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"abstract": "We report two patients with minocycline-induced pigmentation of the sclerae. Cutaneous pigmentation is a well-recognized complication of minocycline therapy, but only five cases of pigmentation of the sclerae have been described previously. These five patients have a number of features in common with the two reported here. We propose that these patients represent the most severe end of the spectrum of minocycline-induced cutaneous changes. Patients should be warned about the possibility of the occurrence of pigmentary changes before starting therapy.",
"affiliations": "Department of Dermatology, Bristol Royal Infirmary, U.K.",
"authors": "Sabroe|R A|RA|;Archer|C B|CB|;Harlow|D|D|;Bradfield|J W|JW|;Peachey|R D|RD|",
"chemical_list": "D000900:Anti-Bacterial Agents; D008911:Minocycline",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-0963",
"issue": "135(2)",
"journal": "The British journal of dermatology",
"keywords": null,
"medline_ta": "Br J Dermatol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D006801:Humans; D008297:Male; D008911:Minocycline; D010859:Pigmentation Disorders; D015422:Scleral Diseases",
"nlm_unique_id": "0004041",
"other_id": null,
"pages": "314-6",
"pmc": null,
"pmid": "8881683",
"pubdate": "1996-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Minocycline-induced discolouration of the sclerae.",
"title_normalized": "minocycline induced discolouration of the sclerae"
} | [
{
"companynumb": "GB-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-136297",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE"
... |
{
"abstract": "Pyoderma gangrenosum (PG) is a rare, ulcerative neutrophilic dermatosis that has been reported in association with certain medications. Recognition of medications that trigger PG may help to better understand the pathogenesis of the condition and to provide earlier diagnosis and treatment for affected patients. Herein, we report a case of new-onset PG following initiation of the checkpoint inhibitor pembrolizumab for the treatment of metastatic cutaneous squamous cell carcinoma. Our case was resistant to intralesional corticosteroid therapy, but ultimately improved with systemic corticosteroids and cessation of pembrolizumab.",
"affiliations": "Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. htsibris@bwh.harvard.edu.",
"authors": "Tsibris|Hillary|H|;Lian|Christine|C|;Ho|Allen|A|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "27(4)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D002294:Carcinoma, Squamous Cell; D006801:Humans; D008297:Male; D061206:Neoplasm Micrometastasis; D010307:Parotid Neoplasms; D061026:Programmed Cell Death 1 Receptor; D017511:Pyoderma Gangrenosum; D012867:Skin; D012878:Skin Neoplasms",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33999581",
"pubdate": "2021-04-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pembrolizumab-associated pyoderma gangrenosum in a patient with metastatic squamous cell carcinoma.",
"title_normalized": "pembrolizumab associated pyoderma gangrenosum in a patient with metastatic squamous cell carcinoma"
} | [
{
"companynumb": "US-MYLANLABS-2021M1040688",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Extranodal natural killer/T-cell lymphoma (ENKTL) is a distinct subtype of non-Hodgkin's lymphoma and is rare in the colon. Synchronous adenocarcinoma and ENKTL of the colon has not been reported in the literature. In the present study, we report a 63-year-old male who suffered from intermittent bloody stools for 2 mo. He did not have fever, body weight loss or night sweat. Endoscopic and imaging studies revealed a 4.5-cm ulcerative mass in the ascending colon and a 3.0-cm polypoid, easy bleeding mass in the sigmoid colon, respectively. Thought to have double carcinoma of the colon, he received simultaneous right hemicolectomy and sigmoidectomy. The pathological diagnosis was a synchronous ENKTL (ascending colon) and adenocarcinoma (sigmoid colon). The literature on synchronous adenocarcinoma and malignant lymphoma of the colon was also reviewed.",
"affiliations": "Department of Anatomic Pathology, Buddhist Dalin Tzu Chi General Hospital, Chiayi 62247, Taiwan.",
"authors": "Tseng|Chih-En|CE|;Shu|Ta-Wen|TW|;Lin|Chih-Wen|CW|;Liao|Kai-Sheng|KS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v19.i11.1850",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "19(11)",
"journal": "World journal of gastroenterology",
"keywords": "Colonic adenocarcinoma; Colonic lymphoma; Epstein-Barr virus; Extranodal natural killer/T-cell lymphoma; Synchronous cancers of the colon",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000230:Adenocarcinoma; D001706:Biopsy; D017024:Chemotherapy, Adjuvant; D003082:Colectomy; D003110:Colonic Neoplasms; D003113:Colonoscopy; D017809:Fatal Outcome; D006801:Humans; D008175:Lung Neoplasms; D054391:Lymphoma, Extranodal NK-T-Cell; D008297:Male; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary; D012811:Sigmoid Neoplasms; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "1850-4",
"pmc": null,
"pmid": "23555176",
"pubdate": "2013-03-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "7567744;21317926;11504842;6389052;21196657;20940198;19118782;3366441;3928946;12691165;15687889;12562254;20601338;12208733;9332679;22792536;984025;9167378",
"title": "Synchronous adenocarcinoma and extranodal natural killer/T-cell lymphoma of the colon: a case report and literature review.",
"title_normalized": "synchronous adenocarcinoma and extranodal natural killer t cell lymphoma of the colon a case report and literature review"
} | [
{
"companynumb": "TW-CONCORDIA PHARMACEUTICALS INC.-GSH201809-003160",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"dru... |
{
"abstract": "BACKGROUND\nSome evidence suggests that off-label use of mirtazapine (15 mg) is effective in treatment of acute antipsychotic-associated akathisia (AAA). We analyzed whether a lower dose of mirtazapine (7.5 mg) maintained its antiakathisia properties while exhibiting better tolerability in patients with schizophrenia and mood disorders who developed acute AAA.\n\n\nMETHODS\nMedical charts were retrospectively evaluated for 12 patients with AAA. All scored at least 2 (mild akathisia) on the Barnes Akathisia Rating Scale (BARS) and were treated with mirtazapine (7.5 mg) for a mean of 10.3 days.\n\n\nRESULTS\nThere was a statistically significant decrease in the BARS subjective, distress, and global (P < 0.01 to P < 0.001), but not objective (P = 0.63), subscales. Five participants (41.6%) fulfilled the predefined criterion of response, a decrease of at least 2 points on the BARS global subscale. The positive antiakathisia effect of mirtazapine was observed predominantly in aripiprazole-treated patients. Mirtazapine (7.5 mg) was well tolerated, and no clinically significant adverse effects, primarily drowsiness or increased appetite, were reported.\n\n\nCONCLUSIONS\nA large-scale controlled evaluation is warranted to substantiate clinical utility of off-label use of mirtazapine (7.5 mg) for patients with AAA.",
"affiliations": null,
"authors": "Poyurovsky|Michael|M|;Weizman|Abraham|A|",
"chemical_list": "D014150:Antipsychotic Agents; D058830:Serotonin 5-HT2 Receptor Antagonists; D000078785:Mirtazapine",
"country": "United States",
"delete": false,
"doi": "10.1097/JCP.0000000000000972",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0271-0749",
"issue": "38(6)",
"journal": "Journal of clinical psychopharmacology",
"keywords": null,
"medline_ta": "J Clin Psychopharmacol",
"mesh_terms": "D000328:Adult; D017109:Akathisia, Drug-Induced; D014150:Antipsychotic Agents; D005260:Female; D006801:Humans; D008297:Male; D001523:Mental Disorders; D008875:Middle Aged; D000078785:Mirtazapine; D056687:Off-Label Use; D017063:Outcome Assessment, Health Care; D058830:Serotonin 5-HT2 Receptor Antagonists; D055815:Young Adult",
"nlm_unique_id": "8109496",
"other_id": null,
"pages": "609-611",
"pmc": null,
"pmid": "30300293",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Very Low-Dose Mirtazapine (7.5 mg) in Treatment of Acute Antipsychotic-Associated Akathisia.",
"title_normalized": "very low dose mirtazapine 7 5 mg in treatment of acute antipsychotic associated akathisia"
} | [
{
"companynumb": "IL-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-194117",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"dr... |
{
"abstract": "Immune checkpoint inhibitors, such as nivolumab, a programmed death receptor-1 (PD-1) inhibitor, have dramatically improved the treatment of advanced melanomas. Chemosaturation with percutaneous hepatic perfusion (PHP) delivers chemotherapy in high doses directly to the liver and is a potentially effective treatment modality in metastatic uveal melanoma with liver metastases. Its safety and effectiveness have not been studied in patients also receiving immunotherapy. A 46-year-old male with a history of uveal melanoma of the right eye was found to have liver metastases. He was treated with PHP using high-dose melphalan for 6 months with a partial response followed by progression. Two months after his last PHP treatment, the patient was started on nivolumab. After two doses of nivolumab, the patient developed severe hepatitis that progressed to fulminant hepatic failure and death despite treatment with high-dose corticosteroids and mycophenolate mofetil. Nivolumab and other immune checkpoint inhibitors have been effective in treating advanced melanoma and extending life. However, there are serious immune adverse events that can occur. While hepatitis after taking nivolumab has been documented, fulminant hepatic failure is rare. We believe that prior PHP treatment contributed to the severity of the hepatitis and, ultimately, fulminant hepatic failure. To our knowledge, this is the only case of fulminant hepatic failure secondary to a checkpoint inhibitor with preceding PHP. Specific precautions should be made in patients who have been exposed to PHP in the past, and further studies should be done to assess the safety of using checkpoint inhibitors after PHP.",
"affiliations": "The University of Texas at Austin Dell Medical School, Austin, Texas, USA.;Texas Oncology, Austin, Texas, USA.",
"authors": "Teal|Lindsey|L|;Yorio|Jeffrey|J|https://orcid.org/0000-0002-2750-2823",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/8870334",
"fulltext": "\n==== Front\nCase Rep Oncol Med\nCase Rep Oncol Med\nCRIONM\nCase Reports in Oncological Medicine\n2090-6706\n2090-6714\nHindawi\n\n10.1155/2021/8870334\nCase Report\nFulminant Hepatic Failure after Chemosaturation with Percutaneous Hepatic Perfusion and Nivolumab in a Patient with Metastatic Uveal Melanoma\nTeal Lindsey 1\nhttps://orcid.org/0000-0002-2750-2823\nYorio Jeffrey jeff.yorio@usoncology.com\n2\n1The University of Texas at Austin Dell Medical School, Austin, Texas, USA\n2Texas Oncology, Austin, Texas, USA\nAcademic Editor: Ossama W. Tawfik\n\n2021\n29 3 2021\n2021 887033428 4 2020\n1 3 2021\n11 3 2021\nCopyright © 2021 Lindsey Teal and Jeffrey Yorio.\n2021\nThis 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.\nImmune checkpoint inhibitors, such as nivolumab, a programmed death receptor-1 (PD-1) inhibitor, have dramatically improved the treatment of advanced melanomas. Chemosaturation with percutaneous hepatic perfusion (PHP) delivers chemotherapy in high doses directly to the liver and is a potentially effective treatment modality in metastatic uveal melanoma with liver metastases. Its safety and effectiveness have not been studied in patients also receiving immunotherapy. A 46-year-old male with a history of uveal melanoma of the right eye was found to have liver metastases. He was treated with PHP using high-dose melphalan for 6 months with a partial response followed by progression. Two months after his last PHP treatment, the patient was started on nivolumab. After two doses of nivolumab, the patient developed severe hepatitis that progressed to fulminant hepatic failure and death despite treatment with high-dose corticosteroids and mycophenolate mofetil. Nivolumab and other immune checkpoint inhibitors have been effective in treating advanced melanoma and extending life. However, there are serious immune adverse events that can occur. While hepatitis after taking nivolumab has been documented, fulminant hepatic failure is rare. We believe that prior PHP treatment contributed to the severity of the hepatitis and, ultimately, fulminant hepatic failure. To our knowledge, this is the only case of fulminant hepatic failure secondary to a checkpoint inhibitor with preceding PHP. Specific precautions should be made in patients who have been exposed to PHP in the past, and further studies should be done to assess the safety of using checkpoint inhibitors after PHP.\n==== Body\n1. Introduction\n\nMelanoma incidence continues to rise, and unresectable metastatic melanoma is associated with high mortality [1]. Uveal melanoma is a rare subtype of melanoma that progresses to metastatic disease in over 50% of patients [2]. Approximately 20-30% of patients will die of systematic metastases within 5 years of being diagnosed [3]. The development of immune checkpoint inhibitors, particularly those targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death-1 (PD-1), has dramatically improved long-term prognosis for patients with advanced cutaneous melanomas [4–7]. However, responses in advanced uveal melanoma have been very limited, so there remains no FDA-approved standard of care for metastatic uveal melanoma [8].\n\nImmune checkpoints mediate immune response and prevent tissue damage [5]. Immune checkpoint receptors, such as PD-1 and CTLA-4, serve as an “off switch” for T-cell functions in tissues, such as destroying other cells [6]. Tumor cells take advantage of this by upregulating ligands for PD-1, thereby blocking the antitumor response. Anti-PD-1 inhibitors block this PD-1 pathway and serve as an “on switch” to allow for the antitumor response to take place and cause tumor regression.\n\nAnti-PD-1 inhibitors, such as nivolumab, serve as an ideal treatment option for uveal melanoma due to their low side effect profile. However, anti-PD-1 inhibitors have been known to induce relatively mild immune-related adverse events (irAEs) such as fatigue, pruritis, and arthritis [9, 10]. Serious adverse events occur in <10% of patients taking nivolumab and include interstitial pneumonitis, hepatitis, hypothyroidism, diarrhea/colitis, adrenal insufficiency, and pituitary insufficiency [9, 11, 12]. The incidence of grade 3 or 4 immune-related hepatitis is only seen in about 1% of patients, while fulminant hepatic failure has only rarely been reported [9, 13].\n\nChemosaturation with percutaneous hepatic perfusion (PHP) is a therapy that delivers chemotherapy in high doses directly to the liver with the goal of targeting hepatic metastases [14, 15]. One phase III randomized trial in patients primarily with uveal melanoma with liver metastases demonstrated a significant improvement in progression-free survival (PFS) from 1.6 months to 5.4 months when compared to the best available care. Further clinical trials are being done in the United States, but it is currently used as a treatment for uveal melanoma in other countries [16]. Early animal studies have shown high rates of bone marrow depression, but studies have not measured the effect it may have when given with immunotherapy [15].\n\nWe present the case of a patient with metastatic uveal melanoma treated with PHP followed by nivolumab who developed fulminant hepatic failure.\n\n2. Case Presentation\n\nA 46-year-old man with no significant past medical history presented with blurry vision and was ultimately diagnosed with choroidal melanoma of the right eye. He underwent plaque brachytherapy and was followed with surveillance imaging. Fifteen months after his original diagnosis, MRI abdomen revealed multiple hepatic lesions. A CT-guided liver biopsy of one of the lesions was performed, and pathology confirmed metastatic uveal melanoma. Initial staging showed only liver metastases. The patient travelled to the United Kingdom and received four cycles of chemosaturation with PHP using high-dose melphalan over a 6-month period. Repeat imaging initially showed a partial response to this treatment in the liver. After 6 months, the patient started to complain of rib pain and back pain. A PET/CT scan revealed diffuse bony metastases. He was treated with palliative radiation prior to initiation of nivolumab at 3 mg/kg every two weeks.\n\nShortly after the first cycle of nivolumab, he began having mild right upper quadrant pain, low-grade fevers, diaphoresis, and fatigue. Two weeks later, he was given a second dose of nivolumab. Then, one week after that, his right upper quadrant abdominal pain worsened, and he was found to have an aspartate aminotransferase (AST) level of 310 U/L, alanine aminotransferase (ALT) of 187 U/L, alkaline phosphatase of 713 U/L, and total bilirubin of 3.8 mg/dL (Figure 1). Clinical exam revealed marked hepatomegaly. Given his extensive liver metastases, there was an initial question about progression of his disease versus an autoimmune hepatitis, so a PET/CT scan was performed revealing an enlarged liver along with diffusely homogenous uptake in the liver. This suggested a diffuse inflammatory process involving the entire liver rather than progression of metastatic disease which would have shown more heterogeneous FDG avidity corresponding to the sites of tumor activity (Figure 2).\n\nThe patient was admitted to the hospital, and further lab workup including anti-nuclear antibodies, anti-smooth muscle antibodies, anti-liver kidney antibodies, anti-mitochondrial antibodies, and IgG levels was all unremarkable. The patient was started on high-dose intravenous Solumedrol and liver function tests (LFTs), and symptoms initially improved during his first few hospital days. However, on the fourth hospital day (day 26 in Figure 1), his condition dramatically declined. His LFTs rose rapidly to the thousands, resulting in fulminant liver failure. He then developed acute renal failure, anion gap metabolic acidosis, and hyperkalemia. The patient was placed on a bicarbonate drip, and efforts were made to reverse his acidosis to stabilize him; however, his condition continued to decline and LFTs continued to worsen (AST: 7,708 U/L, ALT: 3,131 U/L, alkaline phosphatase: 817 U/L, and total bilirubin: 11.9 mg/dL). Mycophenolate mofetil 1,000 mg IV was administered with no improvement. The patient was not a liver transplant candidate because of his metastatic cancer diagnosis. The fulminant hepatic failure was irreversible and led to death secondary to cardiorespiratory arrest.\n\n3. Discussion\n\nTo our knowledge, this is the first reported case of fulminant hepatic failure secondary to nivolumab in a patient with prior PHP treatment. Immune-related hepatitis from PD-1 inhibitors is usually mild-to-moderate and self-limited, but in less than 1.0% of the patients, the hepatitis is considered severe [17]. This is a result of impaired self-tolerance from the loss of T-cell inhibition and can lead to autoimmune-related inflammation in normal, noncancerous tissues. These adverse events can usually be treated by modulating the immune system with steroids or other immunosuppressing agents, but in some cases, such as this one, it can be fatal.\n\nMild-to-moderate hepatitis usually occurs between 6 and 14 weeks after starting treatment; however, the patient in our case developed hepatitis in under 4 weeks after starting treatment [18]. One study found that liver toxicity was most commonly seen after 2 to 6 cycles of nivolumab, which aligns with our case [17]. However, there is no established timeline for fulminant liver failure, as it is rare and has only been reported a handful of times in the literature. One case of fulminant hepatic failure due to nivolumab was reported in October 2018 [19]. However, this patient was also taking a CTLA-4 inhibitor, ipilimumab, concurrently. The combination of CTLA-4 and PD-1 blockade is known to cause a higher incidence of hepatitis than single-drug immunotherapy, with the incidence being 6.9% and 1%, respectively [20]. Another patient taking nivolumab after carboplatin and gemcitabine suffered from fulminant hepatic failure [21]. In 2018, a patient with malignant melanoma underwent 17 cycles of nivolumab before developing grade 4 ALT elevation [22]. After steroids, his ALT did not recover to normal range, even after 5 months. Fulminant hepatic failure has also been seen with the PD-1 inhibitor, pembrolizumab [23].\n\nIn this case, the patient had been previously exposed to PHP to treat liver metastases from uveal melanoma. As discussed above, in phase 3 randomized controlled trials (RCTs), PHP has been shown to be efficacious when compared to chemotherapy, but it can also lead to adverse events. One RCT found the rate of grade 3 or 4 hepatic dysfunction, diagnosed by hyperbilirubinemia, to be 14.3% [16]. There were also 5.7% of patients in the RCT that discontinued treatment because of hepatic toxicity, diagnosed by hyperbilirubinemia (5.7%), increase in ALT (2.9%), and increase in AST (2.9%) [16]. One retrospective review of 14 patients who underwent PHP found 1 patient who had hepatic failure that resulted in death [24].\n\nThere is limited knowledge regarding concurrent immunotherapy and PHP treatment, as patients undergoing immunotherapy have been excluded from PHP RCTs [16]. However, there is a case report of a man who began immunotherapy with ipilimumab 10 weeks after PHP, resulting in gallbladder toxicity [25]. In our case, the patient had normal LFTs after receiving PHP and before starting nivolumab. It was not until he received two doses of nivolumab that his LFTs began to quickly escalate. Given his prior PHP treatments, he may have been at increased risk for immune-related hepatitis from nivolumab.\n\n4. Conclusion\n\nIn conclusion, since fulminant hepatic failure from nivolumab alone is rare and PHP is also known to cause hepatic toxicity and hepatic failure, we believe that PHP preceding nivolumab contributed to fulminant hepatic failure. Healthcare providers should use caution in starting immunotherapy for patients who have previously received PHP therapy. Careful monitoring of liver function tests and early intervention for hepatic deterioration should be implemented in all patients receiving immunotherapy.\n\nAbbreviations\n\nALT: Alanine aminotransferase\n\nAST: Aspartate aminotransferase\n\nCTLA-4: Cytotoxic T-lymphocyte-associated protein 4\n\nLFT: Liver function test\n\nPD-1: Programmed death 1 receptor\n\nPD-L1: Programmed death 1 receptor ligand\n\nPHP: Percutaneous hepatic perfusion\n\nRCT: Randomized controlled trial.\n\nData Availability\n\nThe datasets generated and/or analyzed during the current study are not publicly available due to individual privacy but are available from the corresponding author on reasonable request.\n\nConsent\n\nConsent for publication was unable to be obtained from family members after multiple attempts. No identifiers have been used.\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nAuthors' Contributions\n\nAll authors contributed to the collection of data and writing of the manuscript. All authors read and approved the final manuscript.\n\nFigure 1 Liver function tests before, during, and after 2 cycles of nivolumab. The dates are numbered starting with the first day of the first cycle of nivolumab. AST: aspartate aminotransferase; ALT: alanine aminotransferase; day 1∗: start of the 1st cycle of nivolumab; day 14∗: start of the 2nd cycle of nivolumab; day 22∗: 1st dose of corticosteroids. The graph shows the rapid increase in liver function tests after the patient began taking nivolumab and the minor response after being treated with corticosteroids. It also depicts the timeline until the patient perspired.\n\nFigure 2 PET/CT scan of the abdomen. (a) One month prior to the first cycle of nivolumab: multiple intrahepatic lesions. (b) Day 22 after the first cycle of nivolumab: significant hepatomegaly due to hepatitis, significant increased metabolic activity of the entire liver, and new abdominal ascites. The PET/CT scan of the patient abdomen depicts the changes in the patient's liver before and after starting nivolumab. The second picture shows the large size of the liver when the patient developed autoimmune hepatitis.\n==== Refs\n1 Matthews N. H. Li W. Q. Qureshi A. A. Weinstock M. A. Cho E. Epidemiology of melanoma Exon Publications 2017 30 3 22\n2 Singh A. D. Turell M. E. Topham A. K. Uveal melanoma: trends in incidence, treatment, and survival Ophthalmology 2011 118 9 1881 1885 10.1016/j.ophtha.2011.01.040 2-s2.0-80052494912 21704381\n3 Kujala E. Mäkitie T. Kivelä T. Very long-term prognosis of patients with malignant uveal melanoma Investigative Ophthalmology & Visual Science 2003 44 11 4651 4659 10.1167/iovs.03-0538 2-s2.0-0142200859 14578381\n4 Komatsubara K. M. Carvajal R. D. Immunotherapy for the treatment of uveal melanoma: current status and emerging therapies Current Oncology Reports 2017 19 7 p. 45 10.1007/s11912-017-0606-5 2-s2.0-85019214085\n5 Pardoll D. M. The blockade of immune checkpoints in cancer immunotherapy Nature Reviews. Cancer 2012 12 4 252 264 10.1038/nrc3239 2-s2.0-84858766182 22437870\n6 Boussiotis V. A. Chatterjee P. Li L. Biochemical signaling of PD-1 on T cells and its functional implications Cancer Journal (Sudbury, Mass) 2014 20 4 265 271 10.1097/PPO.0000000000000059 2-s2.0-84905966344 25098287\n7 Hodi F. S. Chiarion-Sileni V. Gonzalez R. