t\n16\t\t72/Male\t\tNo\t\tNo\t\tFew weeks, not specified\t\n17\t\t45/Female\t\tNo\t\tNo\t\tRapid death, not specified\t\n18\t\t57/Male\t\tFOLFIRINOX\t\tYes\t\tN.R.\t\n19\t\t72/Female\t\tPelareorep, carboplatin, paclitaxel\t\tNo\t\t8 weeks\t\n20\t\t58/Female\t\tNo\t\tNo\t\t1 week\t\n21\t\t80/Male\t\tNo\t\tYes\t\tN.R.\t\n22\t\t58/Male\t\tNo\t\tNo\t\t5 weeks\t\n23\t\t54/Male\t\tCapecitabine, irinotecan, topotecan, bevacizumab\t\tYes\t\t45 weeks\t\n24\t\t59/Male\t\tNo\t\tNo\t\t2 weeks\t\n25\t\t51/Male\t\tNab-paclitaxel plus gemcitabine\t\tNo\t\t12 weeks\t\nPresent case\t\t59/Female\t\tNab-paclitaxel plus gemcitabine\t\tYes\t\t23 weeks\t\nN.R.: not reported, 125IUdR: 5-iodo-2’-deoxyuridine labeled with 125-I, FOLFIRINOX: fluorouracil, leucovorin, irinotecan, and oxaliplatin\n\nNevertheless, nab-PTX+GEM appears to be a reasonable treatment. Previous reports have indicated that it seems to be a relatively effective regimen (9-25). Moreover, combinations of fluorouracil+leucovorin+irinotecan+oxaliplatin and erlotinib+gemcitabine are used as first-line regimens for unresectable PDAC, as with nab-PTX+GEM; however, no articles have described the treatment outcomes of these regimens for LMC from PDAC. If nab-PTX+GEM is administered for LMC from PDAC, then careful neurological examinations and frequent brain MRI scans are necessary to avoid missing a progression of LMC.\n\nWe herein described the treatment outcome of nab-PTX+GEM for LMC from PDAC. This case is extremely rare in terms of the development of LMC from PDAC without multi-organ metastasis at the initial presentation. The patient died of LMC progression despite control of the primary PDAC lesion by nab-PTX+GEM. An autopsy confirmed that the LMC progression was the cause of death. Thus, the difference in the treatment response to nab-PTX+GEM between the LMC from PDAC and the primary PDAC lesion was verified. The number of cases of CNS metastasis from PDAC is expected to continuingly increase with improvements in systemic therapies and longer survival times. Future similar case reports will hopefully continue to provide more information to improve the prognosis of CNS metastasis from PDAC.\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\n\nWe thank Angela Morben, DVM, ELS, for editing a draft of this manuscript.\n==== Refs\n1. Rudnicka H , Niwinska A , Gruszfeld A , Pienkowski T . Diagnosis and treatment of carcinoid meningitis: a challenge to the neurologist and oncologist. Pol J Neurol Neurosurg 37 : 811-824, 2003.\n2. Chamberlain MC . Neurotoxicity of intra-CSF liposomal cytarabine (DepoCyt) administered for the treatment of leptomeningeal metastases: a retrospective case series. J Neurooncol 109 : 143-148, 2012.22539243\n3. Chamberlain MC , Sandy AD , Press GA . Leptomeningeal metastasis: a comparison of gadolinium-enhanced MR and contrast-enhanced CT of the brain. Neurology 40 : 435-438, 1990.2314584\n4. Groves MD , Glantz MJ , Chamberlain MC , et al . A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies. Neuro Oncol 10 : 208-215, 2008.18316473\n5. Niwińska A , Rudnicka H , Murawska M . Breast cancer leptomeningeal metastasis: propensity of breast cancer subtypes for leptomeninges and the analysis of factors influencing survival. Med Oncol 30 : 408, 2013.23322521\n6. Lee JL , Kang YK , Kim TW , et al . Leptomeningeal carcinomatosis in gastric cancer. J Neuro Oncol 66 : 167-174, 2004.\n7. Le Rhun E , Taillibert S , Chamberlain MC . Carcinomatous meningitis: leptomeningeal metastases in solid tumors. Surg Neurol Int 4 : S265-S288, 2013.23717798\n8. Park KS , Kim M , Park SH , Lee KW . Nervous system involvement by pancreatic cancer. J Neuro Oncol 63 : 313-316, 2003.\n9. Galatioto S , Savettieri G . Meningeal carcinomatosis secondary to a primary pancreatic tumour. Acta Neurol (Napoli) 30 : 359-367, 1975(in Italian).1229842\n10. Kurzaj E , Kopczynski S , Barowska Lehman J , Ludwiczak R . Subdural haematoma associated with dural carcinomatosis in a patient with primary carcinoma of the pancreas. Neurochirurgia (Stuttg) 23 : 13-17, 1980.7352044\n11. Ferreira Filho AF , Cardoso F , Di Leo A , et al . Carcinomatous meningitis as a clinical manifestation of pancreatic carcinoma. Ann Oncol 12 : 1757-1759, 2001.11843255\n12. Grira MT , Ben Jemaa HM , Lammouchi TM , Benammou SA . Meningitis revealing pancreatic carcinoma. Neurosciences (Riyadh) 12 : 256-258, 2007.21857581\n13. Hirota M , Yagi Y , Yamashita K , Okamoto K , Sato T , Ichihara T . A long survival case of unresectable pancreatic cancer by chemoradiotherapy with gemcitabine as the key drug. Gan To Kagaku Ryoho 35 : 2413-2416, 2008(in Japanese, Abstract in English).19098414\n14. Rebischung C , Hoffmann D , Stefani L , et al . First human treatment of resistant neoplastic meningitis by intrathecal administration of MTX plus 125IUdR. Int J Radiat Biol 84 : 1123-1129, 2008.19061137\n15. Minchom A , Chan S , Melia W , Shah R . An unusual case of pancreatic cancer with leptomeningeal infiltration. J Gastrointest Cancer 41 : 107-109, 2010.20069465\n16. Blows SJ , Morgan R , Dhariwal U , Petts G , Roncaroli F . Pancreatic adenocarcinoma presenting with sudden onset bilateral deafness secondary to metastatic leptomeningeal infiltration. Age Ageing 41 : 818-819, 2012.22743150\n17. Anne M , Ahmad N , Lee P , Aziz M , Lebowicz Y . An unusual presentation of isolated leptomeningeal disease in carcinoma of unknown primary with pancreatic features. J Investig Med High Impact Case Rep 1 : 2324709613494830, 2013.\n18. Rao R , Sadashiv SK , Goday S , Monga D . An extremely rare case of pancreatic cancer presenting with leptomeningeal carcinomatosis and synchronous intraparenchymal brain metastasis. Gastrointest Cancer Res 6 : 90-92, 2013.23936550\n19. Hong CS , Kurt H , Elder JB . Asynchronous leptomeningeal carcinomatosis from pancreatic cancer: a case report and review of the literature. Clin J Gastroenterol 7 : 434-440, 2014.26184025\n20. Naqvi SA , Ahmed I . Carcinomatous meningitis: a rare complication of pancreatic adenocarcinoma. J Coll Physicians Surg Pak 25 : 458-459, 2015.26101003\n21. Yoo IK , Lee HS , Kim CD , et al . Rare case of pancreatic cancer with leptomeningeal carcinomatosis. World J Gastroenterol 21 : 1020-1023, 2015.25624740\n22. Trinh VT , Medina-Flores R , Chohan MO . Leptomeningeal carcinomatosis as primary manifestation of pancreatic cancer. J Clin Neurosci 30 : 124-127, 2016.26972704\n23. Johnson WR , Theeler BJ , Van Echo D , Young P , Kwok M . Treatment of leptomeningeal carcinomatosis in a patient with metastatic pancreatic cancer: a case report and review of the literature. Case Rep Oncol 11 : 281-288, 2018.29867436\n24. Ikeda Y , Yoshida M , Ishikawa K , et al . Pancreatic cancer with leptomeningeal carcinomatosis: case report and literature review. Int Cancer Conf J 9 : 96-100, 2020.32257762\n25. Ceccon G , Wollring M , Brunn A , et al . Leptomeningeal carcinomatosis in a patient with pancreatic cancer responding to nab-paclitaxel plus gemcitabine. Case Rep Oncol 13 : 35-42, 2020.32095126\n26. Kesari S , Batchelor TT . Leptomeningeal metastases. Neurol Clin 21 : 25-66, 2003.12690644\n27. Chang EL , Maor MH . Standard and novel radiotherapeutic approaches to neoplastic meningitis. Current Oncol Rep 5 : 24-28, 2003.\n28. Lai R , Abrey LE , Rosenblum MK , DeAngelis LM . Treatment-induced leukoencephalopathy in primary CNS lymphoma: a clinical and autopsy study. Neurology 62 : 451-456, 2004.14872029\n29. Bhowmik A , Khan R , Ghosh MK . Blood brain barrier: a challenge for effectual therapy of brain tumors. Biomed Res Int 2015 : 320941, 2015.25866775\n30. Lee DW , Lee KH , Kim JW , Keam B . Molecular targeted therapies for the treatment of leptomeningeal carcinomatosis: current evidence and future directions. Int J Med Sci 17 : 1074-1085, 2016.\n31. Von Hoff DD , Ervin T , Arena FP , et al . Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369 : 1691-1703, 2013.24131140\n\n",
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"title": "Treatment Outcome of Nab-paclitaxel Plus Gemcitabine for Leptomeningeal Carcinomatosis from Pancreatic Ductal Adenocarcinoma: An Autopsy Case Report.",
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"abstract": "An 18-year-old female who was 14 weeks pregnant first noted vision loss in her left eye six days prior to admission. Ophthalmologic examination revealed 20/20 vision in the right eye and count fingers vision in the left eye. A marked relative afferent pupillary defect was present in the left eye. Ophthalmoscopic examination revealed a trace optic nerve pallor temporally in the left eye without associated disc oedema or haemorrhage. Magnetic resonance imaging of the brain demonstrated a heterogeneous mass of the left sphenoid sinus extending superiorly causing compression of the intracranial portion of the left optic nerve, and laterally into the left cavernous sinus. The patient underwent transphenoidal resection of the tumour whose histologic morphology revealed a grade 2 osteosarcoma. Following resection, vision returned to 20/20 in the left eye. The patient has been treated with chemotherapy with close monitoring of her pregnancy.",
"affiliations": "Department of Ophthalmology.;Department of Pathology, Loyola University Medical Center Maywood, IL USA.;Department of Ophthalmology.",
"authors": "Malalis|Julia F|JF|;Lee|John M|JM|;Jay|Walter M|WM|",
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"title": "Primary Osteosarcoma of the Skull Base in a Pregnant Patient.",
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"abstract": "In contrast to primary colorectal cancer (CRC) little is known about the genomic landscape of metastasized CRC. Here we present whole genome sequencing data of metastases of 429 CRC patients participating in the pan-cancer CPCT-02 study (NCT01855477). Unsupervised clustering using mutational signature patterns highlights three major patient groups characterized by signatures known from primary CRC, signatures associated with received prior treatments, and metastasis-specific signatures. Compared to primary CRC, we identify additional putative (non-coding) driver genes and increased frequencies in driver gene mutations. In addition, we identify specific genes preferentially affected by microsatellite instability. CRC-specific 1kb-10Mb deletions, enriched for common fragile sites, and LINC00672 mutations are associated with response to treatment in general, whereas FBXW7 mutations predict poor response specifically to EGFR-targeted treatment. In conclusion, the genomic landscape of mCRC shows defined changes compared to primary CRC, is affected by prior treatments and contains features with potential clinical relevance.",
"affiliations": "Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.;Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.;Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.;Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.;Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.;Center for Personalized Cancer Treatment, Rotterdam, The Netherlands.;Center for Personalized Cancer Treatment, Rotterdam, The Netherlands.;Center for Personalized Cancer Treatment, Rotterdam, The Netherlands.;Center for Personalized Cancer Treatment, Rotterdam, The Netherlands.;Center for Personalized Cancer Treatment, Rotterdam, The Netherlands.;Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.;Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.;Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.;Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands. s.wilting@erasmusmc.nl.",
"authors": "Mendelaar|Pauline A J|PAJ|http://orcid.org/0000-0002-1496-9627;Smid|Marcel|M|http://orcid.org/0000-0003-0605-1901;van Riet|Job|J|http://orcid.org/0000-0001-7767-7923;Angus|Lindsay|L|http://orcid.org/0000-0002-7928-1102;Labots|Mariette|M|;Steeghs|Neeltje|N|;Hendriks|Mathijs P|MP|http://orcid.org/0000-0001-6687-5393;Cirkel|Geert A|GA|;van Rooijen|Johan M|JM|;Ten Tije|Albert J|AJ|;Lolkema|Martijn P|MP|http://orcid.org/0000-0003-0466-2928;Cuppen|Edwin|E|;Sleijfer|Stefan|S|;Martens|John W M|JWM|http://orcid.org/0000-0002-3428-3366;Wilting|Saskia M|SM|http://orcid.org/0000-0002-2838-841X",
"chemical_list": "D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human",
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"fulltext": "\n==== Front\nNat Commun\nNat Commun\nNature Communications\n2041-1723\nNature Publishing Group UK London\n\n33495476\n20887\n10.1038/s41467-020-20887-6\nArticle\nWhole genome sequencing of metastatic colorectal cancer reveals prior treatment effects and specific metastasis features\nhttp://orcid.org/0000-0002-1496-9627\nMendelaar Pauline A. J. 1\nhttp://orcid.org/0000-0003-0605-1901\nSmid Marcel 1\nhttp://orcid.org/0000-0001-7767-7923\nvan Riet Job 123\nhttp://orcid.org/0000-0002-7928-1102\nAngus Lindsay 1\nLabots Mariette 45\nSteeghs Neeltje 56\nhttp://orcid.org/0000-0001-6687-5393\nHendriks Mathijs P. 57\nCirkel Geert A. 58\nvan Rooijen Johan M. 59\nTen Tije Albert J. 510\nhttp://orcid.org/0000-0003-0466-2928\nLolkema Martijn P. 15\nCuppen Edwin 1112\nSleijfer Stefan 15\nhttp://orcid.org/0000-0002-3428-3366\nMartens John W. M. 15\nhttp://orcid.org/0000-0002-2838-841X\nWilting Saskia M. s.wilting@erasmusmc.nl\n\n1\n1 grid.5645.2 000000040459992X Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands\n2 grid.5645.2 000000040459992X Cancer Computational Biology Center, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands\n3 grid.5645.2 000000040459992X Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands\n4 grid.12380.38 0000 0004 1754 9227 Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands\n5 Center for Personalized Cancer Treatment, Rotterdam, The Netherlands\n6 grid.430814.a Department of Medical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek, Amsterdam, The Netherlands\n7 Department of Medical Oncology, Northwest Clinics, Alkmaar, The Netherlands\n8 grid.414725.1 0000 0004 0368 8146 Department of Medical Oncology, Meander Medical Center, Amersfoort, The Netherlands\n9 grid.416468.9 0000 0004 0631 9063 Department of Medical Oncology, Martini Hospital, Groningen, The Netherlands\n10 grid.413711.1 Department of Medical Oncology, Amphia Hospital, Breda, The Netherlands\n11 grid.7692.a 0000000090126352 Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands\n12 Hartwig Medical Foundation, Amsterdam, The Netherlands\n25 1 2021\n25 1 2021\n2021\n12 57430 6 2020\n21 12 2020\n© The Author(s) 2021, corrected publication 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.\nIn contrast to primary colorectal cancer (CRC) little is known about the genomic landscape of metastasized CRC. Here we present whole genome sequencing data of metastases of 429 CRC patients participating in the pan-cancer CPCT-02 study (NCT01855477). Unsupervised clustering using mutational signature patterns highlights three major patient groups characterized by signatures known from primary CRC, signatures associated with received prior treatments, and metastasis-specific signatures. Compared to primary CRC, we identify additional putative (non-coding) driver genes and increased frequencies in driver gene mutations. In addition, we identify specific genes preferentially affected by microsatellite instability. CRC-specific 1kb-10Mb deletions, enriched for common fragile sites, and LINC00672 mutations are associated with response to treatment in general, whereas FBXW7 mutations predict poor response specifically to EGFR-targeted treatment. In conclusion, the genomic landscape of mCRC shows defined changes compared to primary CRC, is affected by prior treatments and contains features with potential clinical relevance.\n\nMolecular landscapes of metastatic colorectal cancers (mCRC) have often been restricted to coding regions or low numbers of patients. Here the authors present a whole-genome landscape of 429 mCRC patients, revealing the mutational impact of prior therapies and potential actionable targets.\n\nSubject terms\n\nCancer genomics\nColorectal cancer\nMetastasis\nissue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\n\nPrimary colorectal cancer (CRC) can be divided into a major group of chromosomally instable tumors and a minor group of hypermutated, chromosomally stable tumors due to microsatellite instability (MSI) or POLE mutations1. Parallel to the described genomic subtype division, transcriptomic analysis was used to identify four consensus molecular subtypes (CMSs) with distinguishing features including prognosis2.\n\nMolecular analysis of CRC revealed specific genetic alterations with clinical implications. Mutations in KRAS and BRAF predict failure to treatment with EGFR-inhibitors, whereas copy number alterations of ERBB2 or IGF2, and the occurrence of chromosomal translocations leading to fusion genes such as NAV2/TCF7L1, are potentially drug targetable1,3.\n\nAlthough the molecular knowledge of primary CRC has contributed to a better understanding of its pathogenesis, cancer-related mortality usually occurs as a consequence of distant metastases, in which ongoing mutational processes and selective treatment pressure can result in altered molecular characteristics4.\n\nTo date, in-depth analyses of large series of colorectal cancer metastases are limited to studies using either whole-exome sequencing (WES) or targeted sequencing of cancer-associated genes4–6. Although these studies yielded extensive knowledge on the presence of specific genomic aberrations in mCRC, they do not necessarily reflect its complete molecular landscape. For optimal identification of mutational signatures, the power provided by whole-genome sequencing (WGS) data greatly exceeds that of WES7. Next to this, WGS simultaneously allows for the determination of MSI, structural rearrangements, chromothripsis, and kataegis. In addition, clinically relevant genetic alterations within noncoding regions were recently reported in primary CRC8. To date, the only other study which reported in detail on WGS data of colorectal metastases included 12 patients4.\n\nHere, we provide a comprehensive description of the molecular landscape of metastatic CRC (mCRC). We use WGS data obtained from a large multicenter, prospective collection of snap-frozen metastatic tissue biopsies from 429 patients starting a new line of systemic treatment9. In addition, matched RNA-seq data are available for 91 patients. The observed metastatic molecular landscape is compared to WGS data of primary CRC cohorts (Supplementary Table 1), associated with prior treatments as well as treatment response, and evaluated for clinical utility.\n\nResults\n\nCohort description\n\nClinical characteristics of our included cohort of 429 patients are summarized in Table 1. Median tumor purity (0.53 (IQR 0.38–0.67) was estimated on the obtained sequencing data and was not significantly different between biopsy sites. Based on a previously described WGS data analysis algorithm9 14 samples (3%) were scored as microsatellite instable (MSI), which is in concordance with the observed MSI frequency in mCRC in literature (4%)10.Table 1 Cohort description.\n\nPatient details\tNumber of patients\t\nTotal cohort\t\t429\t\nGender\tFemale\t174\t\n\tMale\t255\t\nAge (median (IQR,Range))\t64 (IQR 56–72, range 25–88)\t\nPrior-treatment details\t\t\n Systemic prior treatment: yes\t284\t\nTreatment regimen\tManuscript code\t\t\n5-FU/capecitabine–oxaliplatin doublet (CAPOX, FOLFOX)\tPLAT/PYR\t121\t\n+bevacizumab\tPLAT/PYR + targeted\t134\t\n5-FU—Topisomerase inhibitor doublet (Irinotecan based, FOLFIRI)\tTOP/PYR\t26\t\n+bevacizumab/panitumumab\tTOP/PYR + targeted\t9\t\n5-FU/capecitabine monotherapy\tPYRmon\t39\t\n+bevacizumab\tPYR + targeted\t36\t\nTopoisomerase inhibitor (Irinotecan) monotherapy\tTOPmono\t67\t\n+bevacizumab\tTOP + targeted\t7\t\nOxaliplatin + bevacizumab/panitumumab\tPLAT + targeted\t5\t\nPanitumumab/cetuximab/encorafenib+binimetinib/bevacizumab/regorafenib\tTargeted mono\t35\t\n5-FU/capecitabine–oxaliplatin–irinotecan triplet (FOLFOXIRI)\tCHEMCOM\t2\t\n+bevacizumab\tCHEMCOM + targeted\t5\t\nOther\tDiverse\t15\t\n Systemic prior treatment: no\t124\t\n Systemic prior treatment: unknown\t21\t\n Radiotherapeutic prior treatment: yes\t109\t\nRT + systemic treatment\t68\t\nChemoradiation\t33\t\nRadiotherapy only\t8\t\n Radiotherapeutic prior treatment: no\t299\t\n Radiotherapeutic prior treatment: unknown\t21\t\nBiopsy details\tNumber of patients\t\nOrigin\t\t\n\tLiver\t287\t\n\tSoft tissue\t84\t\n\tLymph node\t24\t\n\tLung\t21\t\n\tOther\t13\t\nTechnical details\t\n\tTumor purity\t0.53 (IQR 0.38–0.67)\t\n\tRead coverage (median)\t102.6× (IQR 94.6×–112.0×)\t\nPatient Characteristics. PLAT/PYR (5-FU/capecitabine–oxaliplatin doublet (CAPOX, FOLFOX)), PLAT/PYR + targeted (bevacizumab added), TOP/PYR + targeted (bevacizumab added), PYRmono (5-FU/capecitabine monotherapy), PYR + targeted (bevacizumab added), TOP/PYR (5-FU-Topisomerase inhibitor doublet (Irinotecan based)), TOPmono (Topoisomerase inhibitor (Irinotecan) monotherapy), TOP + targeted (bevacizumab added), PLAT + targeted (Oxaliplatin + bevacizumab/panitumumab), Targeted mono (panitumumab, cetuximab, encorafenib + binimetinib, bevacizumab, regorafenib), CHEMCOM (5-FU/capecitabine–oxaliplatin–irinotecan triplet (FOLFOXIRI)), CHEMCOM + targeted (bevacizumab added), Other (diverse).\n\nBased on the treatment data, the cohort can be divided in patients who did (n = 284) and who did not (n = 124) receive any systemic treatment prior to the moment the biopsy was taken. Within the group of prior-treated patients, 13 different combinations of treatment regimens were defined as specified in the materials and methods and listed in Table 1.\n\nFor 91 cases RNA-seq data were available, allowing us to determine their Consensus Molecular Subtype (CMS). Remarkably, using the CMS-classifier package, none of the metastatic CRC samples were classified as CMS3, whereas 10 were classified as CMS1, 41 as CMS2, and 14 as CMS4. The remaining 26 samples (29%) could not be classified into one of the 4 subtypes, which might be partly due to the presence of normal cells of noncolon origin in our metastatic setting. Indeed, using the alternative CMSCaller algorithm, which is less dependent on signals from the tumor microenvironment, reduced the number of unclassified samples to 14 (15%), whereas still only 3 samples were classified as CMS311. Twenty-two samples were classified as CMS1, 25 as CMS2, 3 as CMS3, and 27 as CMS4.\n\nRegardless of the calling algorithm used, the estimated tumor cell percentage was significantly lower in biopsies classified as CMS4 than in the other subtypes (medians CMS1: 52.5 and 45%; CMS2 61 and 61%; CMS3: none and 66% and CMS4: 34.5 and 42%; KWH; p = 0.0007 and p = 0.0156 for CMS Classifier and CMSCaller, respectively), which is concordant with the described high-stroma content in this subtype2.\n\nThe molecular landscape of mCRC\n\nFrom the WGS data of all 429 cases, we distilled somatically acquired single nucleotide variants (SNVs), multiple nucleotide variants (MNVs), structural variants (SVs), insertions/deletions (InDels), and copy number variants (CNVs). The overall tumor mutational burden (TMB) representing the amount of SNVs, MNVs and InDels per Megabase (Mb), ranged from 0.96 to 366.15 with a median of 7.01 (95% CI 6.62–7.47). Using GISTIC2.0, we identified 55 recurrent CNVs (29 gains and 26 losses) within our entire cohort, containing a number of already known and putative driver genes (Supplementary Data 1). Chromothripsis was observed in 47 cases (11%), whereas kataegis was observed in 102 cases (24%), involving just a single chromosomal region in two-third of cases, with a maximum of 10 regions in one single case. Presence of kataegis was associated with MSI and high TMB (≥10; test for trend p = 0.00014). In fact, 9 out of 13 MSI cases had at least two kataegis regions.\n\nWe further evaluated the type and size of SVs observed in our cohort (Fig. 1). A broad range of differently sized Tandem Duplications (TD; ~14–93 kb) with a peak at 26 kb was observed, which was clearly distinct from the TD sizes previously observed in other cancers (~11 kb in BRCA1-mutated, ~231 kb in CCNE1-activated, and ~1.7 Mb TDs in CDK12-mutated cancer, respectively)12. Inversions in mCRC are usually over 10 Mb in size, while deletions range from ~10 kb to 1 Mb, with a distinct peak at ~128 kb. Events within this latter peak include many recurrent deletions in known Common Fragile Site (CFS) genes: e.g., FHIT, RBFOX1, and MACROD2. This phenomenon involving frequent deletions of CSF genes was recently described in primary CRC as well13.Fig. 1 Size distributions of the different types of structural variants.\n\nRidge-plot of the density of genomic sizes of structural variants in metastatic CRC. INV inversions (blue), DUP tandem duplications (purple), DEL deletions (orange). Source data are provided as a Source Data file.\n\nUsing the ratio of nonsynonymous to synonymous substitutions caused by the somatic nucleotide mutations (SNV and InDels; dN/dS analysis), 23 genes were identified as putative driver genes (q < 0.05, Fig. 2, Table 2). In 99.1% of cases (425 out of 429) at least one of these 23 putative driver genes was mutated. Testing for mutual exclusivity only revealed already known associations: KRAS with BRAF/NRAS/RNF43/TP53 (q = 1.06E-7, q = 1.54E-4, q = 0.004, and q = 0.017, respectively), and APC with RNF43/BRAF (both q = 1.54E-4; Supplementary Fig. 1). For those genes also present in the targeted panel used by Yaeger et al.6, comparable mutation frequencies were observed in both cohorts (Table 2).Fig. 2 Oncoplot of metastatic CRC depicting identified driver genes and somatic mutations (SNV, InDels, and MNV).\n\nTop panel: genes identified by dN/dS as driver genes per type of mutation; purple: frameshift variant; orange: other variant; blue: stop/gain variant; green: structural variant. Bottom panel: first track: clinical information: sex (male: orange; female: green) and second track: biopsy site. Track three (PLAT/PYR ± targeted) indicates which patients have been treated with platinum-based therapy (PLAT; e.g., oxaliplatin) and a pyrimidine-targeting drug (PYR; e.g., 5-FU), with or without the addition of another targeted treatment (±targeted; e.g., bevacizumab). Tracks four to six depict the distribution of the consensus molecular subtypes (CMS), tumor mutational burden (TMB), and the number of structural variant deletions of size 10kb–1Mb (DEL_CFS), partly associated with Common Fragile Sites (CFS), respectively. Source data are provided as a Source Data file.\n\nTable 2 Mutation frequency driver genes.\n\n\tMetastatic CRC\tPrimary CRC—(TCGA, combined studies cBioportal)\tMetastatic CRC—(Yaeger et al.)\t\nGene\tdN/dS q-value\tMutations (N)\tMutations (%)\tMutations (N)\tMutations (%)\tFisher p-value\tFDR Hochberg\t% change in meta\tMutations (N)\tMutations (%)\tFisher p-value\tFDR Hochberg\t\nTP53\t0\t317\t73.9\t1123\t57.6\t2.04E-10\t4.7E-09\t16.3\t246\t76.6\t0.395\t1\t\nZFP36L2\t0\t42\t9.8\t97\t5.0\t3.61E-04\t0.008\t4.8\tNot present\t\t\t\t\nKRAS\t0\t203\t47.3\t744\t38.2\t5.88E-04\t0.012\t9.1\t127\t39.6\t0.037\t0.487\t\nAPC\t0\t336\t78.3\t1372\t70.4\t8.86E-04\t0.018\t7.9\t241\t75.1\t0.335\t1\t\nPIK3CA\t0\t68\t15.9\t445\t22.8\t0.001\t0.023\t−7.0\t49\t15.3\t0.840\t1\t\nB2M\t5.37E-03\t8\t1.9\t91\t4.7\t0.007\t0.128\t−2.8\t2\t0.6\t0.202\t1\t\nSMAD4\t0\t74\t17.2\t243\t12.5\t0.010\t0.164\t4.8\t47\t14.6\t0.367\t1\t\nATM\t9.50E-04\t33\t7.7\t227\t11.6\t0.017\t0.266\t−4.0\t18\t5.6\t0.306\t1\t\nFBXW7\t0\t51\t11.9\t301\t15.4\t0.061\t0.912\t−3.6\t25\t7.8\t0.068\t0.814\t\nAMER1\t0\t37\t8.6\t209\t10.7\t0.220\t0.913\t−2.1\t11\t3.4\t0.004\t0.067\t\nARID1A\t1.13E-09\t39\t9.1\t201\t10.3\t0.480\t0.913\t−1.2\t15\t4.7\t0.022\t0.333\t\nBCL9\t5.27E-02\t28\t6.5\t107\t5.5\t0.419\t0.913\t1.0\tNot present\t\t\t\t\nBCL9L\t2.24E-06\t27\t6.3\t133\t6.8\t0.750\t0.913\t−0.5\tNot present\t\t\t\t\nBRAF\t0\t56\t13.1\t273\t14.0\t0.644\t0.913\t−1.0\t38\t11.8\t0.657\t1\t\nELF3\t5.37E-03\t7\t1.6\t51\t2.6\t0.299\t0.913\t−1.0\tNot present\t\t\t\t\nLMTK3\t1.33E-02\t15\t3.5\t56\t2.9\t0.530\t0.913\t0.6\tnot present\t\t\t\t\nNRAS\t0\t26\t6.1\t125\t6.4\t0.913\t0.913\t−0.4\t14\t4.4\t0.329\t1\t\nPTEN\t4.30E-08\t17\t4.0\t123\t6.3\t0.069\t0.913\t−2.3\t14\t4.4\t0.854\t1\t\nRNF43\t2.20E-02\t28\t6.5\t162\t8.3\t0.239\t0.913\t−1.8\t21\t6.5\t1.000\t1\t\nSMAD3\t5.68E-03\t11\t2.6\t72\t3.7\t0.309\t0.913\t−1.1\t11\t3.4\t0.518\t1\t\nSOX9\t0\t41\t9.6\t177\t9.1\t0.782\t0.913\t0.5\t16\t5.0\t0.025\t0.352\t\nTCF7L2\t1.07E-09\t50\t11.7\t177\t9.1\t0.103\t0.913\t2.6\t19\t5.9\t0.007\t0.116\t\nTGIF1\t1.33E-02\t18\t4.2\t62\t3.2\t0.300\t0.913\t1.0\tNot present\t\t\t\t\nTwenty-three genes identified as putative driver genes using the ratio of nonsynonymous to synonymous substitutions caused by the somatic nucleotide mutations (SNV and InDels; dN/dS analysis). P-values are derived from the Fisher exact test (two-sided) and corrected for multiple testing using the FDR (Hochberg) method.\n\nSimilarly, for 15 noncoding genes an enriched mutation rate was observed compared to surrounding nonannotated regions (Table 3), suggesting these genes are relevant for the oncogenic process. These noncoding genes include PTENP1, a known tumor suppressor in CRC14, MALAT1, for which an increased mutation rate was already described in a pan-cancer analysis15, and LINC00672, described to promote chemo-sensitivity16.Table 3 Mutation frequency noncoding genes.\n\n\tMetastatic CRC\tPrimary CRC - (ICGC)\t\t\nENSG\tSymbol\tSize\tChr\tType\tMutation rate\tFDR Hochberg\tMutations (N)\tMutations (%)\tMutations (N)\tMutations (%)\tFisher p-value\tFDR Hochberg\t\nENSG00000273001\tAL731533.2\t577\t10\tlncRNA\t0.067591\t0\t6\t1.4\t0\t0\t0.001291\t3.87E-03\t\nENSG00000280325\tAC074183.2\t921\t7\tTEC\t0.033659\t0\t25\t5.8\ta\ta\t\t\t\nENSG00000261584\tAL513548.1\t1723\t6\tlncRNA\t0.012768\t9.93E-24\t14\t3.3\t3\t0.3\t3.84E-05\t2.09E-04\t\nENSG00000259834\tAL365361.1\t3480\t1\tlncRNA\t0.007184\t2.48E-09\t17\t4.0\t0\t0\t5.62E-09\t7.30E-08\t\nENSG00000264920\tAC018521.5\t4583\t17\tlncRNA\t0.00851\t1.02E-08\t16\t3.7\t1\t0.1\t2.06E-07\t1.85E-06\t\nENSG00000231784\tDBIL5P\t2676\t17\tTranscribed_unitary_pseudogene\t0.008595\t6.26E-07\t18\t4.2\t1\t0.1\t2.39E-08\t2.63E-07\t\nENSG00000273033\tLINC02035\t5475\t3\tlncRNA\t0.006758\t9.54E-06\t23\t5.4\t0\t0.0\t6.15E-12\t8.61E-11\t\nENSG00000266979\tLINC01180\t3985\t17\tlncRNA\t0.005521\t1.18E-05\t13\t3.0\t1\t0.1\t5.00E-06\t4.00E-05\t\nENSG00000272070\tAC005618.1\t3147\t5\tlncRNA\t0.006991\t4.19E-05\t18\t4.2\t1\t0.1\t2.39E-08\t2.63E-07\t\nENSG00000251562\tMALAT1\t8828\t11\tlncRNA\t0.005551\t0.000283\t30\t7.0\t19\t2.2\t4.19E-05\t2.09E-04\t\nENSG00000261094\tAC007066.2\t2710\t9\tlncRNA\t0.008118\t0.000287\t11\t2.6\t2\t0.2\t1.86E-04\t7.43E-04\t\nENSG00000263874\tLINC00672\t4216\t17\tProtein_coding\t0.005455\t0.000493\t14\t3.3\t2\t0.2\t9.70E-06\t6.79E-05\t\nENSG00000180764\tPIPSL\t3349\t10\tTranscribed_processed_pseudogene\t0.006569\t0.0013\t14\t3.3\t34\t3.9\t0.640\t0.640\t\nENSG00000237984\tPTENP1\t3995\t9\tTranscribed_processed_pseudogene\t0.005507\t0.0013\t15\t3.5\t22\t2.5\t0.376\t0.640\t\nENSG00000240859\tAC093627.4\t5916\t7\tlncRNA\t0.006085\t0.0048\t18\t4.2\t2\t0.2\t1.66E-07\t1.66E-06\t\nFifteen noncoding genes with an enriched mutation rate compared to surrounding nonannotated regions. P-values are derived from the Fisher exact test (two-sided) and corrected for multiple testing using the FDR (Hochberg) method.\n\naENSG not recognised by ICGC data portal.\n\nTo further investigate the mechanisms underlying the observed SNVs and MNVs, we used the latest COSMIC mutational signatures (v3) to establish the presence and contribution of these predefined mutational signatures in metastatic CRC17. We identified 11 single base signatures (SBS) and 9 double base signatures (DBS) that had a relative contribution of at least 10% in minimally 10 cases and as such were considered dominant signatures in mCRC; SBS1, SBS5, SBS8, SBS9, SBS17b, SBS18, SBS35, SBS39, SBS40, SBS41, SBS44, DBS2-9, and DBS11. De novo signature calling using the Non-negative Matrix Factorization algorithm (NMF)18 did not identify additional signatures besides the known COSMIC signatures in our cohort.\n\nEffects of systemic prior treatment on the genomic landscape\n\nPatients receiving prior systemic treatment (n = 284) showed a significantly higher TMB, a higher number of SVs, a higher number of affected GISTIC CNV regions (7.58 versus 5.82; 208 versus 148; 31 versus 28, respectively; MWU p-values < 0.005), and more frequent occurrence of chromothripsis (6.5 versus 13.4%; Fisher exact test p = 0.042) compared to patients (n = 124) without prior systemic treatment. More specifically, we observed altered relative contributions for several mutational signatures in defined prior-treatment groups compared to treatment-naive patients (n = 124, Fig. 3 and Supplementary Data 2; MWU, FDR p < =5.15E-7). Patients who were prior-treated with a combination therapy of PLAT/PYR + target showed increased relative contributions of SBS8, SBS17b, SBS35, and DBS5 compared to treatment-naive patients. These results are supported by previous studies in which DBS5 and SBS35 signatures were linked to the effect of platinum (PLAT) compounds, while SBS17b was detected specifically in 5-FU or capecitabine (PYR) exposed tumors19. SBS8 was previously indirectly associated with prior platinum treatment in metastatic breast cancer17,20.Fig. 3 Mutational signatures in prior-treated cases compared to untreated cases.\n\nRelative contribution (%) of several single and double base mutational signatures (SBS/DBS) in patients receiving prior treatment with platinum, pyrimidine antagonist, and targeted anti-EGFR treatment (PLAT/PYR + target; orange, n = 134) compared to untreated patients (blue, n = 124). Horizontal lines indicate the median. P-values are derived from the MWU test (two-sided) and corrected for multiple testing using the FDR (Hochberg) method. Source data are provided as a Source Data file.\n\nRemarkably, even though TMB was increased in patients who received prior treatment compared to treatment-naive patients, no specific mutations (coding or noncoding) were associated with any of the defined prior-treatment groups or with prior treatment in general. With regard to the GISTIC-defined CNVs, we found increased frequencies of gains at 6p22.1, 6p21.1, and 18p11.32 as well as losses at 3p14.2 and 8p21.3 in patients who received prior treatment (Supplementary Table 2; chi-square FDR < 0.05). More specifically, gains of 6p22.1 and 6p21.1 were also associated with a prior-treatment regimen containing PLAT/PYR ± target whereas loss at 8p21.3 was only associated with PLAT/PYR + target.\n\nComparing metastatic CRC to primary CRC\n\nThe above described characteristics of our metastatic cohort were related to previous reports on primary CRC to identify changes potentially linked to the metastatic process (Supplementary Table 1). Therefore, we compared the observed relative contributions of the 20 dominant mutational signatures in our cohort to primary CRC data described by Alexandrov et al. (PCAWG cohort)17. For this analysis only the 124 untreated metastatic CRC cases from our cohort were included, since multiple treatments are known to specifically affect these mutational signatures17,19,20. SBS1, 8 and 41, as well as DBS2, 4, and 6 showed a significantly increased relative contribution in untreated metastatic cases (MWU, FDR ≤ 0.01; Fig. 4), suggesting they may be associated with the metastatic process. Etiologies for these signatures are either unknown (SBS8/41, DBS1) or appear age-related (SBS1, DBS2/DBS4), although DBS2 has also been linked to exposure to tobacco smoking and other endogenous and exogenous mutagens. Mutation frequencies per gene were compared between primary CRC (TCGA-DFCI cohort) and our total metastatic cohort. For this purpose, we selected genes mutated in primary CRC (TCGA-DFCI cohort) with >5% prevalence and complemented these with here identified metastatic driver genes regardless of their prevalence in primary CRC. Increased frequencies were only observed in driver genes TP53, ZFP36L2, KRAS, and APC (Fisher exact test, FDR ≤ 0.012). A decreased frequency was observed for 21 non-driver genes (Supplementary Table 3) and 1 driver gene, namely PIK3CA (Table 2). With respect to the identified putative noncoding drivers (Table 3), all of them were enriched in mCRC compared to primary CRC, except for PIPSL and PTENP1 (ICGC dataset; Fisher exact test, FDR < 5.74E-4).Fig. 4 Mutational signatures in primary CRC and untreated metastatic CRC.\n\nRelative contribution (%) of several single and double base mutational signatures (SBS/DBS) in primary CRC tumors (purple, n = 73)17, compared to untreated metastatic CRC tumors (green, n = 124). Horizontal lines indicate the median. P-values are derived from the MWU test (two-sided) and corrected for multiple testing using the FDR (Hochberg) method. Source data are provided as a Source Data file.\n\nDistinct mutational signature patterns in mCRC patients\n\nUnsupervised hierarchical clustering using the 20 dominant mutational signatures complemented with mutational signatures previously described in primary CRC (SBS15/17a/28/37 and DBS10), and mutational signatures showing a dominant relative contribution (>25%) in at least one of our samples (SBS10a/10b), revealed three major and three minor groups of patients (Fig. 5).Fig. 5 Unsupervised hierarchical clustering of metastatic CRC using relative contribution of preselected mutational signatures.\n\nHeatmap representing the median-centered relative contribution of mutational signatures between samples. Values were scaled from red (relative contribution above median) to yellow (relative contribution below median). Included single and doublet base signatures (SBS/DBS) are indicated at the right to which etiologies are added when known. Grouping of samples is shown by the dendrogram at the top. Source data are provided as a Source Data file.\n\nThe three major groups are found in cluster 1, cluster 3, and cluster 6. Clusters 1 and 6 are labeled “prior treatment” and “primary-like” as they are enriched for either patients with or without prior treatment compared to all other clusters (Fisher’s exact test: p = 4.588E-25 and p = 4.754E-15, respectively) and are characterized by higher relative contributions of signatures related to prior treatment (SBS5/8/35/17a/17b and DBS5) and signatures known from primary CRC (SBS1/5/18/40, DBS9), respectively. Samples from Cluster 6 are enriched (Fisher’s exact p = 0.005) for samples with >5% contribution of the recently described E. coli mutational signature in CRC as well21. Cluster 3 was labeled ‘mCRC-specific’ as it contains both patients with (n = 63) and without (n = 31) prior treatment characterized by higher relative contributions of signatures SBS9/37/39/41, which, except for SBS37, are rarely detected in primary CRC. Etiologies for SBS37/39/41 are unknown, whereas SBS9 mutations have been partly associated with polymerase eta (Pol η) function during somatic hypermutation in lymphoid cells. In vitro, Pol η activity has been associated with anticancer drugs resistance, specifically cisplatin and 5-FU22–24. Indeed we find that the majority of patients (13 out of 15) in cluster 3 with a high SBS9 contribution (≥10%) had already received prior treatment, although this did not reach statistical significance (Fisher’s exact test p = 0.07).\n\nThe remaining minor groups are found in Clusters 2, 4, and 5. Samples in clusters 2 and 4 are defined by a large contribution of DBS8 and DBS2, respectively. Cluster 5, labeled ‘high TMB’, contains 14 samples, which were all characterized by a high TMB (defined as >10/Mb) compared to only 82 out of the 415 remaining samples (20%) in the other clusters. High contributions of DNA mismatch repair associated signatures SBS15/44 and DBS7 characterize the 13 MSI samples in this cluster, whereas the one remaining sample showed high contributions of SBS10a/b, associated with polymerase epsilon (POLE) mutations.\n\nMSI-specific gene mutations\n\nWe subsequently investigated whether specific somatic gene mutations were associated with each of the six clusters described above and found this was true only for the high TMB cluster (cluster 5). To correct for the higher likelihood of finding any mutation in a high TMB sample, we applied a permutation test25,26, which identified 28 genes as significantly more frequently mutated in the high TMB cluster versus all other samples (Fisher exact test, FDR and permutation p < 0.05, see Supplementary Table 4). As these 28 genes are large (cDNA size range 1.5–22 kb) and often contain substantial numbers of microsatellites and mononucleotide stretches (range 4–126), we evaluated whether their observed mutation frequency in MSI cases was significantly higher than the frequency distribution observed for all other genes with a comparable number (±10%) of MSI-prone coding sequences. Except for TNXB, for which we were unable to establish a reliable control distribution, all identified genes were significantly more frequently mutated in MSI cases compared to control genes containing similar numbers of MSI-prone sequences (one sample sign test; all p ≤ 0.0001). These results suggest that mutations in these genes are selected for during the disease process in MSI tumors. The top 2 genes, ACVR2A and UBR5, are known targets of the MSI process27. LRP1 mutations were found to reduce its expression in CRC and were associated with MSI status and poor outcome28. Although the other 25 identified genes were not previously associated with MSI status, three of these genes (KMT2C, KMT2D, and FAT1) were present in the Yaeger dataset of mCRC samples6. Mutations in all three overlapping genes were significantly enriched in MSI cases (n = 16) compared to microsatellite stable (MSS) cases (n = 305) in this dataset as well (all Fisher p < =9.19E-7).\n\nAssociation between molecular landscape and treatment response\n\nThe observed molecular characteristics were associated with response to current treatment for the 286 patients in our cohort with recorded treatment response. These results should be interpreted with caution due to the heterogeneity of our cohort in terms of both treatment line and type of prior treatments received, which may introduce bias. We studied ordinal response (PD, SD, and PR) to any treatment as well as to specific treatment regimens. In total, 123 items were used as input in the regression model, consisting of five themes (full list in Supplementary Data 3): clinical parameters (age, gender, prior treatment, and radiotherapy), counts (TMB, kataegis, chromothripsis, total number of SV by type and the number of 10kb–1Mb deletions), mutational signatures (DBS/SBS), driver genes (including noncoding genes), and GISTIC-defined CNVs. Items that reached univariate statistical significance (p < 0.05) were used in a multivariable penalized ordinal regression model for treatment response (Table 4).Table 4 Multivariate LASSO analysis.\n\nType\tItem\tAll treatments\tOxaliplatin containing\tPLAT/PYR\tTarget-mono\tTOP/PYR\t\nClinical\tPrior Treatment\t0.57\t\t\t\t\t\nGender\t\t0.77\t\t−1.14\t−1.10\t\nCounts\tnr of Tandem Duplications\t\t\t\t1.19\t\t\nnr of 10kb–1Mb deletions\t0.01\t\t\t\t\t\nMutational Signatures\tDBS2\t−0.02\t\t\t\t\t\nDBS5\t0.13\t\t\t\t\t\nDBS11\t−0.03\t\t\t\t\t\nSBS17b\t0.07\t0.13\t\t\t\t\nSBS39\t0.04\t\t\t\t\t\nSBS41\t\t\t−0.21\t\t\t\nDriver Genes\tAPC\t0.23\t\t\t\t\t\nKRAS\t0.78\t\t\t\t\t\nPIK3CA\t0.22\t\t\t\t\t\nFBXW7\t\t\t\t17.65\t\t\nNon-coding\tLINC00672\t0.90\t\t\t\t\t\nGISTIC Regions\tGain 17q12\t(ERBB2*)\t0.44\t\t\t\t\t\nGain 18p11.32\t(CETN1*)\t0.59\t\t\t\t\t\nGain 20q11.1\t(BCL2L1*)\t0.12\t\t\t\t\t\nGain 8p11.21\t(KAT6A)\t\t−0.78\t−1.56\t\t\t\nGain 7p21.3\t(VWDE)\t\t\t\t\t3.68\t\nGain 7q31.2\t(MET*)\t\t\t\t\t3.59\t\nGain 7p12.3\t(PKD1L1)\t\t\t\t\t3.04\t\nGain 7q34\t(no genes in peak)\t\t\t\t\t3.59\t\nGain 14q23.1\t(no genes in peak)\t\t\t\t\t1.64\t\nLoss 18q12.2\t(hsa-mir-924*)\t\t−1.52\t−3.30\t2.79\t\t\nLoss 6q26\t(PARK2)\t\t\t−1.38\t\t\t\nLoss 9p21.3\t(CDKN2A*)\t\t\t−1.88\t\t\t\nLoss 16q23.1\t(WWOX)\t\t\t−1.70\t\t\t\nLoss 4q22.1\t(CCSER1)\t\t\t\t2.66\t\t\nLoss 4q35.1\t(IRF2)\t\t\t\t1.78\t\t\nLoss 18q21.2\t(SMAD4)\t\t−1.35\t−3.30\t2.79\t\t\nLoss 18q23\t(NFATC1*)\t\t−1.14\t−3.30\t\t\t\nLoss Xp22.31\t(STS*)\t\t\t\t−1.40\t1.78\t\nLoss 14q23.3\t(GPHN)\t\t\t\t\t−2.09\t\nItems that reached univariate statistical significance (p < 0.05) were used in a multivariable penalized ordinal regression model for treatment response. Univariate regression was performed for genomic features (Supplementary Data 3) using the ‘polr’ function from the MASS R package (v7.3-51.4) and subsequently those with a univariate two-sided p-value <0.05 were selected for multivariable ordered LASSO regression using the ordinalNet R package (v2.7). Regression coefficients are shown for features that remained significant in the multivariable model.\n\n*Multiple genes present in region; bold: known Fragile Site region\n\nOverall we found that, next to receiving prior treatment(s), the number of 10kb–1Mb deletions, mutations in KRAS, APC, PIK3CA, and LINC00672, mutational signatures SBS17b/39, DBS2/5/11, and gains at 18p, 17q, and 20q were associated with treatment response regardless of treatment type in mCRC patients. For SBS17b this effect was more pronounced when specifically investigating patients treated with platinum as described before17. CNVs were predominantly associated with response to PLAT/PYR or PYRmono treatment, whereas mutations in FBXW7 were associated with poor response to targeted treatment. FBXW7 mutations were detected in 51 patients from our cohort, including 21 KRAS wild-type patients. Of these 21 patients, five were treated with panitumumab monotherapy, all of whom had PD as best response. This suggests that, next to somatic KRAS mutations, somatic FBXW7 mutations may provide an additional negative selection marker for anti-EGFR treatment. This finding is in concordance with previous reports on FBXW7 mutation prevalence in nonresponding patients on anti-EGFR treatment29,30.\n\nPotential clinical implications\n\nWGS data of our cohort of 429 patients with metastatic CRC revealed several potential molecular features that might be associated with sensitivity to particular anticancer agents. A high TMB (here defined as >10 mutations per Mb) has been suggested as a potential selection tool for tumors that may respond to immunotherapy31. In our cohort, 96 (22%) samples showed a TMB > 10, of which 13 were MSI. A gradual increase in TMB was observed with the number of prior treatments (test for trend, p = 4.39E-13). For the subset of samples of which we also had RNA-seq data available, we calculated the Tumor Infiltrating Leukocyte (TIL) score as a proxy for the immunogenicity of the tumor32. Interestingly, we did not observe a significantly higher TIL score in the TMB-high samples (n = 21) compared to the other samples (n = 63; MWU; p = 0.39), whereas the average TIL score in MSI samples is significantly higher compared to both MSS samples with a high TMB and with a low TMB (Kruskal–Wallis test (p = 0.037) followed by Dunn’s pairwise comparison (Benjamini–Hochberg corrected p = 0.012 and p = 0.021 for MSI compared to MSS with high and low TMB, respectively (See Supplementary Fig. 2). Although far from definite, these results support the on-label use of immunotherapy in MSI tumors and suggest that merely using TMB may not be sufficient to identify the tumors with immunogenic potential in the metastatic setting.\n\nOther on-label markers found in our cohort include a targetable BRAF V600E mutation in 40 patients, as well as 130 RAS/RAF wild-type patients that did not receive targeted anti-EGFR treatment yet. However, our data suggest that mutations in FBXW7, observed in 21 out of these 130 RAS/RAF wild-type patients, should be considered as a contra-indication for the use of anti-EGFR treatment. Molecular biomarkers for potential off-label use that were found in our cohort include amplifications of ERBB2 (HER2), MET and CDK4, loss of BRCA1 and BRCA2 through deletion or high impact mutations, loss of TSC1 and TSC2 through high impact mutations, and possible fusions of PDGFRB. In addition, 23 patients in our cohort carried a KRAS G12C mutation, for which an inhibitor may become available in the near future33.\n\nIn summary, for 55% of our patients one or more targeted treatments are potentially available based on the molecular profile of their cancer (Fig. 6).Fig. 6 Actionable genes.\n\nData from OncoKB were matched to affected genes observed in our mCRC cohort. Numbers indicate the number (and percentage) of affected patients. Source data are provided as a Source Data file.\n\nDiscussion\n\nThis study encompasses a WGS-based, comprehensive description of the molecular landscape of metastatic CRC and aims to put this landscape into perspective by associating it with prior systemic treatments, comparing it to primary CRC and relating it to treatment response.\n\nIn general, the genomic landscape of CRC remains relatively stable in metastatic disease. However, compared to primary CRC, our metastatic CRC cohort showed significant enrichment for mutations in 4 out of 23 coding and 12 out of 15 noncoding (putative) driver genes. From the identified putative drivers, only mutations in PIK3CA were significantly decreased in mCRC. Six of our identified coding driver genes are not present in the current CRC-specific MSK-IMPACT panel, namely ZFP36L2, BCL, BCL9L, ELF3, LMTK3, and TGIF1.\n\nWithin the mCRC cohort we observed clear effects of received prior treatments on the total numbers of aberrations, CNVs, and mutational signatures, with the latter sufficiently dominant to show up as a separate group after hierarchical clustering. Remarkably, we also observed an mCRC-specific cluster characterized by signatures which are rarely found in primary CRC and are not associated with any treatment (SBS9/39/41). SBS9 is associated with Pol η activity, an error-prone polymerase encoded by the POLH gene, which mediates translesion synthesis and is induced by replication stress34. Interestingly, high levels of Pol η have been associated with cancer therapy resistance in vitro22–24. We did observe that the majority of patients with a high relative SBS9 contribution had already received prior treatment; however, unfortunately, sample numbers were too low to directly associate SBS9 contribution with POLH expression in our dataset. Another predominant cluster group consisted of metastatic MSI samples. In these samples we observed a significant enrichment of mutations in a specific set of genes compared to other similarly MSI-prone genes, suggesting these genes are preferentially affected or selected for during disease progression.\n\nThe varying number and types of received prior treatments within our cohort hampered the search for prognostic and predictive biomarkers. However, we found that, next to already known events, the number of LINC00672 mutations and 10kb–1Mb deletions were associated with treatment response irrespective of the type of treatment. Strikingly, many of these recurrent deletions occur in known Common Fragile Site (CFS) genes, as described in primary CRC as well13, implicating replication stress as one of driving mechanisms35. In addition, FBXW7 mutations were predictive for poor response to EGFR-targeted treatments in our prospective cohort. This is in line with previous observations showing that FBXW7 mutations were enriched in unresponsive patients compared to patients responding well to EGFR-targeted treatments29,30.\n\nThe current study gives a detailed description of the genomic landscape of metastatic CRC. More specifically, our study identifies treatment-induced changes, metastasis-specific alterations, and associations between molecular traits and response to treatment. In addition, we provide prospective validation for FBXW7 mutations as a predictive biomarker for poor response to EGFR-targeted treatment. Combined with future studies, this catalogue of molecular alterations will speed up the identification of resistance mechanisms, the determination of metastasis-driving processes, and, ultimately, the improvement of metastatic CRC patient care.\n\nMethods\n\nPatient cohort and study procedures\n\nColorectal cancer patients included in this study were selected from the previously described cohort of the Center for Personalized Cancer Treatment (CPCT) consortium (CPCT-02 Biopsy Protocol, ClinicalTrial.gov no. NCT01855477), which was approved by the medical ethics committee of the University Medical Center Utrecht, the Netherlands9. All patients have given explicit consent for whole-genome sequencing and data sharing for cancer research purposes. Upon our data request for all CRC patients thus far, we were provided with the data of all patients registered as metastatic CRC patients included between April 2016 and January 2019 (n = 487). Patients who received systemic treatment which is not normally given to colorectal cancer patients (e.g., carboplatin, paclitaxel, sunitinib, and etoposide) were excluded to avoid erroneous inclusion of patients suffering from another type of cancer (n = 28). When multiple biopsies were included for one patient (n = 29), only the first biopsy was included in our analyses. In total, we included 429 distinct CRC patients in our analyses. Based on the provided information regarding all forms of systemic treatment patients received before the study biopsy took place (further referred to as “prior treatment”), we coded the (groups of) active agents using the following abbreviations: PLAT (oxaliplatin), PYR (fluoropyrimidines), TOP (topoisomerase inhibitor; Irinotecan), +targeted (when bevacizumab or panitumumab was added), CHEMCOM (triplet combination therapy). Prior-treatment regimens were grouped based on their working mechanism to enable the analysis of their effect on the genomic landscape. Treatment related analyses were performed using combinations of the abbreviations mentioned above. For detailed information see Table 1.\n\nWhole-genome sequencing; identification of somatic changes\n\nWhole-genome sequencing of paired tumor/normal was performed in all cases. In short, raw sequencing data were processed using bcl2fastq (versions 2.17 to 2.20), mapped to the human reference genome GRCh37 using BWA-mem v0.7.Sa and GATK BQSR and Haplotype Caller v3.4.46 and Strelka v1.0.14 were used to call somatic mutations. Within our cohort, 98% of the biopsies of metastatic lesions showed a coverage of at least 30× (95% with >60× coverage), whereas for the normal blood 98% had >10× coverage and 94% >20× coverage. The identification of copy number changes was performed using GISTIC v2.0.2336 with the following parameters: genegistic 1; gcm extreme; maxseg 4000; broad 1; brlen 0.98; conf 0.95; rx 0; cap 3; saveseg 0; armpeel 1; smallmem 0; res 0.01; ta 0.1; td 0.1; savedata 0; savegene 1; and qvt 0.19,20.\n\nRNA sequencing and CMS calling\n\nMatched RNA was isolated from the same frozen tissue for 91 CRC patients on an automated setup (QiaSymphony) according to supplier’s protocols (Qiagen) using the QIAsymphony RNA Kit for tissue and quantified by Qubit. A total of 50–100 ng of RNA was used as input for library preparation using the KAPA RNA HyperPrep Kit with RiboErase (Human/Mouse/Rat) (Roche). Barcoded libraries were equimolarly pooled and sequenced using standard settings (Illumina) on either a NextSeq 500 (V2.5 reagents) generating 2 × 75 read pairs or a NovaSeq 6000 generating 2 × 150 read pairs. BCL output was converted to FASTQ using bcl2fastq (versions 2.17–2.20) using default parameters and sequence reads were trimmed for adapter sequences using fastp (v0.20.0). The resulting FASTQ files were mapped to GRCh38 using STAR (v2.6.1d)37. Sambamba (v0.7.0)38 was used to mark duplicates and index the resulting BAM files. Gene annotation was derived from GENCODE Release 30 (https://www.gencodegenes.org/), raw read counts were obtained with featureCounts (v1.6.3)39 and normalized using GeTMM40. Normalized data were used to (1) determine CMS with both the single-sample prediction parameter from the “CMSclassifier” package (v1.0.0) (https://github.com/Sage-Bionetworks/CMSclassifier)2 and CMSCaller v(0.99.1)11, and (2) calculate the Tumor Infiltrating Lymphocytes (TIL) score by averaging the expression of TIL-genes32\n\nIdentification of mutational signatures and driver genes\n\nMutational signatures (COSMIC v3)17 were called using R package MutationalPatterns v1.10.018, focusing on single and double base signatures. This package was also used to perform de novo signature calling using the Non-negative Matrix Factorization (NMF) method. Detection of kataegis and chromothripsis was performed as previously described41. In short, to call kataegis only SNVs were considered to establish segments based on the intermutational distance. Segments were determined using a piecewise constant fitting model and were called as kataegis when at least five SNVs were present showing an intermutational distance of ≤2 kb. Chromothripsis-like events were called using the Shatterseek R package (v0.4). Driver genes, i.e., genes under selective pressure, were identified by the dN/dS model using R package dndscv (v0.0.1.0)42. A global q ≤ 0.05 was used to select statistically significant driver genes. The R package discover v0.9.243 was used to test for mutual exclusivity. To identify noncoding genes with an enriched mutation rate, we first established a baseline mutation rate based on all identified SNVs, MNVs and Indels found in nonannotated regions, as we assume these regions are not under any selective pressure. Nonannotated regions were based on GENCODE annotation (version33) and for each of these regions we calculated a mutation rate (number of mutations/size of region). Next, a mutation rate (number of mutations/size of noncoding gene) was calculated for all somatic mutations annotated as ‘noncoding transcript variant’. The signed-rank test with Hochberg’s multiple testing correction was used to determine whether the mutation rate of a recurrent noncoding gene (mutated in at least 5% of the cohort) exceeded the baseline mutation rate. Per noncoding gene a specific baseline was determined using only nonannotated regions (>1 kb) in an area of 2 Mb surrounding the respective noncoding gene.\n\nVerification in publicly available datasets\n\nTo compare mutational signatures, publicly available WGS data from 73 primary colorectal cases were used17. We downloaded the matrix of counts for single and double base substitutions of primary cases and analyzed these in the same manner as the metastatic CRC cases to call mutational signatures. Observed frequencies of mutated genes in metastatic CRC were verified and compared in two publicly available datasets. Dataset 1, the Yaeger dataset, contained 321 unique metastatic CRC patients that were profiled for mutations by targeted sequencing6. Dataset 2, the TCGA-DFCI dataset, contained 1949 unique primary CRC patients that were profiled for mutations in coding regions (accessed via cBioPortal January 21, 2020). Prior to analysis, synonymous mutations were removed and multiple mutations within the same gene were aggregated per patient. Dataset 3, the ICGC dataset, was used to compare mutation frequencies of noncoding genes and contained 866 unique primary CRC patients with available mutation data (accessed via the ICGC data portal, release 28). The used cohorts are summarized in Supplementary Table 1.\n\nEstimating MSI-prone sequences\n\nTo evaluate preferentially mutated genes in MSI cases, the number of MSI-prone sequences in a gene are of interest. Data of the Microsatellite Database (MSDB, https://data.ccmb.res.in/msdb/, June 2, 2020) were filtered for repeats annotated to human exons44. For each gene, the number of repeats was summed. In addition, a custom Perl script was used to count mononucleotide stretches of lengths between 6 and 13 (the latter is the minimum length used in MSDB) as we noticed many InDels in our data in mononucleotide stretches less than 13 bases long. Exon sequences of the Consensus CDS database (https://www.ncbi.nlm.nih.gov/CCDS/) were used to count the number of mononucleotide stretches per gene.\n\nAssociations with response to treatment\n\nTreatment response was evaluated according to RECIST (v.1.1) every 8 to 12 weeks depending on the treatment regimen and was defined as response (partial or complete), stable disease, or progressive disease45. For regression analyses, the best overall response was used as outcome measure. Genomic features (at least 5 events per group) were associated with response to treatment in a 2-step procedure using ordinal LASSO (least absolute shrinkage and selection operator) regression, which is suited for datasets with a relatively high number of predictors in comparison to cases and protects against overfitting. First, univariate regression was performed for genomic features (Supplementary Data 3) using the ‘polr’ function from the MASS R package (v7.3–51.4) and subsequently those with a univariate p-value <0.05 were selected for multivariable ordered LASSO regression using the ordinalNet R package (v2.7).\n\nIdentification of potentially actionable events\n\nOncoKB (accessed on March 31, 2020) was used to identify clinically actionable genes from the list of mutated genes in our cohort, using only genes with level 1 and 2 evidence46. In case OncoKB listed a specific gene alteration as actionable genomic aberration, we only counted patients that harbored that specific mutation or CNV. For genes for which only ‘Oncogenic mutations’ were listed by OncoKB, we only included patients if the gene had a mutation with ‘High impact’ consequence (i.e., a nonsense or frameshift mutation). To evaluate patients eligible for an anti-EGFR therapy, we included only patients that were triple wild-type for KRAS, NRAS, and BRAF, and excluded those patients that had already received anti-EGFR therapy prior to biopsy.\n\nStatistics\n\nIn general, a Pearson’s Chi-squared test or Fisher’s exact test (in case of too few expected events) was used to evaluate the categorical data while continuous variables were evaluated using either a Mann–Whitney U test (MWU) or a Kruskal–Wallis H (KWH) test depending on the number of categories. All statistical tests were two-sided and considered statistically significant when P < 0.05. Stata 13.0 (StataCorp) and R (v3.6.0) were used for the statistical analyses. Multiple testing using the Hochberg procedure to correct P values was applied when necessary. The statistical test used is specified throughout the results section.\n\nReporting summary\n\nFurther information on research design is available in the Nature Research Reporting Summary linked to this article.\n\nSupplementary information\n\nSupplementary Information\n\nPeer Review File\n\nDescription of Additional Supplementary Files\n\nSupplementary Data 1\n\nSupplementary Data 2\n\nSupplementary Data 3\n\nReporting Summary\n\nSource data\n\nSource Data\n\nSupplementary information\n\nSupplementary information is available for this paper at 10.1038/s41467-020-20887-6.\n\nAcknowledgements\n\nWe thank the Hartwig Medical Foundation, and Stichting Stelvio for Life for financial support of clinical studies and WGS analyses. We thank the Center for Personalized Cancer Treatment for proving the clinical data. We would like to thank all local principal investigators, medical specialists, and nurses of all contributing centers for their help with patient accrual. We are particularly grateful to all participating patients and their families.\n\nAuthor contributions\n\nP.A.J.M., M.S., S.S., J.W.M.M., and S.M.W. wrote the manuscript, which all authors reviewed. M.S. and J.V.R. performed the bioinformatics analyses. P.A.J.M., L.A., and S.S. managed clinical data assessment. M.L., N.S., M.P.H., G.A.C., J.M.V.R., and A.J.T.T. are main clinical contributors. M.P.L. and S.S. are members of the CPCT-02 study team and/or CPCT board. E.C. coordinated the sequencing of samples and contributed to the bioinformatics analyses.\n\nData availability\n\nThe WGS, RNA-seq, and corresponding clinical data used in this study was made available by the Hartwig Medical Foundation (Dutch nonprofit biobank organization) after signing a license agreement stating data cannot be made publicly available via third party organizations. Therefore, the data are available under restricted access and can be requested upon by contacting the Hartwig Medical Foundation (https://www.hartwigmedicalfoundation.nl/applying-for-data/) under the accession code DR-058. Publicly available datasets that were used in this study are listed in Supplementary Table 1. The Yaeger data used in this study are available in the cBioPortal for Cancer Genomics (http://www.cbioportal.org/study?id=crc_msk_2017). The TCGA-DFCI data used in this study have been deposited in the cBioPortal for Cancer Genomics which we accessed on January 21, 2020 (https://www.cbioportal.org/study/summary?id=coadread_tcga; https://www.cbioportal.org/study/summary?id=coadread_tcga_pub; https://www.cbioportal.org/study/summary?id=coadread_tcga_pan_can_atlas_2018; https://www.cbioportal.org/study/summary?id=coadread_dfci_2016). The ICGC data used in this study have been deposited in the ICGC data portal (release 28) (https://dcc.icgc.org/projects/COAD-US; https://dcc.icgc.org/projects/COCA-CN; https://dcc.icgc.org/projects/READ-US). The remaining data are available within the Article, Supplementary Information or available from the authors upon request. Source data are provided with this paper.\n\nCode availability\n\nThe bioinformatical code used for data processing is available at https://github.com/hartwigmedical/pipeline5.\n\nCompeting interests\n\nThe authors declare no competing interests.\n\nPeer review information Nature Communications thanks Kin Chan, Silvia Marsoni and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nThese authors contributed equally: Pauline A.J. Mendelaar, Marcel Smid.\n\nChange history\n\n5/27/2021\n\nA Correction to this paper has been published: 10.1038/s41467-021-23629-4\n==== Refs\nReferences\n\n1. Atlas N Comprehensive molecular characterization of human colon and rectal cancer Nature 2012 487 330 337 22810696\n2. Guinney J The consensus molecular subtypes of colorectal cancer Nat. 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"keywords": null,
"medline_ta": "Nat Commun",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D059248:Chemoradiotherapy; D015331:Cohort Studies; D015179:Colorectal Neoplasms; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D000073336:Whole Genome Sequencing",
"nlm_unique_id": "101528555",
"other_id": null,
"pages": "574",
"pmc": null,
"pmid": "33495476",
"pubdate": "2021-01-25",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "26508446;19097774;26457759;30785829;24916345;24259968;30510241;31064846;26031544;25697820;29929481;32025012;24227677;21527027;27986087;20577206;26855534;31226844;23318258;28890946;29507659;31748536;32106218;30297532;26553136;31469863;31666701;30429477;32025018;25125662;32166014;27111033;31645765;31570896;31594944;23104886;29695279;28128360;30017478;22810696;25394515;29316426;28611049;28232485;28854643;29056346",
"title": "Whole genome sequencing of metastatic colorectal cancer reveals prior treatment effects and specific metastasis features.",
"title_normalized": "whole genome sequencing of metastatic colorectal cancer reveals prior treatment effects and specific metastasis features"
} | [
{
"companynumb": "NL-AMGEN-NLDSP2021027480",
"fulfillexpeditecriteria": "2",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PANITUMUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin lymphomas characterized by an infiltration of malignant monoclonal T lymphocytes into the skin. Mycosis fungoides (MF), the most common subtype, and the rarer Sézary syndrome (SS), are considered the classical forms of CTCL, which, because of a varying presentation and lack of genetic and immunophenotypical markers, can often have a delayed diagnosis. With skin-directed topical treatment being the mainstay of therapy in the early stages, there is an absence of long-term curative therapies for advanced disease. Recent insight into the pathogenesis of CTCL has identified new potential therapeutic targets including the monoclonal antibody therapies, brentuximab vedotin and mogamulizumab. Brentuximab vedotin, an anti-CD30 antibody-drug conjugate, received extended approval by the US FDA in 2017 to include primary cutaneous anaplastic large-cell lymphoma and CD30-expressing MF. Mogamulizumab, an anti-CCR4 antibody, received FDA approval in 2018 for relapsed or refractory MF and SS. Further targets and therapies continue to be investigated, including the monoclonal antibody therapy alemtuzumab, an anti-CD52 antibody, and the immune checkpoint blockade therapies, pembrolizumab and nivolumab. These new and emerging targets and therapies may lead to a promising broadening of CTCL treatment options in the future.",
"affiliations": "1 Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada.;1 Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada.",
"authors": "Van-de-Velde|Vanessa|V|;Zhou|Youwen|Y|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D007093:Imidazoles; D000077594:Nivolumab; D000074323:Alemtuzumab; D000079963:Brentuximab Vedotin; C582435:pembrolizumab; C402365:resiquimod; C549035:mogamulizumab",
"country": "United States",
"delete": false,
"doi": "10.1177/1203475419840629",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1203-4754",
"issue": "23(3)",
"journal": "Journal of cutaneous medicine and surgery",
"keywords": "CTCL; Cancer; Sézary syndrome; dermatology; monoclonal antibodies; mycosis fungoides",
"medline_ta": "J Cutan Med Surg",
"mesh_terms": "D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D000079963:Brentuximab Vedotin; D002986:Clinical Trials as Topic; D006801:Humans; D007093:Imidazoles; D007167:Immunotherapy; D016410:Lymphoma, T-Cell, Cutaneous; D000077594:Nivolumab; D012878:Skin Neoplasms",
"nlm_unique_id": "9614685",
"other_id": null,
"pages": "319-327",
"pmc": null,
"pmid": "30943788",
"pubdate": "2019",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Existing and Emerging Therapies for Cutaneous T-Cell Lymphoma.",
"title_normalized": "existing and emerging therapies for cutaneous t cell lymphoma"
} | [
{
"companynumb": "CA-SEATTLE GENETICS-2019SGN01057",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BRENTUXIMAB VEDOTIN"
},
"drugadditiona... |
{
"abstract": "From 1970 to 1988, thousands of children have been treated with human growth hormone (hGH) to supply pituitary gland deficiency. In France, 51 of the 968 children treated by hGH lots produced between January 1984 and March 1985 had developed Creutzfeldt-Jakob disease (CJD) by the end of 1996. The authors' objective was to investigate which of the 13 hGH lots produced during this period might be implicated in the iatrogenic transmission of CJD. In this paper, the authors describe a model that was developed to compute the probability for each lot of being contaminated. The validity of the model was assessed by a simulation study that showed a good agreement between the estimated and the simulated number of contaminated lots. The model suggested that about half of the lots distributed during this period might have been contaminated by the infectious agent that causes CJD. The risk of iatrogenic CJD for patients exposed to contaminated hGH lots was estimated to be 0.06 (95% confidence interval 0.05-0.07).",
"affiliations": "Unité de Recherches Epidémiologiques en Neurologie et Psychopathologie, INSERM U360, Paris, France.",
"authors": "Huillard d'Aignaux|J|J|;Alpérovitch|A|A|;Maccario|J|J|",
"chemical_list": "D019382:Human Growth Hormone",
"country": "United States",
"delete": false,
"doi": "10.1093/oxfordjournals.aje.a009492",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9262",
"issue": "147(6)",
"journal": "American journal of epidemiology",
"keywords": null,
"medline_ta": "Am J Epidemiol",
"mesh_terms": "D007562:Creutzfeldt-Jakob Syndrome; D004340:Drug Contamination; D005602:France; D019382:Human Growth Hormone; D006801:Humans; D016015:Logistic Models; D008432:Mathematical Computing; D015233:Models, Statistical; D016017:Odds Ratio",
"nlm_unique_id": "7910653",
"other_id": null,
"pages": "597-604",
"pmc": null,
"pmid": "9521187",
"pubdate": "1998-03-15",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A statistical model to identify the contaminated lots implicated in iatrogenic transmission of Creutzfeldt-Jakob disease among French human growth hormone recipients.",
"title_normalized": "a statistical model to identify the contaminated lots implicated in iatrogenic transmission of creutzfeldt jakob disease among french human growth hormone recipients"
} | [
{
"companynumb": "FR-ROCHE-2327272",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "UNSPECIFIED INGREDIENT"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nOndansetron improves the success of oral rehydration in children with gastroenteritis. In postoperative adults, ondansetron has been shown to prolong the corrected QT (QTc). The aim of the study was to evaluate the effect of ondansetron on the QT at peak effect and at 1-hour postpeak effect in pediatric patients.\n\n\nMETHODS\nThis was an observational study looking at patients aged 6 months to 18 years receiving intravenous ondansetron for nausea, vomiting, or the inability to take fluids in the emergency department. Patients had electrocardiogram performed at baseline, at ondansetron's peak effect, and 1 hour postpeak effect. A paired samples Student t test compared QTc change at peak effect to zero. Peak effect of intravenous ondansetron is 3 minutes.\n\n\nRESULTS\nOne hundred patients were included. Fifty-five percent of patients were female with a mean age of 8.3 years. The mean (range) baseline QTc was 435 (388 to 501) milliseconds. The mean (range) change in QTc at peak effect of ondansetron was 3 (-40 to 65) milliseconds (P = 0.072). The change in QTc 1-hour postpeak effect of ondansetron was 3 (-43 to 45) milliseconds (P = 0.082). No change at peak effect or 1-hour postpeak effect was clinically significant.\n\n\nCONCLUSIONS\nOndansetron does not affect the QTc of pediatric patients receiving the medication for nausea, vomiting, or inability to take fluids in the emergency department. No changes in the QTc are clinically significant. To date, there have been no studies evaluating the effect of ondansetron in this acutely ill population; therefore, a larger study should be completed to confirm these data.",
"affiliations": null,
"authors": "Krammes|Sarah Kline|SK|;Jacobs|Todd|T|;Clark|John M|JM|;Lutes|R Esther|RE|",
"chemical_list": "D000932:Antiemetics; D017294:Ondansetron",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000000757",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "34(1)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000293:Adolescent; D000932:Antiemetics; D002648:Child; D002675:Child, Preschool; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007223:Infant; D008133:Long QT Syndrome; D008297:Male; D017294:Ondansetron; D010865:Pilot Projects; D014839:Vomiting",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "38-41",
"pmc": null,
"pmid": "27261956",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Effect of Intravenous Ondansetron on the QT Interval of Patients' Electrocardiograms.",
"title_normalized": "effect of intravenous ondansetron on the qt interval of patients electrocardiograms"
} | [
{
"companynumb": "US-EMCURE PHARMACEUTICALS LTD-2019-EPL-0127",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ONDANSETRON"
},
"drugadditi... |
{
"abstract": "The impact of thiopurine methyltransferase (TPMT) genotype on thiopurine dose intensity, myelosuppression and treatment outcome was investigated in the United Kingdom childhood acute lymphoblastic leukaemia (ALL) trial ALL97. TPMT heterozygotes had significantly more frequent cytopenias and therefore required dose adjustments below target levels significantly more often than TPMT wild-type patients although the average dose range was similar for both genotypes. Event-free survival (EFS) for patients heterozygous for the more common TPMT*1/*3A variant allele (n = 99, 5-year EFS 88%) was better than for both wild-type TPMT*1/*1 (n = 1206, EFS 80%, P = 0·05) and TPMT*1/*3C patients (n = 17, EFS 53%, P = 0·002); outcomes supported by a multivariate Cox regression analysis. Poor compliance without subsequent clinician intervention was associated with a worse EFS (P = 0·02) and such non-compliance may have contributed to the poorer outcome for TPMT*1/*3C patients. Patients prescribed escalated doses had a worse EFS (P = 0·04), but there was no difference in EFS by dose intensity or duration of cytopenias. In contrast to reports from some USA and Nordic trials, TPMT heterozygosity was not associated with a higher rate of second cancers. In conclusion, TPMT*1/*3A heterozygotes had a better EFS than TPMT wild-type patients. Thiopurine induced cytopenias were not detrimental to treatment outcome.",
"affiliations": "Academic Unit of Clinical Pharmacology, University of Sheffield, Sheffield, UK.",
"authors": "Lennard|Lynne|L|;Cartwright|Cher S|CS|;Wade|Rachel|R|;Vora|Ajay|A|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D008780:Methyltransferases; C022745:thiopurine methyltransferase",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.13240",
"fulltext": "\n==== Front\nBr J HaematolBr. J. Haematol10.1111/(ISSN)1365-2141BJHBritish Journal of Haematology0007-10481365-2141John Wiley and Sons Inc. Hoboken 10.1111/bjh.13240BJH13240Research PaperPaediatricsThiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics L. Lennard et alLennard Lynne \n1\nCartwright Cher S. \n1\nWade Rachel \n2\nVora Ajay \n3\n1 Academic Unit of Clinical PharmacologyUniversity of SheffieldSheffieldUK2 Clinical Trials Service UnitOxfordUK3 Department of Paediatric HaematologyChildren's HospitalSheffieldUK* \nCorrespondence: Dr Lynne Lennard, University of Sheffield, Academic Unit of Clinical Pharmacology, Department of Human Metabolism, Medical School Floor E, Beech Hill Road, Sheffield, S10 2RX.\n\nE‐mail: l.lennard@sheffield.ac.uk\n29 11 2014 4 2015 169 2 10.1111/bjh.2015.169.issue-2228 240 28 8 2014 04 11 2014 © 2014 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Summary\nThe impact of thiopurine methyltransferase (TPMT) genotype on thiopurine dose intensity, myelosuppression and treatment outcome was investigated in the United Kingdom childhood acute lymphoblastic leukaemia (ALL) trial ALL97. TPMT heterozygotes had significantly more frequent cytopenias and therefore required dose adjustments below target levels significantly more often than TPMT wild‐type patients although the average dose range was similar for both genotypes. Event‐free survival (EFS) for patients heterozygous for the more common TPMT*1/*3A variant allele (n = 99, 5‐year EFS 88%) was better than for both wild‐type TPMT*1/*1 (n = 1206, EFS 80%, P = 0·05) and TPMT*1/*3C patients (n = 17, EFS 53%, P = 0·002); outcomes supported by a multivariate Cox regression analysis. Poor compliance without subsequent clinician intervention was associated with a worse EFS (P = 0·02) and such non‐compliance may have contributed to the poorer outcome for TPMT*1/*3C patients. Patients prescribed escalated doses had a worse EFS (P = 0·04), but there was no difference in EFS by dose intensity or duration of cytopenias. In contrast to reports from some USA and Nordic trials, TPMT heterozygosity was not associated with a higher rate of second cancers. In conclusion, TPMT*1/*3A heterozygotes had a better EFS than TPMT wild‐type patients. Thiopurine induced cytopenias were not detrimental to treatment outcome.\n\nthiopurine methyltransferasemercaptopurinethioguaninecytopeniasacute lymphoblastic leukaemiaLeukaemia and Lymphoma ResearchMedical Research Council source-schema-version-number2.0component-idbjh13240cover-dateApril 2015details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.7.5 mode:remove_FC converted:26.01.2016\n==== Body\nMercaptopurine and thioguanine (2‐amino 6‐mercaptopurine, tioguanine) are purine analogue drugs that have been used as cytotoxic agents in the treatment of leukaemias for over 50 years (Burchenal et al, 1953; Murphy et al, 1955). Both these thiopurine drugs are metabolized to form thioguanine nucleotide metabolites (TGNs), which have cytotoxic and immunosuppressive properties. Incorporation of TGN into DNA initiates subsequent cytotoxicity (Tidd & Paterson, 1974; Warren et al, 1995; Karran, 2006) and TGN inhibition of intracellular signalling pathways induces apoptotic cell death whilst one TGN, thioguanine triphosphate, suppresses lymphocyte activation by binding to RAC1 in place of endogenous guanine triphosphate (Tiede et al, 2003; Poppe et al, 2006; Marinkovic et al, 2014).\n\nTGN production from the inactive thiopurine drug is regulated by the polymorphic enzyme thiopurine methyltransferase (TPMT). Thioguanine forms TGNs directly but mercaptopurine forms additional intermediate nucleotide metabolites; one of these, mercaptopurine nucleotide (mercaptopurine riboside 5′‐monophosphate or 6‐thioinosinic acid) is a good substrate for TPMT, and the resulting methyl‐mercaptopurine nucleotide metabolites (MeMPNs) are formed at the expense of TGNs. TPMT deficiency (1 in 300 individuals) is associated with bone marrow failure when such patients are treated with standard doses of thiopurine drugs (Lennard et al, 1989; Evans et al, 1991; McBride et al, 2000); a less severe myelosuppression can develop in TPMT heterozygotes (‘intermediate’ activity, 11% of subjects), (Weinshilboum & Sladek, 1980; Lennard et al, 1990; Relling et al, 1999a).\n\nFor thiopurine drugs the therapeutic window between toxicity and efficacy is narrow. For children with acute lymphoblastic leukaemia (ALL) treated with mercaptopurine, those individuals with lower TPMT activities and/or higher TGN levels have a lower relapse‐risk (Lennard & Lilleyman, 1989; Schmeigelow et al, 1995; Relling et al, 1999a). Traditionally, daily oral mercaptopurine is taken during the long‐term maintenance phase of chemotherapy in childhood ALL. Within the United Kingdom (UK) ALL protocols this phase of treatment lasts for 2 to 3 years and maintains the disease remission that has been induced by other potent cancer chemotherapeutic agents; the central role of mercaptopurine in maintaining disease remission is illustrated by the worse outcome observed in all attempts to shorten the duration of mercaptopurine‐containing maintenance chemotherapy such that the duration of total therapy falls below 2 years (Schrappe et al, 2000; Richards et al, 1996).\n\nIn the UK Medical Research Council national ALL trial ALL97, children and young adults were randomized to receive either mercaptopurine or thioguanine in the maintenance phase. The clinical results of the ALL97 thiopurine randomization have been previously reported and showed no difference in efficacy between thioguanine and mercaptopurine. A lower risk of central nervous system (CNS) relapse for thioguanine was offset by an increased risk of death in remission, (mainly due to infections), and an increased risk of thioguanine‐induced veno‐occlusive disease (VOD) (Lennard et al, 2006; Vora et al, 2006). We have previously reported the TPMT genotype‐phenotype discordance and the superiority of TPMT genotyping for the detection of the TPMT heterozygote in this patient cohort, together with the influence of TPMT genotype on thiopurine metabolite accumulation (Lennard et al, 2013). In this paper we report on the influence of the TPMT genetic polymorphism on thiopurine dose intensity and myelosuppression, and the resulting impact on treatment outcome.\n\nMethods\nPatients and chemotherapy\nALL97 [International Standard Randomized Controlled Trial Number (ISRCTN) registration number ISRCTN26727615] was a randomized comparison of dexamethasone versus prednisone and mercaptopurine versus thioguanine in patients aged 1 to 18 years. The patient cohort has been previously described (Vora et al, 2006). Treatment centres obtained local ethics committee approval and informed consent from patients and/or parents before entering children into the trial. The trial had an add‐on thiopurine biological study. ALL97 was modified in November 1999 and termed ALL97/99, but the randomizations and biological studies were retained, as was the registered ALL97 trial name. Details of the treatment regimens and modifications have been previously reported (Mitchell et al, 2005, 2009; Vora et al, 2006). ALL97 closed to accrual in June 2002. At closure, all of the children randomized to thioguanine who had not finished maintenance chemotherapy were transferred to mercaptopurine.\n\nDuring maintenance patients received daily oral randomized thiopurine, weekly methotrexate, monthly intravenous vincristine and 5 days of randomized steroid. Maintenance was given for 2 years in ALL97 but was increased to 3 years, for boys only, in ALL97/99. When ALL97 was superseded by ALL97/99, all boys had maintenance increased to 3 years; effectively only boys diagnosed in 1997 received 2 years maintenance. The thiopurine dose was titrated to toxicity from a standard protocol dose (thioguanine 40 mg/m2 and mercaptopurine 75 mg/m2; 100% protocol dose) for both TPMT heterozygous and wild‐type patients. Patients with TPMT deficiency (homozygous for two variant low activity alleles) were titrated from a starting dose of 10% protocol dose (7·5 mg/m2 mercaptopurine, 4·0 mg/m2 thioguanine). The dose titration protocols for the ALL97 and ALL97/99 phases of the trial have been described elsewhere (Vora et al, 2006). Briefly, ALL97 had a more aggressive titration protocol, with dose adjustments every 4 weeks if the neutrophil counts remained above 1·0 × 109/l and platelet counts above 100 × 109/l, whilst ALL97/99 dose adjustments occurred at the start of each 12‐week maintenance cycle to maintain the neutrophil count between 0·75 and 1·5 × 109/l and platelet count over 75 × 109/l. For both ALL97 and ALL97/99, the thiopurine dose was reduced if the neutrophil count fell below 0·75 × 109/l (or platelet count 75 × 109/l) and withdrawn if neutrophil counts fell <0·5 × 109/l (or platelet counts <50 × 109/l).