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial The Lancet Oncology 2018 19 11 1480 1492 10.1016/S1470-2045(18)30700-9 2-s2.0-85056160653 30361170\n8 Yang J. Manson D. K. Marr B. P. Carvajal R. D. Treatment of uveal melanoma: where are we now? Therapeutic Advances in Medical Oncology 2018 10, article 1758834018757175 10.1177/1758834018757175 2-s2.0-85049799231\n9 Robert C. Long G. V. Brady B. Nivolumab in previously untreated melanoma without BRAF mutation The New England Journal of Medicine 2015 372 4 320 330 10.1056/NEJMoa1412082 2-s2.0-84925222119 25399552\n10 Naidoo J. Page D. B. Li B. T. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies Annals of Oncology 2015 26 12 2375 2391 10.1093/annonc/mdv383 2-s2.0-84949988089 26371282\n11 Topalian S. L. Hodi F. S. Brahmer J. R. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer The New England Journal of Medicine 2012 366 26 2443 2454 10.1056/NEJMoa1200690 2-s2.0-84862859820 22658127\n12 Gelsomino F. Vitale G. D’errico A. Bertuzzi C. Andreone P. Ardizzoni A. Nivolumab-induced cholangitic liver disease: a novel form of serious liver injury Annals of Oncology 2016 28 3 671 672 10.1093/annonc/mdw649 2-s2.0-85018258494\n13 Spain L. Diem S. Larkin J. Management of toxicities of immune checkpoint inhibitors Cancer Treatment Reviews 2016 44 51 60 10.1016/j.ctrv.2016.02.001 2-s2.0-84975728236 26874776\n14 de Leede E. M. Burgmans M. C. Meijer T. S. Prospective clinical and pharmacological evaluation of the Delcath system’s second-generation (GEN2) hemofiltration system in patients undergoing percutaneous hepatic perfusion with melphalan Cardiovascular and Interventional Radiology 2017 40 8 1196 1205 10.1007/s00270-017-1630-4 2-s2.0-85018366341 28451811\n15 Moeslein F. M. McAndrew E. G. Appling W. M. Evaluation of Delcath systems’ generation 2 (GEN 2) melphalan hemofiltration system in a porcine model of percutaneous hepatic perfusion Cardiovascular and Interventional Radiology 2014 37 3 763 769 10.1007/s00270-013-0826-5 2-s2.0-84901654434 24402644\n16 Hughes M. S. Zager J. Faries M. Results of a randomized controlled multicenter phase III trial of percutaneous hepatic perfusion compared with best available care for patients with melanoma liver metastases Annals of Surgical Oncology 2016 23 4 1309 1319 10.1245/s10434-015-4968-3 2-s2.0-84947945370 26597368\n17 Abdel-Rahman O. ElHalawani H. Fouad M. Risk of elevated transaminases in cancer patients treated with immune checkpoint inhibitors: a meta-analysis Expert Opinion on Drug Safety 2015 14 10 1507 1518 10.1517/14740338.2015.1085969 2-s2.0-84942294585 26394770\n18 Weber J. S. Kähler K. C. Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab Journal of Clinical Oncology 2012 30 21 2691 2697 10.1200/JCO.2012.41.6750 2-s2.0-84864052441 22614989\n19 Bhave P. Buckle A. Sandhu S. Sood S. Mortality due to immunotherapy related hepatitis Journal of Hepatology 2018 69 4 976 978 10.1016/j.jhep.2018.06.012 2-s2.0-85052759681 30093162\n20 Fujiwara N. Friedman S. L. Goossens N. Hoshida Y. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine Journal of Hepatology 2018 68 3 526 549 10.1016/j.jhep.2017.09.016 2-s2.0-85035013654 28989095\n21 Sarmen S. Tara S. Acute liver failure from anti-PD-1 antibody nivolumab in a patient with metastatic lung squamous cell carcinoma Austin Oncology 2016 1 2 p. 1006\n22 Matsubara T. Nishida T. Higaki Y. Nivolumab induces sustained liver injury in a patient with malignant melanoma Internal Medicine 2018 57 12 1789 1792 10.2169/internalmedicine.9851-17 2-s2.0-85046402242 29434164\n23 Wu Z. Lai L. Li M. Zhang L. Zhang W. Acute liver failure caused by pembrolizumab in a patient with pulmonary metastatic liver cancer: a case report Medicine 2017 96 51 p. e9431 10.1097/MD.0000000000009431 2-s2.0-85039757213 29390572\n24 Boone B. A. Perkins S. Bandi R. Hepatic artery infusion of melphalan in patients with liver metastases from ocular melanoma Journal of Surgical Oncology 2018 117 5 940 946 10.1002/jso.24984 2-s2.0-85047825989 29878390\n25 Idris A. F. Martin M. J. Davidson I. R. O’Sullivan G. J. Jamaludin A. A. Donnellan P. P. Ocular melanoma liver metastases treated by percutaneous hepatic perfusion with melphalan followed by ipilimumab: a case report Journal of Clinical Oncology 2017 31 15, article e20008 10.1200/jco.2013.31.15_suppl.e20008\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2021()",
"journal": "Case reports in oncological medicine",
"keywords": null,
"medline_ta": "Case Rep Oncol Med",
"mesh_terms": null,
"nlm_unique_id": "101581035",
"other_id": null,
"pages": "8870334",
"pmc": null,
"pmid": "33859852",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "26874776;29434164;29497459;28508938;29878390;25098287;26371282;26394770;27993797;22437870;22614989;28989095;21704381;22658127;25399552;30093162;24402644;26597368;14578381;28451811;29390572;30361170",
"title": "Fulminant Hepatic Failure after Chemosaturation with Percutaneous Hepatic Perfusion and Nivolumab in a Patient with Metastatic Uveal Melanoma.",
"title_normalized": "fulminant hepatic failure after chemosaturation with percutaneous hepatic perfusion and nivolumab in a patient with metastatic uveal melanoma"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/21/0135380",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MELPHALAN HYDROCHLORIDE"
},
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{
"abstract": "OBJECTIVE\nUnexplained liver injury including fibrosis and portal hypertension has rarely been reported among patients with HIV in the absence of co-infection with hepatitis B (HBV) or hepatitis C (HCV). We describe a series of HIV mono-infected patients with evidence of non-cirrhotic portal hypertension.\n\n\nMETHODS\nHIV-infected patients with evidence of portal hypertension who were anti-HBV and anti-HCV negative and HBV and HCV RNA polymerase chain reaction (PCR) negative were identified from patients managed by the Victorian statewide HIV referral service located at The Alfred Hospital, Melbourne. Portal hypertension was defined as either radiological or endoscopic evidence of varices, portal vein flow obstruction, or elevated hepatic venous pressure gradient (HPVG).\n\n\nRESULTS\nFive patients were found to have portal hypertension. These patients were male, aged 41 to 65 years, with known duration of HIV infection between 11 to 25 years. All had been treated with antiretroviral therapy, including didanosine. Tests for metabolic, autoimmune, and hereditary causes of liver disease failed to establish an etiology for the liver injury. All had radiological or endoscopic findings of varices, and four patients had radiological features of portal vein obstruction or flow reversal. Only one patient underwent HPVG measurement, which was elevated. Non-invasive fibrosis assessment revealed increased liver stiffness in three (out of four) patients, and no cirrhotic features were found on those who underwent liver biopsy.\n\n\nCONCLUSIONS\nTo our knowledge, this is the largest published series of non-cirrhotic portal hypertension in HIV mono-infected patients in Australia. Further research is needed to understand what relationship, if any, HIV or its treatments might have on liver injury over time.",
"affiliations": "Department of Gastroenterology, The Alfred Hospital Infectious Diseases Unit, The Alfred Hospital, Australia.",
"authors": "Jackson|Belinda D|BD|;Doyle|Joseph S|JS|;Hoy|Jennifer F|JF|;Roberts|Stuart K|SK|;Colman|John|J|;Hellard|Margaret E|ME|;Sasadeusz|Joseph J|JJ|;Iser|David M|DM|",
"chemical_list": "D044966:Anti-Retroviral Agents",
"country": "Australia",
"delete": false,
"doi": "10.1111/j.1440-1746.2012.07148.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0815-9319",
"issue": "27(9)",
"journal": "Journal of gastroenterology and hepatology",
"keywords": null,
"medline_ta": "J Gastroenterol Hepatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D044966:Anti-Retroviral Agents; D001315:Australia; D054459:Elasticity Imaging Techniques; D004932:Esophageal and Gastric Varices; D015658:HIV Infections; D006801:Humans; D006975:Hypertension, Portal; D008099:Liver; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8607909",
"other_id": null,
"pages": "1512-9",
"pmc": null,
"pmid": "22497527",
"pubdate": "2012-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Non-cirrhotic portal hypertension in HIV mono-infected patients.",
"title_normalized": "non cirrhotic portal hypertension in hiv mono infected patients"
} | [
{
"companynumb": "AU-ABBVIE-15P-008-1377230-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
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"drugadditional": null,
... |
{
"abstract": "A 62-year-old man presented to our hospital with multiple liver metastases of gastric gastrointestinal stromal tumor (GIST) in 2002.T he patient had undergone imatinib treatment for liver metastases as a participant in a clinical trial, and he had achieved complete response (CR) for 89 months.However, imatinib treatment was disrupted at the request of the patient. Progression of liver metastases was observed 18 months later.Imatinib treatment was reinitiated, and a partial response was obtained.Twenty -five months later, progression of disease was observed in segment 7 of the liver on an abdominal computed tomography (CT) scan. Partial imatinib-resistance was diagnosed, and partial resection of the lesion in S7 of the liver was performed in 2013. Imatinib therapy was continued after surgical intervention, and no progression has been detected for 10 months. Despite the beneficial effects of imatinib in patients with advanced GISTs, almost all patients have been reported to develop disease progression when imatinib is interrupted, even in lesions showing radiographic improvement.In the present case, after treatment with imatinib for 7 years, progression of liver metastases was observed upon discontinuation of therapy. Moreover, progression after disruption of imatinib may lead to the emergence of drug-resistant clones. We reported a case of recurrent GIST progressed after interruption of long-term imatinib therapy, which has been reported few times previously.",
"affiliations": "Dept. of Gastroenterological Surgery, Graduate School of Mmedicine, Osaka University.",
"authors": "Nakatsuka|Rie|R|;Takahashi|Tsuyoshi|T|;Miyazaki|Yasuhiro|Y|;Kurokawa|Yukinori|Y|;Yamasaki|Makoto|M|;Miyata|Hiroshi|H|;Nakajima|Kiyokazu|K|;Takiguchi|Shuji|S|;Mori|Masaki|M|;Doki|Yuichiro|Y|",
"chemical_list": "D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "41(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000970:Antineoplastic Agents; D001549:Benzamides; D018450:Disease Progression; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D000068877:Imatinib Mesylate; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D011743:Pyrimidines; D012008:Recurrence; D013274:Stomach Neoplasms; D013997:Time Factors",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2478-80",
"pmc": null,
"pmid": "25731563",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A case of recurrent gastrointestinal stromal tumor progressing after interruption of long-term imatinib therapy.",
"title_normalized": "a case of recurrent gastrointestinal stromal tumor progressing after interruption of long term imatinib therapy"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-97867",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "IMATINIB"
},
"drugadd... |
{
"abstract": "A 72-year-old man presented to the hospital with exacerbation of congestive heart failure. He was given furosemide 40 mg intravenously twice at 4 hours apart. At 4 hours after the second dose of furosemide, his white blood cells (WBC) dropped acutely from 9.8 to 2.4×109/L (reference range 4.1 to 9.3×109/L). With the discontinuation of furosemide, the WBC trended up to 7.1×109/L about 13 hours after the second dose of intravenous furosemide and remained in normal range for the next 3 days. However, when the oral furosemide was started on hospital day 4, there was a mild drop in WBC count, which returned to and maintained at baseline since the next day. The dynamic changes in the patient's WBC were coincident with the use of furosemide. The possible mechanisms of furosemide-associated transient hyperacute leucopenia were discussed.",
"affiliations": "IPC Healthcare/TeamHealth, Lake Mary, Florida, USA.",
"authors": "Ma|Ben-Jiang|BJ|",
"chemical_list": "D004232:Diuretics; D005665:Furosemide",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-218776",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "cardiovascular system; haematology (drugs and medicines)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D004232:Diuretics; D005665:Furosemide; D006333:Heart Failure; D006801:Humans; D007958:Leukocyte Count; D007970:Leukopenia; D008297:Male",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29167185",
"pubdate": "2017-11-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16352777;14573734;12473535;17279201;21366472;15303450;26240596;11684261;23341658;7113249;9691107;15644481",
"title": "Hyperacute leucopenia associated with furosemide.",
"title_normalized": "hyperacute leucopenia associated with furosemide"
} | [
{
"companynumb": "US-TEVA-2017-US-839714",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional": null,
... |
{
"abstract": "This study was performed to analyze the treatment outcome for diffuse large B-cell lymphoma (DLBCL) involving the head and neck and to evaluate the role of radiotherapy in the rituximab era. Fifty-six patients diagnosed with DLBCL involving the head and neck were assessed. All patients were treated with 6 cycles of rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone (R-CHOP). After chemotherapy, radiation was delivered to the head and neck area in a median dose of 36 Gy. Radiation was delivered using 3-dimensional radiotherapy (n = 25) or intensity-modulated radiotherapy (n = 31). Primary endpoints were relapse-free survival (RFS), overall survival (OS), and local control rate. After median follow-up time of 45 months, the 5-year RFS and OS rates were 72% and 61%, respectively. Fourteen (25%) of 56 patients relapsed; 1 had a local relapse, 11 had distant relapses, and 2 had both local and distant relapses. The final local control rate after radiotherapy was 94%. Age, performance status, international prognostic index score, and radiotherapy response were significant prognostic factors for both RFS and OS in the multivariate analysis. Incidence of acute grade 3 and 4 hematologic toxicity was 9% and 4%, respectively. Grade 3 nonhematologic toxicity occurred in 2 (4%) patients, and there was no grade 4 nonhematologic toxicity for the irradiated patients. Excellent local control and survival rates can be achieved with R-CHOP followed by radiotherapy in patients with DLBCL involving the head and neck. Treatment-related toxicity after the introduction of modern radiotherapy was acceptable and limited.",
"affiliations": "Department of Radiation Oncology, St. Vincent's Hospital Department of Radiation Oncology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.",
"authors": "Kwak|Yoo-Kang|YK|;Choi|Byung-Ock|BO|;Kim|Sung Hwan|SH|;Lee|Joo Hwan|JH|;Kang|Dae Gyu|DG|;Lee|Jong Hoon|JH|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000007268",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 28640132MD-D-17-0134810.1097/MD.0000000000007268072685700Research ArticleObservational StudyTreatment outcome of diffuse large B-cell lymphoma involving the head and neck Two-institutional study for the significance of radiotherapy after R-CHOP chemotherapyKwak Yoo-Kang MDaChoi Byung-Ock MDbKim Sung Hwan MDaLee Joo Hwan MDaKang Dae Gyu MSaLee Jong Hoon MDa∗Boros. Laszlo Geza a Department of Radiation Oncology, St. Vincent's Hospitalb Department of Radiation Oncology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.∗ Correspondence: Jong Hoon Lee, Department of Radiation Oncology, St. Vincent's Hospital, 442-723, 93-6, Ji-dong, Paldal-gu, Suwon, Kyeonggi-do, Seoul, Republic of Korea (e-mail: koppul@catholic.ac.kr).6 2017 23 6 2017 96 25 e72685 3 2017 17 5 2017 25 5 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. http://creativecommons.org/licenses/by-nd/4.0Abstract\nThis study was performed to analyze the treatment outcome for diffuse large B-cell lymphoma (DLBCL) involving the head and neck and to evaluate the role of radiotherapy in the rituximab era. Fifty-six patients diagnosed with DLBCL involving the head and neck were assessed. All patients were treated with 6 cycles of rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone (R-CHOP). After chemotherapy, radiation was delivered to the head and neck area in a median dose of 36 Gy. Radiation was delivered using 3-dimensional radiotherapy (n = 25) or intensity-modulated radiotherapy (n = 31). Primary endpoints were relapse-free survival (RFS), overall survival (OS), and local control rate. After median follow-up time of 45 months, the 5-year RFS and OS rates were 72% and 61%, respectively. Fourteen (25%) of 56 patients relapsed; 1 had a local relapse, 11 had distant relapses, and 2 had both local and distant relapses. The final local control rate after radiotherapy was 94%. Age, performance status, international prognostic index score, and radiotherapy response were significant prognostic factors for both RFS and OS in the multivariate analysis. Incidence of acute grade 3 and 4 hematologic toxicity was 9% and 4%, respectively. Grade 3 nonhematologic toxicity occurred in 2 (4%) patients, and there was no grade 4 nonhematologic toxicity for the irradiated patients. Excellent local control and survival rates can be achieved with R-CHOP followed by radiotherapy in patients with DLBCL involving the head and neck. Treatment-related toxicity after the introduction of modern radiotherapy was acceptable and limited.\n\nKeywords\nhead and necklymphomaradiotherapyrituximabOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nLymphoma is classified into Hodgkin lymphoma and non-Hodgkin lymphoma. Non-Hodgkin lymphoma is further categorized according to specific cell types. The most common type of non-Hodgkin lymphoma is diffuse large B-cell lymphoma (DLBCL), which comprises about 30% of all lymphomas.[1] The characteristic of DLBCL is its fast growing and aggressive feature. Staging of DLBCL, like other lymphomas, is done using the Ann Arbor staging system,[2] which classifies the disease according to the extent of the disease since it can develop in any location throughout the body. Among the lymph node groups, the head and neck region contains rich lymphatic chains and blood supplies in a relatively confined area. Although it is unusual to categorize DLBCL according to anatomical sites, we had a question whether the distinguishing anatomical features of the head and neck will influence the clinical features and treatment outcomes of the disease.\n\nStandard treatment for early-stage DLBCL is an abbreviated course (3 cycles) of chemotherapy followed by radiotherapy. In the advanced stage, a full course (6 cycles) of chemotherapy is the main treatment with optional radiotherapy to the initial bulky mass. However, the role of radiotherapy has been controversial and the results of reported studies are conflicting.[3–7] With the introduction of rituximab, the treatment outcomes of DLBCL improved, and the use of radiotherapy is gradually decreasing due to the increased treatment-related toxicity. Actually, the use of combined-modality therapy has significantly decreased after a peak of 47% in 2000 to 32% in 2012 at North America.[8] Three-dimensional conformal radiation therapy (3DCRT) employs several numbers of beams that are shaped to cover the target volume, and it uses conventional beam modifiers (eg, wedges, blocks, and compensating filters) to enhance the radiation conformity. Intensity-modulated radiotherapy (IMRT) can achieve even greater conformity by optimally modulating the intensity of individual beams and more homogeneous dose distribution with sharper fall-off of dose at target boundaries thereby sparing adjacent normal tissues. In terms of radiotherapy technique, the use of IMRT has become generalized recently. In this IMRT era, radiotherapy has become feasible with tolerable toxicity. IMRT is especially effective for treating lesions in the head and neck with acceptable toxicity.\n\nBased on the above subjects, we selected patients with DLBCL of the head and neck and analyzed the clinical features and treatment outcomes. Also, the role of radiotherapy in the treatment of head and neck DLBCL in the rituximab era was examined.\n\n2 Methods and materials\n2.1 Patients\nThe study included data of patients who were diagnosed with DLBCL of the head and neck treated with chemotherapy followed by radiotherapy from January 2006 to March 2015 at 2 tertiary institutions. Inclusion criteria were age ≥20 years, pathologically confirmed DLBCL, and receipt of radiotherapy in the head and neck area. We excluded the patients who did not receive chemotherapy prior to radiotherapy, had immunodeficiency virus infection, and had a history of other malignancies. For diagnosis and clinical workup, history taking, physical examination, complete blood counts, blood chemistry, bone marrow biopsy, tissue biopsy, and imaging studies including neck, chest, abdomen, and pelvis computed tomography (CT), and positron emission tomography (PET) CT were evaluated. All patients were staged according to the Ann Arbor staging system. A total of 56 patients were enrolled. This study was approved by the institutional review boards of each institution.\n\n2.2 Treatment\nAll patients received 6 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP) chemotherapy (rituximab: 375 mg/m2, cyclophosphamide: 750 mg/m2, doxorubicin: 50 mg/m2, vincristine: 1.4 mg/m2, and prednisolone: 100 mg orally, day 1–5).\n\nRadiotherapy simulation was performed in the supine position, and head and shoulder s-frame mask was used for immobilization. Enhanced neck CT was obtained in 3-mm slices. Radiation was delivered using 3-dimensional radiotherapy (n = 25) or IMRT (n = 31). Radiotherapy technique was chosen upon each clinician's policy. In South Korea, national health insurance program covered IMRT technique after July 2011 since IMRT could decrease the toxic effect such as mucositis and xerostomia in head and neck cancer patients. IMRT has been used broadly in the recent time. Thirty-four patients received involved-field radiotherapy (IFRT), and 22 patients received involved-site radiotherapy (ISRT) according to the clinician's policy. ISRT delivers a radiation only to the involved nodes or sites in the prechemotherapy CT images. IFRT covers the whole adjacent lymphatic regions of involved nodes or sites. Therefore, IFRT includes a wider region compared to ISRT, which increases the risk of radiation toxicity but can decrease the risk of locoregional recurrence. Radiation was administered in a median dose of 36 Gy (range, 24–54 Gy) at 1.8 to 2 Gy per fraction, once daily, 5 times a week. Median treatment time was 25 days (range, 14–43 days).\n\n2.3 Assessment\nEnhanced neck CT and PET-CT were used for treatment response assessment. According to the response criteria for malignant lymphoma,[9] complete response (CR) was defined as disappearance of all evidence of disease with Deuville score 3 to 5.[10] Partial response (PR) was defined as regression of measurable disease and no new sites. Progressive disease (PD) was defined as any new lesion or increase by ≥50% of previously involved sites from nadir. Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. International prognostic index (IPI) consisted of age, stage, Eastern Cooperative Oncology Group performance status, extra-nodal involvement, and lactate dehydrogenase level, and it was scored from 0 to 5. In our study, upper normal limit of lactate dehydrogenase level was 230 IU/L.\n\nPatients were interviewed weekly during the treatment, monthly for 3 months after the treatment, and every 3 months thereafter. Overall survival (OS) was defined as the period from the date of pathologic diagnosis to death from any cause. Relapse-free survival (RFS) was defined as the period from the date of pathologic diagnosis to the date of any relapse or death. Local control (LC) was defined as absence of tumor regrowth in the irradiated area. Adverse effects of radiotherapy were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). Incidence of toxicity grade ≥2 was recorded.\n\n2.4 Statistical analyses\nPrimary endpoints of this study were OS, RFS, and local control rate. Secondary endpoints were toxicity caused by multimodality therapy and pattern of relapse after radiotherapy. Kaplan–Meier analysis with the log-rank test was used for the univariate survival analysis. To evaluate the prognostic factors related to recurrence and survival, multivariate analysis was performed with the Cox regression method. A P-value <.05 was considered as a statistically significant one. Factors with P-value <.05 in the univariate analysis were entered for multivariate analysis. All statistical analyses were performed using R software version 3.1.2 (R Foundation for Statistical Computing, Vienna, Austria; www.r-project.org).\n\n3 Results\nTable 1 shows characteristics of the enrolled patients. Median age was 57 years. Among these 56 patients, 46 patients (82%) had a low and low-intermediate IPI score. Patients were further classified according to the location involved; 52% of patients had lesions in Waldeyer ring, 14% of patients had lesions in lymph nodes, 20% of patients had lesions in the nasal cavity and paranasal sinuses, and 14% of patients had lesions in other sites such as the submandibular gland, thyroid, and lacrimal sac (Fig. 1). Nodal disease was defined as lesions involving lymph nodes and Waldeyer ring. Thus, 37 patients (66%) had nodal diseases. Initial Ann Arbor stages III and IV were found in 11 patients (20%); these patients had residual or relapsed disease in the head and neck area only after chemotherapy.\n\nTable 1 Patient characteristics (n = 56).\n\nFigure 1 Pie graph describes the proportion of patients according to the involved site. ∗Other sites: thyroid, lacrimal sac, submandibular gland. PNS = paranasal sinus.\n\n3.1 Treatment response\nMedian time interval for radiotherapy and response evaluation was 2 months. After chemotherapy, 39 patients (74%) achieved CR, 6 patients (11%) had PR, and 8 patients (15%) had PD. After radiotherapy, 38 patients maintained CR; 1 patient showed distant relapse. Among the 6 patients with PR after chemotherapy, 3 patients achieved CR, 2 patients had PR, and 1 patient had PD. Among the 8 patients with PD, 3 patients achieved CR, 2 patients showed PR, and 3 patients still had PD (Fig. 2).\n\nFigure 2 Diagram shows treatment response after chemotherapy and radiotherapy. CR = complete response, PD = progressive disease, PR = partial response.\n\n3.2 Recurrence and survival\nThe median follow-up time was 45 months (range, 11–110 months). The RFS (Fig. 3A) and OS (Fig. 3B) rates at 5 years in all patients were 72% and 61%, respectively. There were 14 (25%) relapsed cases. One patient had a local relapse after radiotherapy, 11 had distant relapses, and 2 had both local and distant relapses. The final local control rate after radiotherapy was 94%. Prognostic factors for RFS and OS are shown in Table 2. In the univariate analysis, age (P = .05), performance status (P = .01), stage (P = .01), IPI score (P < .01), chemotherapy response (P = .04), radiation dose (P = .05), radiation response (P = .01), and radiation modality (P = .03) are prognostic factors for RFS. Age (P = .02), performance status (P = .01), stage (P < .01), IPI score (P < .01), chemotherapy response (P < .01), and radiation response (P < .01) are prognostic factors for OS. In the additional multivariate analysis, age (P = .03), performance status (P = .03), IPI score (P = .02), and radiotherapy response (P = .01) showed a statistical significance for RFS. Regarding OS, age (P = .01), performance status (P < .01), stage (P < .01), IPI score (P < .01), and radiotherapy response (P < .01) were statistically significant factors. There were no significant differences in recurrence and survival with respect to tumor location, chemotherapy response, radiation dose, modality, and field in the multivariate analysis.\n\nFigure 3 Kaplan–Meier estimates of relapse-free (A) and overall (B) survival rate.\n\nTable 2 Prognostic factors for relapse-free and overall survival.\n\n3.3 Toxicity\nTable 3 describes acute hematologic and nonhematologic toxicity. Severe grade 3 or 4 hematologic toxicities occurred in 7 patients (13%). Two patients (4%) suffered from grade 3 nonhematologic toxicities such as oral mucositis and generalized weakness. There was no grade 4 nonhematologic toxicity. Grade 2 or 3 nonhematologic toxicities occurred in 13 patients (23%) and 2 patients (4%), respectively. Dry mouth, oral mucositis, and esophagitis were the most common signs of nonhematologic toxicity. Most of the acute toxicities resolved after 1 or 2 months of radiation completion. In 2 patients, toxicity was observed after 3 months of radiotherapy; 1 had pulmonary fibrosis, and the other had grade 2 dry mouth.\n\nTable 3 Grade 2 or higher acute adverse effects.\n\n4 Discussion\nThis study assessed the patients with head and neck DLBCL treated with chemotherapy followed by radiotherapy. The results showed an excellent local control rate with acceptable toxicities. Only 1 patient suffered from grade 4 toxicity (leucopenia and thrombocytopenia), and the patient recovered after G-CSF administration and transfusion. Since the recommended dose of radiotherapy in lymphoma is relatively low (30–36 Gy in CR and 40–50 Gy in PR) and with the generalized use of IMRT and conformal radiotherapy, tolerable toxicity was achieved in our study. The local control rate was 94%. Since the patient cohort in this study received both chemotherapy and radiotherapy, we could not completely exclude the effects of chemotherapy, but we assume that radiotherapy contributed more to local control since radiotherapy is local therapy whereas chemotherapy contributes more on systemic control.\n\nTo the best of our knowledge, there are no studies reported on head and neck DLBCL. Compared to other randomized trials for non-Hodgkin lymphoma in the pre-rituximab era, survival outcomes were better with additional radiotherapy.[3,5,6] In the modern chemotherapy and rituximab era, there is an ongoing debate about the use of consolidative radiotherapy in non-Hodgkin lymphoma and its usage is actually diminishing. A study by Vargo et al[8] with 59,255 DLBCL patients demonstrated that the use of combined-modality therapy declined from 47% in 2000 to 32% in 2012 with a statistical significance (P < .01). In their study, only 39% of patients received combined-modality therapy, but overall survival was significantly better in the combined modality arm compared to the chemotherapy alone arm (hazard ratio, 0.66; 95% confidence interval, 0.61–0.71; P < .01). Several retrospective studies for DLBCL in single institution were performed in the rituximab era, and the results showed positive effects of adding radiation after chemotherapy in all stages.[11–14]\n\nIn the preretuximab era, the treatment results of some studies that assessed patients with DLBCL treated with chemotherapy alone and combined-modality treatment reported 5-year RFS of 56% to 64% and 61% to 73%, respectively.[5,6,15] These studies also proved benefits of combined-modality treatment compared to chemotherapy alone. In the rituximab era, a subgroup analysis of the RICOVER-60 trial, which was a prospective assessment in the 2 cohorts, treated with R-CHOP with optional IFRT (36 Gy) to bulky disease, was performed and it provided strong support for adding radiation to sites of bulky disease in aggressive B-cell lymphoma.[4] Another prospective phase III trial by the German High-Grade Non-Hodgkin Lymphoma Study Group, named UNFOLDER21/14 trial, randomized patients to either R-CHOP 21 or R-CHOP 14, with secondary randomization to RT or observation.[16] On the planned interim analysis, patients who did not receive radiation had significantly inferior event-free survival than patients who received a combined-modality treatment. Consequently, the 2 arms without radiation were closed early. The final results of UNFOLDER21/14 trial could provide a strong evidence for the supportive role of radiation for DLBCL even in the rituximab era.\n\nThere are some limitations to our study. First of all, the retrospective nature of this study caused inevitable selection and observer biases.[17] Eleven (20%) patients with initially advanced stage III–IV were included in our study. In stages III and IV, it is not appropriate to classify the disease as head and neck DLBCL. However, the included patients had an initial bulky mass in the head and neck area only and were disease-free at sites other than the head and neck after chemotherapy. In this study, patients who received only a combined-modality treatment were included. Thus, a direct comparison of oncologic outcomes between combined modality and chemotherapy alone groups was not available.[18,19] To verify our results, future multicenter trials are needed that will compare chemotherapy alone and chemotherapy plus radiotherapy methods for the treatment of DLBCL involving the head and neck.\n\nIn conclusion, treatment outcomes of DLBCL involving the head and neck treated with R-CHOP followed by radiotherapy were satisfactory with excellent local control and tolerable toxicity. With the recent advances in radiotherapy technology, radiation could be more practicable in patients with the head and neck DLBCL even in the rituximab era.\n\nAbbreviations: CR = complete response, IFRT = involved-field radiotherapy, IMRT = intensity-modulated radiotherapy, IPI = international prognostic index, ISRT = involved-site radiotherapy, LDH = lactate dehydrogenase.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Prosnitz LR Kelsey CR \nPerez CA Brady LW \nNon-Hodgkin lymphomas . Principles and Practice of Radiation Oncology \n6th ed. Philadelphia : Lippincott Williams & Wilkins ; 2013 ;p. 1549 .\n[2] Edge S Byrd DR Compton CC \nHodgkin and non-Hodgkin lymphomas. AJCC Cancer Staging Manual . 7th ed. 2010 ;Chicago, IL : Springer , p. 607–11 .\n[3] Bonnet C Fillet G Mounier N \nCHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: a study by the Groupe d’Etude des Lymphomes de l’Adulte . J Clin Oncol \n2007 ;25 :787 –92 .17228021 \n[4] Held G Murawski N Ziepert M \nRole of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma . J Clin Oncol \n2014 ;32 :1112 –8 .24493716 \n[5] Horning SJ Weller E Kim K \nChemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin's lymphoma: Eastern Cooperative Oncology Group study 1484 . J Clin Oncol \n2004 ;22 :3032 –8 .15210738 \n[6] Miller TP Dahlberg S Cassady JR \nChemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma . N Engl J Med \n1998 ;339 :21 –6 .9647875 \n[7] Dabaja BS Vanderplas AM Crosby-Thompson AL \nRadiation for diffuse large B-cell lymphoma in the rituximab era: analysis of the National Comprehensive Cancer Network lymphoma outcomes project . Cancer \n2015 ;121 :1032 –9 .25492236 \n[8] Vargo JA Gill BS Balasubramani GK \nTreatment selection and survival outcomes in early-stage diffuse large b-cell lymphoma: do we still need consolidative radiotherapy? \nJ Clin Oncol \n2015 ;33 :3710 –7 .26261253 \n[9] Eisenhauer EA Therasse P Bogaerts J \nNew response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) . Eur J Cancer \n2009 ;45 :228 –47 .19097774 \n[10] Meignan M Gallamini A Meignan M \nReport on the First International Workshop on Interim-PET-Scan in Lymphoma . Leuk Lymphoma \n2009 ;50 :1257 –60 .19544140 \n[11] Dorth JA Prosnitz LR Broadwater G \nImpact of consolidation radiation therapy in stage III-IV diffuse large B-cell lymphoma with negative post-chemotherapy radiologic imaging . Int J Radiat Oncol Biol Phys \n2012 ;84 :762 –7 .22420972 \n[12] Kwon J Kim IH Kim BH \nAdditional survival benefit of involved-lesion radiation therapy after R-CHOP chemotherapy in limited stage diffuse large B-cell lymphoma . Int J Radiat Oncol Biol Phys \n2015 ;92 :91 –8 .25721091 \n[13] Phan J Mazloom A Medeiros LJ \nBenefit of consolidative radiation therapy in patients with diffuse large B-cell lymphoma treated with R-CHOP chemotherapy . J Clin Oncol \n2010 ;28 :4170 –6 .20713859 \n[14] Shi Z Das S Okwan-Duodu D \nPatterns of failure in advanced stage diffuse large B-cell lymphoma patients after complete response to R-CHOP immunochemotherapy and the emerging role of consolidative radiation therapy . Int J Radiat Oncol Biol Phys \n2013 ;86 :569 –77 .23540349 \n[15] Reyes F Lepage E Ganem G \nACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma . N Engl J Med \n2005 ;352 :1197 –205 .15788496 \n[16] Ng AK Dabaja BS Hoppe RT \nRe-examining the role of radiation therapy for diffuse large B-cell lymphoma in the modern era . J Clin Oncol \n2016 ;34 :1443 –7 .26903576 \n[17] Lim HW Kim TH Choi IJ \nRadiation therapy for gastric mucosa-associated lymphoid tissue lymphoma: dose-volumetric analysis and its clinical implications . Radiat Oncol J \n2016 ;34 :193 –201 .27730803 \n[18] Lee YH Cho SG Jung SE \nAnalysis of treatment outcomes for primary tonsillar lymphoma . Radiat Oncol J \n2016 ;34 :273 –9 .28030899 \n[19] Choi SH Cho J Kim JS \nRadiotherapy as an effective treatment modality for follicular lymphoma: a single institution experience . Radiat Oncol J \n2015 ;33 :310 –9 .26756031\n\n",
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"title": "Treatment outcome of diffuse large B-cell lymphoma involving the head and neck: Two-institutional study for the significance of radiotherapy after R-CHOP chemotherapy.",
"title_normalized": "treatment outcome of diffuse large b cell lymphoma involving the head and neck two institutional study for the significance of radiotherapy after r chop chemotherapy"
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"abstract": "Relapse is a leading cause of mortality after allogeneic hematopoietic cell transplantation (HCT). Hypomethylating agents (HMAs) have immunomodulatory properties, including augmenting tumor antigen presentation that may enhance the graft-versus-leukemia effect. Moreover, inhibitory effects on T-cell activation and cytokine production may lead to a lower incidence of graft-versus-host disease (GVHD). Our aim was to describe outcomes in patients treated with HMAs for relapse after HCT.\n\n\n\nSubjects were retrospectively identified as patients with relapse or loss of donor chimerism after HCT for myeloid malignancies treated with HMAs at the University of Pittsburgh.\n\n\n\nThirteen patients were identified, with a median age of 57 years and a median time to relapse of 98 days. Nine of 12 (75%) evaluable patients had a complete remission (CR). Grade I-IV acute GVHD involving the liver occurred in 6 patients. Cases of acute liver GVHD were diagnosed clinically based on the elevation of liver function tests. The median survival was 14.3 months from the time of relapse.\n\n\n\nHMAs for relapse after HCT can be effective in inducing a CR. This may be due to epigenetic changes and immunomodulatory effects that enhance the graft-versus-leukemia effect. There may be a risk of GVHD, and further exploration into pathophysiology and predisposing factors are warranted.",
"affiliations": "Division of Hematology/Oncology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, Pa., USA.",
"authors": "Im|Annie|A|;Raptis|Anastasios|A|;Hou|Jing-Zhou|JZ|;Tompkins|Cheryl|C|;Winfield|Melissa|M|;Guay|Mary|M|;Boyiadzis|Michael|M|;Agha|Mounzer|M|",
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"title": "Hypomethylating Agents for Relapse after Allogeneic Hematopoietic Cell Transplantation in Myeloid Malignancies: A Case Series and Review of the Literature.",
"title_normalized": "hypomethylating agents for relapse after allogeneic hematopoietic cell transplantation in myeloid malignancies a case series and review of the literature"
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"abstract": "Tumour necrosis factor α (TNF-α) inhibitors are frequently used for the treatment of immune-mediated diseases. Conversely, cytokine therapy has the potential to paradoxically induce autoimmunity. A number of case reports have emerged concerning sarcoid-like granulomatosis secondary to TNF-α therapy, an adverse effect that typically affects the pulmonary and cutaneous systems. Granulomatous interstitial nephritis (GIN) is a relatively unknown, relatively under-reported consequence of adalimumab therapy that can have important clinical implications. To our knowledge, this is the first case report of GIN secondary to anti-TNF-α therapy necessitating a prolonged period of dialysis and the first report demonstrating the successful use of secukinumab as an alternative immunomodulatory agent.",
"affiliations": "Nephrology Department, Waterford General Hospital, Waterford, Ireland, Nephrology Department, Beaumont Hospital, Dublin, Ireland and Histopathology Department, Beaumont Hospital, Dublin, Ireland.;Nephrology Department, Waterford General Hospital, Waterford, Ireland, Nephrology Department, Beaumont Hospital, Dublin, Ireland and Histopathology Department, Beaumont Hospital, Dublin, Ireland.;Nephrology Department, Waterford General Hospital, Waterford, Ireland, Nephrology Department, Beaumont Hospital, Dublin, Ireland and Histopathology Department, Beaumont Hospital, Dublin, Ireland.;Nephrology Department, Waterford General Hospital, Waterford, Ireland, Nephrology Department, Beaumont Hospital, Dublin, Ireland and Histopathology Department, Beaumont Hospital, Dublin, Ireland.;Nephrology Department, Waterford General Hospital, Waterford, Ireland, Nephrology Department, Beaumont Hospital, Dublin, Ireland and Histopathology Department, Beaumont Hospital, Dublin, Ireland.;Nephrology Department, Waterford General Hospital, Waterford, Ireland, Nephrology Department, Beaumont Hospital, Dublin, Ireland and Histopathology Department, Beaumont Hospital, Dublin, Ireland.;Nephrology Department, Waterford General Hospital, Waterford, Ireland, Nephrology Department, Beaumont Hospital, Dublin, Ireland and Histopathology Department, Beaumont Hospital, Dublin, Ireland.;Nephrology Department, Waterford General Hospital, Waterford, Ireland, Nephrology Department, Beaumont Hospital, Dublin, Ireland and Histopathology Department, Beaumont Hospital, Dublin, Ireland.",
"authors": "Sandys|Vicki|V|;Moloney|Brona|B|;Lane|Louise|L|;Qazi|Junaid|J|;Doyle|Brendan|B|;Barry|Maurice|M|;Leavey|Sean|S|;Conlon|Peter|P|",
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"fulltext": "\n==== Front\nClin Kidney JClin Kidney JckjClinical Kidney Journal2048-85052048-8513Oxford University Press 2964406210.1093/ckj/sfx104sfx104Tubulointerstitial DiseaseGranulomatous interstitial nephritis secondary to adalimumab therapy Sandys Vicki Moloney Brona Lane Louise Qazi Junaid Doyle Brendan Barry Maurice Leavey Sean Conlon Peter Nephrology Department, Waterford General Hospital, Waterford, Ireland, Nephrology Department, Beaumont Hospital, Dublin, Ireland and Histopathology Department, Beaumont Hospital, Dublin, IrelandCorrespondence and offprint requests to: Vicki Sandys; E-mail: sandysv@tcd.ieVicki Sandys and Brona Moloney considered joint first authors.\n\n4 2018 27 9 2017 27 9 2017 11 2 219 221 08 4 2017 09 8 2017 © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA.2017This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nTumour necrosis factor α (TNF-α) inhibitors are frequently used for the treatment of immune-mediated diseases. Conversely, cytokine therapy has the potential to paradoxically induce autoimmunity. A number of case reports have emerged concerning sarcoid-like granulomatosis secondary to TNF-α therapy, an adverse effect that typically affects the pulmonary and cutaneous systems. Granulomatous interstitial nephritis (GIN) is a relatively unknown, relatively under-reported consequence of adalimumab therapy that can have important clinical implications. To our knowledge, this is the first case report of GIN secondary to anti-TNF-α therapy necessitating a prolonged period of dialysis and the first report demonstrating the successful use of secukinumab as an alternative immunomodulatory agent.\n\nacute kidney injuryanti-TNF alphadialysisgranulomatis interstitial nephritissarcoid-like granulomatosis\n==== Body\nBackground\nGranulomatous interstitial nephritis (GIN) is a rare histological diagnosis, present in between 0.5 and 0.9% of native kidney biopsies [1]. Sarcoidosis, infections (particularly tuberculosis) and drugs remain the most common causes [1]. We report a case series of GIN following adalimumab therapy. In the setting of anti-TNF therapy, granulomatous nephritis represents a rare complication that can lead to rapidly progressive renal failure.\n\nCase series\nPatient 1\nA 42-year-old man was referred following investigation for asymptomatic renal decline and moderate hypertension; his blood pressure (BP) was 150/90 mmHg. His creatinine had increased to 168 µmol/L from 82 µmol/L recorded 10 months prior. Medications included only amlodipine and carvedilol. He had been treated with adalimumab for his ankylosing spondylitis (AS) in the preceding 20 months, with significant benefit. On examination, his BP was 144/68 mmHg with a bland urinalysis.\n\nHis initial investigations, including inflammatory markers, chest X-ray and renal ultrasound, were unremarkable. A kidney biopsy was performed (Figure 1) that demonstrated GIN with non-caseating granulomas. He subsequently underwent an extensive evaluation for tuberculosis (TB), including a Quantiferon Gold assay, urine samples for Mycobacterium tuberculosis (MTB) culture, MTB complex DNA quantification, Ziehl–Neelsen staining and TB polymerase chain reaction of the biopsy. These were negative. Human immunodeficiency virus (HIV), brucellosis immunoglobulin G (IgG) and IgM serology and urine culture were negative. His serum angiotensin-converting enzyme (ACE) was mildly elevated at 86 Units of Angiotension Converting Enzyme (UECA) (normal 20–70). Computed tomography (CT) of the thorax, abdomen and pelvic regions illustrated no pathological lymphadenopathy.\n\n\nFig. 1. Renal biopsy from Patient 1: a core of renal parenchyma shows an interstitial inflammatory cell infiltrate including non-caseating granulomata admixed with other inflammatory cells including lymphocytes, plasma cells and occasional eosinophils.\n\nAdalimumab was withdrawn. His kidney function stabilized over a period of 6 months to a creatinine of 120 µmol/L. His serum ACE decreased from 86 to 13 UECA. After 6 months off therapy he developed a severe systemic flare of symptoms of AS. He was started on secukinamab, a novel interleukin (IL)-17 inhibitor, to which he has had an excellent therapeutic response.\n\nPatient 2\nA 58-year-old man was referred with a 4-week history of fatigue, dyspnoea and a dry cough. Routine blood tests revealed an increased creatinine of 250 µmol/L from 97 µmol/L. He had been on adalimumab 40 mg monthly for 5 years for rheumatoid arthritis (RA).\n\nOn physical examination he had bibasal coarse crepitations, with a BP of 140/86 mmHg and a bland urine dipstick. His creatinine increased to 555 µmol/L with a urea of 38 mmol/L, resulting in clinical uraemia. A pyraexia (38.2°C) developed, with rapidly worsening respiratory symptoms. CT of the thorax showed diffuse ground glass change and bilateral mediastinal lymphadenopathy. He was commenced on intermittent haemodialysis. Antimicrobial treatment was initiated with intravenous amoxicillin/clavulanic acid, oral clarithromycin, clindamycin and primaquine.\n\nBlood tests showed a peak corrected calcium of 3.05 mmol/L. Serum ACE levels were elevated at 100 UECA. A vasculitic screen, connective tissue screen, complement levels, serum protein electrophoresis and immunoglobulin levels were normal. Blood cultures, hepatitis, HIV screen, Chlamydia, Brucella, Mycoplasma and leptospirosis serology were negative. Extensive testing to exclude TB as the unifying diagnosis was negative. Bronchoscopy and bronchoalveolar lavage samples were negative for Pneumocystis pneumonia, cytomegalovirus, TB and cryptococcal antigen. There was no relevant travel or occupational exposure to indicate further testing for histoplasmosis. Antimicrobial therapy was discontinued.\n\nRenal biopsy showed granulomatous nephritis without evidence of necrosis. An endobronchial ultrasound and fine-needle aspiration cytology demonstrated granulomatous lymphadenitis.\n\nAdalimumab was withdrawn and empiric prednisolone 60 mg daily was commenced. He remained dialysis dependent for 3 months. Four months after discontinuing adalimumab, dialysis was successfully stopped and steroid therapy was tapered slowly. His kidney function stabilized to a creatinine of 160 μmol/L with resolution of his respiratory symptoms clinically and radiographically. He is currently on methotrexate with good control of his RA.\n\nDiscussion\nSarcoid-like granulomatosis secondary to anti-TNF-α therapy is an emerging clinical entity. Typically patients present with pulmonary and cutaneous reactions [2], with isolated cases reporting orbital involvement [3]. However, data on anti-TNF-α-induced granulomatous renal disease have been limited [4–6].