\n\nThiopurine dosage calculations\nThroughout treatment, drug dosage was recorded weekly and cell counts were recorded at monthly or fortnightly intervals (or more frequently) as appropriate. These hand‐written forms were forwarded and collated by the Clinical Trials Service Unit, Oxford. Databases were designed to capture the thiopurine dosage and cell count information. The database started at Week 8, after the induction and consolidation blocks. High‐risk patients (ALL97 protocol HR1 and ALL97/99 regimen C, which contained additional multi‐drug chemotherapy during the first year) were excluded from the thiopurine dosage analysis, as were children who relapsed or died during the first year of chemotherapy.\n\nPatients included in the thiopurine dosage and cell count analysis had achieved remission by the end of induction and had completed forms detailing at least 95% of maintenance treatment received from Week 8. The total number of weeks that thiopurine could have been prescribed during maintenance cycles was calculated. Some children required a period of cell count recovery following the delayed intensive blocks given during year 1, at the start of a maintenance phase of thiopurine treatment. This time was calculated and subtracted from the total number of weeks that thiopurine could have been prescribed as these cytopenias were influenced by other chemotherapy. The daily thiopurine dose (mg/m2) was totalled and the number of weeks that each child was prescribed the standard protocol dose (100% dose = 75 mg/m2 mercaptopurine or 40 mg/m2 thioguanine), escalated doses (>100%), reduced doses, or that thiopurine was withdrawn, was calculated. To calculate the average daily thiopurine dose, the totalled daily dose (per m2) throughout maintenance was divided by the time (days) that thiopurine could have been prescribed. To enable comparisons between thiopurines and the use of dosage data from those children who switched from thioguanine to mercaptopurine during treatment, the percentage (%) standard protocol dose for each thiopurine was calculated. The % time when thiopurines were withdrawn, or the dose reduced or escalated, was also calculated, as was the % time with neutropenia (neutrophil count <1·0 × 109/l and <0·5 × 109/l) and thrombocytopenia (platelet count <100 × 109/l).\n\nBlood samples\n\nTPMT genotype was determined in a diagnostic lithium heparin blood sample (5 ml), and/or a blood sample taken during remission maintenance chemotherapy. The blood sample protocol has been previously described (Lennard et al, 2013). TPMT activity was also measured in these blood samples; values were previously reported by Lennard et al (2013). Clinicians were informed if the patient had TPMT activity (the thiopurine dose to be adjusted, based on cell counts, from the protocol standard dose) or if the patient was TPMT‐deficient (start the thiopurine dose at 10% of the protocol standard dose, adjust on the basis of cell counts). During remission maintenance chemotherapy blood samples were requested at the earliest point in interim maintenance when patients were tolerating thiopurines at the standard protocol, or the maximum tolerated dose; thiopurine metabolites measured in this sample served as a reference value. Within the thiopurine study of the ALL97 trials, additional blood samples were forwarded from clinicians on an ad hoc basis when patients were either unduly sensitive to thiopurines, or tolerating high doses (Lennard et al, 2013). Thiopurine metabolite values were fed back to the clinician, as a check on compliance with oral chemotherapy, prior to dose escalation.\n\nThiopurine assays\nThiopurine metabolite concentrations were measured by high performance liquid chromatography (HPLC); the lower limit of detection for TGNs and MeMPNs was 6 and 15 pmol/8 × 108 red cells, respectively (Lennard & Singleton, 1992; Lennard et al, 2013). Blood samples were genotyped for TPMT*3A, TPMT*3B and TPMT*3C, by amplification of exons 7 and 10 of the TPMT gene (TPMT*3A is an exon 7 and 10 double mutant) as previously described (Lennard et al, 2013). TPMT *2 was detected by sequencing exon 5 of the TPMT gene and novel sequence variations were identified by sequencing the TPMT open reading frame from exon 3 to exon 10 as previously described (Otterness et al, 1997; Lennard et al, 2013).\n\nCompliance\nNon‐compliance with oral chemotherapy was suspected when patients maintained high cell counts despite tolerating long‐term thiopurines at ≥100% doses (Lennard et al, 1995). With respect to mercaptopurine, low concentrations of both TGN and MeMPN metabolites (both metabolites < lower quartile concentrations) have been used as an index of partial compliance; these metabolites are products of competing pathways and show an inverse correlation (Lennard et al, 1995). Higher TPMT activity is associated with lower TGN concentrations and higher MeMPNs whilst lower TPMT activity is associated with higher TGNs and lower MeMPNs. Overt mercaptopurine non‐compliance was defined as both TGN and MeMPN metabolites at or below the lower limit of detection. For thioguanine, due to the rapid accumulation of thioguanine‐derived TGNs in the red cell following an oral dose, non‐compliance was suspected if metabolite concentrations were <750 pmol TGNs (Lennard et al, 2013).\n\nStatistical analysis\nThe Anderson‐Darling test was used to examine the fit of observations to a normal distribution. Differences between groups were compared by the Chi‐square statistic, or the Mann‐Whitney test; quartile analysis of the equality of medians was by the Kruskal‐Wallis test, quartile analysis of survival was by the log‐rank test for trend. Outcome analysis was of event‐free survival (EFS), with an event defined as time to relapse or death, as used in previous ALL97 analysis (Vora et al, 2006). Kaplan‐Meier curves were calculated and comparisons between groups were performed by the log‐rank statistic with stratification by age, gender, white blood cell (WBC) count at diagnosis, trial phase (ALL97 or ALL97/99) and steroid received (prednisone, dexamethasone). Overall EFS (from randomization at the start of treatment) was carried out for any analysis involving all patients. For the outcome analysis of dosing and cell count data, patients joined the analysis at the end of year one (i.e., patients with events in year 1 were excluded) and EFS was calculated from this starting point (termed jEFS), stratified by length of maintenance (two or three years). All P values are two‐sided, a P value <0·05 was considered statistically significant. Cox regression multivariate analysis was used to test whether the effects of variables were independent. Analyses were to the annual follow up of 30th April 2011; median follow‐up for survivors 11·3 years (range 9·6 to 14·3 years). Statistical analyses were by SAS (version 9.2; SAS, Cary, NC, USA) or Minitab 16.\n\nResults\nPatient numbers\nThe patient numbers and data available are summarized in Fig 1. There was no difference with respect to gender, age, WBC count at diagnosis, steroid randomization or thiopurine randomization between patients with and without thiopurine data.\n\nFigure 1 Trial data profile. The numbers of individual patients providing blood samples for thiopurine analysis by trial phase, ALL97 and ALL97/99. TPMT, thiopurine methyltransferase.\n\nThiopurine metabolites and TPMT data have been previously reported for the thioguanine versus mercaptopurine randomized cohort in the ALL97 trial (Lennard et al, 2013). This current paper contains an additional 14 children, who were recruited whilst the trial was still open but the mercaptopurine versus thioguanine randomization was closed, who received non‐randomized mercaptopurine.\n\nTPMT genotype and thiopurine metabolites\n\nTPMT genotype was available for 1334 patients (69% of patients entered onto ALL97); 1160 were white and 174 belonged to other ethnic groups (71 Asian (Indian sub‐continent), 44 mixed race, 20 black, 6 Oriental and 33 unknown or non‐Caucasian). 1206 patients were homozygous wild‐type TPMT*1/*1 and 128 patients had low activity variant alleles (99 TPMT*1/*3A; 17 TPMT*1/*3C; 4 TPMT*1/*2; two children with the rare alleles TPMT*1/*9, TPMT*1/*21; three children with novel alleles TPMT*1/*32, TPMT*1/*33, TPMT*1/*34; one compound heterozygote TPMT*2/*3A; one homozygous TPMT*3A/*3A and one TPMT*3C/*3C). The TPMT*3B allele was not detected.\n\nThiopurine metabolite assays were available for 1135 of the 1334 TPMT genotype children, 426 randomized to thioguanine and 709 taking mercaptopurine. The metabolite concentrations differ by genotype (Lennard et al, 2013) and are summarized in Table 1: there was no heterogeneity with respect to gender. Very low metabolite concentrations when supposedly taking high doses thiopurines was a strong indication that non‐compliance with oral chemotherapy was a problem in all TPMT groups. Comparisons between TPMT heterozygotes were not possible with thioguanine (only four TPMT*1/*3C children), but within the mercaptopurine cohort TPMT *1/*3C children (n = 12) had significantly lower TGN concentrations than TPMT *1/*3A children (n = 53) despite having similar drug dosages and TPMT activities (Lennard et al, 2013); TPMT *1/*3C median TGNs 608 pmol/8 × 108 red cells (range 288 to 910) and TPMT *1/*3A median TGNs 802 (range 132 to 2228), median difference 192 pmol (95% confidence interval [CI] 10 to 425), P = 0·05). MeMPN concentrations were also lower in TPMT *1/*3C patients; TPMT *1/*3C median MeMPN 2061 pmol/8 × 108 red cells (range 60 to 10746) and TPMT *1/*3A median MeMPN 4542 (range 84 to 38 386), median difference 2190 pmol (95% CI −54 to 5180), P = 0·06).\n\nTable 1 Thiopurine methyltransferase genotype and metabolite formation\n\n\tWild‐type TPMT*1/*1\n\tHeterozygous TPMT\n\tMedian difference (95%CI)\t\nTG patients\t385\t40\t\t\nTG dose, mg/m2\n\t40 (14–78)\t40 (18–63)\t−1·0 (−2·0 to −0·001), P = 0·0525, NS\t\nTG‐TGNs pmol\t1904 (36–4336)\t2468 (174–6730)\t504 (206 to 802), P = 0·0009\t\nMP patients\t636\t71\t\t\nMP dose mg/m2\n\t75 (6–125)\t74 (14–113)\t−1·0 (−4·0 to 0·000), P = 0·06, NS\t\nMP‐TGNs pmol\t360 (0–1216)\t754 (132–2228)\t394 (326 to 466), P < 0·0001\t\nMP‐MeMPNs pmol\t10702 (0–141772)\t4078 (60–38386)\t−5464 (−7278 to −3808), P < 0·0001\t\nThe thiopurine dose is that tolerated at the time of metabolite measurement. The standard protocol dose was 75 mg/m2 mercaptopurine and 40 mg/m2 thioguanine. Thiopurine metabolite formation differs by genotype, there was no heterogeneity by gender. TPMT, thiopurine methyltransferase; TG, thioguanine cohort; MP, mercaptopurine cohort; TGNs, thioguanine nucleotides; MeMPNs, methylmercaptopurine nucleotides; NS = not significant. TGN and MeMPN units are pmol/8 × 108 red cells. Values are given as median (range). The TPMT variant alleles quantified were TPMT *1/*2 (MP n = 3; TG n = 1), TPMT *1/*3A (MP n = 53; TG n = 33), TPMT *1/*3C (MP n = 12; TG n = 4), TPMT *1/*9 (MP n = 1) and TPMT *1/*21 (TG n = 1) and the novel alleles TPMT *1/*32 TPMT *1/*33 TPMT *1/*34 (n = 1 each taking MP, MP and TG respectively). The above analysis excludes 3 TPMT‐deficient patients. The TPMT*3A/*3A and TPMT *2/*3A patients have been previously reported (Lennard et al, 2013), the TPMT*3A/*3A child eventually settled on 2·5 mg/m2 per day thioguanine and the TPMT *2/*3A child 7·5 mg/m2 mercaptopurine on alternate days; TGNs were 2252 pmol and 1670 pmol, respectively. The TPMT *3C/*3C child had 1784 pmol TGNs at 15 mg/m2 mercaptopurine.\n\nJohn Wiley & Sons, LtdThiopurine dosage and cell counts\nThe average daily dose was 77% of the standard protocol dose and this did not differ between the ALL97 and ALL97/99 phases of the trial (Table 2). As expected in a protocol in which the drug dosage was adjusted based on cell counts, quartile analysis of average % daily dose showed that those patients with higher doses had significantly higher cell counts; from the lower to the higher quartile (Q) of average % dose (Q1 = 3·0 to 65·2%; Q2 = 65·3 to 76·7%; Q3 = 76·8 to 86·8%; Q4 = 86·9 to 162·4%) the median % weeks with a neutrophil count <1·0 × 109/l was 32, 28, 23 and 15, respectively (P < 0·001), the median % weeks with a neutrophil count <0·5 × 109/l was 14·3, 12·5, 9·0 and 5·9, respectively (P < 0·001) and the median % weeks with thrombocytopenia was 10·0, 4·9, 2·3, 2·1, respectively (P < 0·001). There was no difference in the % time with neutropenia between the ALL97 and ALL97/99 phases, but the incidence of thrombocytopenia was greater in ALL97 (Table 2). Throughout both trial phases, thioguanine caused more thrombocytopenia than mercaptopurine but the degree of thrombocytopenia was greater in ALL97 than ALL97/99 (Table 3). Although thioguanine‐related VOD and the resulting endotheliitis may partly account for the excess thioguanine‐related risk of thrombocytopenia, the additional risk in the ALL97 phase is unlikely to be related to VOD as it was more prevalent in the ALL97/99 phase than in ALL97 (Lennard et al, 2006; Vora et al, 2006). The lower platelet counts were more evident in older children (P < 0·0001, Table 2) and was seen in both phases of the trial.\n\nTable 2 Thiopurine dosage and myelosuppression according to clinical features\n\nSubgroup\tn\tAverage dose (% of protocol)\t\nP\n\t% time at no dose\t\nP\n\t% time dose escalated\t\nP\n\t% time with neutropenia (<0·5 × 109/l)\t\nP\n\t% time with thrombocytopenia (<100 × 109/l)\t\nP\n\t\nTrial\t\nALL97\t517\t76·6 (24·2–134·2)\t0·08\t16·8 (0·0–62·2)\t<0·0001\t7·2 (0·0–72·3)\t<0·0001\t23·9 (2·4–57·4)\t0·8\t4·9 (0·0–63·3)\t<0·0001\t\nALL97/99\t565\t76·7 (3·0–162·4)\t14·4 (0·0–97·0)\t3·0 (0·0–84·2)\t23·6 (0·8–62·9)\t2·4 (0·0–81·9)\t\nSex\t\nMale\t576\t79·6 (3·0–162·4)\t<0·0001\t13·8 (0·0–97·0)\t<0·0001\t7·0 (0·0–84·2)\t<0·0001\t22·0 (0·8–62·9)\t<0·0001\t3·0 (0·0–81·9)\t<0·0001\t\nFemale\t506\t72·8 (12·6–155·7)\t18·1 (0·0–47·7)\t3·5 (0·0–76·7)\t25·8 (2·4–62·9)\t4·6 (0·0–67·4)\t\nAge Group\t\n<2\t74\t76·5 (39·5–129·5)\t0·001\t18·0 (7·5–34·1)\t0·02\t3·6 (0·0–65·4)\t0·6\t26·7 (9·0–54·1)\t0·2\t2·8 (0·0–52·5)\t<0·0001\t\n2–9\t865\t77·1 (3·0–162·4)\t15·6 (0·0–97·0)\t4·8 (0·0–84·2)\t23·4 (2·4–62·9)\t3·4 (0·0–76·1)\t\n10+\t143\t68·5 (24·2–134·2)\t17·5 (1·1–47·7)\t6·3 (0·0–72·3)\t25·2 (0·8–62·9)\t8·4 (0·0–81·9)\t\nWBC\t\n<10\t552\t76·5 (12·6–162·4)\t0·4\t15·8 (0·0–62·2)\t0·7\t5·0 (0·0–84·2)\t0·7\t24·0 (0·8–57·4)\t0·5\t4·4 (0·0–67·4)\t0·03\t\n10‐\t186\t76·7 (24·2–136·7)\t15·9 (0·0–40·4)\t4·6 (0·0–68·5)\t23·4 (2·4–62·9)\t2·9 (0·0–76·1)\t\n20‐\t179\t76·9 (39·3–112·8)\t16·9 (2·8–45·7)\t5·5 (0·0–65·4)\t24·4 (4·0–50·6)\t3·4 (0·0–81·9)\t\n50‐\t84\t75·3 (25·7–108·7)\t15·9 (2·7–38·5)\t2·4 (0·0–55·2)\t22·8 (3·4–55·7)\t4·6 (0·0–57·3)\t\n100‐\t81\t77·5 (3·0–105·0)\t15·6 (3·4–97·0)\t6·5 (0·0–45·8)\t21·9 (6·4–62·9)\t3·3 (0·0–53·4)\t\nSteroid\t\nPred\t586\t77·2 (19·5–162·4)\t0·2\t15·2 (0·0–47·7)\t0·005\t5·0 (0·0–84·2)\t0·9\t23·6 (0·8–58·2)\t0·5\t3·4 (0·0–81·9)\t0·02\t\nDex\t496\t76·1 (3·0–155·7)\t16·7 (0·0–97·0)\t4·8 (0·0–76·7)\t23·7 (2·4 –62·9)\t4·3 (0·0–73·8)\t\nValues are given as median (range). The age groups are given as age in years at disease diagnosis. WBC = white blood cell count (x109/l) at disease diagnosis. Pred = randomized and non‐randomized to prednisone. Dex = randomized and non‐randomized to dexamethasone.\n\nJohn Wiley & Sons, LtdTable 3 Differences in cytopenias between the ALL97 and ALL97/99 trial phases\n\nPatients taking MP or TG only\tALL97\tALL97/99\tBoth phases\t\nn\tMedian\tn\tMedian\tn\tMedian\t\nTG, % weeks with thrombocytopenia (<100 × 109/l)\t202\t7·7 (0·0–63·3)\t31\t4·5 (0·0–57·2)\t233\t6·9 (0·0–63·3)\t\nMP, % weeks with thrombocytopenia (<100 × 109/l)\t245\t3·4 (0·0–57·0)\t336\t2·2 (0·0–81·9)\t581\t2·4 (0·0–81·9)\t\nDifference\t\t3·5\t\t1·1\t\t3·5\t\n95% CI\t\t2·3–4·7\t\t0·0–3·1\t\t2·4–4·5\t\n\nP value\t\t<0·0001\t\t0·06\t\t<0·0001\t\nTG, % weeks with neutropenia (<1·0 × 109/l)\t202\t21·7 (2·4–53·2)\t31\t23·4 (9·2–48·8)\t233\t22·2 (2·4–53·2)\t\nMP, % weeks with neutropenia (<1·0 × 109/l)\t245\t25·9 (3·5–57·2)\t336\t24·9 (0·8–62·9)\t581\t25·4 (0·8–62·9)\t\nDifference\t\t−3·8\t\t−1·4\t\t−2·9\t\n95% CI\t\t−5·7 to −1·9\t\t−4·8–2·3\t\t−4·4 to −1·4\t\n\nP value\t\t0·0001\t\t0·5\t\t0·002\t\nTG, % weeks with neutropenia (<0·5 × 109/l)\t202\t9·7 (0·0–31·2)\t31\t9·0 (2·0–26·0)\t233\t9·5 (0·0–31·2)\t\nMP, % weeks with neutropenia (<0·5 × 109/l)\t245\t11·3 (0·0–35·1)\t336\t10·0 (0·0–31·8)\t581\t10·2 (0·0–35·1)\t\nDifference\t\t−1·6\t\t−1·2\t\t−1·1\t\n95% CI\t\t−2·7 to −0·6\t\t−3·3–0·8\t\t−2·0 to −0·3\t\n\nP value\t\t0·002\t\t0·2\t\t0·009\t\nThe above analysis includes only those patients taking randomized mercaptopurine (MP) or thioguanine (TG) throughout maintenance. Values are given as median (range). n = number of patients in each group. CI = confidence interval.\n\nJohn Wiley & Sons, LtdThere was no difference in the % time with a neutrophil count <0·5 × 109/l between the trials (Table 2). There was no difference in % time with neutropenia between thioguanine or mercaptopurine within ALL97/99 (Table 3). Within ALL97, those taking mercaptopurine experienced more neutropenia than those taking thioguanine whilst those taking thioguanine experienced more thrombocytopenia (Table 3). This increased myelosuppression was reflected by an increased duration of drug withdrawal and increased time spent on escalated doses in ALL97 (Table 2) and is a direct reflection of the differing dose titration protocols between the ALL97 and ALL97/99 phases of the trial; the former was more aggressive, adjusting the dose monthly if cell counts remained above threshold whist the latter aimed for controlled myelosuppression with dose adjustment at the start of a 3‐month maintenance cycle to keep cell counts within a therapeutic window.\n\nDespite the difference in dose titration protocols between ALL97 and ALL97/99, throughout both phases of the trial girls experienced more myelosuppression, both episodes of neutropenia and thrombocytopenia, than boys (ALL97 neutropenia <0·5 × 10−9/l, girls 25·6% of time, boys 21·6%, P < 0·0001; ALL97/99 girls 25·8%, boys 22·1%, P < 0·0004. ALL97 thrombocytopenia girls 5·7% of time, boys 4·3%, P = 0·02; ALL97/99 girls 3·5%, boys 2·1%, P = 0·002). The increased myelosuppression experienced by the girls was reflected in thiopurine dose intensity, girls had significantly less time at escalated doses, experienced more dose withdrawal and received a lower average thiopurine dose (Table 2). The average daily dose was lower in girls in both phases of the trial (ALL97 girls 73·6%, boys 80·5%, P < 0·001; ALL97/99 girls 71·0%, boys 78·8%, P < 0·0001). There was no heterogeneity with respect to randomized thiopurine or TPMT genotype.\n\nThiopurine dosage and TPMT genotype\nDose intensity data was available for 818 of the 1334 (61%) children with TPMT genotypes. There was a significant heterogeneity in dose tolerance by genotype (Table 4). Only two children homozygous for TPMT variant alleles (TPMT deficiency) had full dose intensity data available: both of these girls were randomized to mercaptopurine; mercaptopurine tolerance differed between the two. Due to more myelosuppression the TPMT*2/*3A compound heterozygote tolerated an average daily dose of 12·6% (9·45 mg/m2) and the TPMT*3C/*3C homozygous mutant 19·5% (14·6 mg/m2). Comparing the TPMT wild‐type (TPMT*1/*1) patients with the TPMT wild‐type/variant allele heterozygotes, the former had a higher average dose than the latter (78% versus 70% respectively, P < 0·0002) and experienced less time with the dose withdrawn due to cytopenias (15·5% vs. 20·8% of time respectively, P < 0·001).\n\nTable 4 Thiopurine dosage and myelosuppression by TPMT genotype\n\nTPMT subgroup\t\nTPMT genotype\tn\tAverage dose (% of protocol)\t\nP\n\t% time at no dose\t\nP\n\t% time dose escalated\t\nP\n\t% time with neutropenia (<0·5 × 109/l)\t\nP\n\t% time with thrombocytopenia (<100 × 109/l)\t\nP\n\t\nAll genotypes\t\n*1/*1\n\t735\t78·0 (29·8–162·4)\t0·001\t15·5 (0·0–62·2)\t0·0009\t5·8 (0·0–84·2)\t0·05\t23·4 (0·8–62·9)\t0·1\t3·4 (0·0–73·8)\t<0·0001\t\n\n*1/*3A\n\t66\t70·1 (24·2–155·7)\t21·3 (5·1–46·8)\t1·5 (0·0–76·7)\t26·2 (9·7–57·4)\t8·4 (0·0–76·1)\t\n\n*1/*3C\n\t9\t72·5 (3·0–83·1)\t25·0 (10·2–97·0)\t2·4 (0·0–4·9)\t22·4 (13·5–37·3)\t8·8 (1·5–57·0)\t\n\n*1/*2\n\t2\t92·8 (82·8–102·7)\t19·3 (15·8–22·9)\t33·3 (19·3–47·4)\t18·4 (16·9–20·0)\t14·1 (13·7–14·5)\t\n\n*1/*21\n\t1\t57·4\t25·0\t0·0\t39·3\t15·5\t\n\n*1/*9\n\t1\t82·1\t8·6\t2·1\t25·0\t0·7\t\n\n*2/*3A\n\t1\t12·6\t34·6\t0·0\t37·0\t46·9\t\n\n*3C/*3C\n\t1\t19·5\t14·1\t0·0\t15·3\t2·4\t\n\n*1/*33\n\t1\t61·8\t11·9\t10·7\t20·2\t1·2\t\n\n*1/*34\n\t1\t61·9\t19·7\t2·6\t34·2\t14·5\t\nGroup 1\t\n*1/*1 vs\t735\t78·0 (29·8–162·4)\t0·0002\t15·5 (0·0–62·2)\t<0·0001\t5·8 (0·0–84·2)\t0·007\t23·4 (0·8–62·9)\t0·02\t3·4 (0·0–73·8)\t<0·0001\t\nOther #\t81\t70·4 (3·0–155·7)\t20·8 (5·1–97·0)\t2·4 (0·0–76·7)\t25·3 (9·7–57·4)\t8·8 (0·0–76·1)\t\nGroup 2\t\n*1/*1 vs\t735\t78·0 (29·8–162·4)\t0·0009\t15·5 (0·0–62·2)\t<0·0001\t5·8 (0·0–84·2)\t0·01\t23·4 (0·8–62·9)\t0·009\t3·4 (0·0–73·8)\t<0·0001\t\n\n*1/*3A\n\t66\t70·1 (24·2–155·7)\t21·3 (5·1–46·8)\t1·5 0·0–76·7)\t26·2 (9·7–57·4)\t8·4 (0·0–76·1)\t\nGroup 3\t\n*1/*3A vs\t66\t70·1 (24·2–155·7)\t0·6\t21·3 (5·1–46·8)\t0·4\t1·5 (0·0–76·7)\t0·9\t26·2 (9·7–57·4)\t0·3\t8·4 (0·0–76·1)\t0·3\t\n\n*1/*3C\n\t9\t72·5 (3·0–83·1)\t25·0 (10·2–97·0)\t2·4 (0·0–4·9)\t22·4 (13·5–37·3)\t8·8 (1·5–57·0)\t\nGroup 4\t\n*1/*1 vs\t735\t78·0 (29·8–162·4)\t0·04\t15·5 (0·0–62·2)\t0·05\t5·8 (0·0–84·2)\t0·1\t23·4 (0·8–62·9)\t0·9\t3·4 (0·0–73.)\t0·008\t\n\n*1/*3C\n\t9\t72·5 (3·0–83·1)\t25·0 (10·2–97·0)\t2·4 (0·0–4·9)\t22·4 (13·5–37·3)\t8·8 (1·5–57·0)\t\nValues are given as median and (range) when applicable. The TPMT homozygous variant genotype data was excluded from the TPMT subgroup, Group 1 to 4 comparisons. Other # = TPMT *1/*3A, *1/*3C, *1/*2, *1/*21, *1/*9, *1/*33, *1/*34. Vs = versus. n = number of patients in each group.\n\nJohn Wiley & Sons, LtdClinical outcome\nFor the complete trial [n = 1948; 5‐year EFS = 80%, overall survival = 89% (Vora et al, 2006)], there were significant differences by trial part, age group, presenting WBC and steroid, but no difference by gender or randomized thiopurine (Vora et al, 2006; Mitchell et al, 2009). In the subset of patients used in the dosing analysis (n = 1082) the effects of these covariates on overall EFS were similar to the complete trial.\n\nThiopurine metabolites\nTwenty patients taking mercaptopurine (approximately 3% of the mercaptopurine cohort) had overt drug non‐compliance problems (nil metabolites) at some point during maintenance chemotherapy. Partial non‐compliance problems (<Q1 both metabolites for the n = 707 mercaptopurine cohort = <276 pmol TGNs and <4698 pmol MeMPNs) were seen in 10% of patients taking mercaptopurine. Twenty‐nine children taking thioguanine (6% of thioguanine patients) had TGNs <750 pmol/8 × 108 red cells and were considered to have problems with compliance, 12 of these patients (approximately 3% of thioguanine cohort) had TGNs <500 pmol/8 × 108 red cells (Lennard et al, 2013). After stratifying for trial, age group, sex, WBC and steroid used, patients accumulating <750 pmol TGNs/8 × 108 red cells on thioguanine had worse EFS than compliant patients (odds ratio [OR] = 2·58, 95% CI: 1·11–5·7, P = 0·04); the difference was more marked (OR = 3·60, 95% CI: 1·34–9·69, P = 0·02) when the definition of non‐compliance was restricted to <500 pmol TGNs/8 × 108 red cells. However, there was no difference in EFS for non‐compliant mercaptopurine patients for any endpoint examined. For all of the patients with trial metabolite data there was no relationship between thioguanine‐derived TGNs, mercaptopurine‐derived TGNs or mercaptopurine‐derived MeMPNs and EFS (which includes all patients from the start of treatment) or jEFS (which excludes all patients with events in year 1), when the thiopurine metabolites were analysed as either continuous variables or split into quartiles. The results for thiopurine metabolites remained unchanged when stratified by TPMT genotype, trial, age group, sex, WBC or steroid used.\n\nThiopurine dosage\nQuartile analysis of the proportion of time spent on escalated doses showed that those patients who spent more time on escalated doses had a worse outcome (jEFS P = 0·04). There was no heterogeneity of effect of time spent on escalated doses within subgroups defined by genotype, randomized thiopurine or thiopurine taken. Quartile analysis showed no significant trend in jEFS for average % dose thiopurine taken or the proportion of time spent at reduced or no dose. Likewise, there was no significant difference in outcome seen by proportion of time spent with neutropenia or thrombocytopenia. There was no difference in jEFS between those patients who did not experience any episodes of thiopurine‐induced cytopenia and the majority of patients that did. There was no evidence of heterogeneity in sub‐groups defined by TPMT genotype.\n\n\nTPMT genotype\nEFS differed significantly by TPMT genotype (Fig 2). Heterozygous TPMT*1/*3C patients fared worse (5‐year EFS, 53%, 95%CI 29–77%) compared to the other heterozygous TPMT patients (TPMT*1/*3A, *1/*2, *1/*21, *1/*9, *1/*32, *1/*33, *1/*34; EFS 89%, 95%CI 83–95%, P = 0·002) and homozygous TPMT*1/*1 patients (EFS 80%%, 95%CI 78–82%, P = 0·03). TPMT*1/*3A patients (EFS 88%, 95%CI 81–94%) fared significantly better than TPMT*1/*1 (EFS 80%, 95%CI 78–82%) patients (Fig 2). These differences remained after stratifying for ethnic origin. However, numbers of non‐white Caucasian children were small, specifically for the TPMT*1/*3A cohort (n = 99), 1 was Asian and 1 mixed race, and for the TPMT*1/*3C cohort (n = 17), 1 was Asian, 1 black and 2 mixed race. None of the TPMT*1/*3C children had CNS disease at diagnosis or Down syndrome, two had T‐cell immunophenotype and one of these relapsed. Seven TPMT*1/*3C patients were treated on ALL97 (5 girls, 2 boys) and 10 on ALL97/99 (5 girls, 5 boys). The median age of the TPMT*1/*3C children (3 years) was similar to the TPMT*1/*3A children (4 years).\n\nFigure 2 Event‐free survival by TPMT genotype. ALL97 and ALL97/99.\n\nThere was no significant difference between the TPMT*1/*3C and TPMT*1/*3A patients with respect to mean daily dose or incidence of cytopenias, although the number of TPMT*1/*3C patients with full dose intensity data available was small (n = 9), (Table 4). One TPMT*1/*3C patient had difficulty tolerating mercaptopurine (average daily mercaptopurine dose 3%, 10% of time with drug withdrawn), DNA sequencing and measurement of the formation of MeMPN metabolites showed that this boy was not TPMT deficient. However, the TPMT activity (5·6 units/ml packed red cells) was at the extreme lower end of the TPMT heterozygous distribution (Lennard et al, 2013). Despite experiencing thrombocytopenia for 25% of the time (14% with neutropenia also) and drug withdrawal/reduction due to other mercaptopurine ‘sensitivities’, this child (treated on ALL97/99 regimen B) remains in remission.\n\nIn a multivariate Cox regression analysis, the worse survival for TPMT*1/*3C against TPMT*1/*3A (TPMT*1/*3C hazard ratio = 4·5, 95% CI 1·7–11·8, P = 0·003) and for TPMT*1/*3C against TPMT*1/*1 and all other TPMT variant heterozygous genotypes (Table 5) retained significance in models for overall EFS that also included the covariates trial, age group, WBC at diagnosis and steroid randomization.\n\nTable 5 Multivariate Cox regression analysis of overall event‐free survival for TPMT genotype and significant covariates\n\n\tHazard ratio\t95% CI\t\nP\n\t\n\nTPMT genotype\t\n\n*1/*1\n\t1·0\t\t0·003\t\n\n*1/*3A, *1/*2, *1/*21, *1/*9, *1/*32, *1/*33, *1/*34\n\t0·6\t0·4–1·1\t\n\n*1/*3C\n\t3·2\t1·5–6·8\t\nTrial part\t\nALL97\t1·0\t\t0·02\t\nALL97/99\t0·7\t0·6–1·0\t\nAge (per year increase)\t1·1\t1·0–1·1\t<0·0001\t\nLog (WBC) (per unit increase)\t1·1\t1·0–1·2\t0·04\t\nRandomized steroid\t\nPred\t1·0\t\t0·002\t\nDex\t0·7\t0·5–0·9\t\nMultivariate Cox regression analysis of overall event‐free survival defined from the start of treatment. Genotype comparison TPMT *1/*1 vs. (TPMT *1/*3A, *1/*2, *1/*21, *1/*9, *1/*32, *1/*33, *1/*34) versus TPMT*1/*3C, (n = 1189 patients, with n = 251 events). TPMT = thiopurine methyltransferase gene, CI = confidence interval, WBC = white blood cell count at diagnosis, Pred = prednisone, Dex = dexamethasone.\n\nJohn Wiley & Sons, LtdSecond malignancies\nThere were 13 second cancers (8 ALL97, 5 ALL97/99) in 1935 trial patients (0·7%) occurring a median of 4·6 years (range 1·0 to 11·3) from the start of chemotherapy in children aged from 3 to 12 years (median 7) at diagnosis. Of these 13 patients, 12 had TPMT genotypes (11 TPMT*1/*1; 1 TPMT *1/*3A) and 11 had genotype and metabolite data and 7 had dosing data. One child (TPMT wild‐type), aged 4 years at diagnosis, was diagnosed with a brain tumour (grade 2 astrocytoma) 10·3 years after diagnosis. This child had CNS disease at ALL diagnosis and received cranial radiotherapy. There was no association between second cancer and genotype, thiopurine metabolites, thiopurine average % dose or frequency of cytopenias. There was no association between second cancer and type of thiopurine: although a higher proportion of second cancers occurred in those randomized to thioguanine, this difference was not significant (P = 0·41).\n\nDiscussion\nThis study focused on the complex relationships between TPMT genotype, thiopurine dose intensity and myelosuppression, and the effect of these variables on treatment outcome within the ALL97 trials. Within the MRC UKALL X trial, a study of mercaptopurine dose intensity showed that those children who had one or more episodes of neutropenia (cell counts <0·5 × 109/l and dose withdrawal) had a better prognosis than those who never became neutropenic (Chessells et al, 1997). Moreover, within UKALL X, those children randomized to receive intensive blocks were prescribed lower doses of mercaptopurine and became neutropenic more readily; the intensive blocks influenced the subsequent response to mercaptopurine maintenance chemotherapy. A reverse association of neutropenia with worse EFS was seen in a later U.S. study in which all children received intensive blocks of treatment. In a multivariate analysis, a higher dose intensity of mercaptopurine was a significant predictor of improved EFS. The worse EFS observed in those with a lower mercaptopurine dose intensity was due to neutropenia and the subsequent weeks of missed therapy due to low cell counts, rather than lower doses of mercaptopurine (Relling et al, 1999b).\n\nIn the current study, in which all children received intensive blocks, the thiopurine dose intensity (taken either as the % average daily dose prescribed or the time spent on reduced doses or dose withdrawal due to low cell counts) was not associated with treatment outcome. The duration of, or episodes of, neutropenia or thrombocytopenia were not associated with outcome.\n\nThe gender difference in dose tolerance and myelosuppression, initially reported in UKALL X (Chessells et al, 1997), remains within ALL97. However, unlike UKALLX, there is no gender difference in outcome. The latter is perhaps a reflection of the extra year of exposure to thiopurines experienced by the majority of boys. TGN concentrations, metabolite concentrations associated with thiopurine‐induced myelosuppression, differ with respect to TPMT status in both boys and girls. For both genders and both thiopurines, TPMT heterozygous patients accumulated significantly higher TGN concentrations compared to the TPMT wild‐type cohort (Relling et al, 1999a; Lennard et al, 2013). The TPMT heterozygotes tolerated a significantly lower average daily thiopurine dose than the TPMT wild‐type patients and experienced more cytopenias. This is in keeping with recent studies within Berlin‐Frankfürt‐Münster (BFM) protocols that have reported an increased sensitivity of patients with TPMT heterozygosity to mercaptopurine‐induced myelosuppression (Karas‐Kuzelicki et al, 2009; Peregud‐Pogorzelski et al, 2011).\n\nThere is some debate as to whether the TPMT heterozygote should be prescribed a lower thiopurine dose than the TPMT wild‐type patient; not all TPMT heterozygotes are intolerant of thiopurine. The current general advice is a lower starting dose for the TPMT heterozygote with a titration‐upwards approach to an acceptable degree of myelosuppression (Relling et al, 2011, 2013). In the present study, however, the TPMT heterozygotes tolerated significantly lower average % dosages than the TPMT wild‐type patients (70% vs 78% for TPMT wild‐type, a daily‐dose difference of 6 mg/m2 per day mercaptopurine or 3·2 mg/m2 per day thioguanine). However, the range of thiopurine dosages tolerated was wide, with the upper and lower limits similar for both TPMT genotypes. These findings do not support any change in the prescribing criteria (both genotypes start at the same standard protocol dose and titrate to toxicity) for the UK ALL trials with respect to the TPMT heterozygous patient; a similar conclusion to that reached with respect to mercaptopurine dosages in the German BFM protocols (Stanulla et al, 2005).\n\n\nTPMT *1/*3A patients had a better EFS than TPMT *1/*1 patients, the former also experienced more cytopenias and accumulated higher TGN concentrations than the latter. However, neither the reference TGN concentration nor the frequency of cytopenias throughout thiopurine chemotherapy were directly associated with EFS. Survival was inexplicably worse for patients with TPMT*1/*3C than for TPMT*1/*3A patients. Despite similar mercaptopurine dosages and TPMT activities, the TPMT*1/*3C patients accumulated significantly less TGNs and lower MeMPN concentrations than TPMT*1/*3A patients; this could indicate an increased frequency of non‐adherence and suboptimal metabolite exposure in the TPMT*1/*3C cohort. The differences in survival for the TPMT*1/*3C with respect to TPMT*1/*3A patients could explain why, in a previous single nucleotide polymorphism analysis in a smaller cohort of ALL97 patients (Matimba et al, 2014), we found no difference in EFS between TPMT genotypes when analysed as wild‐type or variant allele.\n\nCompliance with oral chemotherapy was a confounding factor in this study. Although low or absent metabolite concentrations may be due to other factors, non‐compliance with oral chemotherapy is the most likely cause in this group of patients. It is possible that some parents may not have followed the clear guidance on evening dosing and avoiding food and milk products within 1 h of the thiopurine dose, and some patients may have had poor absorption due to other causes. However, in such cases, the apparent drug dose is reduced but the inverse relationship between TGN and MeMPN metabolite formation should be maintained. This is in contrast to the very low levels of both metabolites seen in non‐compliance. There are few studies on non‐compliance with oral anticancer therapy in children or adolescents, most studies focus on adults (Verbrugghe et al, 2013). Assessment of mercaptopurine non‐compliance in previous UK ALL trials, by structured interview, associated low metabolite concentrations at high drug doses with admitted failure to take the tablets (Davies et al, 1993). A similar evaluation of non‐compliance in ALL children by clinical (structured interviews and evaluation of medical charts) and laboratory (mercaptopurine metabolite monitoring) indices associated lower non‐compliance with adverse socioeconomic factors (De Oliveira et al, 2004). Non‐compliance perhaps explains the worse outcome for those who spent a longer time on escalated thiopurine dosages; an effect independent of TPMT status. Non‐compliance with thioguanine therapy, as previously defined by low TGN levels (Lennard et al, 2013), was also associated with a worse EFS whilst non‐compliance with mercaptopurine was not. This is perhaps explained by action taken by the clinician to address the non‐compliance identified by the metabolite results in the case of mercaptopurine but not thioguanine, because thioguanine‐derived TGN levels suggestive of non‐compliance were derived after the trial closed (Lennard et al, 2013). If unaddressed, a lower compliance to mercaptopurine is known to increase the relapse risk, and ethnic differences in relapse risk have been associated with increased non‐adherence (Bhatia et al, 2012).\n\n\nTPMT heterozygotes taking mercaptopurine were found to have a lower relapse risk in the Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL‐92 trial (Schmiegelow et al, 2009a) but the benefit was offset by a higher incidence of second cancers (Schmiegelow et al, 2009b). With a median follow‐up of 11·3 years, we have not observed an excess of second cancers in TPMT heterozygotes as reported in the NOPHO and St Jude total therapy trials; the latter studies linking lower TPMT activity with second brain tumours in children who received radiotherapy and with etoposide mediated myeloid leukaemias (Relling et al, 1998, 1999c; Schmiegelow et al, 2009b). Neither NOPHO nor ALL97 include etoposide. In the NOPHO and St Jude trials, high‐dose methotrexate and cranial irradiation are given alongside oral thiopurines, the former is not included in the ALL97 trials whilst the latter was reserved for patients (<5%) with overt CNS disease at diagnosis (Vora et al, 2006). The BFM studies report that TPMT status is not a risk factor for the development of second cancers (Stanulla et al, 2009). In the BFM protocols, some of which contained cranial irradiation, mercaptopurine was given alongside high‐dose methotrexate but at much lower dosages (25 mg/m2 per day) than the NOPHO and St Jude trials (75 mg/m2). The higher doses of mercaptopurine in the latter trials, alongside cranial irradiation and/or high‐dose methotrexate, could have contributed to the development of second malignancies. A subsequent NOPHO trial (NOPHO ALL‐2000) reported that using reduced mercaptopurine dosages for the TPMT heterozygote patient, alongside high‐dose methotrexate, reduced the risk of developing second cancers but this was counterbalanced by an increased risk of relapse for the TPMT heterozygote (Levinsen et al, 2014).\n\nThe data reported here will allow a more informed use of thiopurine drugs. Within the UK ALL trials, thiopurine‐induced cytopenias did not have a detrimental effect on EFS. A reference TGN metabolite concentration, taken at an early stage in thiopurine therapy when the patient is tolerating the drug, is useful for subsequent comparisons of metabolite exposure but is, in itself, not predictive of EFS. Some patients exhibited variable compliance with their oral thiopurine therapy, which was shown to have a negative effect on EFS for thioguanine patients. Other than possible increased non‐compliance problems in TPMT *1/*3C patients, a cohort with a higher proportion of ethnic minorities, the worse survival for the TPMT *1/*3C patients is unexplained. The worse outcome for TPMT *1/*3C will be re‐examined within the UK ALL 2003 trial, the successor to ALL97, in which treatment intensity was adjusted based on minimal residual disease risk stratification. The EFS for ALL2003 (5‐year EFS for low‐risk patients >94%) (Vora et al, 2013) is far superior to the ALL97 trials and this may negate any impact of TPMT.\n\nAuthorship\nLL, RW, AV contributed to the design of the study. AV was a trial co‐ordinator. LL, CSC conducted the biochemical measurements. LL, CSC, RW were involved in data collection and data analysis. LL, CSC, RW, AV were involved in data interpretation. LL wrote the manuscript. All authors were involved in the revision and editing of the manuscript. All authors approved the final version of the manuscript.\n\nCompeting interests\nThe authors have no competing interests.\n\nAcknowledgements\nThe thiopurine studies within ALL97 were supported by Leukaemia and Lymphoma Research. LL, CSC and AV were supported by Leukaemia and Lymphoma Research. RW was supported by the Medical Research Council. We wish to thank all the clinicians who entered patients into this trial and the participating patients and their families. We thank Sue Richards (Clinical Trial Service Unit, Oxford) for her work on the ALL97 trial and for preparing data for our analysis. We thank the trial co‐ordinators (Chris Mitchell, John Lilleyman, Sally Kinsey and Tim Eden) for enabling the thiopurine studies within the ALL97 trial, with a special thanks to John Lilleyman for his sound advice and helpful discussions.\n==== Refs\nReferences\n\n\nBhatia , S. \n, \nLandier , W. \n, \nShangguan , M. \n, \nHageman , L. \n, \nSchaible , A.N. \n, \nCarter , A.R. \n, \nHanby , C.L. \n, \nLeisenring , W. \n, \nYasui , Y. \n, \nKornegay , N.M. \n, \nMascarenhas , L. \n, \nRitchey , A.K. \n, \nCasillas , J.N. \n, \nDickens , D.S. \n, \nMeza , J. \n, \nCarroll , W.L. \n, \nRelling , M.V. \n & \nWong , F.L. \n (2012 ) Nonadherence to oral mercaptopurine and risk of replapse in hispanic and non‐hispanic white children with acute lymphoblastic leukemia: a report from the Children's Oncology Group . 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Journal of Clinical Oncology , 13 , 345 –351 .7531219 \n\n\nSchmiegelow , K. \n, \nForestier , E. \n, \nKristinsson , J. \n, \nSoderhall , S. \n, \nVettenranta , K. \n, \nWeinshilboum , R. \n & \nWesenberg , F. \n (2009a ) Thiopurine methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukaemia: results from the NOPHO ALL‐92 study . Leukaemia , 23 , 557 –564 .\n\n\nSchmiegelow , K. \n, \nAl‐Modhwahi , I. \n, \nAndersen , M.K. \n, \nBehrendtz , M. \n, \nForestier , E. \n & \nHastle , H. \n (2009b ) Methotrexate/6‐mercaptopurine maintenance therapy influences the risk of a second neoplasm after childhood acute lymphoblastic leukaemia: results from the NORPHO ALL92 study . Blood , 113 , 6077 –6084 .19224761 \n\n\nSchrappe , M. \n, \nReiter , A. \n, \nZimmmerman , M. \n, \nHarbott , J. \n, \nLudwig , W.‐D. \n, \nHenze , G. \n, \nGadner , H. \n, \nOdenwald , E. \n & \nRiehm , H. \n (2000 ) Long‐term results of four consecutive trials in childhood ALL performed by the ALL‐BFM study group from 1981 to 1995 . Leukaemia , 14 , 2205 –2222 .\n\n\nStanulla , M. \n, \nSchaeffler , E. \n, \nFlohr , T. \n, \nCario , G. \n, \nSchrauder , A. \n, \nZimmerman , M. \n, \nWelte , K. \n, \nLudwig , W.‐D. \n, \nBartram , C.R. \n, \nZanger , U.M. \n, \nEichelbaum , M. \n, \nSchrappe , M. \n & \nSchwab , M. \n (2005 ) Thiopurine methyltransferase genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukaemia . Journal of the American Medical Association , 293 , 1485 –1489 .15784872 \n\n\nStanulla , M. \n, \nSchaeffeler , E. \n, \nMoricke , A. \n, \nCoulthard , S.A. \n, \nCario , G. \n, \nSchrauder , A. \n, \nKaatsch , P. \n, \nDordelmann , M. \n, \nWelte , K. \n, \nZimmerman , M. \n, \nReiter , A. \n, \nEichelbaum , M. \n, \nRiehm , H. \n, \nSchrappe , M. \n & \nSchwab , M. \n (2009 ) Thiopurine methyltransferase genetics is not a major risk factor for secondary malignant neoplasms after treatment of childhood acute lymphoblastic leukaemia on Berlin‐Frankfurt‐Munster protocols . Blood , 114 , 1314 –1318 .19535798 \n\n\nTidd , D.M. \n & \nPaterson , A.R.P. \n (1974 ) A biochemical mechanism for the delayed cytotoxic reactions of 6–mercaptopurine . Cancer Research , 34 , 738 –746 .4856046 \n\n\nTiede , I. \n, \nFritz , G. \n, \nStrand , S. \n, \nPoppe , D. \n, \nDvorsky , R. \n, \nStrand , D. \n, \nLehr , H.A. \n, \nWirtz , S. \n, \nBecker , C. \n, \nAtreya , R. \n, \nMudter , J. \n, \nHildner , K. \n, \nBartsch , B. \n, \nHoltman , M. \n, \nBlumberg , R. \n, \nWalczak , H. \n, \nIven , H. \n, \nGalle , P.R. \n, \nAhmadian , M.R. \n & \nNeurath , M.F. \n (2003 ) CD28‐dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes . The Journal of Clinical Investigation , 111 , 1133 –1145 .12697733 \n\n\nVerbrugghe , M. \n, \nVerhaeghe , S. \n, \nLauwaert , K. \n, \nBeeckman , D. \n & \nVan Hecke , A. \n (2013 ) Determinants and associated factors influencing medication adherence and persistence to oral anticancer drugs: a systematic review . Cancer Treatment Reviews , 39 , 610 –621 .23428230 \n\n\nVora , A.J. \n, \nMitchell , C.D. \n, \nLennard , L. \n, \nEden , T.O.B. \n, \nKinsey , S.E. \n, \nLilleyman , J.S. \n & \nRichards , S. \n (2006 ) Toxicity and efficacy of thioguanine compared with mercaptopurine in childhood lymphoblastic leukaemia: results of the UK Medical Research Council Randomised Trial ALL97 . Lancet , 368 , 1339 –1348 .17046466 \n\n\nVora , A. \n, \nGoulden , N. \n, \nWade , R. \n, \nMitchell , C. \n, \nHancock , J. \n, \nHough , R. \n, \nRowntree , C. \n & \nRichards , S. \n (2013 ) Treatment reduction for children and young adults with low‐risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial . The Lancet Oncology , 14 , 199 –209 .23395119 \n\n\nWarren , D.J. \n, \nAndersen , A. \n & \nSlordal , L. \n (1995 ) Quantitation of 6‐thioguanine residues in peripheral blood leukocyte DNA obtained from patients receiving 6‐mercaptopurine based maintenance therapy . Cancer Research , 55 , 1670 –1674 .7712473 \n\n\nWeinshilboum , R.M. \n & \nSladek , S.L. \n (1980 ) Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity . American Journal of Human Genetics , 32 , 651 –662 .7191632\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0007-1048",