\n\nOur incident patient illustrated a clear temporal association between the initiation of TNF-α therapy and the development of GIN. The exposure delay of 10 months prior to the onset of disease and the recovery time of 6 months is in keeping with previous studies. In a case series on primarily pulmonary and cutaneous sarcoid-like granulomatosis, the median delay between TNF-α drug onset and diagnosis was estimated at 18 months for etanercept and 11 months for adalimumab [2]. Our second case presented atypically, with a delay in onset of 5 years. Delays of this magnitude have not been reported with adalimumab use but have been seen in isolated cases of infliximab-related sarcoidosis [7]. Similar to our series, serum ACE was positive in six patients and extensive TB testing proved negative [2]. In both patients, cessation of therapy led to an objective improvement in renal indices, suggesting adalimumab as the precipitant of renal dysfunction.\n\nThe mechanism of autoimmune induction by TNF-α agents is poorly understood. Both TNF-α therapies and interferon (IFN)-γ have been reported to induce anti-nuclear antibody production, overt systemic lupus erythematous or sarcoid [2, 4]. It has been suggested that anti-TNF-α therapies may restore a Type 1 T helper cells (Th1) response leading to induction of IFN-γ, subsequently precipitating granulomatosis [2].\n\nNotably, GIN appears to carry a favourable renal prognosis, regardless of the cause. In the largest case series of GIN so far, only 1 of 18 patients required dialysis, although most patients did not recover fully. Secondary fibrosis from healed granulomatous inflammation could represent the mechanism of permanent kidney damage. In this instance, concomitant use of steroids in addition to withdrawal of the offending medication may reduce the risk of renal impairment [8].\n\nTreatment options for the underlying inflammatory disease, such as AS or RA, poses a clinical dilemma. Sarcoid-like granulomatosis has been reported with both TNF soluble receptors and monoclonal TNF antibodies [2, 4, 5]. Conversely, infliximab, adalimumab and etanercept have all been successfully used as alternative rheumatological therapies in patients who have recovered from GIN [7]. Similarly, there have been two cases of primary sarcoid disease causing GIN treated effectively with adalimumab [9]. Given the conflicting nature of the literature, we opted to use secukinumab, an anti-IL-17A monoclonal antibody that has been used in the treatment of both anti-TNF-α-intolerant and anti-TNF-α-naïve patients in AS [10].\n\nTo our knowledge, this is the fourth reported case of GIN secondary to TNF-α therapy. It is the first report of GIN successfully treated using secukinumab as an alternative immunomodulatory treatment. Our incident case was characterized by the absence of systemic symptoms, normoalbuminuria and isolated renal involvement, suggesting the importance of a low threshold for kidney biopsy in patients on anti-TNF therapy who present with an otherwise unexplained increase in creatinine. Although withdrawal of the medication typically leads to recovery, patient 2 remained dialysis dependent for 4 months after diagnosis. Given the asymptomatic presentation of our index case, we furthermore strongly suggest regular monitoring of renal indices while on anti-TNF therapy. GIN secondary to adalimumab is evidently an underrecognized complication that can lead to rapid progressive renal decline.\n\nConflict of interest statement\nNone declared.\n==== Refs\nReferences\n1 \nShivani S , Naima CM , Atta MG. \nGranulomatous interstitial nephritis . Clin Kidney J 2015 ; 8 : 516 –523 26413275 \n2 \nDaïen CI , Monnier A , Claudepierre P \n\nSarcoid-like granulomatosis in patients treated with tumor necrosis factor blockers: 10 cases . Rheumatology (Oxford) 2009 ; 48 : 883–886 19423648 \n3 \nWladis EJ , Tarasen AJ , Roth ZJ \n\nOrbital sarcoid-like granulomatosis after inhibition of tumor necrosis factor-α . Ophthal Plast Reconstr Surg 2016 ; 32 : e30 –2 \n4 \nKorsten P , Sweiss NJ , Nagorsnik U \n\nDrug-induced granulomatous interstitial nephritis in a patient with ankylosing spondylitis during therapy with adalimumab . Am J Kidney Dis 2010 ; 56 : e17 –21 20974510 \n5 \nMorgane V , Jean-Charles C , Nicolas M \n\nRenal sarcoid-like granulomatosis during anti-TNF therapy . Kidney Int 2014 ; 86 : 215 24978390 \n6 \nTong D , Manolios N , Howe G \n\nNew onset sarcoid-like granulomatosis developing during anti-TNF therapy: an under-recognised complication . Intern Med J 2012 ; 42 : 89 –94 22389903 \n7 \nToussirot E , Pertuiset E. , Kantelip B. \n\nSarcoidosis occuring during anti-TNF treatment for inflammatory rheumatic diseases: report of two cases . Clin Exp Rheumatol 2008 ; 26 : 471 –475 18578973 \n8 \nJoss N , Morris S , Young B. \n\nGranulomatous interstitial nephritis. \nCJASN \n2007 , 2 : 222 –230 17699417 \n9 \nvan der Stoep D , Braunstahl GJ , Jende VZ \n\nSarcoidosis during anti-TNF factor a therapy: no relapse after rechallenge . J Rheumatol 2009 ; 36 : 2847 –2848 19966199 \n10 \nGuta R , Beudat L , Moore J \n\nTreatment of sarcoid granulomatous interstitial nephritis with adalimumab . NDT Plus 2009 ; 2 : 139 –142 25949311\n\n",
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"abstract": "Colchicine is a medication most commonly used in the treatment of gout and familial mediterannean fever. A rare complication of therapy is toxicity causing proximal myopathy and polyneuropathy. Colchicine myopathy has been associated with the coadministration of other medications with colchicine, such as statins or tacrolimus, and is more common in patients with renal impairment. Otherwise, it is unclear which patients are at greatest risk of developing this adverse drug reaction. ABCB1 is important to the metabolism of colchicine, so we speculated that it was possible that colchicine myopathy patients may have a particular genotype that is associated with this side effect. We describe two cases of colchicine myopathy which occurred with co-administration of rosuvastatin. From one case, we present the first published data on muscle MRI in this condition. We additionally present an analysis of four genetic polymorphisms in ABCB1 and transcript levels in muscle tissue, and demonstrate the descriptive finding of reduced ABCB1 transcript levels in the colchicine myopathy patients.",
"affiliations": "Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.;Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada.;Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada.;Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.;Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.;Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.;Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.",
"authors": "Gupta|Mehul|M|;Nikolic|Ana|A|;Ng|Denise|D|;Martens|Kristina|K|;Ebadi|Hamid|H|;Chhibber|Sameer|S|;Pfeffer|Gerald|G|",
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"fulltext": "\n==== Front\nFront NeurolFront NeurolFront. Neurol.Frontiers in Neurology1664-2295Frontiers Media S.A. 10.3389/fneur.2019.00553NeurologyCase ReportColchicine Myopathy: A Case Series Including Muscle MRI and ABCB1 Polymorphism Data Gupta Mehul 1Nikolic Ana 2Ng Denise 2Martens Kristina 1Ebadi Hamid 3Chhibber Sameer 3Pfeffer Gerald 13*1Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada2Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada3Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, CanadaEdited by: Massimiliano Filosto, Azienda Socio Sanitaria Territoriale of the Spedali Civili of Brescia, Italy\n\nReviewed by: Charles Kassardjian, University of Toronto, Canada; Anna Pichiecchio, Fondazione Istituto Neurologico Nazionale Casimiro Mondino (IRCCS), Italy\n\n*Correspondence: Gerald Pfeffer gerald.pfeffer@ucalgary.caThis article was submitted to Neuromuscular Diseases, a section of the journal Frontiers in Neurology\n\n24 5 2019 2019 10 55328 2 2019 08 5 2019 Copyright © 2019 Gupta, Nikolic, Ng, Martens, Ebadi, Chhibber and Pfeffer.2019Gupta, Nikolic, Ng, Martens, Ebadi, Chhibber and PfefferThis 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.Colchicine is a medication most commonly used in the treatment of gout and familial mediterannean fever. A rare complication of therapy is toxicity causing proximal myopathy and polyneuropathy. Colchicine myopathy has been associated with the coadministration of other medications with colchicine, such as statins or tacrolimus, and is more common in patients with renal impairment. Otherwise, it is unclear which patients are at greatest risk of developing this adverse drug reaction. ABCB1 is important to the metabolism of colchicine, so we speculated that it was possible that colchicine myopathy patients may have a particular genotype that is associated with this side effect. We describe two cases of colchicine myopathy which occurred with co-administration of rosuvastatin. From one case, we present the first published data on muscle MRI in this condition. We additionally present an analysis of four genetic polymorphisms in ABCB1 and transcript levels in muscle tissue, and demonstrate the descriptive finding of reduced ABCB1 transcript levels in the colchicine myopathy patients.\n\ncolchicinestatinmyopathyvacuolarmuscle MRIpharmacogenetics\n==== Body\nIntroduction\nColchicine-induced myopathy is an autophagic, vacuolar myopathy that occurs as a rare complication of treatment with colchicine (1). The development of colchicine myopathy has been predominantly reported in patients using colchicine in the context of renal failure (1), although it has been associated with other medications such as statins (2), or tacrolimus (3). The clinical presentation typically includes features of a painless proximal myopathy, that develops slowly after prolonged treatment with colchicine (4), but may also develop precipitously with rhabdomyolysis (5). The onset can occur within weeks of initiating colchicine therapy, particularly in those with renal impairment (6). Significant variability can occur in the clinical presentation (7), and colchicine myopathy has also been reported with respiratory muscle weakness (8), making this rare medication side-effect a consideration in a broad range of neuromuscular differential diagnoses (9, 10). The diagnosis is typically confirmed with the finding of a vacuolar myopathy on muscle biopsy (11). Some features of this condition, such as muscle MRI findings, are currently unknown.\n\nOne of the important factors in colchicine's metabolism is ABCB1 (also known as multidrug resistance protein 1, or p-glycoprotein, encoded by ABCB1) (12). There is some indication that genetic variation in ABCB1 may contribute to the variability in colchicine's effectiveness for familial Mediterranean fever (13–15), though the literature appears to be inconclusive (16). The ABCB1 polymorphism which has received greatest study is the c.3435C>T polymorphism (rs1045642), which is associated with marked reduction in ABCB1 expression for the homozygous T genotype (17). This variant usually occurs as a haplotype including the c.2677G>T/A, and/or c.1236C>T polymorphisms (18). Although the effect of this haplotype has been studied for its potential role in colchicine effectiveness in familial mediterranean fever among other diseases (19), it has not yet been considered as a possible contributor to the development of colchicine myopathy.\n\nHere we present two cases of colchicine-induced myopathy, with a description of muscle MRI findings, muscle pathology, sequencing of genetic polymorphisms previously associated with altered colchicine metabolism, and transcript level quantification of ABCB1 from muscle tissue.\n\nMethods\nEthics Statement\nAll participants provided written informed consent for participation in research and for publication of this case series. Control muscle samples were taken from patients with other acquired muscle diseases at the time of clinical muscle biopsy procedures. The study was approved by the University of Calgary Conjoint Health Research Ethics Board (REB15-2763 and REB16-2196).\n\nClinical Case Reviews\nTwo patients with colchicine myopathy were identified from the clinical practice of two of the authors (GP, HE). Both patients provided written informed consent for participation in research and for publication of this case series. Clinical records were reviewed, including laboratory investigations, MRI images, and muscle pathology findings.\n\nGenotyping of ABCB1 polymorphisms: Four polymorphisms in ABCB1 were genotyped based on their prior association with altered colchicine metabolism (rs1128501, rs1128503, rs2032582, rs1045642) (17, 20). DNA was obtained from peripheral blood using QIAamp DNA blood mini kit (Qiagen), amplified using custom primers, and Taq DNA Polymerase (Qiagen), followed by Sanger sequencing using BigDye (Applied Biosystems) on an ABI 3730XL sequencer (Applied Biosystems). Genotypes were determined using Variant Analysis software (Thermo Fisher).\n\nABCB1 Transcript Quantification\nABCB1 transcript quantification was performed on frozen muscle tissue of both patients and four controls. Total RNA was extracted using the RNeasy Fibrous Tissue Mini Kit (Qiagen), followed by reverse transcription with iScript cDNA Synthesis Kit (Bio-Rad) and random hexamers. qPCR was performed using custom primers and Evagreen (Biotium) on a QX200 digital droplet quantitative PCR system (Bio-Rad). Three experimental replicates were performed and included in data analysis and HPRT1 was used as a reference gene. A non-parametric Kruskal–Wallis test was performed using GraphPad Prism 7.0, resulting in overall significance (p-value 0.0312), with Dunn's multiple comparison test being used to compare normalized expression of ABCB1 between controls and patients of interest.\n\nResults\nCase 1\nA 68 years old man started therapy with colchicine for gout at 0.5 mg/day. His other medications included irbesartan, allopurinol, and rosuvastatin. He had a diagnosis of ankylosing spondylitis but was not receiving any active medical therapy for this condition. He had normal renal function. Two weeks after starting colchicine he developed subacute onset of proximal weakness primarily affecting his legs and causing difficulty with gait and rising from a chair. On presentation to hospital he had 2/5 hip flexor weakness, 3/5 hip extension, and 4/5 knee extensor/flexor weakness, with shoulder abduction and adduction 4/5 weakness. On sensory examination he had reduction of vibration sensory thresholds to his knees but otherwise normal proprioception and pinprick testing.\n\nInvestigations demonstrated an elevated CK to a maximum of 2,200 U/L (normal <350 U/L). EMG of the iliopsoas muscle revealed motor units with reduced amplitude and duration, and polyphasia, interpreted as representing myopathic changes. MRI (1.5T) of the leg muscles was acquired in coronal and axial planes with T1 and STIR sequences, from the top of the iliac crests to the ankles bilaterally, and was interpreted as unremarkable (Figure 1). Muscle biopsy showed a vacuolar myopathy confirming the clinical suspicion of colchicine myopathy (Figure 2).\n\nFigure 1 Muscle MRI findings in Case 1. (a) Axial images of STIR MRI sequences through the upper and lower legs show subtle signal change in the right medial thigh, which had been attributed to the patient's muscle biopsy a few days prior. Otherwise, no abnormality was identified on this study. (b) Axial images of T1 MRI sequences through the upper and lower legs show no abnormality.\n\nFigure 2 Muscle pathology findings in Case 1. (a) H&E-FFPE (400x) showing non-rimmed vacuoles; (b) Gomori-trichrome (600x) with non-rimmed vacuoles; (c) Toluidine blue semi thin sections (400x) with empty vacuoles; (d) electron micrograph (1,000x) showing empty vacuoles and Z-line disarray.\n\nColchicine and rosuvastatin were withdrawn and CK levels normalized after 1 week. Weakness improved gradually toward normal during that time, although he still had 4/5 weakness in hip flexion. Follow-up after 2 months demonstrated complete resolution of clinical weakness, and his vibration sensory thresholds normalized (normal thresholds at medial malleoli bilaterally).\n\nEight months later the patient resumed treatment with rosuvastatin and has continued to use this agent without side effects after 2 years of follow-up.\n\nCase 2\nThe patient is a 72 years old man with a medical history of type 2 diabetes mellitus, chronic renal disease (GFR 29 ml/mn, secondary to above-mentioned diabetes), hypertension, and gout. He also had remote renal cell carcinoma, in remission following cryoablation. His medications included irbesartan, acarbose, repaglinide, allopurinol, rosuvastatin, and colchicine. He had three episodes of rhabdomyolysis over a 2 years period, separated by intervals of ~12 months, which presented clinically as proximal weakness, myalgias, and reduced mobility. Rhabdomyolysis was attributed to rosuvastatin, which was discontinued after the second episode, although he subsequently went on to have a reoccurance of rhabdomyolysis off statin therapy. His maximum CK levels were 4,021, 4,568, and 3,212 U/L, respectively in each of the three episodes. CK levels normalized in between episodes. After the third episode, he was referred to a neuromuscular specialist (HE). He had bilateral leg weakness causing difficulty with ambulation. EMG identified fibrillation potentials, positive sharp waves, with decreased amplitude, decreased duration and early recruitment upon muscle activation, interpreted as consistent with necrotizing myopathy. An MRI of the lumbar spine did not show any changes that would explain his weakness but did indicate degenerative disc disease particularly at the L3-5 levels. Muscle biopsy revealed vacuolar myopathy characterized by type I-specific central rimmed vacuoles that were reactive to acid phosphatase and immunoreactive to alpha-B-crystallin (Figure 3). This was interpreted as being consistent with colchicine myopathy. After discontinuation of colchicine the CK normalized over a period of 2 weeks, and the patient's weakness gradually improved such that he returned to ambulating without walking aids. After 1.5 years of follow-up he has not had further episodes of elevated CK.\n\nFigure 3 Muscle pathology findings in Case 2. (a) H&E-frozen (40X) showing rare rimmed vacuoles and increased internal nucleation, (b) Gomori trichrome (100X) highlights granular material of the typical rimmed vacuole, (c) ATPase pH4.3 (100X) shows vacuoles to have a predilection for Type I fibers, and (d) Electron microscopy (10,000X) demonstrates autophagic vacuoles.\n\nGenotyping of ABCB1 Polymorphisms\nCase 1 was heterozygous for the polymorphisms rs1128503, rs2032582, rs1045642, which is potentially consistent with the heterozygous haplotype at positions c.1236/2677/3435. Case 2's sequencing showed a homozygous T genotype at the c.3435 position (reference sequence for these three SNPs). Both cases were homozygous reference sequence for the rs1128501 polymorphism.\n\nABCB1 Transcript Quantification\nDescriptively, both cases had reduced ABCB1 transcript levels compared with all four controls. Transcript levels for Case 1 was significantly reduced compared with two of the controls. Transcript levels from Case 2 did not differ significantly from controls (Figure 4).\n\nFigure 4 ABCB1 Counts Normalized to HPRT1. Expression of ABCB1 normalized to HPRT1 for the two patients of interest and four disease controls, pooled from three assays performed in duplicate. Expression is quantified as the number of droplets containing ABCB1 amplicons in the ddPCR assay. Dunn's multiple comparison tests significant p-values are indicated.\n\nDiscussion\nWe present two cases with colchicine myopathy, and demonstrate their clinical presentation, muscle pathology, muscle MRI, and targeted genetic analysis of ABCB1. This study contributes novel information in several ways. Firstly, this study demonstrates the first muscle MRI data on a patient with colchicine myopathy in the medical literature. Although this MRI study was normal, this is useful information from a clinical perspective, since muscle MRI is otherwise considered an extremely sensitive test for muscle injury and is increasingly used in diagnosis of hereditary, autoimmune, and acquired muscle pathology (21–23). Muscle MRI continues to be studied as a quantitative tool in muscle diseases (24), and is increasingly used in the characterization of unique clinical situations (25–27). The information presented from this case suggests that muscle biopsy is still the preferred test when colchicine-induced myopathy is suspected clinically, and also emphasizes that muscle MRI may not be sensitive for detection of all types of muscle pathology. Muscle MRI has been used in other drug-induced myopathies such as statin myopathy, which can show edema most commonly in the dorsal thigh and superficial dorsal leg muscles (28). Other examples of drug-induced myopathies are caused by use of antiretrovirals, corticosteroids, or cocaine among others, and general patterns of muscle MRI findings have been described (29). Further study of MRI findings in colchicine myopathy will be required to confirm whether any abnormalities can be identified with this imaging modality.\n\nThis study is also the only report in which genetic variation of ABCB1 was considered as a possible contributing factor to colchicine myopathy. Our hypothesis was that genetic variation in ABCB1 (such as the finding of a homozygous c.3435T allele) might be present in both patients, and provide some suggestion of a susceptibility for this rare adverse reaction. It is of potential interest that Case 1 was heterozygous and Case 2 was homozygous for the T allele, but based on this small series we cannot draw any conclusions regarding variants in ABCB1 and colchicine myopathy. These genotypes could have occurred by chance based on the distribution of alleles in the general population [global MAF of 0.498 for the T allele in Gnomad (30), accessed February 22, 2019]. Given our descriptive findings of reduced ABCB1 transcript levels, future study of the c.3435 polymorphism or other genetic factors in a larger series of colchicine myopathy patients could be considered.\n\nTranscript quantification of both cases compared with disease controls using RT-qPCR showed reduced ABCB1 transcript levels although statistical significance was not achieved, probably relating to our small sample size. Future study will be required with larger sample sizes to determine whether other patients also have a reduction of ABCB1 transcript levels. If so, this might allow a way to predict which patients are more susceptible to develop colchicine myopathy or other complications relating to colchicine, based on presumed lower ABCB1 activity.\n\nThe clinical presentation of these cases demonstrated some interesting features. Case 1 developed a painless proximal myopathy with neuropathy after 2 weeks of therapy, which is somewhat atypical for a patient without renal failure (6). In Case 2, there were repeated episodes of rhabdomyolysis as the condition had been attributed to his use of statins, and curiously his CK levels temporarily normalized after discontinuation of statins despite continuing to use colchicine. In both cases, the patients were on both rosuvastatin and colchicine—this raises the possibility that statins may have contributed to the development of colchicine myopathy, which is also supported from prior studies (31). However, the association of statin use with colchicine myopathy is still uncertain (32), despite what appears to be a high level of biological plausibility for this interaction from prior study (33). Further study of the factors that cause this rare reaction to colchicine will improve clinicians' ability to predict which patients will be at greatest risk. This report provides preliminary data that will hopefully be of interest in future studies of muscle MRI and pharmacogenetic interactions for colchicine and myopathy.\n\nData Availability\nAnonymized laboratory data will be made available upon request by any qualified investigator.\n\nEthics Statement\nThis study was carried out in accordance with the recommendations of the Conjoint Health Research Ethics Board of the University of Calgary, with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Conjoint Health Research Ethics Board.\n\nAuthor Contributions\nMG: laboratory data acquisition and interpretation and drafting of manuscript. AN and DN: muscle pathology data acquisition and interpretation. KM: laboratory data acquisition and interpretation and editing of manuscript for intellectual content. HE and SC: interpretation of clinical data and editing of manuscript for intellectual content. GP: drafting of manuscript, interpretation of clinical and laboratory data, supervision of study.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nFunding. MG is the recipient of a Heritage Young Researcher Student (HYRS) Award from Alberta Innovates Health Solutions, and a Markin Undergraduate Research Studentship. GP is the recipient of internal grants from the Department of Clinical Neurosciences, Hotchkiss Brain Institute, and Cumming School of Medicine Clinical Research Fund.