"issue": "169(2)",
"journal": "British journal of haematology",
"keywords": "acute lymphoblastic leukaemia; cytopenias; mercaptopurine; thioguanine; thiopurine methyltransferase",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000293:Adolescent; D000964:Antimetabolites, Antineoplastic; D002648:Child; D002675:Child, Preschool; D005838:Genotype; D006801:Humans; D007223:Infant; D008780:Methyltransferases; D010597:Pharmacogenetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "228-40",
"pmc": null,
"pmid": "25441457",
"pubdate": "2015-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "10406363;10216075;15784872;15952999;16365460;17015055;17046466;17277075;18987654;18987660;19224761;19549269;19535798;21270794;21319286;22564992;23395119;23422873;23428230;23252716;24395436;24624911;24670805;11037857;10580024;15269085;11187912;12697733;4856046;7191632;2758725;2585022;1973780;1960624;1484095;8499854;7531219;7712473;7547211;8667921;9246020;9326194;9529129;13105700",
"title": "Thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics.",
"title_normalized": "thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia the influence of thiopurine methyltransferase pharmacogenetics"
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"activesubstance": {
"activesubstancename": "THIOGUANINE ANHYDROUS"
},
... |
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"abstract": "4-methylpentedrone (4-MPD) is a new psychoactive substance (NPS) belonging to the cathinone class. We report an original case of death mainly involving 4-MPD, along with cocaine, sildenafil, bromazepam and nevirapine. The investigation data and the autopsy findings indicated fatal intoxication in a chemsex context (drug use during sex). 4-MPD concentrations were determined in peripheral blood (1285 ng/mL), cardiac blood (1128 ng/mL), urine (>10,000 ng/mL), bile (1187 ng/mL) and vitreous humor (734 and 875 ng/mL in left and right samples, respectively) by gas chromatography (GC) coupled to tandem mass spectrometry. 4-MPD metabolites were explored by GC coupled to high resolution mass spectrometry. Due to the paucity of data concerning 4-MPD, its use and effects were gathered from online user testimonies. This case illustrates the toxicity of this infrequent pentedrone derivate and confirms the significant overdose risk associated with chemsex.",
"affiliations": "Hospices Civils de Lyon, Edouard Herriot Hospital, Service of Forensic Medicine, Lyon, France. Electronic address: nathalie.cartiser@chu-lyon.fr.;Hospices Civils de Lyon, Edouard Herriot Hospital, Service of Forensic Medicine, Lyon, France.;Hospices Civils de Lyon, Edouard Herriot Hospital, Service of Forensic Medicine, Lyon, France.;Hospices Civils de Lyon, Edouard Herriot Hospital, Service of Forensic Medicine, Lyon, France.;LAT LUMTOX Laboratory, Lyon, France.;LAT LUMTOX Laboratory, Lyon, France.;LAT LUMTOX Laboratory, Lyon, France.;Hospices Civils de Lyon, Edouard Herriot Hospital, Service of Forensic Medicine, Lyon, France; University of Lyon, UCBL1, Faculty of Medicine Lyon-Est, Lyon, France.",
"authors": "Cartiser|Nathalie|N|;Sahy|Anaïs|A|;Advenier|Anne-Sophie|AS|;Franchi|Angélique|A|;Revelut|Kevin|K|;Bottinelli|Charline|C|;Bévalot|Fabien|F|;Fanton|Laurent|L|",
"chemical_list": "C000717800:4-methylpentedrone; D000470:Alkaloids; D008744:Methylamines; D010422:Pentanones; D011619:Psychotropic Drugs; C023665:cathinone; D003042:Cocaine",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2020.110659",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "319()",
"journal": "Forensic science international",
"keywords": "4-Methylpentedrone (4-MPD); Chemsex; Fatal intoxication; Forensic toxicology; New psychoactive substance (NPS)",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000470:Alkaloids; D001646:Bile; D002849:Chromatography, Gas; D003042:Cocaine; D062787:Drug Overdose; D006801:Humans; D008297:Male; D008744:Methylamines; D010422:Pentanones; D011619:Psychotropic Drugs; D012725:Sexual Behavior; D019966:Substance-Related Disorders; D053719:Tandem Mass Spectrometry; D014822:Vitreous Body",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "110659",
"pmc": null,
"pmid": "33370656",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Fatal intoxication involving 4-methylpentedrone (4-MPD) in a context of chemsex.",
"title_normalized": "fatal intoxication involving 4 methylpentedrone 4 mpd in a context of chemsex"
} | [
{
"companynumb": "FR-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2021-BI-073983",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "COCAINE"
},
"dru... |
{
"abstract": "We present a case of Takotsubo cardiomyopathy (TTC) with regional variation in left ventricular function precipitated by intraocular injection of phenylephrine. To our knowledge, this is the first described case of TTC occurring in the setting of an intraocular medication. Contrary to the traditional model of the β2-receptor underlying the pathophysiology behind Takotsubo cardiomyopathy, phenylephrine is a pure α1-agonist implicating alternative mechanisms of myocardial injury resulting in a similar clinical phenotype. One should be alert to the possibility of catecholamine induced TTC occurring in patients subject to medications administered via the intraocular route with the potential for significant systemic absorption.",
"affiliations": "Liverpool Hospital, Sydney, NSW, Australia; Campbelltown Hospital, Sydney, NSW, Australia.;Liverpool Hospital, Sydney, NSW, Australia; Campbelltown Hospital, Sydney, NSW, Australia; University of New South Wales, Sydney, NSW, Australia; Western Sydney University, Sydney, NSW, Australia. Electronic address: ndtp@optusnet.com.au.",
"authors": "Lee|Adam|A|;Nguyen|Phong|P|",
"chemical_list": "D058646:Adrenergic alpha-1 Receptor Agonists; D010656:Phenylephrine",
"country": "Australia",
"delete": false,
"doi": "10.1016/j.hlc.2016.06.1204",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1443-9506",
"issue": "25(12)",
"journal": "Heart, lung & circulation",
"keywords": "Eye drops; Intraocular; Phenylephrine; Stress cardiomyopathy; Takotsubo",
"medline_ta": "Heart Lung Circ",
"mesh_terms": "D058646:Adrenergic alpha-1 Receptor Agonists; D005260:Female; D006801:Humans; D056965:Injections, Intraocular; D008875:Middle Aged; D010656:Phenylephrine; D054549:Takotsubo Cardiomyopathy",
"nlm_unique_id": "100963739",
"other_id": null,
"pages": "e159-e161",
"pmc": null,
"pmid": "27475260",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Takotsubo Cardiomyopathy Due to Systemic Absorption of Intraocular Phenylephrine.",
"title_normalized": "takotsubo cardiomyopathy due to systemic absorption of intraocular phenylephrine"
} | [
{
"companynumb": "AU-ECLAT PHARMACEUTICALS-2016ECL00090",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PHENYLEPHRINE\\PHENYLEPHRINE HYDROCHLORIDE"
... |
{
"abstract": "Pancreatic ductal adenocarcinoma (PDAC) remains deadly despite advances in systemic therapies and surgical techniques. While there is increasing utilization of immune therapies across diverse cancer types, PDAC remains generally resistant to these treatments. We report a case of locally advanced PDAC treated with preoperative radiation and anti-PD-1 immunotherapy guided by preoperative PD-L1 tumor analysis. After 4 months of preoperative therapy, the patient was submitted to resection, demonstrating a near-complete pathologic response on final tumor analysis. We will discuss the relevant literature and current state of immunotherapeutics for PDAC.",
"affiliations": "Department of Surgery, Brooke Army Medical Center, San Antonio, TX, USA.;Department of Hematology and Oncology, Brooke Army Medical Center, San Antonio, TX, USA.;Department of Pathology, Brooke Army Medical Center, San Antonio, TX, USA.;Department of Surgery, Brooke Army Medical Center, San Antonio, TX, USA.;Department of Surgery, Brooke Army Medical Center, San Antonio, TX, USA.;Department of Surgery, William Beaumont Army Medical Center, El Paso, TX, USA.;Department of Hematology and Oncology, Brooke Army Medical Center, San Antonio, TX, USA.;Department of Pathology, Brooke Army Medical Center, San Antonio, TX, USA.;Department of Surgery, Brooke Army Medical Center, San Antonio, TX, USA.;Department of Surgery, Brooke Army Medical Center, San Antonio, TX, USA.;Cancer Vaccine Development Program, San Antonio, TX, USA.;Department of Surgery, Brooke Army Medical Center, San Antonio, TX, USA.",
"authors": "McCarthy|Patrick M|PM|0000-0002-8805-8148;Rendo|Matthew J|MJ|;Uy|Matthew D|MD|;Adams|Alexandra M|AM|;O'Shea|Anne E|AE|;Nelson|Daniel William|DW|;Fenderson|Joshua L|JL|;Cebe|Katherine M|KM|;Krell|Robert W|RW|;Clifton|Guy T|GT|;Peoples|George E|GE|0000-0001-7118-8205;Vreeland|Timothy J|TJ|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OTT.S311661",
"fulltext": "\n==== Front\nOnco Targets Ther\nOnco Targets Ther\nott\nott\nOncoTargets and therapy\n1178-6930\nDove\n\n311661\n10.2147/OTT.S311661\nCase Report\nNear Complete Pathologic Response to PD-1 Inhibitor and Radiotherapy in a Patient with Locally Advanced Pancreatic Ductal Adenocarcinoma\nMcCarthy et al\nMcCarthy et al\nhttp://orcid.org/0000-0002-8805-8148\nMcCarthy Patrick M 1\nRendo Matthew J 2\nUy Matthew D 3\nAdams Alexandra M 1\nO’Shea Anne E 1\nNelson Daniel William 4\nFenderson Joshua L 2\nCebe Katherine M 3\nKrell Robert W 1\nClifton Guy T 1\nhttp://orcid.org/0000-0001-7118-8205\nPeoples George E 5\nVreeland Timothy J 1\n1 Department of Surgery, Brooke Army Medical Center, San Antonio, TX, USA\n2 Department of Hematology and Oncology, Brooke Army Medical Center, San Antonio, TX, USA\n3 Department of Pathology, Brooke Army Medical Center, San Antonio, TX, USA\n4 Department of Surgery, William Beaumont Army Medical Center, El Paso, TX, USA\n5 Cancer Vaccine Development Program, San Antonio, TX, USA\nCorrespondence: Patrick M McCarthy Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., San Antonio, TX, 78234, USATel +1 240 285-0930Fax +1 210 916-6658 Email p.m.mccarthy.0@gmail.com\n01 6 2021\n2021\n14 35373544\n18 3 2021\n05 5 2021\n© 2021 McCarthy et al.\n2021\nMcCarthy et al.\nhttps://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nAbstract\n\nPancreatic ductal adenocarcinoma (PDAC) remains deadly despite advances in systemic therapies and surgical techniques. While there is increasing utilization of immune therapies across diverse cancer types, PDAC remains generally resistant to these treatments. We report a case of locally advanced PDAC treated with preoperative radiation and anti-PD-1 immunotherapy guided by preoperative PD-L1 tumor analysis. After 4 months of preoperative therapy, the patient was submitted to resection, demonstrating a near-complete pathologic response on final tumor analysis. We will discuss the relevant literature and current state of immunotherapeutics for PDAC.\n\nKeywords\n\npancreatic cancer\npembrolizumab\ncomplete response\nPD-L1\nlocally advanced\nimmune checkpoint inhibitor\n==== Body\nIntroduction\n\nPancreatic ductal adenocarcinoma (PDAC) is difficult to treat; the 5 year-survival rate across all stages is 7.9% in the United States.1 Approximately 20% of patients are candidates for surgical intervention at the time of diagnosis.2,3 As a result, there has been increasing interest in expanding the armamentarium of neoadjuvant therapies aimed at decreasing tumor burden and selecting patients with favorable tumor biology prior to curative-intent surgery, particularly for locally advanced4–7 and borderline resectable8–12 PDAC. In contrast to breast, rectal, and esophageal cancers, complete pathologic responses to neoadjuvant chemotherapy occur in only 5–7.5% of cases.13,14\n\nCancer patients have benefited from the development and expansion of personalized medicine and immunotherapy, particularly with the use of immune checkpoint inhibitors (ICI). Drugs targeting CTLA-4, PD-1, and PD-L1 have been far more effective in the management of melanoma15–17 and lung cancer18–22 than cytotoxic chemotherapy alone. The success of ICI in these settings has led to expanded use of these immunotherapies across diverse tumor types. Recently, pembrolizumab received FDA approval for treating metastatic cancers with either high microsatellite instability (MSI-H)23 or high tumor mutational burden-high (TMB-H), regardless of histology.24,25 These and other trials targeting tumor biology or gene expression over specific histologic origin highlight a major paradigm shift in cancer treatment.\n\nDespite this enthusiasm for immune therapy, outcomes with ICI in PDAC patients have been less impressive. In the KEYNOTE-158 trial, even amongst PDAC tumors that were MSI-H/dMMR, overall response rate to pembrolizumab monotherapy was 18.2%; the lowest of all GI tract malignancies.24 While the results of immunotherapy in PDAC have by and large been unimpressive, it is possible that it may still have a role in correctly selected patients. Here, we present the case of a patient with locally advanced PDAC and near pathologic complete response (pCR) after administration of combination pembrolizumab and radiation therapy (RT) and a review of the available literature on the use of personalized medicine and immunotherapy in PDAC.\n\nMaterials and Methods\n\nConsents and Permissions\n\nAll information in this project was obtained in accordance with the Declaration of Helsinki, HIPAA, and our institutional guidelines. The patient described in this case has given informed consent and consent to publish the clinical details contained within this report. Institutional approval was not required to publish the details of the case included in this report.\n\nResults\n\nClinical Presentation\n\nThe patient is an 83-year-old female who presented with progressive flank discomfort over two months with multiple comorbidities and an Eastern Cooperative Oncology Group (ECOG) performance status of 3. Physical examination was non-focal and lab workup was notable for an elevated lipase, mild leukocytosis, and normocytic anemia. An abdominal CT revealed a 10.6×8.0×11.7cm mass arising from the pancreatic body, with partial encasement of the splenic artery (Figure 1A). The mass abutted the stomach and splenic flexure of the colon, with evidence of invasion of both organs (Figure 1B–D) without evidence of metastatic disease. Serum cancer antigen 19–9 (CA 19–9) was 3366 U/mL (reference value <36 U/mL) and carcinoembryonic antigen (CEA) was 67.5 ng/mL (reference value <3.5 ng/mL). Endoscopic biopsy of the pancreatic mass revealed adenocarcinoma consistent with pancreatic origin, which was confirmed on colonoscopy. Immunohistochemical analysis revealed a poorly differentiated carcinoma staining positive for CK7, weakly positive for CDX2, and negative for CK20; further supporting upper gastrointestinal origin and a diagnosis of locally advanced pancreas cancer with colonic invasion. Immunohistochemistry analysis for MLH1, PMS2, MSH2, and MSH6 showed intact expression.Figure 1 Sagittal CT scan representative image demonstrating the tumor's proximity to central arterial vasculature (A). Axial and coronal representative CT images demonstrating tumor proximity to gastric (B and D) and colonic (C) tissues (arrows demarcate points of organ abutment). Representative CT images obtained after 25 Gy of radiotherapy and four cycles of immunotherapy with gold fiducials demarcating the tumor (E–G).\n\nGiven her locally advanced tumor and the need for multi-visceral resection, the multidisciplinary tumor board recommended neoadjuvant systemic therapy. Due to her multiple comorbidities and poor performance status, however, the patient was not a good candidate for multi-agent cytotoxic chemotherapy. Tumor analysis with FoundationOne CDx (Foundation Medicine, Inc. Cambridge, MA) demonstrated a PD-L1 tumor proportion score of 70%, Microsatellite Instability–High (MSI-H) status, and a tumor mutational burden of 49 mutations per megabase.\n\nTreatment and Outcomes\n\nThe patient received stereotactic body radiotherapy (SBRT) (25 Gy/5 five fractions) to the pancreatic mass before commencing pembrolizumab monotherapy at 200mg every three weeks. Interval CT scan after 2 cycles of pembrolizumab showed decreased mass size at 3.6×3.8×3.8cm. Serum CA 19–9 had decreased to 27.7 U/mL. Repeat imaging after a total of 4 cycles showed further tumor volume decrease (3.2×2.7×3.1 cm) and cystic degeneration (Figure 1E–G).\n\nThe patient’s favorable response on imaging led to the recommendation for exploration with resection via distal pancreatectomy with splenectomy. In the operating room, the tumor was inseparable from the posterior gastric wall and transverse mesocolon, necessitating en bloc wedge gastrectomy and resection of 6 cm of transverse colon with primary anastomosis. The patient recovered without complications and was discharged on post-operative day five.\n\nThe pancreatic specimen revealed abundant mucin and necrotic tissue surrounded by a prominent histiocytic and lymphocytic infiltrate with patchy neutrophilic inflammation, indicative of treatment effect, with no residual dysplasia or carcinoma in the pancreas (Figure 2). Thirty-nine lymph nodes were negative for carcinoma. The gastric specimen was also negative for carcinoma. The resected colon contained a 4 mm segment of poorly differentiated adenocarcinoma within the lamina propria surrounded by a prominent histiocytic and lymphocytic infiltrate (Figure 3). The margins and all six colonic lymph nodes were negative for carcinoma. Post-operative CA 19–9 was 26.2 U/mL.Figure 2 Pancreas with treatment effect. H&E stain (A and C) shows areas of necrosis surrounded by lymphocytes consistent with prior tumor bed. CD3 immunohistochemical stain (B and D) highlights CD3+ T lymphocytes surrounding areas of prior tumor bed.\n\nFigure 3 (A) H&E stain; 4x; Colon containing residual carcinoma with lymphocytic infiltrate within tumor (black arrowheads) and area of treatment effect (blue arrows). (B) CK7 IHC stain; 40x; CK7 stain highlighting residual carcinoma within colonic mucosa. (C) CD3 IHC stain; 40x; IHC stain highlighting CD3+ lymphocytes within tumor and area of treatment effect. (D) H&E stain; 400x; High power view of residual carcinoma within the colon with numerous tumor infiltrating lymphocytes.\n\nThe patient has continued to receive pembrolizumab post-operatively, with plans for one year of total therapy. At her most recent follow up five months after surgery she has continued to tolerate therapy well without evidence of disease recurrence.\n\nDiscussion\n\nImmunotherapy is not commonly utilized in the neoadjuvant setting for locally advanced PDAC. ICI are more commonly utilized in the metastatic setting as second- or third-line therapies in patients with MSI-H or dMMR tumors, or as an alternative monotherapy in patients with poor performance status.26,27 Within pancreatic cancer there is little data directly comparing these modalities to cytotoxic chemotherapy in the metastatic setting, even in patients with MSI-H tumors, and few if any data comparing them in the perioperative setting.\n\nWhile chemotherapy for PDAC has improved, dramatic responses remain rare13,14 and the ability to predict treatment response has largely remained elusive. A recent analysis by Perri et al demonstrated an association between pathologic response with radiographic metrics and serum tumor markers, but major and complete responses are quite rare.28 Thus, there is rationale for the expanded use of personalized strategies in the form of targeted therapies and immunotherapies, especially in patients who are expected to not tolerate, or not respond to, cytotoxic chemotherapy. To date, ICI have achieved minimal success.29–31 An early trial including PDAC patients with metastatic disease treated with pembrolizumab published a 0% ORR and a 3.9-month median overall survival (mOS),29 and inclusion of anti-CTLA-4 therapies has produced equally disappointing results. Combinations of ICI and chemotherapy agents have not shown a clear benefit, but some rare reports of dramatic responses are encouraging, such as a patient with metastatic PDAC in a phase Ib trial of ipilimumab and gemcitabine who achieved a durable response of 19.8 months.32 Though there are three ongoing Phase III trials investigating ICI in PDAC (NCT03983057, NCT03977272, NCT03755739), the failure of early phase trials to show substantial treatment effects underscores the immunosuppressive and immune-excluding nature of the tumor microenvironment (TME) and surrounding stroma of PDAC relative to other solid tumor types. Within the TME, multiple cell lines such as macrophages, dendritic cells, and PDAC epithelial cells are manipulated to induce immunosuppressive effects.33 The tumor stroma, consisting of the extracellular matrix, vasculature, and cancer associated fibroblasts, create a mechanical and functional barrier to an effective anti-tumor immune response.34\n\nDespite these challenges, there may be hope for ICI in PDAC with better patient selection. One major issue with these early trials is that patients were enrolled without a requirement for specific mutation burden, PD-L1 expression, or MSI status. Unfortunately, PD-L1 expression as low as 3.9% in all nucleated cells of resected PDAC specimens has been reported in patients who received no NAT.35 There is, however, prospective clinical evidence in multiple solid tumor types indicating that MSI-H and TMB-H tumors may be sensitive to PD-L1 targeted immunotherapy, regardless of PD-L1 expression.36,37 While these markers are also fairly rare in PDAC,38 there is a small subset of patients who may have dramatic responses to immunotherapy. Early trials investigating ICI in PDAC have enrolled patients who have failed initial, cytotoxic chemotherapy treatments. Unfortunately, the recipient of such therapies may experience damage to the immune system that could result in weaker, if any, immunologic response to ICI, potentially altering the results of these studies. Additional research is needed to better understand the complex interaction between the immune system and the TME of a PDAC tumor but, as demonstrated by our case, dramatic effects from immunotherapy are likely to be seen in cases with remarkably high TMB and expression of PD-L1. This is where future research on immunotherapy in PDAC should focus.\n\nThough significant baseline immunogenicity is rare in PDAC, it is possible that another therapy may be able to generate an initial immune response in an otherwise immunologically cold tumor, allowing ICI to exploit and expand this response. One promising strategy that was utilized in our case is the addition of ICI to RT. It has been postulated that the cell lysis caused by ionizing radiation may cause an immune response to a patient’s tumor, leading to an immune response with corresponding upregulation of PD-L1 expression on tumor cells.39,40 Syngeneic mouse tumor models demonstrated improved survival and tumor volume reduction with the combination of RT and PD-L1 blockade compared to single modality, and elevations in tumor cell PD-L1 expression were seen following RT.39,41 Additionally, it has been suggested that RT may have effects on the dense, immunosuppressive tumor microenvironment and stroma of PDAC in a way that increases immune cell response and antigen recognition.42 This promising combination is currently being studied in a number of malignancies,43 but has not been studied extensively in pancreatic malignancies. SBRT followed by durvalumab for pancreatic cancer is currently being studied in the metastatic setting in a Phase I trial; however, early data indicate poor therapy responses, with stable disease marking the best response in 21% of patients.44 There are no studies to date assessing frontline combination radiation and immunotherapy for locally advanced or borderline resectable tumors as successfully implemented in this case; however, there are several promising animal studies and enrolling clinical trials.42 While it is possible that this combination may offer meaningful response in PDAC, it is again likely that patients with some baseline immune response to their tumor will see the most benefit.\n\nFinally, the discovery of frequent somatic mutations within pancreatic cancers has also led to a broadening array of directed therapies. In addition to PD-1/PD-L1 inhibitors, recent trials have begun to enroll patients for treatment with RAS inhibitors, specifically a small-molecule KRASG12C inhibitor, AMG 510.45 At the most recent ASCO scientific assembly, researchers presented a cohort of patients diagnosed with KRASG12C-mutated tumors, including eight with pancreatic cancer. Of these patients, six had achieved stable disease and three had a 30% reduction in tumor burden.46 Given the frequency of KRAS mutations in pancreatic cancer, the promise of RAS inhibitors provides hope for patients with this malignancy. In addition, there is hope that combining ICI with small molecule inhibitors, whether targeting RAS or other common mutations, will lead to synergistic anti-cancer effects.47 While these therapies are in their infancy, especially with regards to use in pancreatic cancer, they demonstrate where the field of oncology is going: towards personalized medicine, with each patient’s treatment being chosen based on their specific tumor’s genetic signature.\n\nConclusion\n\nThe future of oncologic care is personalized medicine, and here we present remarkable success utilizing neoadjuvant pembrolizumab for a PD-L1 high, TMB-H tumor, with radiation that potentially enhanced PD-L1 blockade. This case report adds to the growing body of evidence that RT may alter the immunogenicity of the PDAC TME and allow for the synergistic use of ICI. Furthermore, this case highlights the impressive efficacy of this combination that may be possible in correctly selected patients. This calls for further study on application of ICI in PDAC, particularly in appropriately selected patients. Routine testing for targets of immunotherapies should be strongly considered for frail patients with unresectable or metastatic PDAC.\n\nDisclosure\n\nThe authors declare no potential conflicts of interest.\n==== Refs\nReferences\n\n1. Surveillance Research Program NCI. SEER*Explorer: an interactive website for SEER cancer statistics; 2020. Available from: https://seer.cancer.gov/explorer/. Accessed 510, 2020.\n2. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74 (11 ):2913–2921. doi:10.1158/0008-5472.can-14-0155 24840647\n3. Müller PC, Frey MC, Ruzza CM, et al. Neoadjuvant chemotherapy in pancreatic cancer: an appraisal of the current high-level evidence. Pharmacology. 2020;1–11. doi:10.1159/000510343.31822007\n4. Gemenetzis G, Groot VP, Blair AB, et al. Survival in locally advanced pancreatic cancer after neoadjuvant therapy and surgical resection. Ann Surg. 2019;270 (2 ):340–347. doi:10.1097/sla.0000000000002753 29596120\n5. Hackert T, Sachsenmaier M, Hinz U, et al. Locally advanced pancreatic cancer. Ann Surg. 2016;264 (3 ):457–463. doi:10.1097/sla.0000000000001850 27355262\n6. Kunzmann V, Algül H, Goekkurt E, et al. Conversion rate in locally advanced pancreatic cancer (LAPC) after nab-paclitaxel/gemcitabine- or FOLFIRINOX-based induction chemotherapy (NEOLAP): final results of a multicenter randomised Phase II AIO trial. Ann Oncol. 2019;30 (Supplement_5 ):v253. doi:10.1093/annonc/mdz247\n7. Michelakos T, Pergolini I, Castillo CF-D, et al. Predictors of resectability and survival in patients with borderline and locally advanced pancreatic cancer who underwent neoadjuvant treatment with FOLFIRINOX. Ann Surg. 2019;269 (4 ):733–740. doi:10.1097/sla.0000000000002600 29227344\n8. Murphy JE, Wo JY, Ryan DP, et al. Total neoadjuvant therapy with FOLFIRINOX followed by individualized chemoradiotherapy for borderline resectable pancreatic adenocarcinoma. JAMA Oncol. 2018;4 (7 ):963. doi:10.1001/jamaoncol.2018.0329 29800971\n9. Jang J-Y, Han Y, Lee H, et al. Oncological benefits of neoadjuvant chemoradiation with gemcitabine versus upfront surgery in patients with borderline resectable pancreatic cancer. Ann Surg. 2018;268 (2 ):215–222. doi:10.1097/sla.0000000000002705 29462005\n10. Versteijne E, Suker M, Groothuis K, et al. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: results of the Dutch randomized phase III PREOPANC trial. J Clin Oncol. 2020;38 (16 ):1763–1773. doi:10.1200/JCO.19.02274 32105518\n11. Motoi F, Kosuge T, Ueno H, et al. Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP05). Jpn J Clin Oncol. 2019;49 (2 ):190–194. doi:10.1093/jjco/hyy190 30608598\n12. Ghaneh P, Palmer DH, Cicconi S, et al. ESPAC-5F: four-arm, prospective, multicenter, international randomized phase II trial of immediate surgery compared with neoadjuvant gemcitabine plus capecitabine (GEMCAP) or FOLFIRINOX or chemoradiotherapy (CRT) in patients with borderline resectable pancreatic cancer. J Clin Oncol. 2020;38 (15_suppl ):4505. doi:10.1200/JCO.2020.38.15_suppl.4505\n13. Gillen S, Schuster T, Meyer Zum Büschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010;7 (4 ):e1000267. doi:10.1371/journal.pmed.1000267 20422030\n14. Mellon EA, Jin WH, Frakes JM, et al. Predictors and survival for pathologic tumor response grade in borderline resectable and locally advanced pancreatic cancer treated with induction chemotherapy and neoadjuvant stereotactic body radiotherapy. Acta Oncologica. 2017;56 (3 ):391–397. doi:10.1080/0284186x.2016.1256497 27885876\n15. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373 (1 ):23–34. doi:10.1056/NEJMoa1504030 26027431\n16. Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label Phase 3 study (KEYNOTE-006). Lancet. 2017;390 (10105 ):1853–1862. doi:10.1016/S0140-6736(17)31601-X 28822576\n17. Robert C, Ribas A, Schachter J, et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019;20 (9 ):1239–1251. doi:10.1016/S1470-2045(19)30388-2 31345627\n18. Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter Phase 2 trial. Ann Oncol. 2013;24 (1 ):75–83. doi:10.1093/annonc/mds213 22858559\n19. Reck M, Luft A, Szczesna A, et al. Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer. J Clin Oncol. 2016;34 (31 ):3740–3748. doi:10.1200/jco.2016.67.6601 27458307\n20. Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379 (23 ):2220–2229. doi:10.1056/nejmoa1809064 30280641\n21. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394 (10212 ):1929–1939. doi:10.1016/S0140-6736(19)32222-6 31590988\n22. Rudin CM, Awad MM, Navarro A, et al. Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer: randomized, double-blind, phase III KEYNOTE-604 study. J Clin Oncol. 2020;38 (21 ):2369–2379. doi:10.1200/jco.20.00793 32468956\n23. Marcus L, Lemery SJ, Keegan P, Pazdur R. FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clin Cancer Res. 2019;25 (13 ):3753–3758. doi:10.1158/1078-0432.ccr-18-4070 30787022\n24. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair–deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38 (1 ):1–10. doi:10.1200/jco.19.02105 31682550\n25. FDA. FDA approves pembrolizumab for adults and children with TMB-H solid tumors; 2020. Available from: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors. Accessed 511, 2021.\n26. Sohal DPS, Kennedy EB, Cinar P, et al. Metastatic pancreatic cancer: ASCO guideline update. J Clin Oncol. 2020;38 (27 ):3217–3230. doi:10.1200/jco.20.01364\n27. Network NCC. Pancreatic adenocarcinoma (version 1.2020), 2020. Available from: https://www.nccn.org/professionals/physician_gls/pdf/pancreatic_blocks.pdf. Accessed 810, 2020.\n28. Perri G, Prakash L, Wang H, et al. Radiographic and serologic predictors of pathologic major response to preoperative therapy for pancreatic cancer. Ann Surg. 2021;273 (4 ):806–813. doi:10.1097/SLA.0000000000003442 31274655\n29. Ott PA, Bang Y-J, Piha-Paul SA, et al. T-cell–inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J Clin Oncol. 2019;37 (4 ):318–327. doi:10.1200/jco.2018.78.2276 30557521\n30. Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33 (8 ):828–833. doi:10.1097/cji.0b013e3181eec14c 20842054\n31. O’Reilly EM, Oh D-Y, Dhani N, et al. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma. JAMA Oncol. 2019;5 (10 ):1431. doi:10.1001/jamaoncol.2019.1588 31318392\n32. Kamath SD, Kalyan A, Kircher S, et al. Ipilimumab and gemcitabine for advanced pancreatic cancer: a phase Ib study. Oncologist. 2020;25 (5 ):2. doi:10.1634/theoncologist.2019-0473\n33. Fan JQ, Wang MF, Chen HL, Shang D, Das JK, Song J. Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma. Mol Cancer. 2020;19 (1 ):32. doi:10.1186/s12943-020-01151-3 32061257\n34. Henke E, Nandigama R, Ergün S. Extracellular matrix in the tumor microenvironment and its impact on cancer therapy. Front Mol Biosci. 2020;6 . doi:10.3389/fmolb.2019.00160.\n35. Stromnes IM, Hulbert A, Pierce RH, Greenberg PD, Hingorani SR. T-cell localization, activation, and clonal expansion in human pancreatic ductal adenocarcinoma. Cancer Immunol Res. 2017;5 (11 ):978–991. doi:10.1158/2326-6066.cir-16-0322 29066497\n36. Lal N, Beggs AD, Willcox BE, Middleton GW. An immunogenomic stratification of colorectal cancer: implications for development of targeted immunotherapy. OncoImmunology. 2015;4 (3 ):e976052. doi:10.4161/2162402x.2014.976052 25949894\n37. Gatalica Z, Snyder C, Maney T, et al. Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer Epidemiol Biomarkers Prev. 2014;23 (12 ):2965–2970. doi:10.1158/1055-9965.epi-14-0654 25392179\n38. Eso Y, Seno H. Current status of treatment with immune checkpoint inhibitors for gastrointestinal, hepatobiliary, and pancreatic cancers. Therap Adv Gastroenterol. 2020;13 :175628482094877. doi:10.1177/1756284820948773\n39. Gong J, Le TQ, Massarelli E, Hendifar AE, Tuli R. Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination. J Immunother Cancer. 2018;6 (1 ). doi:10.1186/s40425-018-0361-7\n40. Wang Y, Kim TH, Fouladdel S, et al. PD-L1 expression in circulating tumor cells increases during radio(chemo)therapy and indicates poor prognosis in non-small cell lung cancer. Sci Rep. 2019;9 (1 ). doi:10.1038/s41598-018-36096-7\n41. Azad A, Yin Lim S, D’Costa Z, et al. PD‐L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy. EMBO Mol Med. 2017;9 (2 ):167–180. doi:10.15252/emmm.201606674 27932443\n42. Cellini F, Arcelli A, Simoni N, et al. Basics and frontiers on pancreatic cancer for radiation oncology: target delineation, SBRT, SIB technique, MRgRT, particle therapy, immunotherapy and clinical guidelines. Cancers. 2020;12 (7 ):1729. doi:10.3390/cancers12071729\n43. Talimogene laherparepvec and radiation therapy in treating patients with newly diagnosed soft tissue sarcoma that can be removed by surgery; 2021. Available from: https://ClinicalTrials.gov/show/NCT02923778. Accessed 511, 2021.\n44. Duffy AG, Makarova-Rusher OV, Kleiner DE, et al. A pilot study of immune checkpoint inhibition in combination with radiation therapy in patients with metastatic pancreatic cancer. J Clin Oncol. 2017;35 (15_suppl ):e15786. doi:10.1200/JCO.2017.35.15_suppl.e15786\n45. Bar-Sagi D, Knelson EH, Sequist LV. A bright future for KRAS inhibitors. Nat Cancer. 2020;1 (1 ):25–27. doi:10.1038/s43018-019-0016-8\n46. Fakih M, Desai J, Kuboki Y, et al. CodeBreak 100: activity of AMG 510, a novel small molecule inhibitor of KRASG12C, in patients with advanced colorectal cancer. J Clin Oncol. 2020;38 (15_suppl ):4018. doi:10.1200/JCO.2020.38.15_suppl.4018\n47. Ward AB, Keeton AB, Chen X, et al. Enhancing anticancer activity of checkpoint immunotherapy by targeting RAS. MedComm. 2020;1 (2 ):121–128. doi:10.1002/mco2.10 33073260\n\n",
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"journal": "OncoTargets and therapy",
"keywords": "PD-L1; complete response; immune checkpoint inhibitor; locally advanced; pancreatic cancer; pembrolizumab",
"medline_ta": "Onco Targets Ther",
"mesh_terms": null,
"nlm_unique_id": "101514322",
"other_id": null,
"pages": "3537-3544",
"pmc": null,
"pmid": "34103944",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "25392179;31345627;32913444;28822576;32061257;29066497;32105518;29800971;24840647;31682550;32468956;30280641;27458307;32755482;29462005;33073260;31318392;31740568;29227344;27932443;30557521;32118030;30608598;29596120;27885876;32610592;31274655;25949894;30679441;20422030;22858559;31590988;30787022;26027431;20842054;27355262;29866197;32966993",
"title": "Near Complete Pathologic Response to PD-1 Inhibitor and Radiotherapy in a Patient with Locally Advanced Pancreatic Ductal Adenocarcinoma.",
"title_normalized": "near complete pathologic response to pd 1 inhibitor and radiotherapy in a patient with locally advanced pancreatic ductal adenocarcinoma"
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"abstract": "The diffuse sclerosing variant of papillary thyroid cancer (DSV-PTC) is a rare variant of papillary thyroid cancer (PTC) with different clinicopathological features compared with conventional PTC.\n\n\n\nAn advanced DSV-PTC was diagnosed in a 39-year-old man. The radioiodine posttherapeutic whole-body-scan showed only an uptake in the central neck, whereas the computerized tomography showed multiple latero-cervical and mediastinum lymph node metastases, a single and spiculated lung lesion and multiple bilateral cerebellum metastases. The patient died after 6 months from the initial diagnosis. The histological revision of the thyroid tumor confirmed the diagnosis of DSV-PTC, and its molecular analysis revealed a KIF5B/RET rearrangement that, until now, was described only in a minority of lung adenocarcinoma. Other 18 cases of DSV-PTC were then studied for the presence of KIF5B/RET rearrangement, but all of them were negative.\n\n\n\nThis was a case of DSV-PTC positive for KIF5B/RET rearrangement, but considering that this alteration has been described only in lung adenocarcinoma and that the clinical course was more typical of lung carcinoma, we cannot completely rule out the possibility that this was a metastatic lesion from a lung tumor mimicking a DSV-PTC. As an alternative, we can also hypothesize that this was a case of fusion of two tumoral tissues deriving from a DSV-PTC and a metastasis of a KIF5B/RET positive lung adenocarcinoma. The question of whether the molecular findings, particularly when specifically reported only in some subtypes of human tumors, can overcome the morphological diagnosis is a matter of discussion.",
"affiliations": "Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, 56124 Pisa, Italy.;Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, 56124 Pisa, Italy.;Diagnostic and Interventional Radiology, Department of Translational Research and New Technologies in Medicine and Surgery, University Hospital of Pisa, 56124 Pisa, Italy.;Pathology Unit, Department of Surgical, Medical, Molecular Pathology and Critical Area, University Hospital of Pisa, 56124 Pisa, Italy.;Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, 56124 Pisa, Italy.;Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, 56124 Pisa, Italy.;Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, 56124 Pisa, Italy.;Pathology Unit, Department of Surgical, Medical, Molecular Pathology and Critical Area, University Hospital of Pisa, 56124 Pisa, Italy.;Unit of Pneumology, University Hospital of Pisa, 56124 Pisa, Italy.;Pathology Unit, Department of Surgical, Medical, Molecular Pathology and Critical Area, University Hospital of Pisa, 56124 Pisa, Italy.;Pathology Unit, Department of Surgical, Medical, Molecular Pathology and Critical Area, University Hospital of Pisa, 56124 Pisa, Italy.;Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, 56124 Pisa, Italy.",
"authors": "Viola|David|D|;Giani|Carlotta|C|;Mazzeo|Salvatore|S|;Ugolini|Clara|C|;Ciampi|Raffaele|R|;Molinaro|Eleonora|E|;Agate|Laura|L|;Borrelli|Nicla|N|;Chella|Antonio|A|;Fontanini|Gabriella|G|;Basolo|Fulvio|F|;Elisei|Rossella|R|",
"chemical_list": "C488101:KIF5B protein, human; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D016547:Kinesins",
"country": "United States",
"delete": false,
"doi": "10.1210/jc.2017-00304",
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"issn_linking": "0021-972X",
"issue": "102(9)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": null,
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D000328:Adult; D001707:Biopsy, Needle; D002277:Carcinoma; D002291:Carcinoma, Papillary; D004252:DNA Mutational Analysis; D018450:Disease Progression; D017809:Fatal Outcome; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D006801:Humans; D007150:Immunohistochemistry; D016547:Kinesins; D008197:Lymph Node Excision; D008198:Lymph Nodes; D008297:Male; D009361:Neoplasm Invasiveness; D051096:Proto-Oncogene Proteins c-ret; D018714:Radiotherapy, Adjuvant; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms; D013965:Thyroidectomy",