\n==== Refs\nReferences\n1. Kuncl RW Duncan G Watson D Alderson K Rogawski MA Peper M . Colchicine myopathy and neuropathy . N Engl J Med. (1987 ) 316 :1562 –8 . 10.1056/NEJM198706183162502 3035372 \n2. Sarullo FM Americo L Di Franco A Di Pasquale P . Rhabdomyolysis induced by co-administration of fluvastatin and colchicine . Monaldi Arch Chest Dis. (2010 ) 74 :147 –9 . 10.4081/monaldi.2010.264 21110512 \n3. Yousuf Bhat Z Reddy S Pillai U Doshi M Wilpula E . Colchicine-induced myopathy in a tacrolimus-treated renal transplant recipient: case report and literature review . Am J Ther. (2016 ) 23 :e614 –6 . 10.1097/MJT.0000000000000044 24732905 \n4. Tapal MF . Colchicine myopathy . Scand J Rheumatol. (1996 ) 25 :105 –6 . 10.3109/03009749609069217 8614764 \n5. Frydrychowicz C Pasieka B Pierer M Mueller W Petros S Weidhase L . Colchicine triggered severe rhabdomyolysis after long-term low-dose simvastatin therapy: a case report . J Med Case Rep. (2017 ) 11 :8 . 10.1186/s13256-016-1169-z 28049514 \n6. Wilbur K Makowsky M . Colchicine myotoxicity: case reports and literature review . Pharmacotherapy. (2004 ) 24 :1784 –92 . 10.1592/phco.24.17.1784.52334 15585444 \n7. Marciniak C Babu A Ghannad L Burnstine R Keeshin S . Unusual electromyographic findings associated with colchicine neuromyopathy: a case report . PM R. (2016 ) 8 :1016 –9 . 10.1016/j.pmrj.2016.03.003 26972360 \n8. Tanios MA El Gamal H Epstein SK Hassoun PM . Severe respiratory muscle weakness related to long-term colchicine therapy . Respir Care. (2004 ) 49 :189 –91 . 14744269 \n9. Pasnoor M Barohn RJ Dimachkie MM . Toxic myopathies . Neurol Clin. (2014 ) 32 :647 –70 . 10.1016/j.ncl.2014.04.009 25037083 \n10. Pfeffer G Povitz M . Respiratory management of patients with neuromuscular disease: current perspectives . Degener Neurol Neuromuscul Dis. (2016 ) 6 :111 –8 . 10.2147/DNND.S87323 30050373 \n11. Fernandez C Figarella-Branger D Alla P Harle JR Pellissier JF . Colchicine myopathy: a vacuolar myopathy with selective type I muscle fiber involvement. An immunohistochemical and electron microscopic study of two cases . Acta Neuropathol. (2002 ) 103 :100 –6 . 10.1007/s004010100434 11810174 \n12. Chinn LW Kroetz DL . ABCB1 pharmacogenetics: progress, pitfalls, and promise . Clin Pharmacol Ther. (2007 ) 81 :265 –9 . 10.1038/sj.clpt.6100052 17259950 \n13. Ozen F Silan C Uludag A Candan F Silan F Ozdemir S . Association between ABCB1 (MDR1) gene 3435 C>T polymorphism and colchicine unresponsiveness of FMF patients . Ren Fail. (2011 ) 33 :899 –903 . 10.3109/0886022X.2011.605980 21851199 \n14. Tufan A Babaoglu MO Akdogan A Yasar U Calguneri M Kalyoncu U . Association of drug transporter gene ABCB1 (MDR1) 3435C to T polymorphism with colchicine response in familial Mediterranean fever . J Rheumatol. (2007 ) 34 :1540 –4 . 17610314 \n15. Uludag A Silan C Atik S Akurut C Uludag A Silan F . Relationship between response to colchicine treatment and MDR1 polymorphism in familial Mediterranean fever patients . Genet Test Mol Biomarkers. (2014 ) 18 :73 –6 . 10.1089/gtmb.2013.0293 24180297 \n16. Dogruer D Tug E Bes C Soy M . Lack of an effect of CYP3A4 and MDR1 gene polymorphisms on colchicine pharmacogenetics in the treatment of Familial Mediterranean fever . Genet Mol Res. (2013 ) 12 :3521 –8 . 10.4238/2013.January.24.2 23408444 \n17. Hoffmeyer S Burk O von Richter O Arnold HP Brockmoller J Johne A . Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo . Proc Natl Acad Sci USA. (2000 ) 97 :3473 –8 . 10.1073/pnas.97.7.3473 10716719 \n18. Fung KL Gottesman MM . A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function . Biochim Biophys Acta. (2009 ) 1794 :860 –71 . 10.1016/j.bbapap.2009.02.014 19285158 \n19. Rustemoglu A Gul U Gumus-Akay G Gonul M Yigit S Bozkurt N . MDR1 gene polymorphisms may be associated with Behcet's disease and its colchicum treatment response . Gene. (2012 ) 505 :333 –9 . 10.1016/j.gene.2012.05.040 22705826 \n20. Ruth A Stein WD Rose E Roninson IB . Coordinate changes in drug resistance and drug-induced conformational transitions in altered-function mutants of the multidrug transporter P-glycoprotein . Biochemistry. (2001 ) 40 :4332 –9 . 10.1021/bi001373f 11284689 \n21. Guimaraes JB Nico MA Omond AG Aivazoglou LU Jorge RB Zanoteli E . Diagnostic imaging of inflammatory myopathies: new concepts and a radiological approach . Curr Rheumatol Rep. (2019 ) 21 :8 . 10.1007/s11926-019-0807-z 30762122 \n22. Warman Chardon J Straub V . The role of muscle imaging in the diagnosis and assessment of children with genetic muscle disease . Neuropediatrics. (2017 ) 48 :233 –41 . 10.1055/s-0037-1604111 28669132 \n23. Mercuri E Pichiecchio A Allsop J Messina S Pane M Muntoni F . Muscle MRI in inherited neuromuscular disorders: past, present, and future . J Magn Reson Imaging. (2007 ) 25 :433 –40 . 10.1002/jmri.20804 17260395 \n24. Burakiewicz J Sinclair CDJ Fischer D Walter GA Kan HE Hollingsworth KG . Quantifying fat replacement of muscle by quantitative MRI in muscular dystrophy . J Neurol. (2017 ) 264 :2053 –67 . 10.1007/s00415-017-8547-3 28669118 \n25. Murate K Mizutani Y Maeda T Nagao R Kikuchi K Shima S . A patient with thiamine deficiency exhibiting muscle edema suggested by MRI . Front Neurol. (2018 ) 9 :1083 . 10.3389/fneur.2018.01083 30619043 \n26. Niu Z Pontifex CS Berini S Hamilton LE Naddaf E Wieben E . Myopathy with SQSTM1 and TIA1 variants: clinical and pathological features . Front Neurol. (2018 ) 9 :147 . 10.3389/fneur.2018.00147 29599744 \n27. Soule T Phan C White C Resch L Lacson A Martens K . GNE myopathy with novel mutations and pronounced paraspinal muscle atrophy . Front Neurol. (2018 ) 9 :942 . 10.3389/fneur.2018.00942 30467490 \n28. Peters SA Kley R Tegenthoff M Vorgerd M Nicolas V Heyer CM . MRI in lipid-lowering agent-associated myopathy: a retrospective review of 21 cases . AJR Am J Roentgenol. (2010 ) 194 :W323 –8 . 10.2214/AJR.09.2698 20308477 \n29. Smitaman E Flores DV Mejia Gomez C Pathria MN . MR imaging of atraumatic muscle disorders . Radiographics. (2018 ) 38 :500 –22 . 10.1148/rg.2017170112 29451848 \n30. Lek M Karczewski KJ Minikel EV Samocha KE Banks E Fennell T . Analysis of protein-coding genetic variation in 60,706 humans . Nature. (2016 ) 536 :285 –91 . 10.1038/nature19057 27535533 \n31. Finkelstein Y Aks SE Hutson JR Juurlink DN Nguyen P Dubnov-Raz G . Colchicine poisoning: the dark side of an ancient drug . Clin Toxicol. (2010 ) 48 :407 –14 . 10.3109/15563650.2010.495348 20586571 \n32. Kwon OC Hong S Ghang B Kim YG Lee CK Yoo B . Risk of colchicine-associated myopathy in gout: influence of concomitant use of statin . Am J Med. (2017 ) 130 :583 –7 . 10.1016/j.amjmed.2016.12.006 28065770 \n33. Ching JK Ju JS Pittman SK Margeta M Weihl CC . Increased autophagy accelerates colchicine-induced muscle toxicity . Autophagy. (2013 ) 9 :2115 –25 . 10.4161/auto.26150 \n24184927\n\n",
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"title": "Colchicine Myopathy: A Case Series Including Muscle MRI and ABCB1 Polymorphism Data.",
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"abstract": "BACKGROUND\nTreatment of giant cell arteritis is based on prolonged corticosteroid therapy but adverse side effects are common especially in the elderly.\n\n\nMETHODS\nWe report three patients with giant cell vasculitis treated by tocilizumab, an interleukin-6 receptor antibody, owing to resistance or intolerance to corticosteroid therapy. A favorable outcome was rapidly observed both on clinical and biological data allowing a corticoid therapy sparing.\n\n\nCONCLUSIONS\nTocilizumab is a promising treatment of giant cell arteritis but controlled trials are needed to confirm its efficacy.",
"affiliations": "Service de médecine interne, hôpital Emile-Muller, 20, rue du Dr-Laennec, 68100 Mulhouse, France.;Service de médecine interne, hôpital Emile-Muller, 20, rue du Dr-Laennec, 68100 Mulhouse, France.;Service de médecine interne, hôpital Emile-Muller, 20, rue du Dr-Laennec, 68100 Mulhouse, France.;Service de médecine interne, hôpital Emile-Muller, 20, rue du Dr-Laennec, 68100 Mulhouse, France.;Service de médecine interne, hôpital Emile-Muller, 20, rue du Dr-Laennec, 68100 Mulhouse, France.;Service de médecine interne, hôpital Emile-Muller, 20, rue du Dr-Laennec, 68100 Mulhouse, France.;Service de médecine interne, hôpital Emile-Muller, 20, rue du Dr-Laennec, 68100 Mulhouse, France. Electronic address: martzolffl@ch-mulhouse.fr.",
"authors": "Kieffer|P|P|;Hinschberger|O|O|;Ciobanu|E|E|;Jaeger-Bizet|F|F|;Drabo|A|A|;Mostoufizadeh|T|T|;Martzolff|L|L|",
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"keywords": "Artérite temporale; Giant cell arteritis; IL-6; Maladie de Horton; Temporal arteritis; Tocilizumab; Vascularite; Vasculitis",
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"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D004351:Drug Resistance; D005260:Female; D013700:Giant Cell Arteritis; D006801:Humans; D016896:Treatment Outcome",
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"abstract": "Mycobacterium neoaurum is a rapidly growing non-tuberculous mycobacterium which is ubiquitous in nature. While it can cause line related infections in immunocompromised host, case reports of urinary tract infections, cutaneous infections, pulmonary infections, and meningoencephalitis have also been reported. We report the first case of Mycobacterium neoaurum line related bacteremia with concomitant pulmonary involvement. Our patient responded well to a nine week course of antimicrobials after removal of infected central line.",
"affiliations": "University of Illinois, 219 E. Illinois Ave, Peoria, IL 61603, United States.;University of Illinois, 219 E. Illinois Ave, Peoria, IL 61603, United States.;University of Illinois, 219 E. Illinois Ave, Peoria, IL 61603, United States.;University of Illinois, 219 E. Illinois Ave, Peoria, IL 61603, United States.",
"authors": "Walayat|Saqib|S|;Awwal|Talha|T|;Roy|Moni|M|;Ahmad|Sharjeel|S|",
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"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(18)30002-710.1016/j.idcr.2018.01.004ArticleMycobacterium neoaurum line-related bacteremia with pulmonary involvement: Case report and review of literature Walayat Saqib saqib.k.walayat@osfhealthcare.orgAwwal Talha Roy Moni Ahmad Sharjeel University of Illinois, 219 E. Illinois Ave, Peoria, IL 61603, United States31 1 2018 2018 31 1 2018 11 88 90 7 1 2018 14 1 2018 14 1 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Mycobacterium neoaurum is a rapidly growing non-tuberculous mycobacterium which is ubiquitous in nature. While it can cause line related infections in immunocompromised host, case reports of urinary tract infections, cutaneous infections, pulmonary infections, and meningoencephalitis have also been reported. We report the first case of Mycobacterium neoaurum line related bacteremia with concomitant pulmonary involvement. Our patient responded well to a nine week course of antimicrobials after removal of infected central line.\n==== Body\nIntroduction\nRapidly growing non-tuberculous mycobacteria (NTM) are usually defined as mycobacteria which grow within one week on culture media. They comprise a diverse group of naturally found microorganisms associated with a wide array of infections including soft tissue infections, keratitis, endocarditis, pneumonia, and catheter related bloodstream infections [1]. While tuberculosis is on a decline, the prevalence of rapidly growing non-tuberculosis mycobacteria (NTM) is reportedly on the rise all over the world [[2], [3]]. This rise is postulated to be due to various environmental and host factors such as global warming, increased humidity, use of immunomodulator drugs, and an increase in immunocompromised population [[1], [3], [4]]. Mycobacterium fortuitum, Mycobacterium chelnoae and Mycobacterium abscessus account for most common rapidly growing NTM [1]. Among these M. fortuitum and M. chelonae are notorious for catheter related infections [5]. Mycobacterium neoaurum is a very rarely reported member of this group usually associated with infections in immunocompromised population [1]. It is a rapidly growing pigmented member of parafortuitium complex, first isolated from the soil in 1972 by Tsukamura and Mizuno [[1], [4]]. It has been implicated in wide range of infections including catheter related bloodstream infections, meningoencephalitis, bacteremia, cutaneous infections, pulmonary and urinary tract infections.\n\nCase history\nA 68 year old Caucasian male initially presented to outpatient infectious disease clinic with a chief complaint of intermittent fever for 3–4 weeks. The fever was associated with chills, night sweats, nausea, headaches, and a fifteen pound unintentional weight loss. His past medical history was significant for recurrent small bowel obstruction with multiple previous abdominal surgeries, chronic watery diarrhea, factor V Leiden deficiency, recurrent urinary tract infections, MRSA infection, and type II diabetes. Patient had a trans-psoas Hickman catheter initially placed about 3 years ago for total parenteral nutrition (TPN) and hydration purposes. The catheter was replaced about 2 months ago prior to presentation due to malfunctioning and retraction issues. Vital signs included blood pressure: 98/50 mm-hg, pulse 70 beats per minute, respiratory rate of 18 per minute and temperature of 98 F. There was no focus of infection on physical examination, including the port site. He denied recent travel outside Illinois, had a pet cat at home, and used tap water for drinking. His white cell count was within normal limits, and ESR was elevated 55 (normal limit: 0–15 mm/h).\n\nWork up including blood cultures, Quantiferon gold test, sputum for acid fast bacilli (AFB), and a trans-esophageal echocardiography (TEE) was ordered. Two sets of blood cultures 2 weeks apart were positive for Mycobacterium neoaurum. Work up for histoplasmosis, and human immunodeficiency virus (HIV) was unremarkable. Tagged white blood cell (WBC) scan showed increased uptake in bilateral lungs consistent with pneumonitis. Computed tomography (CT) chest was ordered due to new onset cough which showed numerous bilateral small non calcified centrilobular nodules within upper and lower lobes, consistent with pneumonitis (Fig. 1). Interferon-Gamma Release Assay (IGRA) for TB (QuantiFERON®-TB Gold In-Tube test, Qiagen, NV, Venlo, Netherlands) was also positive. Transesophageal echocardiogram (TEE) showed no vegetation or abnormalities. The Hickman catheter was removed, and catheter tip was sent for AFB cultures. A temporary right femoral central venous catheter was placed. The patient was started on intravenous (IV) cefoxitin 2 g 4 times daily, IV ciprofloxacin 500 mg twice daily, and oral doxycycline 100 mg twice daily. Blood cultures drawn after the initiation of anti-microbial drugs yielded no growth. Catheter tip culture showed growth of acid fast bacilli after 8 days. Culture susceptibilities showed the mycobacterium being susceptible to cefoxitin (MIC: 8 mcg/mL), imipenem (MIC < = 2 mcg/mL), ciprofloxacin (MIC: 0.25 mcg/mL), moxifloxacin (MIC < = 0.25 mcg/mL), amikacin (MIC< = 1 mcg/mL), doxycycline (MIC: 1 mcg/mL), trimethoprim-sulfamethoxazole (MIC: 0.5–9.5 mcg/mL), linezolid (MIC: 4 mcg/mL) and resistant to clarithromycin (MIC > 16 mcg/mL) and tobramycin (MIC: 16 mcg/mL).Fig. 1 CT scan showing pulmonary nodules before treatment.\n\nFig. 1\n\nThe Hickman catheter was replaced a week after negative blood cultures. This 3-drug combination therapy was continued for 6 weeks and patient was transitioned to oral ciprofloxacin and doxycycline with plans for another 6 weeks of treatment. Treatment was stopped three weeks after transition (9 weeks total) as patient developed a diffuse macular erythematous rash on face and arms. CT chest obtained at the time of completion of treatment showed resolution of pulmonary nodules (Fig. 2). The patient was afebrile without further respiratory symptoms, fevers or chills at 6 months’ follow up.Fig 2 CT scan after treatment showing resolution of symptoms.\n\nFig 2\n\nDiscussion\nMycobacterium neoaurum is a rarely reported mycobacterium in humans which can cause a wide variety of infections but is more notorious for catheter related blood stream infection. The first case of human infection was reported in 1987 in an elderly female with cystadenocarcinoma of the ovary who had a Hickman catheter placed for TPN. Patient’s Hickman catheter was left in place and her bacteremia responded to 7 weeks of gentamicin and cefoxitin [6].\n\nMycobacterium neoaurum is ubiquitous in nature and has been isolated from soil, rock, water and dust [7]. Review of literature showed only 21 reported cases in English literature. Patients ranged in age from 15 months to 80 years, median age being 46 years. Male to female ratio was 1:2.4. Malignancy, immunosuppression, recurrent bacterial infections, recent antimicrobials, IV drug use, prosthetic valves, diabetes mellitus, presence of foreign body like pacemaker and multiple comorbid conditions are reported to be risk factors [[1], [8]]. Duration of bacteremia has been reported for up to 2 weeks [5].\n\nMycobacterium neoaurum is extremely hydrophobic and also has the ability to form biofilms, both of which contribute to its ability to cause line related infections [8]. It has the ability to survive at extreme temperatures as well as low pH and low nutrition states. The organism is reported to be resistant to common disinfectants [3]. While Hickman catheters are the most common lines that are infected as seen from our data, it could virtually involve any foreign body including PICC lines, pacemakers, prosthetic valves and AV fistulas. The first pure pulmonary infection was reported in 2006 which was thought to be related to chronic steroids and aspiration [9], while first CNS infection was reported in 2004 in an elderly female with rapidly progressive dementia [10]. However, the evidence of CNS infection was later thought to be contamination rather than true infection [11]. In case of our patient, pulmonary involvement likely occurred due to hematogenous seeding.\n\nMost patients with catheter related infections had no evidence of infection at the catheter site [1]. Fever is almost universal at presentation except in cases of localized infections [5]. Omoryui et al. reported a case of M. neoaurum related hand infection in an immunocompetent patient who presented with non-healing ulcer of the hand. Their patient did not have any systemic signs of infection and inflammatory markers including WBC, ESR and CRP all were normal [12]. The source was thought to be most likely sea water exposure in that case. Earlier, Tsukamura and Mizuno also had originally isolated the organism from sea water in addition to soil. Another interesting case of skin involvement was found in a patient when Mycobacterium neoaurum was reported to cause alopecia in an immuncompetent host [13].\n\nM. neoaurum is usually isolated from routine aerobic blood cultures. It forms smooth, round, yellow,-orange, schotochromogenic colonies in about 5 days on Lowenstein-Jensen agar at 25–35 °C. This helps to differentiate it from other rapid growing mycobacteria such as M. fortuitum and M. chelonae that produce non-chromogenic colonies [5]. This organism can take up to 5 days to grow, slightly longer than other rapid growing mycobacteria, and can be missed if the samples are discarded after 3–4 days [6]. 16s-rDNA sequence analysis is one of the most reliable methods for detection of this organism making it possible to have the diagnosis in as little as one day [6]. This could be useful especially in situations where there is difficulty in identifying the mycobacteria using conventional methods [1].\n\nWhile there are no guidelines for treatment of infection with M. neoaurum, dual antimicrobial therapy is usually recommended to avoid antimicrobial resistance [6]. The American Thoracic Society recommends in-vitro susceptibility testing for rapidly growing mycobacteria [14].\n\nOut of the twelve reported cases of CLABSI due to M. neoaurum, ten underwent catheter removal and antibacterial therapy, while one underwent just catheter removal [20] and another just underwent antimicrobial therapy without catheter removal [6]. A wide variety of antimicrobials have been used including aminoglycosides, macrolides, fluoroquinolones, tetracyclines, cephalosporins, vancomycin, meropenem, linezolid, rifampin and ethambutol. There are no recommendations regarding duration of treatment or drug combinations but mostly 2–4 agents have been reported to be used. Duration of treatment also varied from 3 weeks to 4 months. Brown-Elliot et al. reviewed drug susceptibilities and reported most of the isolates to be susceptible to amikacin (46/46), cefoxitin (46/46), tobramycin (46/46), ciprofloxacin (46/46), doxycycline (21/21), gatifloxicin (38/38), imipenem (46/46), linezolid (46/46), moxifloxacin (23/23), sulfamethoxazole (20/20), tigecycline (22/22), and trimethoprim-sulfamethoxazole (45/45). There is some evidence of resistance to clarithromcyin suggesting the presence of inducible erm gene which is also thought to contribute to macrolide resistance in other species including tuberculosis [[1], [15]]. Our case also showed similar findings with the organism being susceptible to cefoxitin, imipenem, ciprofloxacin, moxifloxacin, amikacin, doxycycline, TMP-SMX, linezolid, tigecycline and resistant to clarithromycin and tobramycin. Nineteen of the twenty one reported infected patients received antimicrobial therapy and all were cured except who was lost to follow up [8] and one possible fatality due to M. neoaurum involving the brain [22]. All the patients who were prescribed anti microbials responded to the drugs. Treatment was well tolerated and no relapse has been reported to date.\n\nIn our case, the patient had multiple comorbid conditions including TPN dependence, multiple abdominal surgeries, short bowel syndrome, and history of recurrent hospitalizations secondary to multiple infections and dehydration. Our patient also had a history of exposure to multiple infections, and a history of exposure to multiple antibacterial agents. All these could have put him at risk for infection. The American Thoracic Society has suggested a diagnostic criteria requiring clinical, radiographic and microbiologic evidence for non-tuberculosis mycobacterial lung disease. Our patient did have symptoms of fevers, night sweats and cough as well as radiographic evidence of multiple lesions which resolved after treatment making it most likely that his lung infection was also due to the NTM [14].\n\nIn conclusion, rapidly growing non-tuberculous mycobacteria such as Mycobacterium neoaurum are being increasingly recognized as an important human pathogen. Testing for these organisms should be considered in patients presenting with fever of unknown origin especially in immunocompromised settings or patients who have foreign bodies such as Hickman catheter present.\n\nAppendix A Supplementary data\nThe following is Supplementary data to this article: \n\nAppendix A Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.idcr.2018.01.004.\n==== Refs\nReferences\n1 Alhusseini M. Miceli M.H. Chandrasekar P. Revankar S. Catheter-related bloodstream infection due to Mycobacterium neoaurum in a patient with acute leukemia Leuk Lymphoma 55 August (8) 2014 1933 1934 24152051 \n2 Prevots D.R. Marras T.K. Epidemiology of human pulmonary infection with non-tuberculous mycobacteria: a review Clin Chest Med 36 March (1) 2015 13 25676516 \n3 De Groote M.A. Huitt G. Infections due to rapidly growing mycobacteria Clin Infect Dis 42 12 2006 1756 1763 16705584 \n4 Tsukamura M. Numerical analysis of rapidly growing, nonphotochromogenic mycobacteria, including Mycobacterium agri (Tsukamura 1972) Tsukamura sp. nov., nom. rev Int J Syst Evol Microbiol 31 July (3) 1981 247 258 \n5 Washer L.L. IV JR Rider J. Chenoweth C.E. Mycobacterium neoaurum bloodstream infection: report of 4 cases and review of the literature Clin Infect Dis 45 July (2) 2007 e10 e13 17578768 \n6 Davison M. McCormack J. Blacklock Z. Dawson D. Tilse M. Crimmins F. Bacteremia caused by Mycobacterium neoaurum J Clin Microbiol 26 1988 762 764 3366872 \n7 McNally C.F. Mangino J.E. Mycobacterium neoaurum : a case report and review of the literature Infect Dis Clin Pract 9 2000 27305 \n8 Awadh H. Mansour M. Shorman M. Bacteremia with an unusual pathogen: Mycobacterium neoaurum Case Rep Infect Dis October 2016 \n9 Y. Morimoto E.D. Chan L. Heifets J.M. Routes pulmonary infection with Mycobacterium neoaurum identified by 16S ribosomal DNA sequence (Reviewed) J Infect 54 2007 e227 e231 17306883 \n10 Kumar A. Pazhayattil G.S. Das A. Conte H.A. Mycobacterium neoaurum causing prosthetic valve endocarditis: a case report and review of the literature Braz J Infect Dis 18 April (2) 2014 235 237 24076109 \n11 Han X.Y. Mycobacterium neoaurum contamination Emerg Infect Dis 11 August (8) 2005 1316 16110582 \n12 Omoruyi O.J. Ip W.Y. To K.K. Hand infection due to Mycobacterium neoaurum J Hand Surg (Eur Vol) 37 July (6) 2012 574 575 22457251 \n13 Martin L.K. Lawrence R. Kossard S. Murrell D.F. Cutaneous Mycobacterium neoaurum infection causing scarring alopecia in an immunocompetent host Br J Dermatol 157 July (1) 2007 204 206 17501949 \n14 Griffith D.E. Aksamit T. Brown-Elliott B.A. Catanzaro A. Daley C. Gordin F. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases Am J Respir Crit Care Med 175 February (4) 2007 367 416 17277290 \n15 Brown-Elliott B.A. Wallace R.J. Petti C.A. Mann L.B. McGlasson M. Chihara S. Mycobacterium neoaurum and Mycobacterium bacteremicum sp. nov. as causes of mycobacteremia J Clin Microbiol 48 December (12) 2010 4377 4385 20881180 \n20 George S. Schlesinger L. Mycobacterium neoaurum —an unusual cause of infection of vascular catheters: case report and review Clin Infect Dis 28 1999 682 683 10194099 \n22 Heckman G.A. Hawkins C. Morris A. Burrows L.L. Bergeron C. Rapidly progressive dementia due to Mycobacterium neoaurum meningoencephalitis Emerg Infect Dis 10 May (5) 2004 924 15200833\n\n",