"nlm_unique_id": "0375362",
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"pages": "3091-3096",
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"pmid": "28911147",
"pubdate": "2017-09-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "KIF5B/RET Rearrangement in a Carcinoma of the Thyroid Gland: A Case Report of a Fatal Disease.",
"title_normalized": "kif5b ret rearrangement in a carcinoma of the thyroid gland a case report of a fatal disease"
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"companynumb": "IT-CURIUM PHARMACEUTICALS-201700287",
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"abstract": "Calcium channel blockers (CCBs) are a commonly prescribed medication that, at toxic levels, are capable of causing severe refractory hypotension, hypoxic respiratory failure and cardiotoxicity. There is little evidence currently guiding the approach to managing CCB overdose, particularly when combined with other antihypertensive agents.\n\n\n\nWe describe the use of veno-venous extracorporeal membrane oxygenation (VV ECMO) in a previously healthy man following combined overdose with amlodipine and lisinopril in a suicide attempt. ECMO was used to provide oxygenation support, allowing for the amlodipine and lisinopril to be metabolized and cleared while also reducing ventilator-induced lung injury (VILI) and avoiding the complications associated with venous-arterial (VA) ECMO, such as differential hypoxemia.\n\n\n\nLimited case reports suggesting the use of ECMO in CCB overdose have employed VA ECMO due to CCB-induced cardiotoxicity. We believe that, if cardiac function has been preserved, VV ECMO should be considered a viable treatment strategy for CCB and ACE-I overdose resulting in refractory hypoxemic respiratory failure.",
"affiliations": "Department of Anesthesiology and Critical Care, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Department of Anesthesiology and Critical Care, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Department of Anesthesiology and Critical Care, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.;Department of Anesthesiology and Critical Care, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.",
"authors": "Haughey|Ryan|R|0000-0002-0782-8359;Vernick|William|W|;Gutsche|Jacob|J|;Laudanski|Krzysztof|K|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors; D002121:Calcium Channel Blockers",
"country": "England",
"delete": false,
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"issue": "34(2)",
"journal": "Perfusion",
"keywords": "amlodipine; calcium channel blocker; extracorporeal membrane oxygenation; overdose; toxicity",
"medline_ta": "Perfusion",
"mesh_terms": "D000806:Angiotensin-Converting Enzyme Inhibitors; D002121:Calcium Channel Blockers; D062787:Drug Overdose; D015199:Extracorporeal Membrane Oxygenation; D006801:Humans; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8700166",
"other_id": null,
"pages": "167-169",
"pmc": null,
"pmid": "30175658",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of veno-venous extracorporeal membrane oxygenation to treat severe combined calcium channel blocker and angiotensin converting enzyme inhibitor overdose.",
"title_normalized": "use of veno venous extracorporeal membrane oxygenation to treat severe combined calcium channel blocker and angiotensin converting enzyme inhibitor overdose"
} | [
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"activesubstancename": "LISINOPRIL"
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"abstract": "Checkpoint inhibitor immunotherapy has revolutionised cancer treatment since its inception. During an inflammatory response, activated cytotoxic T cells expressing programmed cell death protein 1 (PD-1) interact with programmed cell death-ligand 1 (PD-L1) on peripheral tissues to thwart an autoimmune reaction. Cancer cells upregulate PD-L1 expression to evade the immune system and are vulnerable to attack in the presence of PD-1 or PD-L1 checkpoint inhibitors. However, blockade of this pathway also contributes to the unintended side effect of autoimmune endocrinopathies. Atezolizumab, a checkpoint inhibitor against PD-L1, is associated with the rare complication of type 1 diabetes. We present a case of glutamic acid decarboxylase antibody-positive type 1 diabetes developing in a patient with a long-standing history of well-controlled type 2 diabetes following treatment with atezolizumab for metastatic renal cell carcinoma.",
"affiliations": "Department of Medicine, University of Maryland Baltimore, Baltimore, Maryland, USA.;Department of Medicine, University of Maryland Baltimore, Baltimore, Maryland, USA.;Department of Medicine, University of Maryland Baltimore, Baltimore, Maryland, USA ksilver@som.umaryland.edu.",
"authors": "Rahman|Wedad|W|;Conley|Anna|A|;Silver|Kristi D|KD|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D000082082:Immune Checkpoint Inhibitors; D061026:Programmed Cell Death 1 Receptor; C000594389:atezolizumab; D005968:Glutamate Decarboxylase",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-233842",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(7)",
"journal": "BMJ case reports",
"keywords": "chemotherapy; diabetes",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D002292:Carcinoma, Renal Cell; D003922:Diabetes Mellitus, Type 1; D003924:Diabetes Mellitus, Type 2; D005968:Glutamate Decarboxylase; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007167:Immunotherapy; D007680:Kidney Neoplasms; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32616532",
"pubdate": "2020-07-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Atezolizumab-induced type 1 diabetes mellitus in a patient with metastatic renal cell carcinoma.",
"title_normalized": "atezolizumab induced type 1 diabetes mellitus in a patient with metastatic renal cell carcinoma"
} | [
{
"companynumb": "US-TEVA-2020-US-1812720",
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"activesubstancename": "HYDROCORTISONE"
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"abstract": "The long-term effects of acetylcholinesterase inhibitors (AChEIs) used in the treatment of patients with various types of dementia remain unclear, largely due to challenges in the study of their discontinuation. We present several unexpected results from a discontinuation trial that might merit further investigation.\n\n\n\nThis double-blind, placebo-controlled study of the discontinuation of AChEI medications was conducted in 62 US veterans. Participants were randomized to receive continued treatment with their medication (sham-taper group) or to treatment discontinuation via tapering (real-taper group), over a period of 6 weeks. The primary end point was the patient's/family caregiver's decision to discontinue the study medication.\n\n\n\nThe study was underpowered to detect a significant between-group difference in the primary end point, but examination of the discontinuation process generated several unexpected results: (1) recruitment proved extremely challenging for a variety of reasons, with <5% of potentially eligible participants enrolled; (2) all 3 patients with Parkinson disease-associated dementia showed a worsening of symptoms when they discontinued their AChEI medication, but they showed improvement after they restarted it; (3) changes in symptom-scale scores varied quite broadly across participants, regardless of treatment arm; (4) unusual effects were noted in the sham-taper arm; and (5) the only significant predictor of the decision to discontinue the study medication was a worsening in the caregiver's mood.\n\n\n\nThese findings argue for the use of caution in discontinuing AChEIs in patients with Parkinson disease-associated dementia, although there may be potential benefits of a \"drug holiday.\" The findings also urge the consideration of distress on the part of the caregiver while making medication treatment decisions in dementia. Future research must address challenges with recruitment and symptom fluctuations.",
"affiliations": "Geriatric Research, Education, and Clinical Center, Veterans Affairs Bedford Healthcare System, Bedford, Massachusetts; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: lauren.moo@va.gov.;Puget Sound Veterans Affairs Medical Center, Seattle, Washington. Electronic address: erica.martinez@va.gov.;Geriatric Research, Education, and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas; University of Arkansas for Medical Sciences, Little Rock, Arkansas. Electronic address: kalpana.padala@va.gov.;Boise Veterans Affairs Medical Center, Boise, Idaho. Electronic address: megan.dunay@gmail.com.;The Department of Biomedical Sciences, Tufts University School of Medicine, Medford, Massachusetts. Electronic address: calir@bc.edu.;Puget Sound Veterans Affairs Medical Center, Seattle, Washington. Electronic address: sunny.chen@va.gov.;Puget Sound Veterans Affairs Medical Center, Seattle, Washington; The Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington. Electronic address: sthielke@u.washington.edu.",
"authors": "Moo|Lauren R|LR|;Martinez|Erica|E|;Padala|Kalpana|K|;Dunay|Megan A|MA|;Scali|Rachael R|RR|;Chen|Sunny|S|;Thielke|Stephen M|SM|",
"chemical_list": "D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clinthera.2021.05.010",
"fulltext": null,
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"issn_linking": "0149-2918",
"issue": "43(6)",
"journal": "Clinical therapeutics",
"keywords": "Acetylcholinesterase inhibitors; Parkinson disease; dementia; treatment discontinuation",
"medline_ta": "Clin Ther",
"mesh_terms": "D000110:Acetylcholinesterase; D002800:Cholinesterase Inhibitors; D004311:Double-Blind Method; D006801:Humans; D010300:Parkinson Disease",
"nlm_unique_id": "7706726",
"other_id": null,
"pages": "942-952",
"pmc": null,
"pmid": "34127273",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Unexpected Findings During Double-blind Discontinuation of Acetylcholinesterase Inhibitor Medications.",
"title_normalized": "unexpected findings during double blind discontinuation of acetylcholinesterase inhibitor medications"
} | [
{
"companynumb": "US-MYLANLABS-2022M1002268",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DONEPEZIL"
},
"drugadditional": "4",
... |
{
"abstract": "BACKGROUND\nCOVID-19 was a trending topic all year long in 2020. Currently, it is not only a problem for a pulmonologist since it could cause complications to many other organs, including the cardiovascular system. Recent acute COVID-19 infection state has been associated with hypercoagulation and causing microthrombi called immunothrombus. Acute limb ischemia is one of the rare complications but organ-threatening. Unfortunately, unlike coronary artery disease, there is no recent guideline for cardiologists to diagnose and manage acute limb ischemia in pandemic situations CASE PRESENTATION: This case series presented two patients with acute limb injury (ALI)-complicating COVID-19, with chief complaints of pain at their lower extremity. The first patient was an 80-year-old woman who was just dismissed from the hospital due to COVID-19. The distal part of her toe was cyanosed, and her motoric and sensory functions were partially reduced. She was treated with oral drug therapy due to unwillingness to be hospitalized. Interestingly, she had recovered by using oral drug therapy. The second case was a 54-years-old female with several comorbidities such as obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and chronic obstructive pulmonary disease. She had cyanosed foot and weak arterial pulsation. Unfortunately, she passed away due to acute respiratory distress syndrome.\n\n\nCONCLUSIONS\nSeveral internal and external factors cause ALI treatment to be more challenging in the pandemic COVID-19 situation. The diagnosis and management of ALI in COVID-19 patients may not fully comply with the current guideline and are likely to be affected by local hospital regulations. Clinical follow-up might be an essential feature in treating ALI in COVID-19 patients.",
"affiliations": "Primaya Hopsital Tangerang, Jl. MH. Thamrin no.3, Kebon Nanas, Cikokol, Tangerang, Indonesia. stevenphilip07@gmail.com.;Department of Cardiology and Vascular Medicine, Primaya Hospital Tangerang, Tangerang, Indonesia.",
"authors": "Surya|Steven Philip|SP|;Santoso|Rony Marethianto|RM|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1186/s43044-021-00187-0",
"fulltext": "\n==== Front\nEgypt Heart J\nEgypt Heart J\nThe Egyptian Heart Journal\n1110-2608\n2090-911X\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n34191222\n187\n10.1186/s43044-021-00187-0\nCase Report\nA clinical case series of COVID-19-associated acute limb ischemia: real-world situation\nSurya Steven Philip stevenphilip07@gmail.com\n\n1\nSantoso Rony Marethianto 2\n1 Primaya Hopsital Tangerang, Jl. MH. Thamrin no.3, Kebon Nanas, Cikokol, Tangerang, Indonesia\n2 Department of Cardiology and Vascular Medicine, Primaya Hospital Tangerang, Tangerang, Indonesia\n30 6 2021\n30 6 2021\n12 2021\n73 5919 3 2021\n5 6 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/.\nBackground\n\nCOVID-19 was a trending topic all year long in 2020. Currently, it is not only a problem for a pulmonologist since it could cause complications to many other organs, including the cardiovascular system. Recent acute COVID-19 infection state has been associated with hypercoagulation and causing microthrombi called immunothrombus. Acute limb ischemia is one of the rare complications but organ-threatening. Unfortunately, unlike coronary artery disease, there is no recent guideline for cardiologists to diagnose and manage acute limb ischemia in pandemic situations\n\nCase presentation\n\nThis case series presented two patients with acute limb injury (ALI)-complicating COVID-19, with chief complaints of pain at their lower extremity. The first patient was an 80-year-old woman who was just dismissed from the hospital due to COVID-19. The distal part of her toe was cyanosed, and her motoric and sensory functions were partially reduced. She was treated with oral drug therapy due to unwillingness to be hospitalized. Interestingly, she had recovered by using oral drug therapy. The second case was a 54-years-old female with several comorbidities such as obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and chronic obstructive pulmonary disease. She had cyanosed foot and weak arterial pulsation. Unfortunately, she passed away due to acute respiratory distress syndrome.\n\nConclusion\n\nSeveral internal and external factors cause ALI treatment to be more challenging in the pandemic COVID-19 situation. The diagnosis and management of ALI in COVID-19 patients may not fully comply with the current guideline and are likely to be affected by local hospital regulations. Clinical follow-up might be an essential feature in treating ALI in COVID-19 patients.\n\nKeywords\n\nCOVID-19\nAcute limb ischemia\nImmunothrombus\nCase report\nCOVID-19-associated coagulopathy\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nCoronavirus disease 2019 (COVID-19) has been a massive problem in our society and even more distressing for the medical community in 2020. World Health Organization (WHO) declared COVID-19 as a global disaster; moreover, the number of COVID-19 infected patients that we currently know might be an underestimation [1]. As one of the wide-spread infectious diseases, COVID-19 infection has a broad clinical spectrum from sub-clinical (only detected by laboratory test), mild symptoms (mostly outpatient), moderate symptoms (hospitalized non-intensive ward), severe symptoms (intensive ward), and unfortunately, death [2]. Initially, many clinicians believed COVID-19 was only associated with a respiratory infection; however, currently, we know that COVID-19 could affect other organ systems such as the cardiovascular system through angiotensin-converting enzyme 2 (ACE 2) and beyond [3, 4].\n\nThe correlation between COVID-19 and the cardiovascular system is widely known, but our understanding is much better in the heart organ than in blood vessels [5]. A case-control study between COVID-19 patient and control group showed that the case-group had a significantly higher number of lower-extremity arterial thrombus and increased risk of amputation [6]. A single-center study also discovered an escalation of acute limb ischemia cases in the first quarter of 2020 (COVID-19 pandemic) compared to the same period in 2019 [7]. Under normal circumstances, revascularization strategy, either endovascular or surgical techniques, might offer a better result in acute limb injury associated with arterial thrombus [8]. But in a real-world pandemic situation, the ideal situation might be harder to conduct due to internal and external reasons. Anticoagulant therapy might be the best decision that we can perform in the current pandemic situation [9]. This article addressed two patients with a chief complaint of pain in the lower extremity, later diagnosed with acute limb injury (ALI) in COVID-19 patients. The treatment described could be stood as a current recommendation.\n\nCase presentation\n\nCase 1\n\nAn 80-year-old woman presented with acute onset of devastating pain in the right lower extremity since a day ago. The severe aching sensation intensified within a few hours and reached its highest intensity (resting pain) in less than 24 h. There was no previous history of fever, dyspnea, myalgia, or even cough; however, she had just been discharged from the hospital due to confirmed COVID-19 pneumonia 1 week ago and was hospitalized for 15 days. Other than her old age, she only had stage I hypertension and dyslipidemia as her past medical history. She consumed candesartan 1 × 8 mg and multivitamins daily.\n\nHer vital signs in the initial examination were unremarkable (blood pressure 130/80 mmHg, heart rate 100 beats per minute/bpm, respiratory rate 20 times per minute, oxygen saturation 95% in room air). On general examination, we found cyanosed and cold right forefoot (Fig. 1). She had a slight difficulty moving (motoric) her toe and a slight numb (sensory) in her toe. Lower extremity palpation revealed weak pulsation at the posterior and dorsal pedis artery locations, but her popliteal artery was still palpable. Fig. 1 Right forefoot was cyanosed, and lower leg was cold, with reduced movement of toes\n\nOther than a mild decrease in hemoglobin (11.9 gr/dL) and mild leukocytosis, her routine blood examination was normal. The absolute lymphocyte count was 2200/uL. Her PCR test for COVID-19 was negative since last week, and her current immune-serology anti-IgM and IgG SARS-CoV-19 results were non-reactive. Chest X-ray showed normal cardio-thoracic-ratio/CTR and clear lung interstitial. However, Chest CT scan found multiple bilateral honeycomb appearances and ground-glass opacity (Fig. 2). Unfortunately, coagulation markers such as D-dimer PT/aPTT, CRP, and INR were not performed due to the patient’s refusal. Fig. 2 A CT scan of the patient’s chest showing multiple honeycomb appearance and ground-glass opacity (GGO)\n\nDoppler ultrasound examination showed normal flow velocity and spectrum in the common right femoral arteries (triphasic curve). Unfortunately, we found an occlusion and thrombus in the 1/3 proximal right popliteal artery with a minimum flow at the distal part of the posterior tibial and dorsalis pedis arteries. There were no clear signs of collaterals and no evidence of thrombus in the vein (deep vein thrombosis) (Fig. 3). Fig. 3 Normal flow velocity and spectrum in the common right femoral arteries (triphasic curve)\n\nBased on our examination, the patient was diagnosed with acute limb injury classification IIa. Unfortunately, the patient refused to be hospitalized because she was just discharged from the hospital due to COVID-19. We prescribed the patient with aspilet 80 mg, atorvastatin 20 mg, cilostazol 2 × 100 mg, pentoxifylline 2 × 400 mg, candesartan 8 mg, enoxaparin 2 × 0.4 mg subcutaneously, and analgetic drug. In her 1-month follow-up, there was remarkable progress in the clinical appearance. The toe edges appeared to be well-perfused, with complete relief from pain and minimal sign of ischemia. Functionally, she could walk actively with no claudication (Fig. 4). Fig. 4 Four-week follow-up. Clinically improving, but the toe was still cyanosed\n\nCase 2\n\nAnother 54-year-old female presented to our hospital with a chief complaint of high-continuous fever for 1 week. She also had shortness of breath (dyspnea) in the last 7 days and had gradually worsened. She had a productive cough and high-intensity pain in her right leg. At the initial examination, she already had laboratory results with positive PCR result for COVID-19 and a raised D-dimer and fibrinogen. Our patient had many comorbidities such as obesity, type 2 diabetes mellitus, stage 2 hypertension, dyslipidemia, and chronic obstructive pulmonary disease (COPD). She routinely consumed amlodipine 10 mg, ramipril 5 mg, atorvastatin 20 mg, metformin 3 × 500 mg, and TSA capsule for COPD. Her initial vital signs suggested that her condition was unstable with tachypnea, tachycardia, elevated blood pressure 140/90 mmHg, and hyperpyrexia. Her peripheral oxygen saturation was 88-90% with non-rebreathing mask 10 L/min. Physical examination revealed no rhonchi and wheezing, yet chest X-ray indicated bilateral peripheral chest infiltrates. In further examinations of her lower extremities, we found tenderness of the right lower foot, weak pulsation at the posterior tibial and dorsalis pedis arteries. Distal toes were found to be cyanosed (Fig. 5). Fig. 5 Weak pulse at posterior tibial and dorsalis pedis arteries. Cyanosed at toes\n\nRoutine blood count (erythrocyte, leukocyte, hematocrit, hemoglobin, platelets) was showing within normal limits. Urea and creatinine serum level also indicated normal kidney function. Blood glucose level was also within the normal limit. Conversely, her absolute lymphocyte count was low, and neutrophil-lymphocytes-ratio (NLR) was > 3. Coagulation markers, including (D-dimer) and prothrombin time (PT), and activated partial thromboplastin time (aPTT) were dramatically increased. C-reactive protein, one of the markers believed to be associated with the severity of COVID-19 infection, was rapidly increased.\n\nWe performed a Doppler ultrasound examination, which was challenging in a pandemic situation. The Doppler ultrasound result showed normal flow velocity and spectrum in the common right femoral arteries (triphasic curve). Nevertheless, we discovered a significant occlusion and thrombus in the distal right popliteal artery, minimal flow in the distal posterior tibial and dorsalis pedis arteries. There was no clear sign of collaterals flow and no evidence of thrombus at vein (deep vein thrombosis).\n\nThe patient was hospitalized in the isolation ward with a diagnosis of COVID-19 and acute limb ischemia. She consumed aspilet 80 mg, atorvastatin 20 mg, cilostazol 2 × 100 mg, pentoxifylline 2 × 400 mg, amlodipine 10 mg, and ramipril 5 mg. She was also treated with unfractionated heparin (UFH) IV drip with a target control of 1.5×−2× of aPTT. The patient was prepared for further interventional-thrombolytic therapy; unfortunately, her condition worsened into acute respiratory distress syndrome, and our team decided to go on conservative treatment. She was intubated and ventilated. Two weeks later, her condition deteriorated, and she fell into septic shock. The patient had eventually passed away.\n\nDiscussion\n\nAcute limb ischemia (ALI) is a condition of sudden oxygen supply disturbance to the lower extremity. It is a medical emergency related to the viability of the limbs. International consensus prefers Doppler ultrasound (DUS) as the first-line imaging method in lower-extremity arterial diseases (LEAD) and additional imaging with either computed-tomography angiography (CTA) or magnetic resonance angiography (MRA) to determine the optimal revascularization management. However, it does not seem reasonable during the COVID-19 pandemic [10]. Symptoms of ALI might vary, including, not limited to, pain and deterioration of limb function. Limb’s viability must be assessed right after ALI was suspected [11]. Several factors that might affect the clinical presentation of ALI are location and duration of the arterial occlusion, the presence of collateral circulation, and the metabolic changes due to tissue ischemia [12].\n\nA study from Dutch in early 2020 showed that around 31% of 184 critically ill COVID-19 patients admitted to Intensive Care Unit (ICU) had thrombotic complications (27% vein thrombotic and 3.7% arterial thrombotic) [13]. The condition known as COVID-associated coagulopathy (CAC), marked by elevated D-dimer level and the dysregulation of immune systems, is expected to play a central role in the complication of COVID-19 pneumonia patients [14]. In the acute infectious state, there is cross feedback between coagulation and the innate immune system, which develops thrombus called immunothrombus at the cellular level. Previous studies have shown that the pathogen-induced coagulation initially aimed to immobilize and kill the pathogen inside the clot [15]. Monocytes and neutrophils, the first responder of innate immune during an invasion, release an extracellular trap that promotes immunothrombosis right after exposure to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). On the other hand, some types of leukocytes also contribute to fibrinolysis and thrombus formation [16]. Besides infection problems, COVID-19 patients also become susceptible to thromboembolism because of several factors, including prolonged immobilization, hypoxia, diffuse intravascular coagulation (DIC), and use of central vein catheter (CVC) [13].\n\nAfter the virus gets to the respiratory epithelial cell through ACE2, the infected host cell will release DAMPs. Innate immune cells have pattern recognition receptors (PPR), which are essential in recognizing PAMPS and DAMPs, and eventually starting the inflammation cascade [17]. After the inflammatory pathway has been triggered, a pro-inflammatory cytokine, chemokine, and complement will be activated from the inactive form, which serves as the host response and resistance to the pathogen. At some point, over-recruitment of the pro-inflammatory cell, especially in the elderly, could cause damage to the host cell [18]. High pro-inflammatory cytokine, chemokine, and complement levels may trigger the thrombo-inflammatory process. This event has been clinically confirmed through chest computed tomography (Chest CT-Scan) or post-mortem autopsy examination [19, 20]. Viral pathogens, inflammatory cells, and mediators can induce tissue factor expression on monocytes and endothelial cell surfaces. The tissue factor acts as an activator of coagulation [21]. Moreover, inflammation causes imbalances between pro-coagulant and anti-coagulant states [22].\n\nIn case 1 and case 2, both patients were diagnosed with acute limb injury (ALI) with modified Rutherford classification grade IIA. In this situation, the limb organ viability was threatened but saveable if treated promptly [11]. The question is how fast and how ideal can we treat ALI patients in a pandemic situation? The American Heart Association (AHA) and American College of Cardiology (ACC) in Peripheral Artery Disease Guideline stated that prompt diagnosis and treatment must be performed to regain the skeletal muscle and other limbs organ’s function. Differentiation of a threatened and a nonviable limb is mandatory (the absence of arterial signal could indicate threatened limb, and the absence of both arterial and venous signals indicate irreversible condition) [11]. Ankle Brachial Index (ABI) can also be the simplest tool for predicting outcomes (ABI < 0.7 is considered critical) [12]. Despite other imaging modalities, such as DUS, MRA, and CTA, interventional angiography is the gold standard because it coincides with the necessary treatment [10–12, 23]. In the COVID-19 situation, imaging modalities might be challenging to perform due to hospital regulation, and patient transfers from the isolation ward might increase the risk of exposure to other patients. Additional cost for sterilization and protection gowns for the radiology staff might be costly.\n\nAccording to the guideline, grade IIA ALI should undergo an emergency revascularization procedure within 6 h after the diagnosis has been made [13]. Revascularization strategy might consist of either interventional thrombolysis or surgical thromboembolectomy. Based on the underlying pathological process, unfractionated heparin/UFH (5000IU or 70-100 IU/kg) intravenously alongside analgesia with daily monitoring of activated clotting time (ACT) or activated partial thromboplastin time (APTT) are the commonly used initial therapy. However, the randomized control trial regarding the effectiveness of UFH and comparing UFH with other anticoagulants is still limited [12]. The limitation of this article is that we did not know the medication for COVID-19 therapy.\n\nConclusion\n\nThe medical world has been under a catastrophic condition since pandemic COVID-19 in early 2020. Initially, COVID-19 was known to be associated with pneumonia. However, we learn later on that it causes concerning complications. As the number of COVID-19 patients increased, so did acute limb ischemia, especially in severely ill patients. ALI must be diagnosed and managed as soon as possible. Under normal circumstances, diagnosing and managing ALI might not be complicated; however, it is an entirely diverse situation in a pandemic. The challenging part might come from the patient due to refusal, hospital management related to isolation procedure, and sometimes from the clinician. Local hospital regulations might affect the diagnostic procedure and management of ALI during a pandemic. Multiple follow-ups with shorter intervals might be helpful while waiting for a recommendation for ALI in COVID-19 patients.\n\nAbbreviations\n\nCOVID-19 Coronavirus disease 2019\n\nWHO World Health Organization\n\nACE2 Angiotensin-converting enzyme 2\n\nCTR Cardio-thoracic-ratio\n\nCRP C-reactive protein\n\nINR International normalized ratio\n\nPT Prothrombin time\n\nAPTT Activated partial thromboplastin clotting time\n\nCOPD Chronic obstructive pulmonary disease\n\nALI Acute limb injury\n\nUFH Unfractionated heparin\n\nPAMPs Pathogen-associated molecular patterns\n\nDAMPs Damage-associated molecular patterns\n\nDIC Diffuse intravascular coagulation\n\nCVC Central vein catheter\n\nABI Ankle brachial index\n\nMRA Magnetic resonance angiography\n\nCTA Computed tomographic angiography\n\nACT Activated clotting time\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nSPS contributed in making the draft.\n\nRMS contributed in general idea, revision, and final approval.\n\nThe authors read and approved the final manuscript.\n\nFunding\n\nNone.\n\nAvailability of data and materials\n\nNot applicable.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThis study had been approved by ethics committee Primaya Hospital Tangerang, Dr. Adrian H.N., 20th December 2020. All subjects in the study had given consent to participate.\n\nConsent for publication\n\nAll the patients had given written informed consent for publication.\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. Reese H, Danielle Iuliano A, Patel NN, Grag S, Kim L, Silk BJ et al (2020) Estimated incidence of COVID-19 illness and hospitalization – United States, February – September, 2020. Clin Infect Dis ciaa1780\n2. Binns C Low WY Kyung LM The COVID-19 pandemic: public health and epidemiology Asia Pac J Public Health 2020 32 4 140 144 10.1177/1010539520929223 32429675\n3. Mokhtari T, Hassani F, Ghaffari N, Ebrahimi B, Yarahmadi A, Hassanzadeh G (2020) COVID-19 and multiorgan failure: a narrative review on potential mechanisms. J Mol Histol:1–16\n4. Laksono S Setianto B Surya SP Angiotensin converting enzyme 2 (ACE2), COVID-19, and cardiac injury: what cardiologist should know J Med Sci 2020 3 SI 105 110\n5. Nishiga M Wang DW Han Y Lewis DB WU JC. COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives Nat Rev Cardiol 2020 17 9 543 558 10.1038/s41569-020-0413-9 32690910\n6. Goldman IA Ye K Scheinfeld MH Lower-extremity arterial thrombosis associated with COVID-19 is characterized by greater thrombus burden and increased rate of amputation and death Radiology. 2020 297 2 E263 E269 10.1148/radiol.2020202348 32673190\n7. Bellosta R Luzzani L Natalini G Pegorer MA Attisani L Cossu LG Acute limb ischemia in patients with COVID-19 pneumonia J Vasc Surg 2020 72 6 1864 1872 10.1016/j.jvs.2020.04.483 32360679\n8. Olinic DM Stanek A Tataru DA Homorodean C Olinic M Acute limb ischemia: an update on diagnosis and management J Clin Med 2019 8 8 1215 10.3390/jcm8081215\n9. Gubitosa JC Xu P Ahmed A Pergament K COVID-19 associated acute limb ischemia in a patient on therapeutic anticoagulant Cureus. 2020 12 9 e10655 10.7759/cureus.10655 33133825\n10. Aboyans V Ricco JB Bartelink MEBL Bjorck M Brodmann M Cohnert T ESC Guidelines on the diagnosis and treatment of peripheral arterial disease, in collaboration with the European Society for Vascular Surgery (ESVS) Eur J Vasc Endovasc Surg 2017 2018 55 305 368\n11. Gerhard-Herman MD Gornik HL Barret C Barshes NR Corriere MA Crachman DE 2016 AHA/ACC Guideline on the management of patient with lower extremity peripheral artery disease: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines Circulation. 2017 135 12 e686 e725 10.1161/CIR.0000000000000470 27840332\n12. Bjorck M Earnshaw JJ Acosta S Goncalves FB Cochennec F Debus ES European Society for Vascular Surgery (ESVS) 2020 clinical practice guidelines on the management of acute limb ischemia Eur J Vasc Endovasc Surg 2020 59 2 173 218 10.1016/j.ejvs.2019.09.006 31899099\n13. Klok FA Kruip MJHA van der Meer NJM Arbous MS Gommers DAMPJ Kant KM Kaptein FHJ van Paassen J Stals MAM Huisman MV Endeman H Incidence of thrombotic complication in critically ill ICU patients with COVID-19 Thromb Res 2020 191 145 147 10.1016/j.thromres.2020.04.013 32291094\n14. Jayarangaiah A Kariyanna PT Chen X Jayarangaiah A Kumar A COVID-19-associated coagulopathy: an exacerbated immunothombosis response Clin Appl Thromb Hemost 2020 26 1076029620943293 10.1177/1076029620943293 32735131\n15. Loof TG Morgelin M Johansson L Oehmcke S Olin AI Dickneite G Coagulation, an ancestral serine protease cascade, exerts a novel function in early immune defense Blood. 2011 118 9 2589 2598 10.1182/blood-2011-02-337568 21613262\n16. Swystun LL Liaw PC The role of leucocytes in thrombosis Blood 2016 128 6 753 762 10.1182/blood-2016-05-718114 27354721\n17. Boroujeni AS, Sani MRM (2021) Anti-inflmmatory potential of quercetin in COVID-19 treatment. J Inflamm 18(3)\n18. Castejon GL Brough D Understanding the mechanism of IL-1ß secretion Cytokine Growth Factor Rev 2011 22 4 189 195 10.1016/j.cytogfr.2011.10.001 22019906\n19. Grillet F Behr J Calame P Aubry S Delabrousse E Acute pulmonary embolism associated with COVID-19 pneumonia detected with pulmonary CT-angiography Radiology. 2020 296 3 E186 E188 10.1148/radiol.2020201544 32324103\n20. Champbell CM Kahwash R Will complement inhibition be the new target in treating COVID-19 related systemic thrombosis? Circulation. 2020 141 22 1739 1741 10.1161/CIRCULATIONAHA.120.047419 32271624\n21. Goeijenbier M van Wissen M van de Weg C Jong E Gerdes VEA Miejers JCM Review: viral infections and mechanisms of thrombosis and bleeding J Med Virol 2012 84 10 1680 1696 10.1002/jmv.23354 22930518\n22. Esmon CT The interactions between inflammation and coagulation Br J Haematol 2005 131 4 417 430 10.1111/j.1365-2141.2005.05753.x 16281932\n23. Weiss CR Azene EM Majdalany BS AbuRahma AF Collins JD Francois CJ ACR appropriateness criteria sudden onset of cold, painful leg J Am Coll Radiol 2017 14 5S 2307 S313\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1110-2608",
"issue": "73(1)",
"journal": "The Egyptian heart journal : (EHJ) : official bulletin of the Egyptian Society of Cardiology",
"keywords": "Acute limb ischemia; COVID-19; COVID-19-associated coagulopathy; Case report; Immunothrombus",
"medline_ta": "Egypt Heart J",
"mesh_terms": null,
"nlm_unique_id": "9106952",
"other_id": null,
"pages": "59",
"pmc": null,
"pmid": "34191222",
"pubdate": "2021-06-30",
"publication_types": "D016428:Journal Article",
"references": "21613262;28473087;22019906;32673190;27840332;32360679;22930518;32291094;32735131;32271624;28851596;27354721;32324103;33509217;31899099;33237993;16281932;33133825;32429675;33011887;31416204;32690910",
"title": "A clinical case series of COVID-19-associated acute limb ischemia: real-world situation.",
"title_normalized": "a clinical case series of covid 19 associated acute limb ischemia real world situation"
} | [
{
"companynumb": "ID-BIOLOGICAL E. LTD-2121432",
"fulfillexpeditecriteria": "1",
"occurcountry": "ID",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "4",
... |
{
"abstract": "A young pregnant woman, G2P1L1, was admitted for safe confinement at 40 weeks of gestation with Takayasu arteritis. She was diagnosed with Takayasu arteritis in 2016 when she had polyarthritis, hypertension and asymmetrical peripheral pulses. Her CT angiogram showed involvement of branches of aortic arch and coeliac trunk. She had mild pulmonary hypertension and was classified as type V disease (P)+. She was started on immunosuppressant medication and achieved a fair control of symptoms and disease activity. She gave history of treatment for pulmonary tuberculosis for 6 months in 2016 after which she developed polyarthralgia. She is currently asymptomatic and had mild hypertension that was controlled. She was evaluated for evidence of aneurysms/thrombus/aortic insufficiency and taken up for elective caesarean in view of type V disease. Maternal and perinatal outcome was good and she was discharged on her regular medication as per immunology opinion.",
"affiliations": "Obstetrics and Gynaecology, JIPMER, Puducherry, Tamil Nadu, India dasaripapa@gmail.com.;Obstetrics and Gynaecology, JIPMER, Puducherry, Tamil Nadu, India.",
"authors": "Dasari|Papa|P|;Gummadi|Hima Swetha|HS|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-238014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(5)",
"journal": "BMJ case reports",
"keywords": "TB and other respiratory infections; cardiovascular medicine; hypertension; immunology; obstetrics and gynaecology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000792:Angiography; D001013:Aorta, Thoracic; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D011247:Pregnancy; D011256:Pregnancy Outcome; D013625:Takayasu Arteritis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34039540",
"pubdate": "2021-05-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pregnancy outcome in Takayasu arteritis.",
"title_normalized": "pregnancy outcome in takayasu arteritis"
} | [
{
"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2022-04146",
"fulfillexpeditecriteria": "2",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CALCIUM"
},
"drugadditional": ... |
{
"abstract": "Ponatinib (PON) is a key drug for patients with second tyrosine kinase inhibitor (TKI)-resistant/intolerant Philadelphia chromosome-positive leukemia (Ph+ leukemia); however, the occurrence of vascular adverse events (VAEs) in patients treated with PON should be carefully monitored. A retrospective analysis involving seven patients treated with PON was conducted to elucidate the incidence rate and risk factor for the development of VAEs. In the present study, risk assessment and monitoring of VAEs were performed using SCORE Risk Chart and Suita Score (10-year risk for fatal cardiovascular event), respectively. Despite the prophylactic use of aspirin, cerebral infarction and unstable angina occurred in two patients. By contrast, deep vein thrombosis did not improve in a patient treated with edoxaban. Our data suggest that patients with Ph+ leukemia possessing risk factors, medical history of lifestyle diseases, and administration of long-term second TKI treatment require careful monitoring of VAEs and therapeutic intervention to lifestyle diseases.",
"affiliations": "National Cancer Center Hospital East, Pharmaceutical Department.;National Cancer Center Hospital East, Department of Hematology and Oncology.;National Cancer Center Hospital East, Department of Hematology and Oncology.;National Cancer Center Hospital East, Department of Hematology and Oncology.;National Cancer Center Hospital East, Department of Hematology and Oncology.;National Cancer Center Hospital East, Department of Hematology and Oncology.",
"authors": "Sato|Nobue|N|;Yuda|Junichiro|J|;Yamauchi|Nobuhiko|N|;Miyamoto|Kenichi|K|;Kamihara|Yusuke|Y|;Minami|Yosuke|Y|",
"chemical_list": "D000970:Antineoplastic Agents; D007093:Imidazoles; D011724:Pyridazines; C545373:ponatinib",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.60.1623",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "60(12)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Cardiovascular event; Philadelphia chromosome-positive leukemia; Ponatinib",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000970:Antineoplastic Agents; D006801:Humans; D007093:Imidazoles; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D010677:Philadelphia Chromosome; D011724:Pyridazines; D012189:Retrospective Studies",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "1623-1629",
"pmc": null,
"pmid": "31902811",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Vascular adverse events of ponatinib during treatment of Philadelphia chromosome-positive leukemia: a retrospective single-institution analysis.",
"title_normalized": "vascular adverse events of ponatinib during treatment of philadelphia chromosome positive leukemia a retrospective single institution analysis"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-240194",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadd... |
{
"abstract": "BACKGROUND\nNon-HLA alloantibodies and autoantibodies are involved in allograft rejection in kidney and heart transplantation. Their role in intestinal transplantation has not yet been described. We examined the development of antiangiotensin II type I receptor antibodies (anti-AT1R) and antiendothelin type A receptor antibodies associated with the clinical course and histopathological findings of intestinal transplantation recipients.\n\n\nMETHODS\nThirty-seven patients underwent intestinal or multivisceral transplantation. Non-HLA antibodies (non-HLAabs) were screened in 29 transplant recipients. Antibody-levels greater than 12 U/L were considered positive and were evaluated retrospectively regarding rejection episodes.\n\n\nRESULTS\nTwenty patients developed anti-AT1R and/or antiendothelin type A receptor antibodies (non-HLAabs group), 9 did not (control group). The non-HLAabs group had a higher rate of allograft rejection than controls (80% vs 55%), especially a higher rate of antibody-mediated rejections (55% vs 11%, P < 0.01) with detection of donor-specific anti-HLAabs. All rejection episodes in the non-HLAabs group appeared around the time of positive non-HLAabs detection. Five patients had acute cellular rejections at the time of non-HLAabs development, 4 had viral infections.\n\n\nCONCLUSIONS\nOur data suggest that antibody-mediated mechanisms targeting antigens beyond HLA may trigger and accelerate immune responses. Given the possibility of pharmacologic targeting of non-HLA receptors, future studies will focus on the explanation of mechanisms how non-HLAabs may enhance rejection and affect long-term allograft survival.",
"affiliations": "1 Department of General, Visceral and Transplantation Surgery, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany. 2 Institute for Transfusion Medicine and HLA Typing Laboratory, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany. 3 Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany. 4 Department for Nephrology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany.",
"authors": "Gerlach|Undine Ariane|UA|;Lachmann|Nils|N|;Ranucci|Giuseppina|G|;Sawitzki|Birgit|B|;Schoenemann|Constanze|C|;Pratschke|Johann|J|;Dragun|Duska|D|;Pascher|Andreas|A|",
"chemical_list": "C544065:AGTR1 protein, human; D001323:Autoantibodies; D015415:Biomarkers; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D044140:Receptor, Angiotensin, Type 1; D044022:Receptor, Endothelin A",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0000000000001439",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "101(1)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D064591:Allografts; D001323:Autoantibodies; D015415:Biomarkers; D016022:Case-Control Studies; D005260:Female; D005858:Germany; D006084:Graft Rejection; D006801:Humans; D056724:Immunity, Humoral; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D007422:Intestines; D007518:Isoantibodies; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D044140:Receptor, Angiotensin, Type 1; D044022:Receptor, Endothelin A; D013997:Time Factors; D016896:Treatment Outcome; D014777:Virus Diseases; D014781:Viscera; D055815:Young Adult",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "141-149",
"pmc": null,
"pmid": "27495766",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Non-HLA Antibodies May Accelerate Immune Responses After Intestinal and Multivisceral Transplantation.",
"title_normalized": "non hla antibodies may accelerate immune responses after intestinal and multivisceral transplantation"
} | [
{
"companynumb": "PHHY2017DE001778",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drug... |
{
"abstract": "Patients with NHL and two or three factors of the International Prognostic Index (IPI) have a poor prognosis. We performed a prospective trial of intensive induction therapy followed with high-dose consolidation in such patients to determine the feasibility of this approach, as well as the response rate and survival. Untreated patients with aggressive lymphoma under the age of 60 with two or three adverse prognostic factors (disseminated stage, increased serum LDH, ECOG performance status >1) were prospectively included between June 1995 and April 1998 in a trial evaluating intensive induction chemotherapy with the ACE regimen (adriamycin day 1; cyclophosphamide days 1-2; etoposide days 1-3), with G-CSF support. Patients in complete remission after induction received one course of intensification with stem cell support (BEAM regimen), whereas patients in partial response received two intensifications (BEAM, then ICE regimens). Thirty-three patients (median age 38 years) were included. All patients presented WHO grade 4 leukopenia and 84% grade 3-4 thrombocytopenia during induction. There was one toxic death during induction. Twenty-nine patients proceeded to high-dose consolidation, including 12 patients who received a second high-dose treatment. The overall response rate was 88% (95% CI 76-99%), both after induction therapy and treatment completion. Thirty-nine percent of the patients had achieved complete remission after induction, and 73% after treatment completion. With a median follow-up after treatment onset of 29 months, the projected 3-year overall survival was 71% (95% CI 64-78%) and the event-free survival 58% (95% CI 50-66%). Event-free survival was significantly shorter in patients who did not achieve CR after induction therapy or after treatment completion. Early therapeutic intensification after intensive induction chemotherapy is feasible in patients with poor prognosis aggressive NHL and shows promising response and survival rates.",
"affiliations": "Service d'Hématologie, Centre Hospitalier Lyon Sud, Pierre Bénite, France.",
"authors": "Dumontet|C|C|;Thieblemont|C|C|;Espinouse|D|D|;Bouafia|F|F|;Hequet|O|O|;Salles|G|G|;Coiffier|B|B|",
"chemical_list": "D003561:Cytarabine; D005047:Etoposide; D008558:Melphalan; D002330:Carmustine",
"country": "England",
"delete": false,
"doi": "10.1038/sj.leu.2401955",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-6924",
"issue": "14(12)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002330:Carmustine; D003131:Combined Modality Therapy; D003561:Cytarabine; D018450:Disease Progression; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005047:Etoposide; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "2159-65",
"pmc": null,
"pmid": "11187906",
"pubdate": "2000-12",
"publication_types": "D016430:Clinical Trial; D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "A prospective study of intensive induction therapy with high-dose consolidation in patients with aggressive non-Hodgkin's lymphoma and two or three adverse prognostic factors.",
"title_normalized": "a prospective study of intensive induction therapy with high dose consolidation in patients with aggressive non hodgkin s lymphoma and two or three adverse prognostic factors"
} | [
{
"companynumb": "FR-PFIZER INC-2018146676",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "We describe the case of a patient with adenocarcinoma of the colon treated with FOLFOX-4 (5-Fluorouracil, Folinic acid, Oxalyplatin), with subsequent appearance of atypical hemolytic uremic syndrome (aHUS). From 1999 to 2009, 13 cases of atypical HUS receiving chemotherapy with oxaliplatin have been described, as well as some sporadic cases. None of these cases has been treated with eculizumab. This is the first report of a patient with aHUS secondary to Oxalyplatin treated with Eculizumab. This treatment induced a complete remission of the syndrome and, later on, it has been discontinued with clinical and laboratory permanent remission. We identified some genetic mutations in this patient that might have a pathogenic role in the determining aHUS when associated with exposure to Oxalyplatin. Oxalyplatin withdrawal and its replacement to Irinotecan allowed the patient to receive first line chemotherapy continuation (FOLFIRI) with the same life expectancy and the same symptoms free period.",
"affiliations": null,
"authors": "Zanchelli|Fulvia|F|;Tampieri|Elena|E|;Gozzetti|Francesco|F|;Monti|Mattia|M|;Martelli|Davide|D|;Graziani|Romina|R|;Zuffa|Eliana|E|;Vincenzi|Daniele|D|;Gamboni|Alessandro|A|;Buscaroli|Andrea|A|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; D011725:Pyridines; C431073:oxiplatin; C481642:eculizumab; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0393-5590",
"issue": "34(1)",
"journal": "Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia",
"keywords": null,
"medline_ta": "G Ital Nefrol",
"mesh_terms": "D000230:Adenocarcinoma; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D065766:Atypical Hemolytic Uremic Syndrome; D003110:Colonic Neoplasms; D005260:Female; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008875:Middle Aged; D009944:Organoplatinum Compounds; D011725:Pyridines; D012074:Remission Induction",
"nlm_unique_id": "9426434",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28177095",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Atypical hemolytic uremic syndrome related to Oxalyplatin Cancer Chemotherapy responsive to Eculizumab.",
"title_normalized": "atypical hemolytic uremic syndrome related to oxalyplatin cancer chemotherapy responsive to eculizumab"
} | [
{
"companynumb": "IT-PFIZER INC-2017075810",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CETUXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Carbamazepine is known to produce the side effect of euphoria. As such, it lends itself to being a drug of abuse, particularly in the adolescent population. This retrospective study evaluated carbamazepine abuse, treatment course, and associated morbidity in Chinese adolescents. The median dose of carbamazepine resulting in overdose was 2,000 mg (800-5,000). Patients were largely from urban-rural fringe areas (76.47%, 52.94%) with school performance within the last 1/3 range and (52.94%) unsupervised by parents. 35.29% experienced an obvious sense of euphoria. All patients had nervous system symptoms, 6 (35.29%) cases developed coma (GCS < 8), and 5 (29.41%) cases experienced convulsion. Four cases were treated with hemodialysis. The incidence rate in young patients with repeat carbamazepine use and without the supervision of parents was higher than that in first-time users (5/7 versus 4/10), but the difference was not significant. The toxic dose of repeat users was 3428 ± 1035 mg, significantly higher than that of 1470 ± 646 mg in first-time users (P = 0.001). Carbamazepine can produce a sense of euphoria, which is more likely to lead to its abuse and overdose in adolescents. To prevent carbamazepine abuse and overdose will be critical in educating at-risk adolescents and preventing associated morbidities in the future.",
"affiliations": "Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.;Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.",
"authors": "Xu|Wei|W|;Chen|Yu-Lin|YL|;Zhao|Ying|Y|;Wang|Li-Jie|LJ|;Li|Jiu-Jun|JJ|;Liu|Chun-Feng|CF|0000-0001-5360-616X",
"chemical_list": "D002220:Carbamazepine",
"country": "United States",
"delete": false,
"doi": "10.1155/2018/3201203",
"fulltext": "\n==== Front\nBiomed Res IntBiomed Res IntBMRIBioMed Research International2314-61332314-6141Hindawi 10.1155/2018/3201203Research ArticleA Clinical Study of Toxication Caused by Carbamazepine Abuse in Adolescents Xu Wei Chen Yu-Lin Zhao Ying Wang Li-Jie Li Jiu-Jun http://orcid.org/0000-0001-5360-616XLiu Chun-Feng zhliu258@hotmail.comDepartment of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, ChinaAcademic Editor: Ji-Fu Wei\n\n2018 22 3 2018 2018 32012036 10 2017 6 2 2018 Copyright © 2018 Wei Xu et al.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Carbamazepine is known to produce the side effect of euphoria. As such, it lends itself to being a drug of abuse, particularly in the adolescent population. This retrospective study evaluated carbamazepine abuse, treatment course, and associated morbidity in Chinese adolescents. The median dose of carbamazepine resulting in overdose was 2,000 mg (800–5,000). Patients were largely from urban-rural fringe areas (76.47%, 52.94%) with school performance within the last 1/3 range and (52.94%) unsupervised by parents. 35.29% experienced an obvious sense of euphoria. All patients had nervous system symptoms, 6 (35.29%) cases developed coma (GCS < 8), and 5 (29.41%) cases experienced convulsion. Four cases were treated with hemodialysis. The incidence rate in young patients with repeat carbamazepine use and without the supervision of parents was higher than that in first-time users (5/7 versus 4/10), but the difference was not significant. The toxic dose of repeat users was 3428 ± 1035 mg, significantly higher than that of 1470 ± 646 mg in first-time users (P = 0.001). Carbamazepine can produce a sense of euphoria, which is more likely to lead to its abuse and overdose in adolescents. To prevent carbamazepine abuse and overdose will be critical in educating at-risk adolescents and preventing associated morbidities in the future.\n\nNational Natural Science Foundation of China817716218127072681372039Natural Science Foundation of Liaoning Province20170541023\n==== Body\n1. Introduction\nCarbamazepine is often used for treatment of seizure disorders and neuropathic pain [1]. It is used off-label as a second-line treatment for bipolar disorder and in combination with an antipsychotic when treatment with a conventional antipsychotic alone has failed [2]. Carbamazepine, as a tricyclic drug, can produce a sensation of euphoria. This is generally noted as a side effect of long-term use, as seen in individual reports [3, 4]. However, experts have vigilantly pointed out in some case reports that its abuse potential may be brought about by the euphoric effect of the drug [4, 5].\n\nSubstance use in adolescents is an important public health concern. Previous research [5, 6] has identified adolescence as the peak period for initiation of substance use, an epidemic which imparts large health burdens in this age group. Substance use often progresses to abuse, and in adolescents this may involve tobacco, alcohol, and/or illicit drugs (e.g., cannabis, amphetamine-type stimulants, cocaine, opioids, and novel psychoactive substances or so-called legal highs). It is well accepted that tobacco and alcohol abuse occurs across all continents and countries to varying extents. While drug abuse is frequently reported in the countries of South Africa, America, and Northern Europe [5], there are few reports in other areas of the world, perhaps due to lack of data or relevant studies.\n\nSubstance use in Chinese adolescents is rarely reported. Moreover, little is known about carbamazepine use in adolescents who have progressed to abuse and/or overdose. Thus, the objective of the present study was to characterize patterns of carbamazepine use and resulting morbidities in a population of adolescents admitted to the pediatric intensive care unit of Shengjing Hospital of China Medical University. To our knowledge, this is the first such study of carbamazepine abuse and overdose. We analyzed and summarized social data along with clinical management of these patients and wish this study could attract the concerns about carbamazepine abuse from all social circles and provide some help for the clinical treatment of patients with carbamazepine toxication.\n\n1.1. Patients\nA retrospective review was conducted of all available adolescent patients admitted to the pediatric intensive care unit with carbamazepine overdose between January 2015 and July 2016 at Shengjing Hospital, China Medical University. This study was approved by the Medicine Ethics Committee of Shengjing Hospital of the China Medical University (2016PS288K). Clinical data were collected in a manner that maintained patient privacy; patient records and information were anonymized and deidentified prior to analysis.\n\nDiagnostic criteria [7] of toxication included (1) a history of carbamazepine use; (2) carbamazepine concentration in venous blood ≥ 12 μg/ml as tested after admission; (3) clinical findings of change of consciousness, altered mental status, or limb movement disorders; and/or (4) respiratory depression. There were no exclusion criteria.\n\n2. Methods\nWe ensure that our manuscript reporting adheres to the STROBE guidelines for the reporting of this observational study.\n\nBlood carbamazepine concentration was tested using the TDxFLx System (Abbott, USA) in the standard fashion. Within two hours after hospital admission, two ml of venous blood was collected from each patient. The test was completed within two hours after the serum was separated.\n\nA data collection form was used to obtain information from the patients' legal guardians including birth history, personal growth and development history, parent marital and economic status, guardian status, school location, school performance, and past medication history of patients. Patients were asked about their reason for carbamazepine use, feelings after use of the drug, and medication status of similar age neighborhood peers. Other clinical data were collected by medical staff.\n\nA database was established using Excel software (2007) with double entry of the following clinical data: age, gender, home address, course of disease, guardian status, history of substance use, concomitant medication, blood drug concentration, main laboratory tests, course of treatment, and prognosis.\n\n2.1. Statistical Analysis\nData analysis was conducted using the SPSS 13.0 software. Discrete variables were expressed as counts (percentages), and continuous variables were expressed as means ± standard deviation (SD). Differences in the demographic and clinical characteristics of patient groups were assessed using the chi-square test for categorical variables. Continuous variables were analyzed using Student's t-test; P ≤ 0.05 was considered statistically significant.\n\n3. Results\n3.1. Demographics\n\nTable 1 displays descriptive characteristics of the study. The patients (see supplementary Table S1) ranged in age from 12 to 14 years with the majority of individuals being female (58.82%) and from urban-rural fringe areas (82.35%). All patients were students of grades 6-7, with 52.94% (n = 9) having school performance at the 33rd percentile or less. In all, 52.94% (n = 9) patients were not supervised by their parents more than one year. Of these, five were living with their grandparents due to their parents being divorced (n = 3) or working in foreign areas (n = 2). Additionally lack of parental supervision was due to enrollment in boarding school (n = 3) and there was one case in which the patient's father was imprisoned and their mother was lost.\n\n3.2. Substance Use\nAll patients were admitted to the hospital for carbamazepine overdose. The median dose ingested was 2,000 mg (range 800–5,000 mg) with a drug dose ≤ 1,500 mg in 4 cases. The lowest carbamazepine blood level detected within six hours of admission was 15.34 μg/ml. The majority of patients (70.59%) had carbamazepine blood levels greater than 20 μg/ml (upper limit monitored in our hospital). All 17 cases were treated by a full gastric lavage within 1.5 hours after ingestion of carbamazepine. Self-reported reasons for carbamazepine use included being a “cool thing” associated with personal loyalty (41.18%), a funny thing (23.53%), a sense of euphoria after repeated use (23.53%), and lack of desire to attend school (11.76%). Of all patients, 41.18% used the medication two or more times. With regard to other factors of importance, 35.29% experienced a conscious sense of euphoria, 11.76% used methadone, 11.76% drank coca cola, 5.88% had a history of alcohol abuse, and 5.88% (n = 1) used methadone and drank coca cola. All patients had an average of 4 classmates (range 2–10 classmates) with carbamazepine abuse (dose: 200–1,500 mg).\n\n3.3. Clinical Manifestations\nClinical manifestations of carbamazepine overdose occurred 1.94 ± 1.14 hours after ingestion. The median time for hospital admission due to overdose was 6 hours (range 2–24 hours) after ingestion of carbamazepine. Frequently encountered clinical manifestations were dizziness and headache (100%), disequilibrium (88.24%), vomiting (76.47%), syncope (76.47%), and conscious disturbance (64.71%). All eleven patients found to have conscious disturbance underwent MRI examination. Five of these patients were found to have white matter edema and the remaining cases were unremarkable. Less frequent sequelae noted as a result of carbamazepine overdose included Glasgow Coma score (GCS) < 8 (35.29%), aspiration pneumonia (35.29%), convulsions (29.41%), coma and skin abrasion (23.53%), and coma and convulsion (11.76%). Paroxysmal hypopnea during coma occurred in four cases (23.53%) but there were no cases of respiratory failure. Fever was noted in 23.53% of patients, as well as urinary and fecal incontinence in 17.65% of patients. In addition, 35.29% had mild arrhythmias (sinus bradycardia (n = 3), sinus tachycardia (n = 1), and multiple premature ventricular contractions (n = 2)) but no circulatory dysfunction. At one hour after admission, 64.71% had leukocytosis > 10 × 109/L with a dominant elevation of neutrophils. Elevated blood glucose > 7 mmol/L was noted in 35.29% (n = 6) of the patient population. Four patients (23.53%) experienced mild hypokalemia and one (5.88%) experienced mild hyponatremia. Pathologic alterations in blood levels of C-reactive protein, procalcitonin, hemoglobin, platelets, creatinine, and aminotransferases were not found in any patients.\n\n3.4. Treatment and Prognosis\nAll 17 patients were treated with full gastric lavage within six hours of admission. Of the nine patients found to have coma (GCS < 8) or convulsion, four were treated with 2-3 cycles of hemodialysis. The remaining five cases did not receive such treatment due to personal reasons. There was no significant difference noted in the length of coma, number of convulsions, length of stay, or prognosis, in patients treated with hemodialysis when compared with those who did not undergo hemodialysis. Other treatment included catharsis, fluid replacement, and diuresis. All patients were discharged with full recovery.\n\n3.5. Carbamazepine Use Patterns\nAs is shown in Table 1, patients were divided into two groups: first-time carbamazepine users and repeat carbamazepine users; their demographic factors and clinical course were assessed within each group. There was no significant difference between these two groups with regard to gender, school performance in the 33rd percentile or less, concomitant medication, a sense of euphoria, GCS < 8, or convulsion. More frequent carbamazepine abuse was observed in patients without parental supervision more than one year (P ≈ 0.05). At the time of overdose, repeat carbamazepine users had higher toxic doses than first-time carbamazepine users, and this difference was significant (P = 0.01). There was no significant difference in the time to admission between the two groups.\n\n4. Discussion\nIn China, substance use in adolescents is frequently reported, and similarly to the majority of countries most of these reports focus on tobacco and alcohol [8, 9]. Alcohol abuse is markedly elevated [10] in Chinese left-behind children, as these children lack parental guardianship and are ultimately at risk for adverse behaviors and suicide [11]. In contrast to left-behind children, most Chinese teenagers living in urban areas are the only child in their families and due to strict family management are infrequently involved with substance abuse. Due to economic factors, adolescents residing in rural areas are less likely to experience drugs abuse when compared with those that reside in urban areas. At present, there is a paucity of literature specific to carbamazepine abuse and addiction. In this study, most patients with carbamazepine abuse were from urban-rural fringe areas and lacked parental supervision, thus permitting access to and abuse of drugs. Carbamazepine is a prescription drug that should not be easily accessed by adolescents. However, in some areas it can be conveniently bought from drugstores without certification or limitation to the quantity purchased. Clearly, such loose management opens the door to the potential for substance use and abuse.\n\nAlong with other national data about adolescent and teenage behavior, trends in risky behavior may be gleaned by surveillance through poison centers. With over 5,000 annual reports to the poison centers about intentional exposures on school property, school personnel, parents, and guardians must be cognizant of pharmaceutical and nonpharmaceutical substances used for abuse, misuse, or suicide [12]. This study describes demographics and use patterns of adolescents admitted for carbamazepine overdose. Importantly, none of the patients in this study had a history of suicidal ideation. A carbamazepine intoxication with suicide attempt is a relatively common clinical problem in adult, which could lead to death [13]. The mortality rate due to carbamazepine toxicity is around 13% [14]. Indeed, children in this study all showed an active attitude to life—their substance use was attributed to inadequate care or psychological immaturity without full recognition of the toxicity and side effects of drugs, as demonstrated by self-reported reasons for use of carbamazepine. Reasons for carbamazepine use were not liking to attend school in two patients and feeling that learning was boring or poor school performance in 13 patients. Thus, more care for these children was needed from the schools, the guardians, and the society to help them understand and enjoy learning, such that they had a productive school life. The study showed when children have a sense of euphoria after one dosing, they are more likely to take multiple doses. Based on the data in this study from first-time users, the incidence rate of euphoria was relatively low. However, the concomitant use of methadone or coca cola could overlap the central excitation effect of carbamazepine, thus facilitating the production of a sense of euphoria [15].\n\nChildren of 12 or 13 years of age are in a rapid stage of developing cognition and cannot accurately judge social phenomena; they are known to have strong curiosity and an urgent need to be accepted by the society. In this framework, their tendency toward substance use to attain happiness or to make more friends is understood. In other studies of drug abuse and overdose in adolescents, the guardianship of parents played a crucial role in behavior restriction, cognitive education, and psychological health [16, 17]. Of the repeat users in the present study (n = 7), five were without parental guardianship more than one year. Without question, this lack of guardianship was detrimental to their psychological heath and recognition of drug hazards, to the point where they believed such harmful freedom of action might provide them with a sense of safety. Our analysis showed that the percentage of children without parental guardianship was far higher than the demographic data in the local areas. Moreover, poor school performance was more outstanding in this age group, and the majority of children had school performance at the middle to low levels. This brings into question whether the education neglect of parents contributes to the occurrence of mental disorders or a low awareness of dangers in children.\n\nIn this study, patients generally presented with apparent clinical manifestations within one to two hours after ingestion, and then they were rapidly sent to the hospital by their classmates or teachers who had a wary awareness after finding the toxication symptoms. Different from suicidal poisoning or accidental poisoning, the major clinical manifestation of patients was the nervous system symptoms after timely gastric lavage and other effective treatment. Respiratory depression was seen in a single patient for whom mechanical ventilation-assisted respiration was not required. Arrhythmias were common and not malignant; severe arrhythmia and circulatory disorders were not observed. Six cases were diagnosed as aspiration pneumonitis. Of those, two cases presented with significant fever and cough productive of sputum. The remaining four cases presented with crackles in the lungs and had inflammatory changes in chest imaging. Therefore, aspiration pneumonitis could not be distinguished from pulmonary edema caused by carbamazepine toxicity as reported [18]. Chronic carbamazepine toxicity is noted by decrease in circulating leukocytes, while acute toxicity is related to a marked increase of leukocytes [19]. However, it is unclear whether the stress reaction or other mechanisms are involved. In the present study, no patients had pathologic levels of liver enzymes, myocardial enzymes, or serum creatinine, also differing from the clinical manifestations of toxicity in a study of 33 epileptic patients [20].\n\nHigh-dose carbamazepine abuse (up to 5,000 mg) was noted in this study but there were no deaths. In human beings, the lethal dose of carbamazepine is not clarified yet. According to the American Food and Drug Administration [21], four cases of death induced by carbamazepine overdose have been reported. Two cases were with adults at a dose of 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man died of pneumonia and hypoxic encephalopathy) and two cases were with children at 4 g (a 14-year-old girl died of a cardiac arrest) and 1.6 g (a 3-year-old girl died of aspiration pneumonia). The result of no death in our study might be because toxicity was found in a timely manner, and all patients were treated by an active, full gastric lavage and other measures to promote toxicant excretion within six hours after medication ingestion. As for blood purification treatment, plasmapheresis or hemodialysis was used in case reports [22, 23]. In this study, four patients were treated by plasmapheresis for severe coma or convulsion, but five patients refused blood purification treatment due to personal reasons. Clinically, there were no significant differences in the total treatment time and prognosis between these two groups. Therefore, whether blood purification is required in carbamazepine overdose needs to be further studied.\n\nOur study is the first report of carbamazepine abuse and addiction in Chinese adolescents. Carbamazepine abuse in Chinese adolescents older than 14 years is unknown yet as in China, the patients older than 14 years need to seek medical care in the adult departments. The mechanism of carbamazepine abuse should be further addressed as this was a limitation of the present study. Additionally, the relevant social, mental, educational, and euphoric factors should be deeply investigated. Moreover, an epidemiological study of carbamazepine abuse in adolescents is also needed. However, in a view of carbamazepine abuse, addiction, and overdose, the responses to substance use in adolescents will differ substantially depending on their age, stage of life, level of substance use, and their socioenvironmental context. In thinking about the responses to substance use in adolescents, one must first take into account the differences to the adult population that adolescents experience during this period of rapid growth and development. These include the rapid physiological development during puberty, which can affect cognitive reasoning, emotional regulation, and risk taking [6, 24]. To address this issue requires increased societal engagement, reasonable guardianship of parents, proper education from schools, and the advocacy of pediatricians. Of course, the identification and medical care capacity of toxicity resulting from substance use are the most fundamental guarantee for the life safety of the concerned children.\n\n5. Conclusion\nCarbamazepine can produce a sense of euphoria, which is more likely to lead to its abuse and toxicity in adolescents who are living in the urban-rural fringe areas, have poor school performance, and are not supervised by parents. The main manifestation of carbamazepine toxicity is the nervous system symptoms, and the prognosis is good after active treatment based on timely detection. Strengthening drug management and adding relevant education for adolescents are suggested. In fact, the pediatricians and government shall take bigger responsibilities for propaganda and education about the damage of carbamazepine and other drugs to child health and the prevention of substance use in children [25]. In China, there is a long way for such work: at present, pediatricians lack resources to devote themselves to the demographic studies and large-sized epidemiological surveys, and no sufficiently effective channels are available to publicize the damage and seriousness of substance use at a professional level.\n\nAcknowledgments\nThe National Natural Science Foundation of China (NSFC, 81771621, 81270726, and 81372039) supported this work. The Natural Science Foundation of Liaoning Province (no. 20170541023) also supported this work. The authors thank Dr. Ni Yang, Yujing Tong, Jian Rong, and Liang Pei as they had done a lot of work in managing all these patients and provided detailed medical records.\n\nData Availability\nMost raw data of this study has been showed in Table 1; some of them were hidden due to the privacy policy. If anyone needs the whole database they could have access to it through email of Dr. Wei Xu: tomxu.123@163.com. But most of the data are in Chinese.\n\nEthical Approval\nThis study was approved by the Medicine Ethics Committee of Shengjing Hospital of China Medical University (2016PS288K). Clinical data were collected in a manner that maintained patient privacy; patient records and information were anonymized and deidentified prior to analysis. All lab results were collected based on clinical needs.\n\nConsent\nAll legal guardians of patients involved in this study signed informed consent on paper for children or adolescents (≦18 years old).\n\nDisclosure\nThe funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this article.\n\nAuthors' Contributions\nWei Xu and Chun-Feng Liu have made substantial contributions to conception; Wei Xu designed and wrote the manuscript; Yu-Lin Chen, Ying Zhao, Li-Jie Wang, and Jiu-Jun Li collected the data; Li-Jie Wang and Jiu-Jun Li discussed and reviewed the manuscript. All authors read and approved the final manuscript.\n\nSupplementary Materials\nSupplementary Materials Supplemental Table 1: main characteristics of all 17 patients.\n\nClick here for additional data file.\n\n Table 1 Demographic factors and clinical course for first-time and repeat users of carbamazepine.\n\n \tFirst-time users (n = 10)\tRepeat users (n = 7)\t\nP\n\t\nGender (male, %)\t4 (40%)\t3 (42.86%)\t0.646\t\nSchool performance within the last 1/3 range (n, %)\t4 (40%)\t5 (71.43%)\t0.218\t\nNo supervision of parents (n, %)\t4 (40%)\t5 (71.43%)\t0.052\t\nConcomitant medication (n, %)\t2 (20%)\t3 (42.86%)\t0.314\t\nToxic dose (mean, mg)\t1470 ± 646\t3428 ± 1035\t0.001\t\nSense of euphoria (n, %)\t2 (20%)\t4 (57.14%)\t0.145\t\nTime to admission (mean, h)\t6.5 ± 4.19\t10.71 ± 9.63\t0.310\t\nGCS < 8 (n, %)\t3 (30%)\t3 (42.86%)\t0.484\t\nConvulsion (n, %)\t3 (30%)\t2 (28.57%)\t0.686\n==== Refs\n1 Alrashood S. T. Carbamazepine Profiles of Drug Substances, Excipients and Related Methodology 2016 41 133 321 2-s2.0-84959097844 10.1016/bs.podrm.2015.11.001 \n2 Ceron-Litvoc D. Soares B. G. Geddes J. Litvoc J. de Lima M. S. Comparison of carbamazepine and lithium in treatment of bipolar disorder: A systematic review of randomized controlled trials Journal of Psychopharmacology 2009 24 1 19 28 2-s2.0-60549114337 10.1002/hup.990 \n3 Hosseini S. H. Ahmadi A. Abuse potential of carbamazepine for euphorigenic effects Drug Research 2015 65 4 223 224 2-s2.0-84896550122 10.1055/s-0034-1370942 24668573 \n4 Sullivan G. Davis S. Is carbamazepine a potential drug of abuse? Journal of Psychopharmacology 1997 11 1 93 94 2-s2.0-0030909323 10.1177/026988119701100119 9097899 \n5 Degenhardt L. Stockings E. Patton G. Hall W. D. Lynskey M. 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Management of a severe carbamazepine overdose with continuous venovenous hemodiafiltration The American Journal of Emergency Medicine 2010 28 2 260 e2 2-s2.0-76249109894 10.1016/j.ajem.2009.06.013 \n24 Hall W. D. Patton G. Stockings E. Why young people's substance use matters for global health The Lancet Psychiatry 2016 3 3 265 279 2-s2.0-84959469817 10.1016/S2215-0366(16)00013-4 26905482 \n25 Ammerman S. Ryan S. Adelman W. P. The impact of marijuana policies on youth: Clinical, research, and legal update Pediatrics 2015 135 3 e769 e785 2-s2.0-84924310000 10.1542/peds.2014-4147 25624385\n\n",
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"mesh_terms": "D000293:Adolescent; D002220:Carbamazepine; D002648:Child; D003128:Coma; D062787:Drug Overdose; D005260:Female; D006801:Humans; D008297:Male; D006435:Renal Dialysis; D012131:Respiratory Insufficiency; D012189:Retrospective Studies; D012640:Seizures; D019966:Substance-Related Disorders",
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"title": "A Clinical Study of Toxication Caused by Carbamazepine Abuse in Adolescents.",
"title_normalized": "a clinical study of toxication caused by carbamazepine abuse in adolescents"
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"abstract": "Crizotinib is an efficacious and well-tolerated drug in the management of ALK-positive lung cancer. Crizotinib treatment, however, is rarely complicated by the occurrence of acute interstitial lung disease (ILD) that is often fatal. There is no treatment for this serious adverse event. We report a female non-small cell lung cancer patient who developed ILD after a few days of crizotinib therapy. She showed a significant improvement after a high dose of pulse corticosteroid therapy, both radiologically and clinically. Unfortunately, the patient subsequently developed an aspergillosis superinfection leading to death. Our experience suggests that high-dose steroid therapy may be efficacious in the management of a severe complication of crizotinib therapy. However, potent antifungal therapy should be considered to prevent the risk of severe aspergillosis.",
"affiliations": "Department of Medical Oncology, Centre Hospitalier, Montelimar, France.;Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology, Brescia, Italy.;Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology, Brescia, Italy.;Section of Anatomic Pathology, Oncology and Experimental Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.;Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology, Brescia, Italy.;Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology, Brescia, Italy.;Pneumology Unit, Spedali Civili Hospital, University of Brescia, Brescia, Italy.;Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology, Brescia, Italy.",
"authors": "Deiana|Laura|L|;Grisanti|Salvatore|S|;Ferrari|Vittorio|V|;Tironi|Andrea|A|;Brugnoli|Giulia|G|;Ferrari|Laura|L|;Bozzola|Giordano|G|;Berruti|Alfredo|A|",
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"doi": "10.1159/000381209",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000381209cro-0008-0169Published online: March, 2015Aspergillosis Superinfection as a Cause of Death of Crizotinib-Induced Interstitial Lung Disease Successfully Treated with High-Dose Corticosteroid Therapy Deiana Laura a*Grisanti Salvatore bFerrari Vittorio bTironi Andrea dBrugnoli Giulia bFerrari Laura bBozzola Giordano cBerruti Alfredo baDepartment of Medical Oncology, Centre Hospitalier, Montelimar, FrancebDepartment of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology, Brescia, ItalycPneumology Unit, Spedali Civili Hospital, University of Brescia, Brescia, ItalydSection of Anatomic Pathology, Oncology and Experimental Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy*Laura Deiana, Department of Medical Oncology, Centre Hospitalier, Quartier de Beausseret BP 249, F-26216 Montelimar (France), E-Mail lauradeiana@gmail.comJan-Apr 2015 18 3 2015 18 3 2015 8 1 169 173 Copyright © 2015 by S. Karger AG, Basel2015This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Crizotinib is an efficacious and well-tolerated drug in the management of ALK-positive lung cancer. Crizotinib treatment, however, is rarely complicated by the occurrence of acute interstitial lung disease (ILD) that is often fatal. There is no treatment for this serious adverse event. We report a female non-small cell lung cancer patient who developed ILD after a few days of crizotinib therapy. She showed a significant improvement after a high dose of pulse corticosteroid therapy, both radiologically and clinically. Unfortunately, the patient subsequently developed an aspergillosis superinfection leading to death. Our experience suggests that high-dose steroid therapy may be efficacious in the management of a severe complication of crizotinib therapy. However, potent antifungal therapy should be considered to prevent the risk of severe aspergillosis.\n\nKey Words\nCrizotinibNon-small cell lung cancerAcute interstitial lung disease\n==== Body\nCase Presentation\nCrizotinib is a tyrosine kinase inhibitor of ALK, c-MET and ROS1 currently approved as a second-line treatment for ALK-rearranged lung cancer in advanced non-small cell lung cancer [1].\n\nDespite its manageable toxic profile, crizotinib administration is rarely complicated by the occurrence of interstitial lung disease (ILD) that is often life threatening and for which there is no proven effective therapy.\n\nA 55-year-old female nonsmoker was diagnosed with lung adenocarcinoma with multiple metastases on pleura, chest wall, liver and brain. The patient received whole-brain radiation therapy followed by 6 chemotherapy cycles with pemetrexed and cisplatin. A CT scan revealed disease stabilization after 3 cycles and disease progression on liver after 6 cycles. Second-line chemotherapy with docetaxel was interrupted after 3 cycles due to inefficacy. Since fluorescence in situ hybridization analysis demonstrated the presence of an ALK rearrangement, the patient received oral crizotinib 250 mg twice daily. After a 10-day treatment, she developed severe dyspnea requiring hospitalization. On admission, no fever and no demonstrable infection was documented. Arterial blood gas determination showed PaO2 60 mm Hg, PaCo2 36 mm Hg and Ph 7.45. Hemochrome and routine chemistry were within normality. The high-resolution CT scan revealed the appearance of diffuse extensive bilateral ground-glass opacities involving both lungs (fig. 1a, b). Bronchoscopy with bronchoalveolar lavage was performed, and the bronchoalveolar lavage fluid was negative for infective etiology such as bacteria, fungal elements and acid-fast bacilli. Crizotinib treatment was discontinued, and a high-dose pulse corticosteroid therapy with desametasone 12 mg every 6 h was prescribed in association with an empirical antibiotic treatment with meropenem, ciprofloxacin, trimethoprim-sulfamethoxazole and fluconazole. Oxygen via mask at a high flow rate of 10 l/min was introduced. The patient obtained an immediate benefit with improvement of arterial blood gas parameters (PaO2 75 mm Hg without oxygen), and a CT scan after 2 weeks showed a partial remission of the disease (fig. 1c). After 3 days, however, a sudden worsening of the dyspnea and the clinical status was documented, leading to patient death 10 days later. Histological evaluation of autopsy lung tissue showed areas of interstitial organizing fibrosis, carcinomatous lymphangitis and, more importantly, fungal hyphae consistent with aspergillus spp. invading alveoli and vessels (fig. 2) with areas of ischemic necrosis (invasive aspergillosis). This diffuse mycosis was the presumed cause of the rapid patient deterioration and death.\n\nDiscussion\nCrizotinib is the inhibitor of combined ALK-EML4 c-Met and ROS1 [1, 2]. The inhibition of tumor growth is a key of drug-induced toxicity. From the ALK-EML4 results fusion protein that actives many different pathways including the Ras/Raf/MEK/ERK1/2 cell proliferation module, the JAK/STAT (janus-activated kinase/signal transducer and activator of transcription) cell survival pathway, the PI3K (phosphatidylinositol 3-kinase)/Akt (PKB) pathway and the PLC (phospholipase C) pathway. The Akt activated catalyzes the phosphorylation and activation of mTOR (mammalian target of rapamycin) [3]. Akt/mTOR can be involved in immunosuppressive processes, biomolecular pathways and signals that are crucial in the development of lung injury [4].\n\nInternational guidelines recommend the use of high-dose pulse corticosteroid therapy in the management of ILD [5, 6]. This case report suggests that this treatment, promptly administered, was also efficacious in ILD induced by crizotinib, probably by interrupting the inflammatory cascade before the occurrence of irreversible tissue injury. However, glucocorticoids have potent immunosupressive effects that might have been even potentiated by previous crizotinib treatment that inhibits the mTOR pathway [4].\n\nImmunosuppression favored the occurrence of fatal invasive aspergillosis. We believe that a more effective antifungal therapy than fluconazole, such as liposomal amphotericyn B, voriconazole or caspofungin, would have been more appropriate in the management of our patient [7].\n\nIn conclusion, ILD is a severe complication of crizotinib therapy that can be successfully managed by the early administration of high-dose pulse corticosteroid therapy. However, aggressive antifungal therapy should be concomitantly administered in order to prevent aspergillosis superinfection.\n\nFig. 1 a The tumor lesion before crizotinib administration was mainly necrotic with air-fluid level and had a diameter of about 41 mm, ilo-perihilar right. b After 10 days of crizotinib administration, a CT scan of the chest showed extensive bilateral ground-glass opacities throughout both lungs and a further increase in the solid lesion (excavated), which measured about 60 mm. c After treatment with corticosteroid, a reduction of the ground-glass component occurred bilaterally, while the lesion in the right lower lobe appeared essentially unchanged in morphology and size.\n\nFig. 2 Diffuse invasive aspergillosis observed in autopsy lung tissue (HE ×400).\n==== Refs\nReferences\n1 Shaw AT Ou S-HI Bang Y-J Crizotinib in ROS1 -rearranged non-small-cell lung cancer N Engl J Med 2014 371 1963 1971 25264305 \n2 Shaw AT Kim D-W Nakagawa K Seto T Crinó L Crizotinib versus chemotherapy in advanced ALK-positive lung cancer N Engl J Med 2013 368 2385 2394 23724913 \n3 Roskoski R Jr Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition Pharmacol Res 2013 68 68 94 23201355 \n4 Aparicio G Calvo MB Medina V Comprehensive lung injury pathology induced by mTOR inhibitors Clin Transl Oncol 2009 11 499 510 19661024 \n5 Mukhopadhyay S Parambil JG Acute interstitial pneumonia (AIP): relationship to Hamman-Rich syndrome, diffuse alveolar damage (DAD), and acute respiratory distress syndrome (ARDS) Semin Respir Crit Care Med 2012 33 476 485 23001802 \n6 Rhen T Cidlowski JA Antiinflammatory action of glucocorticoids – new mechanisms for old drugs N Engl J Med 2005 353 1711 1723 16236742 \n7 Maschmeyer G Beinert T Buchheidt D Review Diagnosis and antimicrobial therapy of lung infiltrates in febrile neutropenic patients: guidelines of the infectious diseases working party of the German Society of Haematology and Oncology Eur J Cancer 2009 45 2462 2472 19467584\n\n",