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"title": "Mycobacterium neoaurum line-related bacteremia with pulmonary involvement: Case report and review of literature.",
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{
"abstract": "Romiplostim is a thrombopoietin receptor agonist approved for the treatment of immune thrombocytopenia purpura. When following FDA-approved romiplostim prescribing recommendations to withhold treatment for platelet counts above 400k/µL, some patients exhibit a precipitous decline in their platelet count potentially causing patient harm. We present two cases where stable platelet counts were achieved only through persistent weekly dosing of romiplostim despite platelet counts above 400k/µL on the day of administration. Therefore, continuous weekly dosing of romiplostim despite platelet count being above 400k/µL combined with twice weekly vigilant monitoring is an alternative method of romiplostim dosing that mitigates severe fluctuations in platelets. We also discuss important details, postulated mechanisms, and evidence-based mitigation strategies.",
"affiliations": "1 Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.;3 Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.;4 Department of Clinical Pharmacy Services, University of Texas at MD Anderson Cancer Center, Houston, TX, USA.;3 Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.;2 Department of Pharmacotherapy, University of Utah, Salt Lake City, UT, USA.;3 Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.",
"authors": "Gilreath|Jeffrey A|JA|;Wei|Mei|M|;Paul|Shilpa|S|;Parker|Charles J|CJ|;Stenehjem|David D|DD|;Rodgers|George M|GM|",
"chemical_list": "D011961:Receptors, Fc; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; D013926:Thrombopoietin; C488777:romiplostim",
"country": "England",
"delete": false,
"doi": "10.1177/1078155217752536",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "25(3)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Immune thrombocytopenic purpura; benign hematology; romiplostim; thrombopoietin receptor agonist",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic; D011961:Receptors, Fc; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; D013926:Thrombopoietin",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "719-723",
"pmc": null,
"pmid": "29357781",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dynamic dosing of romiplostim in patients with immune thrombocytopenia purpura: Two case reports.",
"title_normalized": "dynamic dosing of romiplostim in patients with immune thrombocytopenia purpura two case reports"
} | [
{
"companynumb": "US-AMGEN-USASP2019038918",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ROMIPLOSTIM"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nInterscalene block can be chosen for complete anesthesia for shoulder surgery. Phrenic nerve block occurs with almost all interscalene blocks, but is well tolerated in most patients. This may not be the case in selected geriatric patients.\n\n\nMETHODS\nThe patient is a 90-year-old female with osteoarthritis of the left shoulder scheduled for total shoulder anthroplasty. Past medical history revealed hypertension, mild mitral valve insufficiency, and a remote episode of congestive heart failure. She underwent interscalene block with 40 mL of 1.4% mepivacaine, 1:200,000 epinephrine freshly added, alkalinized with sodium bicarbonate.\n\n\nRESULTS\nThe onset of the block was rapid and complete. The patient had minimal intravenous sedation (0.5 mg midazolam) and was resting comfortably with a respiratory rate of 12-14 breaths/min. Approximately 5 minutes after the injection of local anesthetic, the patient was noted to be alert, cyanotic, denying dyspnea, with an oxygen saturation of 75-85%. A chest radiograph revealed elevation of the ipsilateral hemidiaphragm and no pneumothorax or other pathology. Despite supplemental oxygen by face mask, desaturation persisted and general anesthesia was induced. On emergence from anesthesia, the patient had a complete interscalene block. Repeat chest radiograph after resolution of the block revealed return of hemidiaphragm position and no other pathology. The patient was extubated in the recovery room without difficulty. Following extubation the patient demonstrated stable respirations and normal oxyhemoglobin saturation.\n\n\nCONCLUSIONS\nIpsilateral phrenic nerve paralysis caused significant respiratory compromise in an elderly patient without known significant pulmonary disease.",
"affiliations": "Department of General Anesthesiology, The Cleveland Clinic Foundation, Ohio 44195, USA.",
"authors": "Smith|M P|MP|;Tetzlaff|J E|JE|;Brems|J J|JJ|",
"chemical_list": "D010108:Oxyhemoglobins",
"country": "England",
"delete": false,
"doi": "10.1097/00115550-199823020-00017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1098-7339",
"issue": "23(2)",
"journal": "Regional anesthesia and pain medicine",
"keywords": null,
"medline_ta": "Reg Anesth Pain Med",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000768:Anesthesia, General; D005260:Female; D006801:Humans; D009407:Nerve Block; D010108:Oxyhemoglobins; D010791:Phrenic Nerve; D012785:Shoulder Joint",
"nlm_unique_id": "9804508",
"other_id": null,
"pages": "210-3",
"pmc": null,
"pmid": "9570613",
"pubdate": "1998",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Asymptomatic profound oxyhemoglobin desaturation following interscalene block in a geriatric patient.",
"title_normalized": "asymptomatic profound oxyhemoglobin desaturation following interscalene block in a geriatric patient"
} | [
{
"companynumb": "US-PFIZER INC-2021633290",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MEPIVACAINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Acute bacterial endocarditis (ABE) is most commonly due to virulent pathogens, i.e., Staphylococcus aureus. S. aureus ABE may be due to methicillin-sensitive (MSSA) or methicillin-resistant (MRSA) strains and, optimally, ABE should be treated with bactericidal antibiotics. Traditionally, vancomycin has long been used to treat MRSA ABE, but it has been shown that vancomycin may increase the staphylococcal the thickness, resulting in permeability-mediated resistance. We present a case of a 72-year-old male with mitral valve MRSA ABE refractory to daptomycin therapy following initial therapy with vancomycin. We were not able to diminish the intensity of the patient's MRSA bacteremia from his mitral valve ABE, even with high-dose (12 mg/kg day) daptomycin, presumably because of permeability-mediated resistance due to antecedent vancomycin therapy.",
"affiliations": "Infectious Disease Division, Winthrop-University Hospital, Mineola, NY 11501, USA. llusardi@winthrop.org",
"authors": "Cunha|B A|BA|;Pherez|F M|FM|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin; D017576:Daptomycin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10096-008-0692-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-9723",
"issue": "28(7)",
"journal": "European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology",
"keywords": null,
"medline_ta": "Eur J Clin Microbiol Infect Dis",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D017576:Daptomycin; D024881:Drug Resistance, Bacterial; D004697:Endocarditis, Bacterial; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008943:Mitral Valve; D013203:Staphylococcal Infections; D017211:Treatment Failure; D014640:Vancomycin",
"nlm_unique_id": "8804297",
"other_id": null,
"pages": "831-3",
"pmc": null,
"pmid": "19184141",
"pubdate": "2009-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18003803;7752734;18226084;15956145;11157650;18361953;17682996;16324966;16701116;18042628;18591272;15997484;12517819;360377;18214559;16455939;16464892;16505987;16652325;18096352",
"title": "Daptomycin resistance and treatment failure following vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) mitral valve acute bacterial endocarditis (ABE).",
"title_normalized": "daptomycin resistance and treatment failure following vancomycin for methicillin resistant staphylococcus aureus mrsa mitral valve acute bacterial endocarditis abe"
} | [
{
"companynumb": "US-PFIZER INC-2017086419",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DAPTOMYCIN"
},
"drugadditional": "3",
... |
{
"abstract": "Although the antimyeloma effect of lenalidomide is associated with activation of the immune system, the exact in vivo immunomodulatory mechanisms of lenalidomide combined with low-dose dexamethasone (Len-dex) in refractory/relapsed multiple myeloma (RRMM) patients remain unclear. In this study, we analyzed the association between immune cell populations and clinical outcomes in patients receiving Len-dex for the treatment of RRMM. Peripheral blood samples from 90 RRMM patients were taken on day 1 of cycles 1 (baseline), 2, 3, and 4 of Len-dex therapy. Peripheral blood CD3(+), CD4(+), and CD8(+) cell frequencies were significantly decreased by 3 cycles of therapy, whereas NK cell frequency was significantly increased after the 3rd cycle. For the myeloid-derived suppressor cell (MDSC) subset, the frequency of granulocytic MDSCs transiently increased after the 1st cycle, whereas there was an increase in monocytic MDSC (M-MDSC) frequency after the 1st and 3rd cycles. Among 81 evaluable patients, failure to achieve a response of VGPR or greater was associated with a decrease in CD8(+) cell frequency and increase in M-MDSC frequency after 3 cycles of Len-dex treatment. A high proportion of natural killer T (NKT)-like cells (CD3(+)/CD56(+)) prior to Len-dex treatment might predict a longer time to progression. In addition, patients with a smaller decrease in the frequency of both CD3(+) cells and CD8(+) cells by 3 cycles exhibited a longer time to the next treatment. These results demonstrated that early changes in immune cell subsets are useful immunologic indicators of the efficacy of Len-dex treatment in RRMM.",
"affiliations": "Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea.;Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea.;Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea.;Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea.;Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea.;Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea.;Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea.;Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea.;Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea.;Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea.;Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea.;Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea.;Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea.;Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea.;Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, #222 Banpodaero, Seocho-Gu, Seoul, 06591, Korea. ckmin@catholic.ac.kr.",
"authors": "Lee|Sung-Eun|SE|;Lim|Ji-Young|JY|;Ryu|Da-Bin|DB|;Kim|Tae Woo|TW|;Yoon|Jae-Ho|JH|;Cho|Byung-Sik|BS|;Eom|Ki-Seong|KS|;Kim|Yoo-Jin|YJ|;Kim|Hee-Je|HJ|;Lee|Seok|S|;Cho|Seok-Goo|SG|;Kim|Dong-Wook|DW|;Lee|Jong-Wook|JW|;Min|Woo-Sung|WS|;Kim|Myungshin|M|;Min|Chang-Ki|CK|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D013792:Thalidomide; D003907:Dexamethasone; D000077269:Lenalidomide",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00262-016-1861-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-7004",
"issue": "65(8)",
"journal": "Cancer immunology, immunotherapy : CII",
"keywords": "Lenalidomide; Low-dose dexamethasone; Multiple myeloma; Myeloid-derived suppressor cells; Natural killer T-like cells",
"medline_ta": "Cancer Immunol Immunother",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D003907:Dexamethasone; D018450:Disease Progression; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D010641:Phenotype; D013792:Thalidomide",
"nlm_unique_id": "8605732",
"other_id": null,
"pages": "983-94",
"pmc": null,
"pmid": "27342591",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Circulating immune cell phenotype can predict the outcome of lenalidomide plus low-dose dexamethasone treatment in patients with refractory/relapsed multiple myeloma.",
"title_normalized": "circulating immune cell phenotype can predict the outcome of lenalidomide plus low dose dexamethasone treatment in patients with refractory relapsed multiple myeloma"
} | [
{
"companynumb": "KR-CELGENEUS-KOR-2016071004",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "The acronym of malignancy, iatrogenic, intoxication and immobilization, sarcoidosis, hyperparathyroidism and hyperthyroidism, milk-alkali syndrome, and paget is very helpful in diagnosing hypercalcemia. We report on a 94-year-old patient with history of end-stage renal failure secondary to benign nephroangiosclerosis, who was on maintenance hemodialysis during dialysis, his blood chemistry revealed mild hypercalcemia (2.66 mmol/L) with normal level of intact primary hyperparathyroidism (32.37 ng/mL) mandating the discontinuation of Vitamin D[3]. In view of persisting hypercalcemia, denosumab 60 mg/mL was administrated subcutaneously. The serum calcium level showed a decrease and stabilized at near upper limit (2.57 mmol/L). Three weeks later, the serum calcium remained mildly elevated fluctuating between 2.66 and 2.80 mmol/L.",
"affiliations": "Department of Nephrology and Dialysis, Hospital Louis Jaillon, Saint-Claude, France.;Secondary Care, Hospital Louis Jaillon, Saint-Claude, France.;Secondary Care, Hospital Louis Jaillon, Saint-Claude, France.;Department of Nephrology and Dialysis, Hospital Louis Jaillon, Saint-Claude, France.;Secondary Care, Hospital Louis Jaillon, Saint-Claude, France.;Department of Nephrology and Dialysis, Hospital Louis Jaillon, Saint-Claude, France.",
"authors": "Dahmani|Omar|O|;Sophoclis|Christine|C|;Kebir|Malika|M|;Bouguern|Djemai|D|;Sakho|Aboubacry|A|;Demarchi|Pascale|P|",
"chemical_list": "D015415:Biomarkers; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D000069448:Denosumab; D002118:Calcium",
"country": "Saudi Arabia",
"delete": false,
"doi": "10.4103/1319-2442.198239",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1319-2442",
"issue": "28(1)",
"journal": "Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia",
"keywords": null,
"medline_ta": "Saudi J Kidney Dis Transpl",
"mesh_terms": "D000369:Aged, 80 and over; D015415:Biomarkers; D050071:Bone Density Conservation Agents; D002118:Calcium; D000069448:Denosumab; D004164:Diphosphonates; D004351:Drug Resistance; D057915:Drug Substitution; D006801:Humans; D006934:Hypercalcemia; D007676:Kidney Failure, Chronic; D008297:Male; D006435:Renal Dialysis; D016896:Treatment Outcome",
"nlm_unique_id": "9436968",
"other_id": null,
"pages": "154-157",
"pmc": null,
"pmid": "28098117",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Denosumab for the treatment of bisphosphonate resistant hypercalcemia in a hemodialysis patient.",
"title_normalized": "denosumab for the treatment of bisphosphonate resistant hypercalcemia in a hemodialysis patient"
} | [
{
"companynumb": "FR-AMGEN-FRASP2017010142",
"fulfillexpeditecriteria": "2",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM POLYSTYRENE SULFONATE"
},
"drugadditio... |
{
"abstract": "Objective: To understand the effectiveness and safety sofosbuvir/velpatasvir (SOF/VEL) combination ±ribavirin in the treatment of chronic hepatitis C virus (HCV) infection in China. Methods: A total of 96 Chinese adults with chronic HCV infection who were treated with SOF/VEL combination ± ribavirin for 12 weeks between July 2018 and February 2020 were selected. HCV RNA, routine blood test, liver, kidney and coagulation function, abdominal Color Doppler ultrasound or CT and liver stiffness were detected at baseline, 4 weeks of treatment, end of treatment and 12 weeks of follow-up. Adverse events and laboratory abnormalities during the treatment were recorded. A t-test was used to compare the measurement data between the two groups, and the analysis of variance was used for multiple group comparison. Results: A total of 93 cases (96.9%) achieved sustained virological response (SVR12), of which 3 cases had relapsed. 88 cases (91.7%, 88/96) had achieved rapid virological response (RVR). 96 cases (100%) had achieved virological response by the end of treatment (EOT). In patients with decompensated liver cirrhosis, the average baseline Child-Pugh score and Model for End-Stage Liver Disease score was 7.4±1.0, and 11.4±1.7, respectively. Among them, 12 cases of the SOF/VEL combined with RBV treatment had achieved SVR12 (100%) at 12 weeks, while only 3 of the 5 cases of single-tablet regimen of SOF/VEL had achieved SVR12 (60%). There was no significant difference between creatinine levels and baseline during or 12 weeks after treatment. The incidence of adverse events in patients with chronic hepatitis C and compensated cirrhosis was 6.3% (5/79), while that in patients with decompensated cirrhosis was 35.3% (6/17). The most common adverse events were hyperbilirubinemia, fatigue and anemia. There were no serious adverse events, deaths or discontinuation of treatment due to adverse events. Conclusion: SOF/VEL combination ± ribavirin in the treatment of various common genotypes of chronic hepatitis C, compensated cirrhosis, decompensated cirrhosis and hepatocellular carcinoma has higher SVR12 in China, and the tolerance and safety are good.",
"affiliations": "Department of Hepatology, Guangzhou Eighth People's Hospital Affiliated to Guangzhou Medical University, Guangzhou 510060, China.;Infectious Department of Guangdong General Hospital, Guangzhou 510080, China.;Department of Liver Diseases, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen 518052 , China.;Department of Hepatology, Guangzhou Eighth People's Hospital Affiliated to Guangzhou Medical University, Guangzhou 510060, China.;Department of Hepatology, Guangzhou Eighth People's Hospital Affiliated to Guangzhou Medical University, Guangzhou 510060, China.;Department of Hepatology, Guangzhou Eighth People's Hospital Affiliated to Guangzhou Medical University, Guangzhou 510060, China.;Department of Hepatology, Guangzhou Eighth People's Hospital Affiliated to Guangzhou Medical University, Guangzhou 510060, China.",
"authors": "Li|J P|JP|;Chen|X F|XF|;Yan|Q|Q|;Zhang|Y J|YJ|;Xie|Z W|ZW|;Xia|Y|Y|;Guan|Y J|YJ|",
"chemical_list": "D000998:Antiviral Agents; D002219:Carbamates; D006576:Heterocyclic Compounds, 4 or More Rings; D012254:Ribavirin; C000604171:velpatasvir; D000069474:Sofosbuvir",
"country": "China",
"delete": false,
"doi": "10.3760/cma.j.cn501113-20200831-00486",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-3418",
"issue": "28(10)",
"journal": "Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology",
"keywords": "Direct antiviral agent, Sofosbuvir/velpatasvir; Hepatitis C, chronic; Treatment, safety",
"medline_ta": "Zhonghua Gan Zang Bing Za Zhi",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D002219:Carbamates; D002681:China; D004359:Drug Therapy, Combination; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D008103:Liver Cirrhosis; D012254:Ribavirin; D000069474:Sofosbuvir; D016896:Treatment Outcome",
"nlm_unique_id": "9710009",
"other_id": null,
"pages": "831-837",
"pmc": null,
"pmid": "33105927",
"pubdate": "2020-10-20",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Effectiveness and safety of sofosbuvir/velpatasvir combination ± ribavirin in the treatment of Chinese adults with chronic hepatitis C virus infection.",
"title_normalized": "effectiveness and safety of sofosbuvir velpatasvir combination ribavirin in the treatment of chinese adults with chronic hepatitis c virus infection"
} | [
{
"companynumb": "CN-GILEAD-2020-0507166",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "SOFOSBUVIR\\VELPATASVIR"
},
"drugadditional": nu... |
{
"abstract": "The main therapeutic basis for a case of organophosphate poisoning is a combination therapy which includes atropine as an anticholinergic drug and pralidoxime. If the poisoning is severe, a high dose of this combination of medicines may be needed, but this may cause serious side effects: paralytic ileus or even megacolon; however, these gastrointestinal events are very rare. Here, we report a case of organophosphate poisoning where atropine therapy was given and led to drug-associated toxic megacolon.",
"affiliations": "1 Department of Forensic Medicine and Toxicology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;2 Department of Forensic Medicine and Toxicology, Ardabil University of Medical Sciences, Ardabil, Iran.;3 Fellowship in Clinical Toxicology, Tabriz University of Medical Sciences,Tabriz, Iran.;4 Rasoul-e-Akram Hospital Clinical Research Development Center, Iran University of Medical Sciences, Tehran, Iran.",
"authors": "Mostafazadeh|Babak|B|;Farzaneh|Esmaeil|E|;Paeezi|Maryam|M|;Nikkhah|Farahnaz|F|",
"chemical_list": "D000931:Antidotes; D011220:Pralidoxime Compounds; D001285:Atropine; C028797:pralidoxime",
"country": "England",
"delete": false,
"doi": "10.1177/0025817217703520",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-8172",
"issue": "85(4)",
"journal": "The Medico-legal journal",
"keywords": "Organophosphate; atropine; poisoning; toxic megacolon",
"medline_ta": "Med Leg J",
"mesh_terms": "D000931:Antidotes; D001285:Atropine; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D008532:Megacolon, Toxic; D008875:Middle Aged; D062025:Organophosphate Poisoning; D011220:Pralidoxime Compounds",
"nlm_unique_id": "0412004",
"other_id": null,
"pages": "221-223",
"pmc": null,
"pmid": "28403672",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Toxic megacolon as a rare complication following atropine therapy due to organophosphate poisoning: A case report.",
"title_normalized": "toxic megacolon as a rare complication following atropine therapy due to organophosphate poisoning a case report"
} | [
{
"companynumb": "IR-FRESENIUS KABI-FK201810243",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": "065",
"dru... |
{
"abstract": "An 81-year-old woman presented with abdominal distension and right hypochondrial pain. Abdominal contrast computed tomography and magnetic resonance imaging revealed an 11-cm gallbladder tumor. The patient was diagnosed with squamous cell carcinoma of the gallbladder by endoscopic ultrasound-guided fine-needle aspiration from the gastric antrum. Thereafter, the gallbladder tumor enlarged, and cholecysto-duodenal and transverse colon fistulas were formed. A covered metal stent was placed on the transverse colon, and polyglycolic acid sheets were injected into the duodenum to close the fistulas endoscopically. Endoscopic closure is less invasive than surgery and considered effective for patients with poor general health conditions.",
"affiliations": "Department of Gastroenterology, Hematology and Rheumatology, Tsugaru General Hospital, Japan.;Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Japan.;Department of Gastroenterology, Hematology and Rheumatology, Tsugaru General Hospital, Japan.;Department of Gastroenterology, Hematology and Rheumatology, Tsugaru General Hospital, Japan.;Department of Gastroenterology, Hematology and Rheumatology, Tsugaru General Hospital, Japan.;Department of Gastroenterology, Hematology and Rheumatology, Tsugaru General Hospital, Japan.;Department of Gastroenterology, Hematology and Rheumatology, Tsugaru General Hospital, Japan.;Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Japan.;Department of Gastroenterology, Hematology and Rheumatology, Tsugaru General Hospital, Japan.;Department of Gastroenterology, Hematology and Rheumatology, Tsugaru General Hospital, Japan.;Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Japan.",
"authors": "Sato|Satoshi|S|;Chinda|Daisuke|D|;Tanaka|Yusuke|Y|;Kaizuka|Naotoshi|N|;Higuchi|Naoki|N|;Ota|Shinji|S|;Miyazawa|Kuniaki|K|;Kikuchi|Hidezumi|H|;Aizawa|Syu|S|;Iwamura|Hideki|H|;Fukuda|Shinsaku|S|",
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"doi": "10.2169/internalmedicine.6384-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n33390496\n10.2169/internalmedicine.6384-20\nCase Report\nEffective Endoscopic Closure of Cholecysto-duodenal and Transverse Colon Fistulas Due to Squamous Cell Carcinoma of the Gallbladder Using Polyglycolic Acid Sheets and a Covered Metal Stent\nSato Satoshi 12\nChinda Daisuke 23\nTanaka Yusuke 12\nKaizuka Naotoshi 12\nHiguchi Naoki 12\nOta Shinji 12\nMiyazawa Kuniaki 12\nKikuchi Hidezumi 2\nAizawa Syu 1\nIwamura Hideki 1\nFukuda Shinsaku 2\n1 Department of Gastroenterology, Hematology and Rheumatology, Tsugaru General Hospital, Japan\n2 Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Japan\n3 Department of Community Medicine, Hirosaki University Graduate School of Medicine, Japan\nCorrespondence to Dr. Daisuke Chinda, chinda@hirosaki-u.ac.jp\n\n29 12 2020\n1 6 2021\n60 11 17231729\n24 9 2020\n17 11 2020\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/).\nAn 81-year-old woman presented with abdominal distension and right hypochondrial pain. Abdominal contrast computed tomography and magnetic resonance imaging revealed an 11-cm gallbladder tumor. The patient was diagnosed with squamous cell carcinoma of the gallbladder by endoscopic ultrasound-guided fine-needle aspiration from the gastric antrum. Thereafter, the gallbladder tumor enlarged, and cholecysto-duodenal and transverse colon fistulas were formed. A covered metal stent was placed on the transverse colon, and polyglycolic acid sheets were injected into the duodenum to close the fistulas endoscopically. Endoscopic closure is less invasive than surgery and considered effective for patients with poor general health conditions.\n\ngallbladder neoplasms\nsquamous cell carcinoma\ncholecysto-duodenal and transverse colon fistulas\ncovered metal stent\npolyglycolic acid sheet\n==== Body\nIntroduction\n\nSquamous cell carcinoma of the gallbladder is a rare malignancy as it accounts for 0.5-2.4% of all gallbladder carcinomas. Its clinical characteristics include large tumor formation, direct invasion into adjacent organs, and probable formation of gastrointestinal tract fistulas (1-3). In cases of fistulas in which radical operation is difficult, surgical closure of these fistulas under general anesthesia is sometimes performed. However, surgery is often contraindicated for elderly patients and individuals with a poor physical condition (4,5).\n\nThe application of polyglycolic acid (PGA) sheets for perforation after endoscopic submucosal dissection (ESD) and gastrointestinal fistula due to malignant tumor has recently been reported (6-9). Furthermore, endoscopic closure with covered metal stent placement can be performed for colovesical or esophagorespiratory fistulas due to colon or esophageal carcinomas (10-12).\n\nTo our knowledge, endoscopic closure of gastrointestinal fistulas due to squamous cell carcinoma of the gallbladder has not yet been reported. We herein report a case of effective endoscopic closure with a covered metal stent and PGA sheet for cholecysto-duodenal and transverse colon fistulas due to squamous cell carcinoma of the gallbladder.\n\nCase Report\n\nAn 81-year-old woman presented to our hospital complaining of abdominal distension and right hypochondrial pain, and she was admitted for an examination.\n\nMild tenderness in the right hypochondrium was revealed on a physical examination. Laboratory tests revealed elevated serum inflammatory markers (white blood cells, 13,370 /μL; C-reactive protein, 10.4 mg/dL), transaminase, transpeptidase (aspartate transaminase, 36 U/L; alanine aminotransferase, 29 U/L; γ-GTP, 61 U/L), and squamous cell carcinoma antigen (50.3 ng/mL) levels.\n\nAbdominal contrast computed tomography (CT) and magnetic resonance imaging revealed an 11-cm solid tumor in the lower right hepatic lobe attached to the cystic duct (Fig. 1). The gallbladder was not observed despite the lack of a medical history of cholecystectomy. We therefore diagnosed the patient with a gallbladder tumor.\n\nFigure 1. Images of abdominal contrast computed tomography (CT; a, b) and magnetic resonance imaging (MRI; c,d). a-d: CT and MRI revealed a solid tumor of 11 cm in the lower right hepatic lobe and direct invasion into the liver. The tumor was attached to the gallbladder duct and diagnosed as a gallbladder tumor.\n\nEsophagogastroduodenoscopy (EGD) demonstrated a submucosal tumor-like extrinsic compression along the greater curvature of the gastric antrum (Fig. 2a). Endoscopic ultrasound (EUS) detected an isoechoic mass, and direct invasion into the stomach was considered because the border between the tumor and stomach wall was unclear (Fig. 2b). A histological examination by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) revealed cell sheets of stratified squamous epithelium, abnormal keratinization, such as single-cell keratinization, and cancer pearl-like structures. Concentrated irregular nuclei of different sizes were observed in keratinized regions (Fig. 2c, d). Therefore, we diagnosed the patient with squamous cell carcinoma of the gallbladder.\n\nFigure 2. Findings of esophagogastroduodenoscopy (EGD), endoscopic ultrasound (EUS), and a histological examination by endoscopic ultrasound-fine needle aspiration (EUS-FNA). a: EGD revealed submucosal tumor-like extrinsic compression in the greater curvature of the gastric antrum. b: EUS showed an isoechoic mass, and direct invasion into the stomach was considered because the border between the tumor and the stomach wall was unclear. c, d: A histological examination by EUS-FNA revealed sheets of stratified squamous epithelium, abnormal keratinization, such as single-cell keratinization, and cancer pearl structure. Concentrated irregular nuclei of different sizes were described in the keratinized region. Magnification: c ×200, d ×400.\n\nShe was discharged after EUS-FNA with no complications. Two weeks after discharge, she visited our hospital because a pathological definitive diagnosis was obtained. At that time, she had developed a fever (38.0°C) and reported a poor food intake and difficulty walking. Therefore, she was readmitted to our hospital. CT revealed an enlarged gallbladder tumor, surrounding lymph node metastasis, and substantial gas inside the tumor (Fig. 3a). The border between the tumor and gastroduodenal wall was unclear on CT. Furthermore, the border between the tumor and transverse colon was also unclear. Therefore, the formation of fistulas in the gastrointestinal tract was considered (Fig. 3b). EGD demonstrated a 1.5-cm fistula in the duodenal bulb (Fig. 3c). On a radiological examination using Gastrografin (contrast medium; Bayer Yakuhin, Osaka, Japan), Gastrografin flowed into the gallbladder tumor from the duodenal fistula and then flowed out into the transverse colon from the tumor (Fig. 3d).\n\nFigure 3. Findings of computed tomography (CT), esophagogastroduodenoscopy (EGD) and a Gastrografin contrast examination at second admission. a, b: CT revealed an enlarged gallbladder tumor and a large amount of gas inside the tumor (arrowheads). The borders between the tumor and gastric antrum, duodenum, and transverse colon were unclear. Fistulas in the gastrointestinal tract were formed. c: EGD revealed a 1.5-cm fistula in the duodenal bulb (arrowheads). d: Gastrografin flowed into the gallbladder tumor from the duodenal fistula (arrow) and flowed out into the transverse colon from the transverse colon fistula (arrowhead).\n\nBecause the tumor was progressing rapidly, chemotherapy was initiated immediately, starting one week after readmission. According to the standard chemotherapy regimen for gallbladder carcinoma, cisplatin and gemcitabine administration was started. However, food intake and stool through the cholecysto-duodenal and transverse colon fistulas caused intratumoral infection, and chemotherapy was discontinued. Regarding surgical risks, the American Society of Anesthesiologists physical status (ASA-PS) was low (grade 2), while the age-adjusted Charlson comorbidity index (ACCI) was high (11 points). The patient exhibited undernutrition (total protein, 5.6 g/dL; albumin, 2.0 g/dL); furthermore, both she and her family wished to avoid surgery under general anesthesia because she was 81 years old. Based on these results, the patient was diagnosed with a poor physical status and was not considered suitable for surgery, such as fistula closure or bypass surgery.\n\nAs the patient and her family expressed a strong preference for food intake, we decided to attempt endoscopic closure of the fistulas. Closure by clipping or over-the-scope clips (OTSCs) was considered difficult because of the relatively large fistulas in this case. Therefore, we decided to perform closure using a covered metal stent and PGA sheets. Only uncovered metal stents for closure of colon fistulas are considered for insurance coverage in Japan; however, with the consent of the patient and her family, we decided to use a duodenal covered metal stent for the transverse colon fistula. Before treatment, the patient and her family provided their written informed consent.\n\nFirst, a colonoscopic examination was performed after sedation and pain relief with midazolam and pentazocine. Tract stenosis due to direct invasion of the gallbladder tumor was observed in the transverse colon, along with 2 cm of the fistula (Fig. 4a). For endoscopic closure of the fistula and dilation of stenosis, a covered metal stent (Niti-S covered metal stent 20×12 cm; Taewoong Medical, Seoul, Korea) was placed to seal the fistula (Fig. 4b). Second, EGD was performed. Polygolyc acid sheets (10×5 cm, Neoveil sheet; Gunze Medical Japan, Kyoto, Japan) were cut to the appropriate sizes and applied to the duodenal fistula. Two sheets were used in total, and fibrin glue (Beriplast P Combi-Set Tissue adhesion; CSL Behring, Tokyo, Japan) was applied over the top to fix the PGA sheets in position (Fig. 4c). After application of the PGA sheet, a decrease in Gastrografin, which had been flowing into the gallbladder tumor from the duodenal fistula, was apparent on a radiological examination. Endoscopic closure was successfully completed without complications.\n\nFigure 4. Findings of colonoscopy, esophagogastroduodenoscopy (EGD), and abdominal radiography. a: Colonoscopy demonstrated stenosis of the normal tract due to direct invasion of the gallbladder tumor and a 2-cm fistula in the transverse colon. b: A covered metal stent was placed so that the cover material sealed the fistula for fistula closure and removal of stenosis. c: Polyglycolic acid sheets, cut to the appropriate sizes, were applied to the fistula of the duodenum, and then fibrin glue was applied. d: An abdominal radiograph obtained two weeks later shows the absence of stent migration.\n\nAfter performing endoscopic closure of fistulas, fecal vomiting was not observed, and the normal movement of food was achieved. An abdominal radiograph obtained two weeks later did not show stent migration (Fig. 4d). We regularly acquired abdominal radiographs to monitor the position of the stent. Consequently, the patient was able to ingest food orally with no fever. Furthermore, the intratumoral infection was cured, and chemotherapy was resumed. Although the patient died three months after hospitalization due to tumor growth, food intake was possible until one week before her death.\n\nDiscussion\n\nSquamous cell carcinoma of the gallbladder forms large tumor lesions, directly invades adjacent organs, and forms gastrointestinal tract fistulas. However, its distant metastasis is rare (1-3). Its prognosis is poor because many cases are discovered at an advanced stage, and the resection rate is lower than that of adenocarcinoma (2). Our case demonstrated all of these characteristics and presented typical clinical features of squamous cell carcinoma of the gallbladder.\n\nMany previous cases of squamous cell carcinoma of the gallbladder have been diagnosed by a histopathologic examination of postoperative surgical specimens. Recently, the usefulness of EUS has been reported, but there have been few reports of squamous cell carcinoma of the gallbladder being diagnosed by EUS-FNA (13-15), which was the method used to establish this diagnosis in our case.\n\nExtended surgery is recommended in cases of squamous cell carcinoma of the gallbladder that form fistulas when there are no issues regarding surgical tolerance. Cases of squamous cell carcinoma of the gallbladder that have been cured by radical surgery were reported to achieve either the same prognosis as adenocarcinoma cases or a significantly better prognosis (16,17). Therefore, aggressive resection with extended surgery should be performed; however, the resection rate is low due to rapid tumor progression. In cases of fistulas that make radical surgery difficult, surgical closure of fistulas or colostomy under general anesthesia is sometimes performed (4,5). The ASA-PS and ACCI are often used to predict prognostic performance in patients undergoing surgery (18-20). If the ASA-PS or ACCI is high, the patient is considered to have a poor PS (21). In our case, although the ASA-PS was low (grade 2) because of the lack of severe systemic complications aside from mild hypertension, the Charlson comorbidity index was high (11 points) because of her advanced age and the presence of a metastatic solid tumor. In addition, because of undernutrition and her advanced age, the patient wished to avoid surgery, which was considered risky and unsuitable. However, a fever due to the backflow of stool persisted. In addition, the patient and her family were strongly in favor of improving her food intake. We therefore performed endoscopic closure of the fistulas.\n\nEndoscopic closure methods for fistulas, such as clipping and OTSCs, are often used (22,23). Although clipping and OTSCs are effective for small fistulas, these methods are difficult to apply to relatively large fistulas. Recently, PGA sheets, which are often used in the closure of fistulas in respiratory and dental oral areas, have been applied for the treatment or prevention of perforation after ESD (6,7). Because PGA sheets can be cut to the appropriate size for application, they are considered useful for relatively large fistulas where clipping or OTSCs is not suitable. Therefore, we used PGA sheets to close the duodenal fistula in the present case.\n\nStent placement therapy for the digestive tract is used to remove stenosis due to malignancy. Covered metal stents have been used for the management of postoperative leakage and fistulas of the upper gastrointestinal tract, such as the esophagus and stomach. The usefulness of covered metal stents is also reported for postoperative leakage and fistulas of the colon (24-27). Furthermore, endoscopic closure with a covered metal stent is also used for fistulas due to malignant tumors, such as esophageal or colon carcinomas that form esophagorespiratory or colovesical fistulas (10-12). Because stenosis in the transverse colon tract was caused by tumor invasion in our case, we determined the risk of stent dislocation to be low and closed the colon fistula by placing a covered metal stent. The use of colonic covered metal stents is currently approved in Japan; however, at the time of the patient's treatment, only uncovered metal stents were covered by insurance. Therefore, we used a duodenal covered metal stent for the transverse colon fistula after obtaining the consent of the patient and family beforehand. Covered metal stents show a higher risk of migration than do uncovered metal stents. Furthermore, the metal stent may migrate when the tumor size is reduced by chemotherapy. However, the covered metal stent used for the present case has an uncovered portion measuring 15 mm at both ends to prevent migration. In our case, the large tumor compressed the colon where the covered metal stent was placed, and stent migration was prevented. If migration is discovered in the early stage, endoscopic repositioning may be possible. Therefore, it is necessary to confirm the stent position by regular monitoring on abdominal radiographs.\n\nCovered metal stents for colon fistulas, such as those observed in this case, are effective and might be needed in the future. However, in the present case, covered metal stent placement for duodenal fistulas was difficult because the normal tract of the duodenum was not stenotic and was proximal to the pylorus. Therefore, we used PGA sheets to achieve closure of the duodenal fistula. Although complete closure with PGA sheets alone seemed difficult, intratumoral infection was resolved, and resumption of chemotherapy was possible because the backflow of fecal matter into the fistula decreased after placement of the covered metal stent.\n\nIn our case, the fever due to the backflow of stool was alleviated, and food intake became possible following endoscopic closure of the fistulas. In addition, chemotherapy was administered to reduce the fistula and tumor masses. However, chemotherapy could not suppress tumor growth, and the patient died three months after hospitalization. If reduction of the tumor had been achieved by chemotherapy, spontaneous closure of the fistulas and life prolongation may have been possible. A regimen of gemcitabine plus cisplatin has been recommended at evidence level A for unresectable gallbladder carcinoma, but the tissue type is not mentioned (28,29). There are several case reports on chemotherapy using 5-fluorouracil or FOLFOX (folinic acid, fluorouracil and oxaliplatin) as postoperative adjuvant chemotherapy for squamous cell carcinoma of the gallbladder, but no consensus has been reached so far because of the limited number of reports (30). Although gemcitabine and cisplatin, which are considered the standard chemotherapy regimen for unresectable gallbladder carcinoma, were selected in our case, the tumor was not reduced. Chemotherapy regimens for squamous cell carcinoma of the gallbladder should be investigated in future studies.\n\nWe performed endoscopic closure with a covered metal stent and PGA sheet for gastrointestinal fistulas due to squamous cell carcinoma of the gallbladder, which enabled food intake. To our knowledge, there are no previous reports of endoscopic closure of gastrointestinal fistulas due to squamous cell carcinoma of the gallbladder. Covered metal stents and PGA sheets are less invasive than surgery and are considered effective for managing relatively large fistulas in which clipping or OTSCs are not applicable.\n\nInformed consent was obtained from the patient and her family for inclusion in the study.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Henson DE , Albores-Saavedra J , Corle D . Carcinoma of the extrahepatic bile ducts. Histologic types, stage of disease, grade, and survival rates. Cancer 70 : 1498-1501, 1992.1516001\n2. Edmondson HA . Tumors of gallbladder and extra hepatic bile duct. In: Atlas of Tumor Pathology. Sect VII, Fasc 26. Armed Forces Institute of Pathology, Washington DC, 1967: 26-66.\n3. Roa JC , Tapia O , Cakir A , et al . Squaous cell and adenosquamous carcinomas of the gallbladder: clinicopathological analysis of 34 cases identified in 606 carcinomas. Mod Pathol 24 : 1069-1078, 2011.21532545\n4. Costi R , Randone B , Violi V , et al . Cholecystocolonic fistula: facts and myths. A review of the 231 published cases. J Hepatobiliary Pancreat Surg 16 : 8-18, 2009.19089311\n5. Chowbey PK , Bandyopadhyay SK , Sharma A , et al . Laparoscopic management of cholecystoenteric fistulas. J Laparoendosc Adv Surg Tech A 16 : 467-472, 2006.17004870\n6. Takimoto K , Toyonaga T , Matsuyama K . Endoscopic tissue shielding to prevent delayed perforation associated with endoscopic submucosal dissection for duodenal neoplasms. Endoscopy 44 : E414-E415, 2012.23169042\n7. Tsuji Y , Ohata K , Gunji T , et al . Endoscopic tissue shielding method with polyglycolic acid sheets and fibrin glue to cover wounds after colorectal endoscopic submucosal dissection (with video). Gastrointest Endosc 79 : 151-155, 2014.24140128\n8. Kinoshita S , Nishihara Y , Mori H , et al . Polyglycolic acid sheet fibrin glue filling method for esophageal fistula. Video GIE 3 : 294-295, 2018.30276346\n9. Matsuura N , Hanaoka N , Ishihara R , et al . Polyglycolic acid sheets for closure of refractory esophago-pulmonary fistula after esophagectomy. Endoscopy 48 : E78-E79, 2016.26951471\n10. Ahmad M , Nice C , Katory M . Covered metallic stents for the palliation of colovesical fistula. Ann R Coll Surg Engl 92 : W43-45, 2010.20615297\n11. Bethge N , Sommer A , Vakil N . Treatment of esophageal fistulas with a new polyurethane-covered, self-expanding mesh stent: a prospective study. Am J Gastroenterol 90 : 2143-2146, 1995.8540504\n12. Han YM , Song HY , Lee JM , et al . Esophagorespiratory fistulae due to esophageal carcinoma: palliation with a covered Gianturco stent. Radiology 199 : 65-70, 1996.8633174\n13. Hijioka S , Mekky MA , Bhatia V , et al . Can EUS guided FNA distinguish between gallbladder cancer and xanthogranulomatous cholecystitis? Gastrointest Endosc 72 : 622-627, 2010.20630515\n14. Ogura T , Kurisu Y , Masuda D , et al . Can endoscopic ultrasound-guided fine needle aspiration offer clinical benefit for thick-walled gallbladders? Dig Dis Sci 59 : 1917-1924, 2014.24615550\n15. Chambers MR , Hasan MK , Hébert-Magee S . Pearls before bile: Primary squamous cell carcinoma of the gallbladder diagnosed on-site by endoscopic ultrasound-guided fine-needle aspiration. Dig Endosc 28 : 105, 2016.26473633\n16. Kalayarasan R , Javed A , Sakhuja P , et al . Squamous variant of gallbladder cancer: is it different from adenocarcinoma? Am J Surg 206 : 380-385, 2013.23827515\n17. Oohashi Y , Shirai Y , Wakai T , et al . Adenosquamous carcinoma of the gallbladder warrants resection only if curative resection is feasible. Cancer 94 : 3000-3005, 2002.12115390\n18. ASA PHYSICAL STATUS CLASSIFICATION SYSTEM. Last approved by the ASA House of Delegates on December 13, 2020 (original approval: October 15, 2014) [Internet]. Available from: https://www.asahq.org/standards-and-guidelines/asa-physical-status-classification-system\n19. Charlson ME , Pompei P , Ales KL , et al . A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40 : 373-383, 1987.3558716\n20. Charlson M , Szatrowski TP , Peterson J , et al . Validation of a combined comorbidity index. J Clin Epidemiol 47 : 1245-1251, 1994.7722560\n21. Takada T . Tokyo Guidelines 2018: updated Tokyo Guidelines for the management of acute cholangitis/acute cholecystitis. J Hepatobiliary Pancreat Sci 25 : 1-2, 2018.29334699\n22. Kumar M MD , Larsen MC , Thompson CC , et al . Endoscopic management of gastrointestinal fistulae. Gastroenterol Hepatol 10 : 495-452, 2014.\n23. Goenka MK , Goenka U . Endotherapy of leaks and fistula. World J Gastrointest Endosc 7 : 702-713, 2015.26140097\n24. Langer FB , Wenzl E , Prager G , et al . Management of postoperative esophageal leaks with the Polyflex self-expanding covered plastic stent. Ann Thorac Surg 79 : 398-403, 2005.15680802\n25. Edwards CA , Bui TP , Astudillo JA , et al . Management of anastomotic leaks after Roux-en-Y bypass using self-expanding polyester stents. Surg Obes Relat Dis 4 : 594-599, 2008.18722820\n26. Gürbalak EK , Akgün IE , Öz A , et al . Minimal invasive management of anastomosis leakage after colon resection. Case Rep Med 2015 : 374072, 2015.25861277\n27. Cereatti F Fiocca , F Dumont JL , et al . Fully covered self-expandable metal stent in the treatment of postsurgical colorectal diseases: outcome in 29 patients. Therap Adv Gastroenterol 9 : 180-188, 2016.\n28. Valle J , Wasan H , Palmer DH , et al . Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362 : 1273-1281, 2010.20375404\n29. Okusaka T , Nakachi K , Fukutomi A , et al . Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. Br J Cancer 103 : 469-474, 2010.20628385\n30. Verlicchi L , Blons H , Hannoun L , et al . Squamous-cell gallbladder carcinoma: how to treat? J Cell Sci Ther 6 : 212, 2015.\n\n",
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"keywords": "cholecysto-duodenal and transverse colon fistulas; covered metal stent; gallbladder neoplasms; polyglycolic acid sheet; squamous cell carcinoma",
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"title": "Effective Endoscopic Closure of Cholecysto-duodenal and Transverse Colon Fistulas Due to Squamous Cell Carcinoma of the Gallbladder Using Polyglycolic Acid Sheets and a Covered Metal Stent.",
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"abstract": "A 40-year-old woman withuntreated type II diabetes mellitus was discovered withcardiopulmonary arrest in her room. On admission, she had ventricular fibrillation. After cardiopulmonary resuscitation, her own pulse restarted. The plasma glucose was 722 mg/dl and venous PH was 6.704. Abdominal computed tomography revealed gas within the parenchyma of the left kidney. We diagnosed her with emphysematous pyelonephritis and conducted emergency nephrectomy. Urinary and blood cultures were positive for Escherichia coli. Antibiotic therapy was initiated with doripenem and she was restrictively treated with intravenous insulin to control her plasma glucose. On the 8th day of hospital stay, she underwent resection of the small intestine because of necrosis. After multidisciplinary therapy, she was discharged with complete resolution of the infection.",