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"issue": "8(1)",
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"keywords": "Acute interstitial lung disease; Crizotinib; Non-small cell lung cancer",
"medline_ta": "Case Rep Oncol",
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"pages": "169-73",
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"title": "Aspergillosis superinfection as a cause of death of crizotinib-induced interstitial lung disease successfully treated with high-dose corticosteroid therapy.",
"title_normalized": "aspergillosis superinfection as a cause of death of crizotinib induced interstitial lung disease successfully treated with high dose corticosteroid therapy"
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"abstract": "BACKGROUND\nA previous phase II trial in patients with chemorefractory metastatic colorectal cancer demonstrated a 63 % disease control rate with a combination of bevacizumab and sorafenib. This phase I trial sought to determine the maximum tolerable dose (MTD) of bevacizumab and sorafenib combined with standard cytotoxic therapy for advanced gastrointestinal (GI) cancers.\n\n\nMETHODS\nA standard 3 + 3 trial design utilized 3 escalating sorafenib dose levels: (1) 200 mg daily, days 3-7, 10-14; (2) 200 mg twice daily, days 3-6, 10-13; and (3) 200 mg twice daily, days 3-7, 10-14 combined with standard dose FOLFIRI (5-fluouracil, leucovorin, and irinotecan) and bevacizumab (5 mg/kg), repeated every 14 days.\n\n\nRESULTS\nFifteen patients were evaluable for safety and response assessment. There were no dose limiting toxicities (DLTs) at dose level 1 or 2. At dose level 3, two patients experienced DLTs (asymptomatic grade 3 hypophosphatemia, grade 3 dehydration and diarrhea). The MTD was determined to be dose level 2: sorafenib 200 mg twice daily, days 3-6, 10-13 combined with FOLFIRI and bevacizumab at standard doses. Four patients had a partial response and 8 had stable disease as best response (disease control rate of 80 %). Three patients with CRC had disease control >12 months.\n\n\nCONCLUSIONS\nThe MTD of this regimen is sorafenib 200 mg twice daily, days 3-6, 10-13 combined with standard doses of FOLFIRI and bevacizumab. Dual antiangiogenic treatment combined with cytotoxic therapy may provide prolonged disease stabilization for select patients with advanced GI malignancies.",
"affiliations": "Mayo Clinic Rochester, 200 First Street, SW, Rochester, MN, 55905, USA. hubbard.joleen@mayo.edu.;University of Florida Health Oncology, Jacksonville, FL, USA.;Mayo Clinic Scottsdale, Scottsdale, AZ, USA.;Mayo Clinic Jacksonville, Jacksonville, FL, USA.;Regeneron Pharmaceuticals, Basking Ridge, NJ, USA.;Mayo Clinic Rochester, 200 First Street, SW, Rochester, MN, 55905, USA.;Mayo Clinic Rochester, 200 First Street, SW, Rochester, MN, 55905, USA.;Investigational Drug Branch of the Cancer Therapy Evaluation Program, Bethesda, MD, USA.;Mayo Clinic Rochester, 200 First Street, SW, Rochester, MN, 55905, USA.;Mayo Clinic Rochester, 200 First Street, SW, Rochester, MN, 55905, USA.",
"authors": "Hubbard|Joleen M|JM|;Kim|George|G|;Borad|Mitesh J|MJ|;Johnson|Elizabeth|E|;Qin|Rui|R|;Lensing|Janet|J|;Puttabasavaiah|Suneetha|S|;Wright|John|J|;Erlichman|Charles|C|;Grothey|Axel|A|",
"chemical_list": "D010671:Phenylurea Compounds; D009536:Niacinamide; D000068258:Bevacizumab; D000077157:Sorafenib; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "United States",
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"journal": "Investigational new drugs",
"keywords": "Antiangiogenesis; Colorectal cancer; Systemic therapy",
"medline_ta": "Invest New Drugs",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002166:Camptothecin; D005260:Female; D005472:Fluorouracil; D005770:Gastrointestinal Neoplasms; D006801:Humans; D002955:Leucovorin; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009536:Niacinamide; D010671:Phenylurea Compounds; D000077157:Sorafenib; D016896:Treatment Outcome",
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"pmid": "26581401",
"pubdate": "2016-02",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "11006366;15175435;9041202;9458091;15870716;16226705;16133532;17442997;17699864;18669456;18927275;18946061;19097774;20008624;22949147;23168366;23812905;24012098;24639052;25877855",
"title": "Phase I trial of FOLFIRI in combination with sorafenib and bevacizumab in patients with advanced gastrointestinal malignancies.",
"title_normalized": "phase i trial of folfiri in combination with sorafenib and bevacizumab in patients with advanced gastrointestinal malignancies"
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"abstract": "OBJECTIVE\nWhile decreased ocular blood flow is thought to be a possible contributor to glaucoma pathogenesis, it is unclear what role systemic phosphodiesterase inhibitors (PDEi) play. We performed a cross-sectional study of a nationally representative sample of the U.S. population to investigate the relationship between the most commonly used PDEi, sildenafil and theophylline, and self-reported glaucoma.\n\n\nMETHODS\nWe used the National Health and Nutrition Examination Survey 2005-2008 cycles for this observational study. 7,042 participants, aged 40 years and over, responded to a survey item on glaucoma status and were included in the analysis. Multivariable logistic regression models were constructed to evaluate the association between at least 1 year of self-reported PDEi use and prevalent glaucoma. Regressions were adjusted for potential confounding variables, including demographics, socioeconomic status, and general health conditions, and accounted for the complex design of the survey. Sample weights were constructed and used to ensure the generalizability of results.\n\n\nRESULTS\n482 respondents self-reported a diagnosis of glaucoma, of which 11 used sildenafil and 20 used theophylline for at least 1 year. Covariates significantly associated with higher odds of glaucoma prevalence in univariable analyses included older age, black race, former smoking status, diabetes, hyperlipidemia, myocardial infarction, and stroke. Conversely, higher education and income were significantly associated with lower odds of glaucoma prevalence. In regression analyses adjusted for demographic and socioeconomic variables, sildenafil (OR = 4.90, CI: 1.24-19.27, p = 0.025) and theophylline (OR = 3.15, CI: 1.46-6.80, p = 0.005) were significantly associated with higher odds of self-reported glaucoma. These associations held after further adjustment with general health behaviors and conditions for both sildenafil and theophylline.\n\n\nCONCLUSIONS\nUse of sildenafil and theophylline for one or more years was associated with greater prevalence of self-reported glaucoma, a finding which requires further prospective study to assess causality and possible mechanisms of action.",
"affiliations": "Department of Ophthalmology, Stanford University School of Medicine, Stanford, California, United States of America.;Department of Ophthalmology, Stanford University School of Medicine, Stanford, California, United States of America.;Department of Ophthalmology, University of California San Francisco, San Francisco, California, United States of America.",
"authors": "Chen|Stephanie P|SP|;Singh|Kuldev|K|;Lin|Shan C|SC|http://orcid.org/0000-0003-3703-8304",
"chemical_list": "D010726:Phosphodiesterase Inhibitors; D000068677:Sildenafil Citrate; D013806:Theophylline",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0183388",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0183388PONE-D-17-11121Research ArticleMedicine and Health SciencesOphthalmologyEye DiseasesGlaucomaMedicine and Health SciencesHealth CareSocioeconomic Aspects of HealthMedicine and Health SciencesPublic and Occupational HealthSocioeconomic Aspects of HealthPeople and PlacesDemographyMedicine and Health SciencesCardiologyMyocardial InfarctionMedicine and Health SciencesEndocrinologyEndocrine DisordersDiabetes MellitusMedicine and Health SciencesMetabolic DisordersDiabetes MellitusBiology and Life SciencesAnatomyHeadEyesMedicine and Health SciencesAnatomyHeadEyesBiology and Life SciencesAnatomyOcular SystemEyesMedicine and Health SciencesAnatomyOcular SystemEyesBiology and Life SciencesAnatomyBody FluidsBloodBlood FlowMedicine and Health SciencesAnatomyBody FluidsBloodBlood FlowBiology and Life SciencesPhysiologyBody FluidsBloodBlood FlowMedicine and Health SciencesPhysiologyBody FluidsBloodBlood FlowMedicine and Health SciencesDiagnostic MedicineSigns and SymptomsHyperlipidemiaMedicine and Health SciencesPathology and Laboratory MedicineSigns and SymptomsHyperlipidemiaUse of phosphodiesterase inhibitors and prevalence of self-reported glaucoma in the United States Glaucoma and phosphodiesterase inhibitorsChen Stephanie P. ConceptualizationData curationFormal analysisFunding acquisitionInvestigationMethodologyValidationVisualizationWriting – original draftWriting – review & editing1Singh Kuldev ConceptualizationSupervisionWriting – review & editing1http://orcid.org/0000-0003-3703-8304Lin Shan C. ConceptualizationFunding acquisitionMethodologySupervisionValidationVisualizationWriting – review & editing2*1 \nDepartment of Ophthalmology, Stanford University School of Medicine, Stanford, California, United States of America2 \nDepartment of Ophthalmology, University of California San Francisco, San Francisco, California, United States of AmericaBhattacharya Sanjoy EditorBascom Palmer Eye Institute, UNITED STATESCompeting Interests: SL is a consultant for Allergan, Aerie Pharmaceuticals, Aleyegn, and Iridex, and funding from That Man May See, Inc., a non-profit organization. KS is a consultant for Alcon and Allergan. SC has declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials.\n\n* E-mail: shan.lin@ucsf.edu17 8 2017 2017 12 8 e018338821 3 2017 28 7 2017 © 2017 Chen et al2017Chen et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Objective\nWhile decreased ocular blood flow is thought to be a possible contributor to glaucoma pathogenesis, it is unclear what role systemic phosphodiesterase inhibitors (PDEi) play. We performed a cross-sectional study of a nationally representative sample of the U.S. population to investigate the relationship between the most commonly used PDEi, sildenafil and theophylline, and self-reported glaucoma.\n\nMethods\nWe used the National Health and Nutrition Examination Survey 2005–2008 cycles for this observational study. 7,042 participants, aged 40 years and over, responded to a survey item on glaucoma status and were included in the analysis. Multivariable logistic regression models were constructed to evaluate the association between at least 1 year of self-reported PDEi use and prevalent glaucoma. Regressions were adjusted for potential confounding variables, including demographics, socioeconomic status, and general health conditions, and accounted for the complex design of the survey. Sample weights were constructed and used to ensure the generalizability of results.\n\nResults\n482 respondents self-reported a diagnosis of glaucoma, of which 11 used sildenafil and 20 used theophylline for at least 1 year. Covariates significantly associated with higher odds of glaucoma prevalence in univariable analyses included older age, black race, former smoking status, diabetes, hyperlipidemia, myocardial infarction, and stroke. Conversely, higher education and income were significantly associated with lower odds of glaucoma prevalence. In regression analyses adjusted for demographic and socioeconomic variables, sildenafil (OR = 4.90, CI: 1.24–19.27, p = 0.025) and theophylline (OR = 3.15, CI: 1.46–6.80, p = 0.005) were significantly associated with higher odds of self-reported glaucoma. These associations held after further adjustment with general health behaviors and conditions for both sildenafil and theophylline.\n\nConclusions\nUse of sildenafil and theophylline for one or more years was associated with greater prevalence of self-reported glaucoma, a finding which requires further prospective study to assess causality and possible mechanisms of action.\n\nhttp://dx.doi.org/10.13039/100006521Stanford University School of MedicineMedScholars FundChen Stephanie P. http://dx.doi.org/10.13039/100001818Research to Prevent BlindnessCore Granthttp://orcid.org/0000-0003-3703-8304Lin Shan C. http://dx.doi.org/10.13039/100000053National Eye InstituteP30http://orcid.org/0000-0003-3703-8304Lin Shan C. That Man May See, Inc.http://orcid.org/0000-0003-3703-8304Lin Shan C. This study is supported by funding from the Stanford University School of Medicine MedScholars Fund to SC (med.stanford.edu), the Research to Prevent Blindness core grant to SL (www.rpbusa.org), the National Eye Institute P30 grant to SL (nei.nih.gov), and from That Man May See, Inc. to SL (thatmanmaysee.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilitySource data are publicly available from the National Center for Health Statistics section for the National Health and Nutrition Examination Survey, cycles 2005-2008 (wwwn.cdc.gov/nchs/nhanes/default.aspx).Data Availability\nSource data are publicly available from the National Center for Health Statistics section for the National Health and Nutrition Examination Survey, cycles 2005-2008 (wwwn.cdc.gov/nchs/nhanes/default.aspx).\n==== Body\nIntroduction\nGlaucoma is a degenerative optic neuropathy and remains one of the leading causes of blindness in the United States and worldwide. At the beginning of the decade, prevalence of glaucoma in the United States was over 2 million, with numbers projected to increase to over 3 million by 2020 largely due to the aging population [1]. Estimates of the global prevalence of glaucoma were placed at over 57 million individuals in 2015, with 2020 estimates forecasted to rise over 65 million and 2040 estimates over 111 million [2,3]. Though primary open angle glaucoma (POAG) is the most common type of glaucoma, the exact mechanism of disease is still unclear. Damage to the retinal ganglion cell axons that comprise the optic nerve head is caused by a multitude of factors, most important among them elevated intraocular pressure (IOP), also the only known modifiable risk factor in glaucoma [4]. Hence, pharmaceutical and surgical therapies for glaucoma have exclusively targeted control of IOP, with variable success.\n\nMore recently, studies have demonstrated an association between altered, compromised ocular circulation and glaucoma, including a reduction in blood flow and subsequent oxidative stress around the optic nerve head in both POAG and normal tension glaucoma [5–8]. Systemic vasodilators, including some phosphodiesterase inhibitors (PDEi) have wide-ranging therapeutic purposes but may occasionally have unintentional consequences on vision. For instance, phosphodiesterase type 5 inhibitors (PDE5i), well known for applications in erectile dysfunction, can evoke transient visual changes in color perception and light sensitivity due to interference in retinal ganglion cell signaling [9,10].\n\nSildenafil is a PDE5i that is approved for use in the treatment of erectile disorder. Very rarely, there have been case reports of vision-threatening events after sildenafil use. These include non-arteritic ischemic optic neuropathy, angle-closure glaucoma, and optic atrophy [11,12]. Yet, because of sildenafil’s vasodilating actions, it is also conceivable that it can increase optic nerve blood flow and prevent or delay the development of glaucoma. Results have been mixed regarding the effects of sildenafil on ocular hemodynamics, with some studies showing increases in retrobulbar and choroidal blood flow while others have not [13–15]. Furthermore, it appears that acute sildenafil use has no effect on IOP and evidence is lacking for a role in the development and progression of glaucoma [14,16,17].\n\nTheophylline, historically used as a bronchodilator to treat asthma and COPD, is not known to be associated with ocular side effects or any impact on glaucoma pathogenesis. Nevertheless, it is a non-selective PDEi and a xanthine derivative chemically similar to caffeine, which has been postulated to be associated with increased IOP in glaucoma patients [18–20].\n\nIn this study, we sought to investigate the association between PDEi use and prevalent glaucoma in a larger population sample using self-reported data from the National Health and Nutrition Examination Survey (NHANES). NHANES is an annual, nation-wide survey conducted by the National Center for Health Statistics (NCHS) as part of the Center for Disease Control and Prevention. Data is collected from the civilian, non-institutionalized population in the U.S. on health and nutrition. While glaucoma status defined by self-report has been viewed with some skepticism in the literature, we found the wealth of data available in NHANES uniquely suited to explore our hypothesis that use of PDEi medications is associated with lower odds of prevalent glaucoma in the United States.\n\nMethods\nStudy sample\nWe performed a population-based study of a representative sample of American adults surveyed in the NHANES 2005–2008 cycles. Participants are selected through a complex procedure involving multistage probability sampling, with oversampling of certain subgroups. In the 2005–2006 cycle, over-samples include low-income persons, adolescents 12–19 years, person 60+ years of age, African Americans, and Mexican Americans [21]. In 2007–2008, NHANES oversampled the Hispanic population, and participants 40+ years of age saw an increase in numbers whereas 12–19 year-olds saw a decrease [22]. Sample weights are available to provide adjusted, unbiased data generalizable to the entire U.S. population.\n\nMeasures\nGlaucoma status was the primary outcome measure in the analysis. 7,081 participants in the 2005–2008 cycles were aged 40 years and over and eligible for additional questions on eye diseases in the vision portion of the NHANES interview. Participants were asked if an eye doctor has ever told them they have “glaucoma, sometimes called high pressure in your eyes”. Seven thousand and forty two reported whether they had been diagnosed with glaucoma (0.55% missing), and of these, 482 respondents reported a positive history of glaucoma.\n\nUse of the major PDEi, sildenafil and theophylline, was the primary predictor variable of interest. Other PDEi were included in an initial screen, however too few participants in our study sample reported use of other PDEi for meaningful analysis, therefore we did not include them in the rest of our analysis. To ascertain medication use, participants were asked, “Have you taken or used any prescription medicines in the past month?” Though data on dosage was not collected, for those medications listed, participants were further asked, “For how long have you been taking this medicine?” Duration of use was converted to number of days and categorized to <1 year of use or ≥1 year of use. For analytic purposes, we included only participants who reported use of sildenafil or theophylline for ≥1 year.\n\nPossible confounders included as covariates in our analyses included demographic and socioeconomic (SES) variables (self-reported age, gender, race-ethnicity, education level, and annual household income), and general health conditions and behaviors (self-reported cigarette smoking status–never, former, and current). Diabetes, hyperlipidemia (HLD), myocardial infarction (MI), and stroke status were based on self-reports of whether participants were told by a doctor or other health professional they have or had diabetes, high blood cholesterol, a heart attack, or stroke, respectively. Hypertension (HTN) status was ascertained from self-reports of whether a doctor told participants they have high blood pressure on 2 or more occasions.\n\nFor internal validation of self-reported glaucoma, we examined vertical cup-to-disc ratio (CDR) from the retinal imaging segment of NHANES and visual field loss from frequency doubling technology (FDT). We classified vertical CDR >0.7 in at least one eye and FDT defect in either eye as positive for glaucoma. FDT defect was defined as visual field abnormalities using a 2-2-1 algorithm incorporating test reliability indices per NHANES protocol [23].\n\nStatistical analysis\nSTATA/SE 13.1 (StataCorp, College Station, TX) was used to perform all analyses. We compared subgroups with and without glaucoma using survey-adjusted Rao–Scott–Pearson χ2 and Wald tests for categorical and continuous variables, respectively. A 4-year sample weight was constructed by combining the 2-year interview sample weights provided by NCHS for NHANES 2005–2008. This generates estimates representative of the population at the midpoint of the surveyed period. Variance estimates were derived using Taylor Series Linearization, as recommended by NCHS. Given the study design of NHANES, we used the svy set of commands in STATA.\n\nMultivariable logistic regression models were used to determine the odds of prevalent glaucoma in respondents aged 40 years and over that used the PDEi sildenafil or theophylline for 1 year or more. All models were adjusted sequentially for demographics and SES (age, gender, race/ethnicity, education level, and annual household income) as well as general health conditions and behaviors (smoking status, diabetes, HTN, HLD, MI, and stroke). “Don’t know” and “Refuse” responses were considered missing values and excluded from the regression analyses. P-values <0.05 were deemed statistically significant.\n\nResults\nTable 1 shows demographic, SES, and general health behaviors and conditions for the subgroups with and without glaucoma. Out of 7,042 participants aged 40 years and older who were asked about glaucoma, 482 (6.84%) reported a positive diagnosis of glaucoma. Compared to those without, those with self-reported glaucoma were significantly more likely to be older and have different racial-ethnic distributions, less education, and lower income. As well, they were significantly more likely to be former smokers and report histories of diabetes, hyperlipidemia, myocardial infarction, and stroke. These differences are corroborated with univariable analysis of covariates as illustrated in Table 2.\n\n10.1371/journal.pone.0183388.t001Table 1 Demographic and general health characteristics of participants age ≥40 years based on self-reported glaucoma status, in the National Health and Nutrition Examination Survey (NHANES) 2005–2008 (n = 7042).\nCharacteristic\tSelf-Reported Glaucoma\t\nNo (n = 6,560)\tYes (n = 482)\tP Value*\t\nAge, mean (SD), yr\t56.54 (11.91)\t66.86 (13.89)\t<0.001\t\nGender (%)\t\t\t\t\n Female\t52.95\t52.38\t0.868\t\nRace/Ethnicity (%)\t\t\t\t\n Non-Hispanic White\t75.88\t72.46\t0.001\t\n Mexican/Hispanic\t8.79\t6.73\t\n Black\t10.14\t16.67\t\n Other\t5.18\t4.15\t\nEducation (%)\t\t\t\t\n <High school graduate\t19.00\t27.51\t<0.001\t\n High school graduate/some college\t53.86\t57.03\t\n College graduate and beyond\t27.14\t15.46\t\nAnnual household income (%)\t\t\t\t\n <$35,000\t32.81\t47.19\t<0.001\t\n ≥$35,000 to <$65,000\t25.74\t31.24\t\n ≥$65,000\t41.45\t21.57\t\nSmoking status (%)\t\t\t\t\n Never\t49.43\t45.71\t<0.001\t\n Former\t29.85\t41.97\t\n Current\t20.72\t12.32\t\nHealth conditions (%)\t\t\t\t\n Diabetes\t11.08\t23.00\t<0.001\t\n Hypertension\t84.83\t86.18\t0.617\t\n Hyperlipidemia\t47.81\t58.85\t<0.001\t\n Myocardial infarction\t5.02\t9.80\t0.005\t\n Stroke\t4.34\t10.21\t0.011\t\nTests/Imaging (%)\t\t\t\t\n FDT defect, yes\t6.86\t36.07\t<0.001\t\n FDT defect, no\t93.14\t63.93\t\n Vertical CDR >0.7\t11.88\t59.44\t<0.001\t\n Vertical CDR ≤0.7\t88.12\t40.56\t\nFDT: frequency doubling technology, CDR: cup-to-disc ratio. FDT defect defined as abnormal FDT findings in at least 1 eye.\n\n*P values determined using the Wald test for age as a continuous variable and the Rao–Scott–Pearson χ2 test for all other categorical variables.\n\n10.1371/journal.pone.0183388.t002Table 2 Univariable analysis of self-reported glaucoma and possible risk factors in the National Health and Nutrition Examination Survey (NHANES) 2005–2008.\nCharacteristic\tOR\t95% CI\tP value\t\nAge\t1.07\t(1.05–1.08)\t<0.001\t\nFemale sex\t0.98\t(0.74–1.29)\t0.868\t\nRace/Ethnicity\t\t\t\t\n White\t—\t—\t—\t\n Mexican/Hispanic\t0.80\t(0.59–1.09)\t0.149\t\n Black\t1.72\t(1.34–2.21)\t<0.001\t\n Other\t0.84\t(0.42–1.67)\t0.606\t\nEducation\t\t\t\t\n <High school graduate\t—\t—\t—\t\n High school graduate or some college\t0.84\t(0.66–1.07)\t0.156\t\n College graduate and beyond\t0.36\t(0.25–0.52)\t<0.001\t\nAnnual household income\t\t\t\t\n <$35,000\t—\t—\t—\t\n ≥$35,000 to <$65,000\t0.73\t(0.56–0.96)\t0.023\t\n ≥$65,000\t0.39\t(0.29–0.53)\t<0.001\t\nSmoking status\t\t\t\t\n Never\t—\t—\t—\t\n Former\t1.52\t(1.22–1.89)\t<0.001\t\n Current\t0.64\t(0.41–1.02)\t0.059\t\nHealth conditions (%)\t\t\t\t\n Diabetes\t2.40\t(1.97–2.91)\t<0.001\t\n Hypertension\t1.11\t(0.71–1.76)\t0.629\t\n Hyperlipidemia\t1.56\t(1.31–1.86)\t<0.001\t\n Myocardial infarction\t2.06\t(1.42–2.98)\t<0.001\t\n Stroke\t2.50\t(1.43–4.39)\t0.002\t\nTests/Imaging (%)\t\t\t\t\n FDT defect, yes\t7.66\t(5.41–10.86)\t<0.001\t\n Vertical CDR >0.7\t10.87\t(6.08–19.44)\t<0.001\t\nFDT: frequency doubling technology, CDR: cup-to-disc ratio. FDT defect defined as abnormal FDT findings in at least 1 eye. ORs are reported with 95% confidence intervals (CI) with two-sided p-values <0.05 deemed statistically significant.\n\nIn the internal validation analysis of self-reported glaucoma, 36% of respondents with self-reported history of glaucoma had visual field loss in either eye based on FDT abnormalities, and 60% had vertical CDR >0.7 in at least one eye (Table 1). On the other hand, only 7% of participants without self-reported history of glaucoma demonstrated FDT abnormalities and 12% had increased CDR. For both measures, the proportion was significantly higher in those who self-reported a history of glaucoma versus those who did not. Univariable analyses with FDT defect and CDR likewise showed strong, statistically significant associations with self-reported glaucoma (Table 2).\n\nTable 3 shows results from the regression models evaluating the association between sildenafil and theophylline use and prevalent glaucoma. After ≥1 year of use, theophylline (n = 20) was significantly associated with higher odds of glaucoma (OR = 4.83, CI: 1.94–12.04, p = 0.001) whereas sildenafil (n = 11) was not (OR = 3.72, CI: 0.69–20.07, p = 0.122). When adjusted for demographic and SES variables (age, sex, race-ethnicity, education, and income), both sildenafil (OR = 4.90, CI: 1.24–19.27, p = 0.025) and theophylline (OR = 3.15, CI: 1.46–6.80, p = 0.005) use were significantly associated with higher odds of prevalent glaucoma. These associations persisted after further adjustment for health behaviors and conditions (smoking status, diabetes, hypertension, hyperlipidemia, myocardial infarction, and stroke) for the two medications.\n\n10.1371/journal.pone.0183388.t003Table 3 Logistic regression models for the association between self-reported glaucoma and use of sildenafil and theophylline, in the National Health and Nutrition Examination Survey (NHANES) 2005–2008.\nCharacteristic\tOR\t95% CI\tP value\t\nSildenafil use (≥1 year of use)\t\t\t\t\n Unadjusted\t3.76\t(0.72–19.51)\t0.111\t\n Adjusted*\t\t\t\t\n Demographics and SES\t5.07\t(1.28–20.15)\t0.023\t\n Health behaviors/conditions\t9.68\t(2.13–44.02)\t0.005\t\nTheophylline use (≥1 year of use)\t\t\t\t\n Unadjusted\t2.39\t(0.42–13.55)\t0.315\t\n Adjusted*\t\t\t\t\n Demographics and SES\t1.77\t(0.34–9.31)\t0.490\t\n Health behaviors/conditions\t3.87\t(1.22–12.24)\t0.023\t\nSES: socioeconomic status. ORs are reported with 95% confidence intervals (CI) with two-sided p-values <0.05 deemed statistically significant.\n\n*Adjusted models include sequential adjustments for demographics and SES (age, sex, race-ethnicity, education, income) and demographics + general health behaviors/conditions (smoking status, diabetes, hypertension, hyperlipidemia, myocardial infarction, stroke).\n\nDiscussion\nThis investigation suggests that there may be an association between use of the PDEi sildenafil and theophylline (for at least 1 year) and glaucoma diagnosis. Though the mechanisms of association between glaucoma and sildenafil or theophylline use are likely quite different, to our knowledge, this is the first study demonstrating such relationships between PDEi and glaucoma in a nationally representative sample of the U.S. population.\n\nInterestingly, use of these medications was not associated with lower odds of glaucoma, as we had originally hypothesized. This may be because most of the literature reporting increases in ocular blood flow after administration of sildenafil operated on acute time scales in the range of hours [13–15], whereas glaucoma is a chronic disease and therefore unlikely to be affected by rapid changes in ocular hemodynamics. By studying ≥1 year of sildenafil intake, we attempted to model more long-term associations with glaucoma, and indeed found the opposite effect. Perhaps with repeated exposure to sildenafil, blood is ‘shunted’ away from the ocular circulation in favor of the systemic vasculature, resulting in compromised ocular blood flow and subsequent oxidative injury to the optic nerve head that may be a mechanism for the development or progression of glaucoma. Recent studies showing that acute sildenafil administration lowers blood pressure in a mouse model and in patients with resistant hypertension seem to support this possibility [24,25], although further work is necessary to clarify long-term effects.\n\nThe association between theophylline and glaucoma mirrored that of sildenafil in our analysis. While there has been little work regarding the potential effects of theophylline on glaucoma, studies have shown a link between adenosine and IOP. There is evidence that adenosine receptor activation, especially adenosine A1 receptors, lowers intraocular pressure by stimulating the activity of matrix metalloproteinases (MMPs) in the trabecular meshwork, thereby increasing aqueous outflow. This has been demonstrated in animal models [26–28], human trabecular cell lines [29,30], and Phase 2 trials with a novel adenosine A1 receptor agonist [31]. Theophylline’s role in glaucoma may therefore stem from its action as a nonselective adenosine receptor antagonist. Not only could it block aqueous outflow by inhibiting the activation of MMPs, but it has also been implicated in enhancing the reductions in retinal blood flow induced by elevated IOP [32].\n\nIn addition to sildenafil and theophylline, other PDEi have been implicated as predictors of higher risk of glaucoma as well. Several studies have shown that heavy caffeinated coffee intake is associated with a higher risk of developing pseudoexfoliation glaucoma or suspected pseudoexfoliation glaucoma compared to those who do not drink coffee [33]. It appears that compounds found in coffee, among them caffeine, elevates plasma homocysteine concentrations after consumption, and hyperhomocystinemia has been associated with pseudoexfoliation glaucoma, perhaps by contributing to the buildup of exfoliation material in the eye [34–37]. Caffeine may further play a role in pseudoexfoliation glaucoma secondary to its non-selective adenosine receptor antagonist and PDEi actions, potentially exacerbating elevated IOP and disrupting normal ocular vasculature via the processes aforementioned.\n\nA major advantage of this study is the use of NHANES, a population-based survey with results generalizable to the civilian, non-institutionalized US. We were also able to account for various potential confounders of the association between PDEi use and glaucoma. However, analyzing NHANES also poses a number of limitations, one of which is the cross-sectional nature of the data. Indeed, we are unable to determine the temporal relationship between PDEi use and glaucoma. Purely observational results are therefore presented, as true causation cannot be determined without longitudinal assessments. We also cannot account for the possible effect of recall bias, as the variables used in our analysis were all self-reported via the NHANES questionnaire.\n\nIn addition, glaucoma status was defined by self-report rather than objective measurements from funduscopic exams and photos. Given how the question was phrased, there is a risk self-reported glaucoma includes respondents with ocular hypertension as well. We acknowledge that a diagnosis of glaucoma would ideally be supported by appropriate examination findings and testing. However, though NHANES does provide data on structural and functional parameters of glaucoma, including vertical CDR and visual field loss via FDT testing, the number of respondents with missing data is large, precluding use of these measures to substantiate self-reported cases without severely restricting the study sample size. As well, CDR and FDT testing are themselves imperfect tools in diagnosing glaucoma. While flawed, self-reporting of glaucoma has been shown to be over 96% specific and may underestimate prevalence of disease, suggesting that those who do report a diagnosis of glaucoma likely have the condition [38]. Moreover, there is good to substantial concordance between patient’s self-reported history of glaucoma and a medical record diagnosis [39,40].\n\nFinally, a primary limitation stems from the small number of participants who reported taking sildenafil or theophylline despite the large number of respondents included in the analysis. Limited numbers barred us from studying the relationship of other PDEi with glaucoma as well. Nevertheless, the methodology used to construct NHANES enables us to weight the data to be nationally representative, and our statistically significant regression results identify possible associations that can be the starting point for further investigation.\n\nIn summary, this early, exploratory study supports a possible association between sildenafil or theophylline use and glaucoma. We offer two distinct, possible hypotheses for how each medication can be associated with glaucoma–sildenafil through inhibition of PDE5, increase in cGMP, vasodilation, and subsequent shunting of blood away from the ocular circulation while theophylline through nonselective inhibition of adenosine receptors leading to reduced MMP activity and decreased aqueous outflow. If substantiated by further study, prospective randomized trials will need to be performed to determine whether there is a true causal association between PDEi use and glaucoma development and whether use of sildenafil and theophylline can influence the course of disease progression.\n==== Refs\nReferences\n1 The Eye Diseases Prevalence Research Group*. Prevalence of open-angle glaucoma among adults in the United States . Arch Ophthalmol \n2004 ;122 :532 –8 . doi: 10.1001/archopht.122.4.532 \n15078671 \n2 Kapetanakis VV , Chan MPY , Foster PJ , Cook DG , Owen CG , Rudnicka AR . Global variations and time trends in the prevalence of primary open angle glaucoma (POAG): a systematic review and meta-analysis . Br J Ophthalmol \n2016 ;100 :86 –93 . doi: 10.1136/bjophthalmol-2015-307223 \n26286821 \n3 Tham Y-C , Li X , Wong TY , Quigley HA , Aung T , Cheng C-Y . Global Prevalence of Glaucoma and Projections of Glaucoma Burden through 2040: A Systematic Review and Meta-Analysis . 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"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "12(8)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000368:Aged; D003430:Cross-Sectional Studies; D005260:Female; D005901:Glaucoma; D006801:Humans; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors; D000068677:Sildenafil Citrate; D013806:Theophylline; D014481:United States",
"nlm_unique_id": "101285081",
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"pages": "e0183388",
"pmc": null,
"pmid": "28817686",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "12567109;23078191;16276285;20706731;19279343;26286821;17473737;22918628;24974815;11564641;21771280;14973526;10648261;7714784;12202524;22537615;9071223;11944862;27246899;10844068;27769330;22678051;9856774;10676804;9683148;10541153;24302588;12450889;15126148;18369062;7785681;9301479;15078671;26558263;28052870;11730651",
"title": "Use of phosphodiesterase inhibitors and prevalence of self-reported glaucoma in the United States.",
"title_normalized": "use of phosphodiesterase inhibitors and prevalence of self reported glaucoma in the united states"
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"abstract": "Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy.\n\n\n\nWe conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks.\n\n\n\nIn the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels.\n\n\n\nIn patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo. (Funded by Pfizer; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain ClinicalTrials.gov numbers, NCT01465763 , NCT01458951 , and NCT01458574 , respectively.).",
"affiliations": "From the Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla (W.J.S.); Pfizer, Collegeville, PA (C.S., W.N., G.F., N.L., D.Y., D.W., H.Z.); Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Department of Gastroenterology, Academic Medical Center, Amsterdam (G.R.D.); the Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium (S.V.); Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (S.S.); the Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan (S.D.); Robarts Clinical Trials, Robarts Research Institute, Western University, London (B.G.F.), and McMaster University, Hamilton (W.R.) - both in Ontario, Canada; Pfizer, Groton, CT (A.M., P.H.); and the Networking Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic de Barcelona, Barcelona (J.P.).;From the Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla (W.J.S.); Pfizer, Collegeville, PA (C.S., W.N., G.F., N.L., D.Y., D.W., H.Z.); Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Department of Gastroenterology, Academic Medical Center, Amsterdam (G.R.D.); the Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium (S.V.); Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (S.S.); the Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan (S.D.); Robarts Clinical Trials, Robarts Research Institute, Western University, London (B.G.F.), and McMaster University, Hamilton (W.R.) - both in Ontario, Canada; Pfizer, Groton, CT (A.M., P.H.); and the Networking Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic de Barcelona, Barcelona (J.P.).;From the Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla (W.J.S.); Pfizer, Collegeville, PA (C.S., W.N., G.F., N.L., D.Y., D.W., H.Z.); Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Department of Gastroenterology, Academic Medical Center, Amsterdam (G.R.D.); the Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium (S.V.); Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (S.S.); the Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan (S.D.); Robarts Clinical Trials, Robarts Research Institute, Western University, London (B.G.F.), and McMaster University, Hamilton (W.R.) - both in Ontario, Canada; Pfizer, Groton, CT (A.M., P.H.); and the Networking Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic de Barcelona, Barcelona (J.P.).;From the Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla (W.J.S.); Pfizer, Collegeville, PA (C.S., W.N., G.F., N.L., D.Y., D.W., H.Z.); Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Department of Gastroenterology, Academic Medical Center, Amsterdam (G.R.D.); the Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium (S.V.); Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (S.S.); the Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan (S.D.); Robarts Clinical Trials, Robarts Research Institute, Western University, London (B.G.F.), and McMaster University, Hamilton (W.R.) - both in Ontario, Canada; Pfizer, Groton, CT (A.M., P.H.); and the Networking Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic de Barcelona, Barcelona (J.P.).;From the Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla (W.J.S.); Pfizer, Collegeville, PA (C.S., W.N., G.F., N.L., D.Y., D.W., H.Z.); Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Department of Gastroenterology, Academic Medical Center, Amsterdam (G.R.D.); the Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium (S.V.); Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (S.S.); the Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan (S.D.); Robarts Clinical Trials, Robarts Research Institute, Western University, London (B.G.F.), and McMaster University, Hamilton (W.R.) - both in Ontario, Canada; Pfizer, Groton, CT (A.M., P.H.); and the Networking Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic de Barcelona, Barcelona (J.P.).;From the Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla (W.J.S.); Pfizer, Collegeville, PA (C.S., W.N., G.F., N.L., D.Y., D.W., H.Z.); Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Department of Gastroenterology, Academic Medical Center, Amsterdam (G.R.D.); the Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium (S.V.); Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (S.S.); the Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan (S.D.); Robarts Clinical Trials, Robarts Research Institute, Western University, London (B.G.F.), and McMaster University, Hamilton (W.R.) - both in Ontario, Canada; Pfizer, Groton, CT (A.M., P.H.); and the Networking Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic de Barcelona, Barcelona (J.P.).;From the Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla (W.J.S.); Pfizer, Collegeville, PA (C.S., W.N., G.F., N.L., D.Y., D.W., H.Z.); Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Department of Gastroenterology, Academic Medical Center, Amsterdam (G.R.D.); the Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium (S.V.); Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (S.S.); the Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan (S.D.); Robarts Clinical Trials, Robarts Research Institute, Western University, London (B.G.F.), and McMaster University, Hamilton (W.R.) - both in Ontario, Canada; Pfizer, Groton, CT (A.M., P.H.); and the Networking Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic de Barcelona, Barcelona (J.P.).;From the Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla (W.J.S.); Pfizer, Collegeville, PA (C.S., W.N., G.F., N.L., D.Y., D.W., H.Z.); Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Department of Gastroenterology, Academic Medical Center, Amsterdam (G.R.D.); the Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium (S.V.); Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (S.S.); the Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan (S.D.); Robarts Clinical Trials, Robarts Research Institute, Western University, London (B.G.F.), and McMaster University, Hamilton (W.R.) - both in Ontario, Canada; Pfizer, Groton, CT (A.M., P.H.); and the Networking Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic de Barcelona, Barcelona (J.P.).;From the Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla (W.J.S.); Pfizer, Collegeville, PA (C.S., W.N., G.F., N.L., D.Y., D.W., H.Z.); Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Department of Gastroenterology, Academic Medical Center, Amsterdam (G.R.D.); the Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium (S.V.); Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (S.S.); the Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan (S.D.); Robarts Clinical Trials, Robarts Research Institute, Western University, London (B.G.F.), and McMaster University, Hamilton (W.R.) - both in Ontario, Canada; Pfizer, Groton, CT (A.M., P.H.); and the Networking Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic de Barcelona, Barcelona (J.P.).;From the Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla (W.J.S.); Pfizer, Collegeville, PA (C.S., W.N., G.F., N.L., D.Y., D.W., H.Z.); Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Department of Gastroenterology, Academic Medical Center, Amsterdam (G.R.D.); the Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium (S.V.); Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (S.S.); the Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan (S.D.); Robarts Clinical Trials, Robarts Research Institute, Western University, London (B.G.F.), and McMaster University, Hamilton (W.R.) - both in Ontario, Canada; Pfizer, Groton, CT (A.M., P.H.); and the Networking Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic de Barcelona, Barcelona (J.P.).;From the Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla (W.J.S.); Pfizer, Collegeville, PA (C.S., W.N., G.F., N.L., D.Y., D.W., H.Z.); Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Department of Gastroenterology, Academic Medical Center, Amsterdam (G.R.D.); the Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium (S.V.); Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (S.S.); the Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan (S.D.); Robarts Clinical Trials, Robarts Research Institute, Western University, London (B.G.F.), and McMaster University, Hamilton (W.R.) - both in Ontario, Canada; Pfizer, Groton, CT (A.M., P.H.); and the Networking Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic de Barcelona, Barcelona (J.P.).;From the Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla (W.J.S.); Pfizer, Collegeville, PA (C.S., W.N., G.F., N.L., D.Y., D.W., H.Z.); Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Department of Gastroenterology, Academic Medical Center, Amsterdam (G.R.D.); the Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium (S.V.); Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (S.S.); the Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan (S.D.); Robarts Clinical Trials, Robarts Research Institute, Western University, London (B.G.F.), and McMaster University, Hamilton (W.R.) - both in Ontario, Canada; Pfizer, Groton, CT (A.M., P.H.); and the Networking Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic de Barcelona, Barcelona (J.P.).;From the Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla (W.J.S.); Pfizer, Collegeville, PA (C.S., W.N., G.F., N.L., D.Y., D.W., H.Z.); Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Department of Gastroenterology, Academic Medical Center, Amsterdam (G.R.D.); the Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium (S.V.); Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (S.S.); the Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan (S.D.); Robarts Clinical Trials, Robarts Research Institute, Western University, London (B.G.F.), and McMaster University, Hamilton (W.R.) - both in Ontario, Canada; Pfizer, Groton, CT (A.M., P.H.); and the Networking Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic de Barcelona, Barcelona (J.P.).;From the Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla (W.J.S.); Pfizer, Collegeville, PA (C.S., W.N., G.F., N.L., D.Y., D.W., H.Z.); Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Department of Gastroenterology, Academic Medical Center, Amsterdam (G.R.D.); the Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium (S.V.); Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (S.S.); the Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan (S.D.); Robarts Clinical Trials, Robarts Research Institute, Western University, London (B.G.F.), and McMaster University, Hamilton (W.R.) - both in Ontario, Canada; Pfizer, Groton, CT (A.M., P.H.); and the Networking Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic de Barcelona, Barcelona (J.P.).;From the Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla (W.J.S.); Pfizer, Collegeville, PA (C.S., W.N., G.F., N.L., D.Y., D.W., H.Z.); Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Department of Gastroenterology, Academic Medical Center, Amsterdam (G.R.D.); the Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium (S.V.); Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (S.S.); the Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan (S.D.); Robarts Clinical Trials, Robarts Research Institute, Western University, London (B.G.F.), and McMaster University, Hamilton (W.R.) - both in Ontario, Canada; Pfizer, Groton, CT (A.M., P.H.); and the Networking Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic de Barcelona, Barcelona (J.P.).;From the Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla (W.J.S.); Pfizer, Collegeville, PA (C.S., W.N., G.F., N.L., D.Y., D.W., H.Z.); Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Department of Gastroenterology, Academic Medical Center, Amsterdam (G.R.D.); the Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium (S.V.); Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (S.S.); the Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan (S.D.); Robarts Clinical Trials, Robarts Research Institute, Western University, London (B.G.F.), and McMaster University, Hamilton (W.R.) - both in Ontario, Canada; Pfizer, Groton, CT (A.M., P.H.); and the Networking Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic de Barcelona, Barcelona (J.P.).;From the Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla (W.J.S.); Pfizer, Collegeville, PA (C.S., W.N., G.F., N.L., D.Y., D.W., H.Z.); Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Department of Gastroenterology, Academic Medical Center, Amsterdam (G.R.D.); the Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium (S.V.); Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (S.S.); the Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan (S.D.); Robarts Clinical Trials, Robarts Research Institute, Western University, London (B.G.F.), and McMaster University, Hamilton (W.R.) - both in Ontario, Canada; Pfizer, Groton, CT (A.M., P.H.); and the Networking Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic de Barcelona, Barcelona (J.P.).;From the Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla (W.J.S.); Pfizer, Collegeville, PA (C.S., W.N., G.F., N.L., D.Y., D.W., H.Z.); Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (B.E.S.); the Department of Gastroenterology, Academic Medical Center, Amsterdam (G.R.D.); the Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium (S.V.); Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (S.S.); the Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan (S.D.); Robarts Clinical Trials, Robarts Research Institute, Western University, London (B.G.F.), and McMaster University, Hamilton (W.R.) - both in Ontario, Canada; Pfizer, Groton, CT (A.M., P.H.); and the Networking Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic de Barcelona, Barcelona (J.P.).",
"authors": "Sandborn|William J|WJ|;Su|Chinyu|C|;Sands|Bruce E|BE|;D'Haens|Geert R|GR|;Vermeire|Séverine|S|;Schreiber|Stefan|S|;Danese|Silvio|S|;Feagan|Brian G|BG|;Reinisch|Walter|W|;Niezychowski|Wojciech|W|;Friedman|Gary|G|;Lawendy|Nervin|N|;Yu|Dahong|D|;Woodworth|Deborah|D|;Mukherjee|Arnab|A|;Zhang|Haiying|H|;Healey|Paul|P|;Panés|Julian|J|;|||",
"chemical_list": "D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D053612:Janus Kinases",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa1606910",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-4793",
"issue": "376(18)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D000328:Adult; D016009:Chi-Square Distribution; D003093:Colitis, Ulcerative; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D053612:Janus Kinases; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D012074:Remission Induction",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "1723-1736",
"pmc": null,
"pmid": "28467869",
"pubdate": "2017-05-04",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis.",
"title_normalized": "tofacitinib as induction and maintenance therapy for ulcerative colitis"
} | [
{
"companynumb": "DE-PFIZER INC-2015300900",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TOFACITINIB CITRATE"
},
"drugadditional": "1",... |
{
"abstract": "Introduction Intravenous high-dose vitamin C therapy is widely used in naturopathic and integrative oncology; however, a study reviewing its effects has never been performed in Singapore. This article serves to document administration of supportive vitamin C therapy for cancer patients in Singapore.\n\n\n\nThe clinical response of 9 cancer patients of differing stages to the regular administration of large doses (25-100 g/d) of intravenous vitamin C (IVC; ascorbic acid) is outlined. Tumor pathology and patient health were verified by doctors who do not practice vitamin C treatment.\n\n\n\nCases suggesting survival beyond prognosis, improvement in quality of life, safe coadministration with and improved tolerance of conventional therapy, and deterioration in clinical condition following withdrawal of vitamin C therapy are documented clinically. Some patients experience the Jarisch-Herxheimer reaction-the release of endotoxin from microorganism death resulting in pimples, fever, and body odor-for a few hours after the therapy, but these are resolved quickly with no lasting effects.\n\n\n\nRandomized trials of IVC therapy are recommended because it has minimal side effects and has shown promising results.",
"affiliations": "Hosanna Clinic, Singapore.;Gene Oasis Research and Innovation, Singapore glendachongsl@gmail.com.;Gene Oasis Research and Innovation, Singapore Tianjin University, Tianjin 300072, PR China.",
"authors": "Raymond|Yuen Chuen Fong|YC|;Glenda|Chong Sze Ling|CS|;Meng|Lim Kah|LK|",
"chemical_list": "D001205:Ascorbic Acid",
"country": "United States",
"delete": false,
"doi": "10.1177/1534735415622010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1534-7354",
"issue": "15(2)",
"journal": "Integrative cancer therapies",
"keywords": "ascorbic acid; cancer; high-dose vitamin C therapy; intravenous vitamin C; nutrition therapy",
"medline_ta": "Integr Cancer Ther",
"mesh_terms": "D000328:Adult; D000368:Aged; D001205:Ascorbic Acid; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D011379:Prognosis; D011788:Quality of Life; D012846:Singapore",
"nlm_unique_id": "101128834",
"other_id": null,
"pages": "197-204",
"pmc": null,
"pmid": "26679971",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article",
"references": "15578707;23396969;20511723;15896248;18287873;23477602;22438782;11336777;384241;1787808;24867961;16157892;15907674;15068981;24177629;15753373;3880867;9389750;18626751;24022818;4430016;17237035",
"title": "Effects of High Doses of Vitamin C on Cancer Patients in Singapore: Nine Cases.",
"title_normalized": "effects of high doses of vitamin c on cancer patients in singapore nine cases"
} | [
{
"companynumb": "SG-MYLANLABS-2016M1029882",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEFITINIB"
},
"drugadditional": "3",
... |
{
"abstract": "We report a case series of 2 patients with unilateral acetabular insufficiency fractures who received allogeneic peripheral blood stem cell transplantation for hematologic malignancies complicated by chronic graft vs host disease. These were managed with uncemented cup and cage total hip arthroplasty and stabilization of posterior column with plating. Osteonecrosis of the acetabulum is an uncommon musculoskeletal complication of chronic graft vs host disease. The orthopedic impact of this disease should not be overlooked. Surgical intervention with this construct can provide necessary stability to improve patient function.",
"affiliations": "Department of Orthopaedics and Rehabilitation, Oregon Health and Sciences University, Portland, OR, USA.;Department of Orthopaedics and Rehabilitation, Oregon Health and Sciences University, Portland, OR, USA.",
"authors": "Nielsen|Warren|W|;Schabel|Kathryn|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.artd.2020.11.012",
"fulltext": "\n==== Front\nArthroplast Today\nArthroplast Today\nArthroplasty Today\n2352-3441 Elsevier \n\nS2352-3441(20)30225-9\n10.1016/j.artd.2020.11.012\nCase Report\nAcetabular Insufficiency Fractures in the Setting of Graft vs Host Disease: A Report of Two Cases\nNielsen Warren BS Schabel Kathryn MDschabel@ohsu.edu∗ Department of Orthopaedics and Rehabilitation, Oregon Health and Sciences University, Portland, OR, USA\n∗ Corresponding author. 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA. Tel.: +1 503 494 6406. schabel@ohsu.edu\n05 1 2021 \n2 2021 \n05 1 2021 \n7 54 59\n20 8 2020 10 11 2020 16 11 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We report a case series of 2 patients with unilateral acetabular insufficiency fractures who received allogeneic peripheral blood stem cell transplantation for hematologic malignancies complicated by chronic graft vs host disease. These were managed with uncemented cup and cage total hip arthroplasty and stabilization of posterior column with plating. Osteonecrosis of the acetabulum is an uncommon musculoskeletal complication of chronic graft vs host disease. The orthopedic impact of this disease should not be overlooked. Surgical intervention with this construct can provide necessary stability to improve patient function.\n\nKeywords\nAcetabular insufficiencyOsteonecrosisAvascular necrosisGraft versus host diseaseArthroplasty\n==== Body\nIntroduction\nGraft vs host disease (GVHD) can manifest with multisystemic effects. GVHD can occur after allogeneic peripheral blood stem cell transplantation (PBSCT) and can have orthopedic implications such as osteonecrosis. The incidence of osteonecrosis after allogeneic stem cell transplantation is 4-19% [[1], [2], [3], [4]], and the risk is increased in patients with GVHD [5]. Most studies described involve the femoral head [[1], [2], [3], [4],[6], [7], [8], [9], [10], [11], [12]]. Osteonecrosis of the acetabulum, although rare, can lead to significant complications. These include interruption of the articular surface, insufficiency fracture, and protrusio acetabulum. Osteonecrosis of the acetabulum presents particular difficulty in fixation; poor bone quality can impact long-term patient outcomes and implant survivorship. Implant survivorship of THA in patients with allogeneic peripheral stem cell transplantation at 5 years is up to 93% [11], although it can be as low as 74.8% at 10 years [13]. Therefore, THA and fracture fixation in this setting require an approach that combines primary and revision arthroplasty skills to enable immediate weight bearing and pain relief. We present 2 cases of allogeneic PBSCT complicated by GVHD, with resultant acetabular osteonecrosis leading to acetabular insufficiency fracture and the surgical reconstruction that followed.\n\nCase histories\nCase 1\nCase 1 is a 60-year-old woman with a history of diffuse large B-cell lymphoma who underwent 8 cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin [vincristine], and prednisolone). Her disease recurred and was treated with radiolabeled tositumomab with maintenance on rituximab. Relapse occurred once more, and she received salvage chemotherapy with R-ICE (rituximab, ifosfamide, etoposide, carboplatin) followed by autologous PBSCT. She underwent human leukocyte antigen (HLA)-matched allogeneic PBSCT after fludarabine-melphalan conditioning for relapse involving the central nervous system. This was complicated by GVHD, primarily affecting the gastrointestinal tract, that improved with 20-mg prednisone BID (0.5 mg/kg/day). After several dose escalations and relapses, she was tapered off prednisone three times, but after two severe episodes of pericarditis in the absence of steroids, she remained on 10-mg prednisone daily.\n\nShe presented to orthopedics with 1 month of acute, “aching” left-sided groin pain, global left hip weakness, difficulty ambulating (newly required a four-wheel walker), and ecchymosis in her inguinal crease. Physical examination revealed severe pain with hip internal and external rotation, as well as adduction and abduction. She could conduct passive hip flexion to 90 degrees but had pain with resisted hip flexion. Magnetic resonance imaging (MRI) of the pelvis and hip was obtained by her primary care provider before orthopedic referral, and AP of the pelvis was obtained as seen in Figure 1. Initial radiography in Figure 1 and MRI demonstrated comminuted minimally displaced fracture of the acetabulum involving the anterior and posterior columns with acetabular protrusio fracture and superior displacement of the femur of 3.5 cm. Interruption of the anterior and posterior columns is better visualized on iliac oblique and obturator oblique views seen in Figure 2, Figure 3.Figure 1 AP pelvis x-ray upon initial presentation showed displaced acetabular fracture and interruption of the femoroacetabular joint space.\n\nFigure 2 Left obturator oblique better demonstrates insufficiency fracture of the posterior wall and anterior column.\n\nFigure 3 Left iliac oblique further demonstrates osteonecrosis of the acetabulum and fracture extending through the posterior column.\n\n\n\nOwing to severe disability and pain, and acetabular insufficiency (pathologic) fracture and joint collapse, posterior THA and posterior column stabilization was undertaken. Posterolateral approach was taken to optimize exposure of acetabular fracture and perform THA. Complex THA was performed using a cage construct. Pelvic size thwarted the use of a cup and cage construct. Findings include fragmentation of medial acetabulum with transverse-type insufficiency or pathologic fracture. Acetabular pathologic fracture was repaired, or stabilized, with 8-hole reconstruction plate bent for the left posterior column. Morselized femoral head autograft was placed at the base of the protruded acetabulum. Dome screws of antiprotrusio cage were placed before ilium cage screws, and 5 mL of synthetic bone graft and 30 mL of cancellous bone allograft was injected behind cage. Postoperative x-ray is demonstrated in Figure 4. Her postoperative activity restrictions included posterior hip precautions, and weightbearing as tolerated with an assistive device, with weaning as she was able.Figure 4 Day 0 postoperative AP pelvis x-ray. THA with cage construct and iliac plating.\n\n\n\nAt her 3-month follow-up visit, she was able to fully weight bear on her left lower extremity without pain or assistive device. Imaging obtained at that time is seen in Figure 5. At 5 months postoperatively, she underwent right total knee arthroplasty because of osteoarthritis present before the acetabular osteonecrosis and was progressing very well with physical therapy. Unfortunately, 16 months after complex left THA, she succumbed to complications of diffuse large B-cell lymphoma and GVHD.Figure 5 Three months postoperative AP pelvis. Revealed intact cage hardware, posterior column plating, and THA. Interval ileum healing was perceived.\n\n\n\nCase 2\nCase 2 is a 51-year-old woman with a history of acute myelogenous leukemia (AML), secondary myelodysplastic syndrome (MDS), GVHD, steroid-induced diabetes, and restrictive pulmonary disease. Autologous PBSCT was undertaken for AML 9 years before presentation. Matched unrelated donor PBSCT was conducted 1 year before presentation, after fludarabine-melphalan conditioning. GVHD characterized by gastrointestinal symptoms and florid skin rash complicated PBSCT 4 months before presentation. Steroid dosage during GVHD was started at 1 mg/kg/day (60 mg BID) with rapid resolution of symptoms leading to taper of steroids down to 0.5 mg/kg/day after 1 week. She developed recurrence of pulmonary symptoms and gastrointestinal symptoms with tapering and was restarted on 1 mg/kg/day.\n\nShe presented to orthopedics with 2 months of right hip pain, primarily in her deep inguinal crease. She required a walker for ambulation and was limited to very short distances because of pain. The examination was remarkable for BMI = 44, anasarca, and painful and limited right hip rotation with only 10 degrees of passive external and internal rotation. Radiographs taken at that time are seen in Figure 6. MRI performed at that time showed hypointensity of the supra-acetabular ilium with some T2 hyperintensity measuring 2.5 cm transverse × 2.4 cm AP suggestive of osteonecrosis, although without collapse. There was also osteonecrosis of the left femoral head, without collapse. Given significant comorbid conditions including bilateral lower extremity edema and severe open-leg ulcerations, surgery was not initially recommended.Figure 6 AP right hip obtained upon initial presentation to PCP with right hip pain. Revealing subchondral lucency of the right femoral head. No acetabular involvement noted.\n\n\n\nGiven ongoing severe pain and disability, she underwent medical optimization taking 13 months, although during that time, she developed progressive osteonecrosis of the acetabulum. The progression of this can be seen in Figure 7, Figure 8 obtained 1 month later. Her fracture initially demonstrated disruption of the right iliopubic line with sclerosis of the supraacetabular ilium with superior displacement of the femoral head into the ilium consistent with protrusio fracture. This was further evaluated with a CT of the pelvis, which demonstrated comminution of anterior and posterior columns and 14 gapping of articular surface along anterosuperior acetabulum and medullary sclerosis of the surrounding ilium. Follow-up radiography seen in Figure 8 demonstrated increased displacement of anterior and posterior columns with medial acetabular wall displacement measuring 8 mm. Figure 8 was ultimately used for templating her implants. Iliac oblique and obturator oblique views at this time seen in Figure 9, Figure 10 better demonstrate involvement of the anterior and posterior column, medial protrusion of the acetabulum. She was no longer able to ambulate with a walker and was wheelchair bound. Her steroid dose then was 5 mg, 5 days per week, and 10 mg, 2 days per week. Treatment options discussed with patient included Girdlestone resection, THA, and THA with antiprotrusio cage or cup and cage construct. Reconstruction was preferred by patient over Girdlestone resection as she was hoping to resume ambulation and activities of daily living (ADLs). Surgery was pursued with posterior THA, with cage construct and posterior column plating. This fixation was used as the size of the pelvis was not large enough to facilitate a cup/cage construct. Medial acetabulum bony deficiency with both columns, or transverse-type insufficiency fracture or pelvic discontinuity variant, was encountered. After femoral neck cut was made, A 7-hole pelvic reconstruction plate was contoured, and a posterior column plated from ischium to ileum with good fixation using 4 small fragment screws. After the cage was placed, 10 mL of synthetic bone graft with 30 mL of allograft cancellous chips was placed posteriorly to cage. There were no intraoperative complications, and she was discharged home after 2 days. Two weeks postoperatively, she had a 2-day admission for viral gastroenteritis. She also underwent kyphoplasty for three (T9, T11, L1) vertebral compression fractures 2 months postoperatively. There were no readmissions or emergency department visits for postoperative complications.Figure 7 AP pelvic x-ray 6 months since onset of symptoms and 10 months preoperatively. Revealing displaced healing right acetabular fracture. Disruption of the right iliopubic line and sclerosis of the right supra-acetabular ilium. Sclerosis of the right femoral head was also observed.\n\nFigure 8 AP pelvis x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Showing comminuted displaced right acetabular transverse fracture also involving the posterior and medial acetabular walls. Right femoral head is also eroded and aspherical. This film was used for templating.\n\nFigure 9 Right iliac oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively demonstrating transverse plus posterior acetabular wall fracture with 1.5 cm medial displacement of medial acetabular wall.\n\nFigure 10 Right obturator oblique x-ray 13 months since onset of symptoms and 1.5 months preoperatively. Further demonstrating comminuted posterior acetabular wall insufficiency fracture, aspherical and eroded femoral head, and some bony callus.\n\n\n\nOne-month postoperatively, her pain was decreasing, and function with ADLs increased, although she required a walker because of back pain and deconditioning. Her gait was smooth, not antalgic, with the walker. Two views of AP pelvis performed at that time are seen in Figure 11. One-year postoperatively, her pain had resolved, she still required a walker, and she was noted to have Trendelenburg gait. AP pelvis 1 year postoperatively, seen in Figure 12, showed well-positioned THA with no lucencies or subsidence. Unfortunately, 3 years postoperatively, she died of causes related to her MDS and GVHD.Figure 11 Portable pelvis x-ray 1-month postoperatively. Intact cup and cage construct implants, near anatomic alignment of acetabular fracture.\n\nFigure 12 AP pelvis x-rays 1-year postoperatively. Interval acetabular healing was seen. Diffuse osteopenia but no evidence of implant failure.\n\n\n\nDiscussion\nPatients with hematologic malignancies are having increased remission and survivorship after autologous and allogenic hematopoietic stem cell transplantations [14,15]. Allogeneic stem cell transplantation is unique as opposed to autologous transplant as it can lead to GVHD. GVHD is a systemic immune reaction by donor cells against host cells [16]. Several studies have demonstrated the increased risk of osteonecrosis because of GVHD [5,9,11,17,18]. GVHD is thought to cause osteonecrosis because of an inflammatory process in the intraosseous vasculature. Sixou et al. [19] found histologic evidence of vasculitis attributed to GVHD. This vasculitis exacerbates risk factors associated with osteonecrosis inclusive to patients with hematologic malignancies including systemic glucocorticoids, chemotherapeutics, and irradiation [5].\n\nUnique to the presented cases is osteonecrosis of the acetabulum and the timeline to develop osteonecrosis. Case 1 took 5 years for manifestation of acetabular osteonecrosis after initiation of steroids for GVHD. Case 2 took 13 months until acetabular osteonecrosis began after onset of GVHD. In 11 patients (19 hips, 8 patients with bilateral osteonecrosis) studied by Schulte and Beelen, onset of osteonecrosis after allogeneic stem cell transplant ranged from 5 to 57 months, with an average of 25 months [9,18]. However, all these cases were of the femoral head, and the hematologic malignancies were AML, MDS, CML, and ALL. It is unclear in the presented cases what circumstances led to osteonecrosis of the acetabulum. Location and timeline could be attributed to age. Bizot et al. [17] had 16 patients with osteonecrosis secondary to GVHD, although the oldest patient was 47 years old at the time of surgery (average age 13 ± 8 years). The patients presented were 60 and 52 years old at the time of surgery.\n\nSeveral other studies have identified osteonecrosis risk factors in hematologic malignancies; Schulte and Beelen demonstrated that the most impactful risk factors were chronic GVHD and cumulative steroid intake, followed by female gender, younger age, and conditioning therapy before transplant. Advanced disease stages, bone mineral density, and body composition did not have a significant impact on osteonecrosis [9,18]. The disease process of lymphoma itself may contribute; Chalmers et al. showed that lymphoma was the underlying diagnosis in 33% of THAs in patients with a history of stem cell transplant. However, not all of these patients had a history of GVHD [13].\n\nIn these cases, owing to the insufficiency fractures of the acetabular with effective pelvic discontinuity (PD) and the tenuous vascular supply of surrounding bone, THA was conducted with cage construct and bridge plating of the posterior column. This construct has shown efficacy in cases with PD and severe acetabular bone loss in revision THA [[20], [21], [22], [23]]. Plating is primarily studied in revision arthroplasty cases with PD [24,25]. Plating was chosen to restore continuity, optimize contact of viable bone, and add stability to the reconstruction. This fixation technique of posterior column plating with antiprotrusion cage placement led to stability with improved ADLs, restoration of ambulation with full weightbearing, and resolution of pain at 1 year for both cases. Certainly, the perioperative risk of significant surgical or medical complications is high for patients with GVHD; therefore, this technique should be considered in situations with tenuous blood supply and insufficiency fractures in the setting of hematologic malignancy and GVHD.\n\nSummary\nThese cases are unique reports of osteonecrosis focal to the acetabulum, in patients with history of stem cell transplant and subsequent GVHD. The impact of this disease process should not be overlooked in patients with hematologic malignances and GVHD. Surgical treatment with multifaceted construct, in these cases with an antiprotrusio cage bolstered by posterior column plating, can relieve pain and improve mobility.\n\nConflict of interest\nDr. Schabel obtains research support from Zimmer Biomet, unrelated to this work. She is also a board member for the Oregon Association of Orthopaedists.\n\nSupplementary data\nConflict of Interest Statement for Nielsen\n Conflict of Interest Statement for Schabel\n \n\nStatements of informed consent were obtained from patients and family members of deceased patients.\n==== Refs\nReferences\n1 Campbell S. Sun C. Kurian S. Predictors of avascular necrosis of bone in long-term survivors of hematopoietic cell transplantation Cancer 115 2009 4127 19536905 \n2 Enright H. Haake R. Weisdorf D. Avascular necrosis of bone: a common serious complication of allogeneic bone marrow transplantation Am J Med 89 1990 733 2252042 \n3 Fink J. Leisenring W. Sullivan K. Sherrard D. Weiss N. Avascular necrosis following bone marrow transplantation: a case-control study Bone 22 1998 67 9437515 \n4 Socie G. Cahn J. Carmelo J. Avascular necrosis of bone after allogeneic bone marrow transplantation: analysis of risk factors for 4388 patients by the Societe Francaise de Greffe de Moelle (SFGM) Br J Haematol 97 1997 865 9217190 \n5 Ebeling P.R. Thomas D.M. Erbas B. Hopper J.L. Szer J. Grigg A.P. Mechanisms of bone loss following allogeneic and autologous hemopoietic stem cell transplantation J Bone Miner Res 14 1999 342 10027899 \n6 Socié G. Loiseau P. Tamouza R. Both genetic and clinical factors predict the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation Transplantation 72 2001 699 11544434 \n7 Socie G. Selimi F. Sedel L. Avascular necrosis of bone after allogeneic bone marrow transplantation: clinical findings, incidence and risk factors Br J Haematol 86 1994 624 8043445 \n8 Tauchmanovà L. De Rosa G. Serio B. Avascular necrosis in long-term survivors after allogeneic or autologous stem cell transplantation: a single center experience and a review Cancer 97 2003 2453 12733144 \n9 Schulte C. Beelen D. Avascular osteonecrosis after allogeneic hematopoietic stem-cell transplantation: diagnosis and gender matter Transplantation 78 2004 1055 15480174 \n10 Torii Y. Hasegawa Y. Kubo T. Osteonecrosis of the femoral head after allogeneic bone marrow transplantation Clin Orthop Relat Res 382 2001 124 \n11 Zadegan F. Raould A. Bizot P. Nizard R. Sedel L. Osteonecrosis after allogeneic bone marrow transplantation Clin Orthop Relat Res 466 2008 287 18196408 \n12 Thorne J. Evans W. Alison R. Fournasier V. Avascular necrosis of bone complicating treatment of malignant lymphoma Am J Med 71 1981 751 7304645 \n13 Chalmers B. Ledford C. Stats J. Mabry T. Hanssen A. Abdel M. What risks are associated with primary THA in recipients of hematopoietic stem cell transplantation? Clin Orthop Relat Res 475 2017 475 27542147 \n14 Laudi N. Arora M. Burns L.J. Long-term follow-up after autologous hematopoietic stem cell transplantation for low-grade non-Hodgkin lymphoma Biol Blood Marrow Transplant 11 2005 129 15682074 \n15 D’Souza A. Fretham C. Current uses and outcomes of hematopoietic stem cell transplantation (HCT): CIBMTR Summary Slides, 2018 2018 https://www.cibmtr.org/ReferenceCenter/SlidesReports/SummarySlides/_layouts/15/WopiFrame.aspx?sourcedoc=/ReferenceCenter/SlidesReports/SummarySlides/Documents/2018%20Summary%20Slides%20-%20final%20-%20for%20web%20posting.pptx&action=default \n16 Zeiser R. Blazar B.R. Pathophysiology of chronic graft-versus-host disease and therapeutic targets N Engl J Med 377 2017 2565 29281578 \n17 Bizot P. Witvoet J. Sedel L. Avascular necrosis of the femoral head after allogeneic bone-marrow transplantation J Bone Joint Surg Br 78-B 1996 878 \n18 Schulte C. Beelen D. Low pretransplant bone-mineral density and RapidBone loss do not increase risk for AvascularOsteonecrosis after allogeneic hematopoietic StemCell transplantation Transplantation 79 2005 1748 15973180 \n19 Sixou L. Lassoued S. Attal M. Symptomatic osteonecrosis in recipients of nonautologous bone marrow transplants Rev Rhum Engl Ed 62 1995 359 7655869 \n20 Abolghasemian M. Tangsaraporn S. Drexler M. The challenge of pelvic discontinuity: cup-cage reconstruction does better than conventional cages in mid-term Bone Joint J 96-b 2014 195 24493184 \n21 Amenabar T. Rahman W.A. Hetaimish B.M. Kuzyk P.R. Safir O.A. Gross A.E. Promising mid-term results with a cup-cage construct for large acetabular defects and pelvic discontinuity Clin Orthop Relat Res 474 2016 408 25712864 \n22 Hipfl C. Janz V. Lochel J. Perka C. Wassilew G.I. Cup-cage reconstruction for severe acetabular bone loss and pelvic discontinuity: mid-term Results of a Consecutive Series of 35 Cases Bone Joint J 100-b 2018 1442 30418066 \n23 Li H. Qu X. Mao Y. Dai K. Zhu Z. Custom acetabular cages offer stable fixation and improved hip scores for revision THA with severe bone defects Clin Orthop Relat Res 474 2016 731 26467611 \n24 Martin J.R. Barrett I. Sierra R.J. Lewallen D.G. Berry D.J. Construct rigidity: keystone for treating pelvic discontinuity J Bone Joint Surg Am 99 2017 e43 28463925 \n25 Berry D.J. Lewallen D.G. Hanssen A. Cabanela M. Pelvic discontinuity in revision total hip arthroplasty J Bone Joint Surg Am 81 1999 1692 10608380\n\n",
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"keywords": "Acetabular insufficiency; Arthroplasty; Avascular necrosis; Graft versus host disease; Osteonecrosis",
"medline_ta": "Arthroplast Today",
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"title": "Acetabular Insufficiency Fractures in the Setting of Graft vs Host Disease: A Report of Two Cases.",
"title_normalized": "acetabular insufficiency fractures in the setting of graft vs host disease a report of two cases"
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"abstract": "Restrictive cardiomyopathy (RCM) is a rare cardiomyopathy in children, and its prognosis until now, has been poor. Recently some sarcomeric mutations have been reported as disease-causing genes of RCM. However, the genotype-phenotype correlation is not fully understood. Additionally, prognostic factors including sudden death in patients with RCM have not been elucidated. We report our experience in treating twin sisters with RCM or hypertrophic cardiomyopathy with RCM phenotype, both carriers of the same mutation in TNNI3, which encodes one of the major sarcomeric proteins in myofibrils. They were both diagnosed with RCM by cardiac catheterization at the age of 11 years. Despite appropriate follow-up and medical treatment, one died suddenly at the age of 11 years and the other also died at the age of 15 years due to heart failure while awaiting heart transplantation. In addition to our cases, other reports of younger fatal cases with RCM carrying TNNI3 mutations may suggest it as one of the prognostic factors. Genetic diagnosis is important in the clinical diagnosis, management, and treatment of cardiomyopathy. <Learning objective: Our cases involved twin sisters diagnosed with restrictive cardiomyopathy (RCM) with rare mutations in the cardiac troponin I. Based on their clinical course, this mutation appears to have a poor prognosis. It was reported that RCM was caused by sarcomere gene mutations, however, the relationship between genotype and phenotype is not clearly defined. To elucidate the prognosis of this rare disease not only the genetic mutations but the accumulation of various clinical outcomes is important.>.",
"affiliations": "Department of Pediatrics and Developmental Medicine, Hokkaido University, Graduate School of Medicine, Sapporo, Hokkaido, Japan.;Department of Pediatrics and Developmental Medicine, Hokkaido University, Graduate School of Medicine, Sapporo, Hokkaido, Japan.;Department of Pediatrics and Developmental Medicine, Hokkaido University, Graduate School of Medicine, Sapporo, Hokkaido, Japan.;Department of Pediatrics and Developmental Medicine, Hokkaido University, Graduate School of Medicine, Sapporo, Hokkaido, Japan.;Department of Pediatrics and Developmental Medicine, Hokkaido University, Graduate School of Medicine, Sapporo, Hokkaido, Japan.;Department of Pediatrics, Kushiro Red Cross Hospital, Kushiro, Hokkaido, Japan.;Department of Pediatrics and Developmental Medicine, Hokkaido University, Graduate School of Medicine, Sapporo, Hokkaido, Japan.;Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.",
"authors": "Ueno|Michihiko|M|;Takeda|Atsuhito|A|;Yamazawa|Hirokuni|H|;Takei|Kohta|K|;Furukawa|Takuo|T|;Suzuki|Yasuto|Y|;Chida-Nagai|Ayako|A|;Kimura|Akinori|A|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1016/j.jccase.2020.10.017",
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"issn_linking": "1878-5409",
"issue": "23(4)",
"journal": "Journal of cardiology cases",
"keywords": "Cardiac troponin I; Mutation; Restrictive cardiomyopathy; Twins",
"medline_ta": "J Cardiol Cases",
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"pages": "154-157",
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"pubdate": "2021-04",
"publication_types": "D002363:Case Reports",
"references": "16020591;21533915;25741868;22112859;29907873;12531876;30279906;16288990;22843787;19449150",
"title": "A case report: Twin sisters with restrictive cardiomyopathy associated with rare mutations in the cardiac troponin I gene.",
"title_normalized": "a case report twin sisters with restrictive cardiomyopathy associated with rare mutations in the cardiac troponin i gene"
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