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"authors": "Yamamichi|Gaku|G|;Tsutahara|Koichi|K|;Kuribayashi|Sohei|S|;Kawamura|Masataka|M|;Nakano|Kosuke|K|;Kishimoto|Nozomu|N|;Tanigawa|Go|G|;Matsushima|Asako|A|;Fujimi|Satoshi|S|;Takao|Tetsuya|T|;Yamaguchi|Seiji|S|",
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... |
{
"abstract": "OBJECTIVE\nGlioblastoma is one of the most frequent primitive brain tumors. Patients who experience tumor relapse after surgery and concomitant radiochemotherapy have a dismal prognosis. The objective of this study is to analyze efficacy data in terms of overall survival (OS) and progression- free survival (PFS) following combination therapy with bevacizumab (BVZ) and irinotecan among patients with relapsed glioblastoma. Safety data will also be reviewed and all results will be compared with data of the literature.\n\n\nMETHODS\nIn this single-center retrospective study, all records of patients treated with BVZ and irinotecan for a relapsed glioblastoma were analyzed. Each chemotherapy cycle was repeated every 15 days until progression. Magnetic resonance imaging and neurologic examination were repeated every 6 weeks during treatment.\n\n\nRESULTS\nForty-five patients were analyzed. The median number of BVZ-irinotecan cycles was 8 (range 1-38). Median PFS was 26 weeks and median OS was 28 weeks. Eighteen of the 45 patients (40% of cases) had an objective response 6 months after initiation of treatment. Two patients had to discontinue treatment due to toxicity.\n\n\nCONCLUSIONS\nThe results of the SV1 study are consistent with those found in phase II studies evaluating the same treatment. The irinotecan-BVZ combination is effective in relapsed glioblastoma with acceptable toxicity. Biomarkers predictive of response to BVZ should help in the selection of patients who could benefit from treatment.",
"affiliations": null,
"authors": "Rivoirard|Romain|R|;Chargari|Cyrus|C|;Guy|Jean-Baptiste|JB|;Nuti|Christophe|C|;Peoc'h|Michel|M|;Forest|Fabien|F|;Falk|Alexander Tuan|AT|;Garin|Clemence|C|;Adjabi|Anissa|A|;Hoarau|Delphine|D|;Fotso|Marie-Jeannette|MJ|;Langrand Escure|Julien|J|;Moriceau|Guillaume|G|;Fournel|Pierre|P|;Boutet|Claire|C|;Magné|Nicolas|N|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000443719",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-3157",
"issue": "61(5)",
"journal": "Chemotherapy",
"keywords": null,
"medline_ta": "Chemotherapy",
"mesh_terms": "D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D001921:Brain; D001932:Brain Neoplasms; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma; D006402:Hematologic Diseases; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "0144731",
"other_id": null,
"pages": "269-74",
"pmc": null,
"pmid": "27057742",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical Impact of Bevacizumab in Patients with Relapsed Glioblastoma: Focus on a Real-Life Monocentric SurVey (SV1 Study).",
"title_normalized": "clinical impact of bevacizumab in patients with relapsed glioblastoma focus on a real life monocentric survey sv1 study"
} | [
{
"companynumb": "FR-PFIZER INC-2016245792",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "In Npc1 null mice, a model for Niemann Pick Disease Type C1, it has been reported that hepatocyte insulin receptor function is significantly impaired, consistent with growing evidence that membrane fluidity and microdomain structure have an important role in insulin signal transduction. However, whether insulin receptor function is also compromised in human Niemann Pick disease Type C1 is unclear. We now report a girl who developed progressive dementia, ataxia and opthalmoplegia from 9 years old, followed by severe acanthosis nigricans, hirsutism and acne at 11 years old. She was diagnosed with Niemann Pick Disease type C1 (OMIM#257220) based on positive filipin staining and reduced cholesterol-esterifying activity in dermal fibroblasts, and homozygosity for the p.Ile1061Thr NPC1 mutation. Further analysis revealed her also to be heterozygous for a novel trinucleotide deletion (c.3659 + 1_3659 + 3delGTG) at the end of exon 20 of INSR, encoding the insulin receptor, leading to deletion of Trp1193 in the intracellular tyrosine kinase domain. INSR mRNA and protein levels were normal in dermal fibroblasts, consistent with a primary signal transduction defect in the mutant receptor. Although the proband was significantly more insulin resistant than her father, who carried the INSR mutation but was only heterozygous for the NPC1 variant, their respective degrees of IR were very similar to those previously reported in a father-daughter pair with the closely related p.Trp1193Leu INSR mutation. This suggests that loss of NPC1 function, with attendant changes in membrane cholesterol composition, does not significantly modify the IR phenotype, even in the context of severely impaired INSR function.",
"affiliations": "Department of Endocrinology, Birmingham Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, United Kingdom.",
"authors": "Kirk|J|J|;Porter|K M|KM|;Parker|V|V|;Barroso|I|I|;O'Rahilly|S|S|;Hendriksz|C|C|;Semple|R K|RK|",
"chemical_list": "D015703:Antigens, CD; D015415:Biomarkers; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D012333:RNA, Messenger; C435941:INSR protein, human; D011972:Receptor, Insulin",
"country": "United States",
"delete": false,
"doi": "10.1007/s10545-010-9107-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0141-8955",
"issue": "33 Suppl 3()",
"journal": "Journal of inherited metabolic disease",
"keywords": null,
"medline_ta": "J Inherit Metab Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D015703:Antigens, CD; D015415:Biomarkers; D002352:Carrier Proteins; D002478:Cells, Cultured; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D005347:Fibroblasts; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins; D008969:Molecular Sequence Data; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C; D010375:Pedigree; D010641:Phenotype; D012333:RNA, Messenger; D011972:Receptor, Insulin; D012720:Severity of Illness Index",
"nlm_unique_id": "7910918",
"other_id": null,
"pages": "S227-32",
"pmc": null,
"pmid": "20521171",
"pubdate": "2010-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "17950007;11742409;16705075;2192845;2544998;8390949;18089699;15232309;10521297;17212584;19400697;15943586;15542393;16126423;2546147;1330507",
"title": "Loss of NPC1 function in a patient with a co-inherited novel insulin receptor mutation does not grossly modify the severity of the associated insulin resistance.",
"title_normalized": "loss of npc1 function in a patient with a co inherited novel insulin receptor mutation does not grossly modify the severity of the associated insulin resistance"
} | [
{
"companynumb": "GB-LUPIN PHARMACEUTICALS INC.-2015-01717",
"fulfillexpeditecriteria": "2",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"... |
{
"abstract": "Due to a lack of reference values for blood concentration of metformin in the literature, the forensic evaluation of metformin findings in blood samples is difficult. Interpretations with regard to the assessment of blood concentrations as well as an estimation of the ingested metformin amounts are often vague. Furthermore, post mortem evaluation of death due to lactic acidosis because of metformin is difficult since renal performance or lactate concentrations can not always reliably be determined after death. To describe a concentration range in clinical samples after chronic use of metformin, metformin serum concentrations were determined in serum samples of 95 diabetic patients receiving daily doses of 500mg-3000mg of metformin. The analyses of metformin was carried out using a validated high performance liquid chromatograph coupled to triple quadrupole mass spectrometry (LC-QQQ-MS). On average, metformin concentrations were 1846ng/mL (<LoQ-5560ng/mL) and independent of the prescribed daily dose. There was no correlation between plasma concentration and glomerular filtration rate except for the 1700mg daily dose collective (R2=0.707). Results of the herein presented study are useful for the interpretation of analytical metformin findings in forensic toxicology. The utility of the described concentration range is demonstrated by discussing a death case involving a fatal lactate acidosis after metformin intake and renal failure. Usefulness of the parameters metformin blood concentration, lactate concentration and glomerular filtration rate in post mortem cases of lactic acidosis due to metformin intoxication are discussed.",
"affiliations": "University Bonn, Institute of Forensic Medicine, Forensic Toxicology, Stiftsplatz 12, 53111 Bonn, Germany. Electronic address: cohess@uni-bonn.de.;University Bonn, Institute of Forensic Medicine, Forensic Toxicology, Stiftsplatz 12, 53111 Bonn, Germany.;University Bonn, Institute of Forensic Medicine, Forensic Toxicology, Stiftsplatz 12, 53111 Bonn, Germany.;Herz- und Diabeteszentrum NRW, Ruhr-Universitaet Bochum, Georgstrasse 11, 32545 Bad Oeynhausen, Germany.;Herz- und Diabeteszentrum NRW, Ruhr-Universitaet Bochum, Georgstrasse 11, 32545 Bad Oeynhausen, Germany.",
"authors": "Hess|C|C|;Unger|M|M|;Madea|B|B|;Stratmann|B|B|;Tschoepe|D|D|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2018.03.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "286()",
"journal": "Forensic science international",
"keywords": "Clinical samples; Forensics; LC–QQQ-MS; Lactic acidosis; Metformin; Plasma concentrations; Post mortem",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000140:Acidosis, Lactic; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002853:Chromatography, Liquid; D003924:Diabetes Mellitus, Type 2; D003928:Diabetic Nephropathies; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D013058:Mass Spectrometry; D008687:Metformin; D008875:Middle Aged; D009395:Nephritis, Interstitial",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "106-112",
"pmc": null,
"pmid": "29574345",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Range of therapeutic metformin concentrations in clinical blood samples and comparison to a forensic case with death due to lactic acidosis.",
"title_normalized": "range of therapeutic metformin concentrations in clinical blood samples and comparison to a forensic case with death due to lactic acidosis"
} | [
{
"companynumb": "DE-GLENMARK PHARMACEUTICALS-2018GMK034470",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXAZEPAM"
},
"drugadditional... |
{
"abstract": "Gastrointestinal bleeding after kidney transplantation is a complication that can occur from immunosuppressant use. We present a case of refractory small bowel bleeding treated successfully with thalidomide after multiple failed attempts of conventional treatment. A 65-year-old male patient with diabetic nephropathy underwent living donor kidney transplantation. The surgery was uneventful, however, he developed immunosuppressant-induced melena with unstable vital signs 11 days later. There were a total of 4 bleeding episodes until the 90th postoperative day, and he received a total of 290 units of red blood cell transfusion during this period. Endoscopic clipping, transarterial embolization, and 2 surgical interventions failed to stop the bleeding. A trial of thalidomide 100 mg per day finally stopped the bleeding and the patient was discharged on the 110th postoperative day with a functioning renal graft. This case shows that thalidomide can be a safe option to treat immunosuppressant-induced refractory gastrointestinal bleeding in the setting of kidney transplantation. Additionally, this is the first case that reports the survival of a renal graft after more than 3000 mL of transfusion.",
"affiliations": "Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea.;Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea; Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.;Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea.;Department of Surgery, Chungbuk National University Hospital, Cheongju, Korea.;Charm Vein Center, Seoul, Korea.;Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea; Department of Surgery, Seoul National University College of Medicine, Seoul, Korea. Electronic address: tslee@snubh.org.",
"authors": "Heo|Yoonjung|Y|;Park|Hyung Sub|HS|;Shin|Chang Sik|CS|;Yoo|Kwon Cheol|KC|;Kim|Daehwan|D|;Lee|Taeseung|T|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D007166:Immunosuppressive Agents; D013792:Thalidomide; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2019.07.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "51(9)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000368:Aged; D020533:Angiogenesis Inhibitors; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D019520:Living Donors; D008297:Male; D008551:Melena; D008875:Middle Aged; D011183:Postoperative Complications; D016559:Tacrolimus; D013792:Thalidomide",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "3092-3098",
"pmc": null,
"pmid": "31623898",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Treatment of Life-Threatening Small Bowel Bleeding With Thalidomide After Living Donor Kidney Transplantation: A Case Report.",
"title_normalized": "successful treatment of life threatening small bowel bleeding with thalidomide after living donor kidney transplantation a case report"
} | [
{
"companynumb": "KR-ASTELLAS-2019US050968",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": null,... |
{
"abstract": "Metastatic spread to the heart from neoplasms is very rare, often silent and rarely gains clinical attention. Usually, it correlates with widespread metastatic disease and is suggestive of a poor prognosis. Most cardiac metastases (CM) are detected following post-mortem studies with only a handful reported antemortemly. Here, we report a case of an asymptomatic cardiac metastasis from esophageal carcinoma and a review of the literature. In late July 2014, a 73-year-old woman diagnosed with locally advanced esophageal squamous cell carcinoma was admitted to our institution. Cardiothoracic metastases were not detected at basal computed tomography (CT) scan. The patient was submitted to concurrent cisplatin and radiotherapy. Just before surgery, a CT scan revealed two metastases in the right ventricle and in the interventricular septum. Transthoracic echocardiography and an endomyocardial biopsy confirmed the diagnosis of squamous cell carcinoma from the esophageal origin. In February 2015, chemotherapy was started, but after two courses of gemcitabine, a pulmonary embolism and then a congestive heart failure caused death of the patient on April 2015. Reviewing the literature, 14 cases with an antemortem diagnosis of CM from esophageal cancer were reported. Our patient should be the fifteenth case with an uncommon presentation without symptoms or signs in the diagnosis. Our case highlights that patients should be evaluated using echocardiography for CM, even if asymptomatic.",
"affiliations": "Oncology, Belcolle Hospital, Viterbo, ITA.;Cardiology, San Camillo-Forlanini Hospital, Rome, ITA.;Cardiology, Belcolle Hospital, Viterbo, ITA.;Radiology, San Camillo-Forlanini Hospital, Rome, ITA.;Oncology, Belcolle Hospital, Viterbo, ITA.",
"authors": "Signorelli|Carlo|C|;Pergolini|Amedeo|A|;Zampi|Giordano|G|;Vallone|Andrea|A|;Ruggeri|Enzo Maria|EM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.6387",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.6387GastroenterologyOncologyCardiologyAsymptomatic Cardiac Metastases From Esophageal Cancer: A Case Report Of Ante-mortem Detection And Literature Review Muacevic Alexander Adler John R Signorelli Carlo 1Pergolini Amedeo 2Zampi Giordano 3Vallone Andrea 4Ruggeri Enzo Maria 1\n1 \nOncology, Belcolle Hospital, Viterbo, ITA \n2 \nCardiology, San Camillo-Forlanini Hospital, Rome, ITA \n3 \nCardiology, Belcolle Hospital, Viterbo, ITA \n4 \nRadiology, San Camillo-Forlanini Hospital, Rome, ITA \nCarlo Signorelli carlo.signorelli@asl.vt.it15 12 2019 12 2019 11 12 e638720 11 2019 15 12 2019 Copyright © 2019, Signorelli et al.2019Signorelli 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/25281-asymptomatic-cardiac-metastases-from-esophageal-cancer-a-case-report-of-ante-mortem-detection-and-literature-reviewMetastatic spread to the heart from neoplasms is very rare, often silent and rarely gains clinical attention. Usually, it correlates with widespread metastatic disease and is suggestive of a poor prognosis. Most cardiac metastases (CM) are detected following post-mortem studies with only a handful reported antemortemly. Here, we report a case of an asymptomatic cardiac metastasis from esophageal carcinoma and a review of the literature. In late July 2014, a 73-year-old woman diagnosed with locally advanced esophageal squamous cell carcinoma was admitted to our institution. Cardiothoracic metastases were not detected at basal computed tomography (CT) scan. The patient was submitted to concurrent cisplatin and radiotherapy. Just before surgery, a CT scan revealed two metastases in the right ventricle and in the interventricular septum. Transthoracic echocardiography and an endomyocardial biopsy confirmed the diagnosis of squamous cell carcinoma from the esophageal origin. In February 2015, chemotherapy was started, but after two courses of gemcitabine, a pulmonary embolism and then a congestive heart failure caused death of the patient on April 2015. Reviewing the literature, 14 cases with an antemortem diagnosis of CM from esophageal cancer were reported. Our patient should be the fifteenth case with an uncommon presentation without symptoms or signs in the diagnosis. Our case highlights that patients should be evaluated using echocardiography for CM, even if asymptomatic.\n\ncardiac metastasesesophageal cancerante-mortem detectioncancer case reportcardiac imagingThe 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\nCardiac metastases (CM) are very rare, often silent and rarely gain clinical attention. As in the primary tumors, the most frequent symptoms are congestive heart failure, valvular heart disease, pericardial effusion, electrocardiographic changes, dysrhythmia, syncope, embolism, cardiomegaly and it may arise suddenly. However, signs are often overlooked. Usually, it correlates with widespread metastatic disease and is suggestive of a poor prognosis. Although cardiac dissemination of malignant disease is a common finding during an autopsy, it rarely produces clinical symptoms [1]. Most of CM are detected following post-mortem studies with only a handful reported antemortemly. Epidemiological information is predominantly based on autopsy studies with incidences ranging from 2.3%-18.3% of cancer patients and from 0.2%-6.5% in unselected autopsy series [2-3]. Metastatic spread of cancers to the heart is more common than primary cardiac tumors. CM from tumors arising from the esophagus and pericardial effusions caused by metastatic cancer are rare; squamous cell carcinoma causing these events is extremely uncommon. It may appear during the evolution of this neoplasm and the tumor spread to the heart is usually caused by direct invasion. Not infrequently, cardiac tumor invasion contributes to the mechanism of death. The most of cardiac tumors are metastases mainly from pleural mesothelioma, melanoma, lung adenocarcinoma, undifferentiated carcinomas, lung squamous cell carcinoma, breast carcinoma, ovarian carcinoma, lymphomyeloproliferative neoplasms, bronchioalveolar carcinoma, gastric carcinoma, renal carcinoma, and pancreatic carcinoma and occur more commonly on the right side than the left side of the heart [2]. Only tumors of the central nervous system have not been proven to develop CM. Right ventricular metastases from esophageal cancer are even rare, with few such cases reported in the literature to date, being focused more on imaging findings from cardiac echocardiography [4]. Compared to metastases to the myocardium, direct extension to pericardium or regional lymphatic invasion are a more frequent route for invading the heart [2]. Since most of CM appear in the terminal stage of cancer, the prognosis is grave and therapeutic options are limited to palliative treatment of symptoms and chemotherapy. Here, we report a case of ante-mortem detection of asymptomatic CM from esophageal carcinoma and a review of the literature.\n\nCase presentation\nIn July 2014, a 73-year-old woman was diagnosed with locally advanced stenosing squamous cell carcinoma of the middle third of the esophagus (maximum diameter 40 mm) and was admitted to our institution. The patient had been suffering from chronic bronchitis secondary to tobacco consumption. Symptoms referred by the patient included dysphagia, weight loss, and right shoulder blade pain. Routine blood tests, including tumor markers and electrocardiogram (ECG) were normal. A computed tomography (CT) scan showed only the esophageal cancer with regional pathological lymph nodes. No basal evidence of cardiothoracic metastases. Transthoracic echocardiography revealed an ejection fraction of about 60%. The patient was planned to receive primary treatment with two courses of concurrent cisplatin (60 mg/mq) and radiotherapy (50 Gy totally with daily fractionation of 2 Gy). The patient had a clinical benefit. In November, just before undergoing surgery, a CT scan and an endoscopy showed a reduction of both the esophageal mass and lymph-nodes but revealed the presence of two suspected metastases with a maximum diameter of 50 mm, one in the right ventricle and one in the interventricular septum (Figures 1-2).\n\nFigure 1 Computed tomography (CT) scan of the heart\nAxial plane contrast-enhanced.\n\nFigure 2 Computed tomography (CT) scan of the heart\nMulti planar reformation contrast-enhanced. Evidence of filling defect within the right ventricular cavity in correspondence with the interventricular septum.\n\nThe transthoracic echocardiography (as seen in Figure 3) and a magnetic resonance imaging (MRI) confirmed the two CM occupying the right ventricle near to the outflow tract and adherent to the interventricular septum (Figures 4-7).\n\nFigure 3 Transthoracic echocardiography\nA. Short-axis, great vessels off-axis view, showing a lobulated, cerebriform mass in the right ventricle near to the outflow tract. B. Short-axis, middle ventricle view, showing a mass occupying the right ventricle, adherent to the interventricular septum, with an anechoic central core. C. Subcostal view, showing a mass, with multiple anechoic foci, occupying a large amount of the right ventricle.\n\nFigure 4 Cardiac magnetic resonance imaging (MRI)\nFour chambers cine MRI.\n\nFigure 5 Cardiac magnetic resonance imaging (MRI)\nFour chambers cine MRI.\n\nFigure 6 Cardiac magnetic resonance imaging (MRI)\nTSE_T1 2 chambers cine MRI targeted for the study of the right ventricle.\n\nFigure 7 Cardiac magnetic resonance imaging (MRI)\nTurbo inversion recovery magnitude (TIRM) MRI. Confirmation of the expansive formation already observed on computed tomography-scan, another expansive lesion in the free wall of the right ventricle; evidence of necrosis within the mass.\n\nAn endomyocardial biopsy revealed the diagnosis of squamous cell carcinoma from esophageal origin, p63+, cytokeratin 7 and 20-, CDX2- (Figure 8).\n\nFigure 8 Photomicrograph of cardiac metastases biopsy\nA. Histopathological examination of the specimen shows that the tumor is a squamous cell carcinoma p63 immunostaining (hematoxylin and eosin stain; original magnification, ×100). B. Squamous cell carcinoma infiltrating the myocardial striated muscle, E-E. C. Squamous cell carcinoma p63 immunostaining. High magnification.\n\nBoth surgery and radiotherapy were not indicated as therapeutic options by a multidisciplinary oncology group. As the patient preference was to be treated, in February 2015 chemotherapy with gemcitabine was started, but after two courses a pulmonary embolism and then a congestive heart failure conducted her to death in April.\n\nDiscussion\nThe presented case reports an ante-mortem diagnosis of CM from known esophageal cancer. As more of 90% of CM is silent, diagnosis is often difficult and mostly discovered at necropsy. If symptoms or signs are present, they are often overshadowed in the setting of widespread metastatic disease and the patient usually die from other metastatic lesions. Since the introduction of 2D-echocardiography, multislice CT, and MRI, CM have been more frequently diagnosed in vivo. Up until now, only 14 cases with an ante-mortem diagnosis and treatment of intracardiac metastases from esophageal cancer have been described in the literature (Table I).\n\nTable 1 Literature review of cardiac metastases from esophageal cancer with an ante-mortem diagnosis\nAuthor (year)\tAge\tSex\tType\tPrimary Tx\tInterval to cardiac metastasis\tRecurrence diagnosis modality\tLocation\tSymptoms or signs\tPathologic confirmation by\tRecurrence Tx\tCause of death\tTime to death from cardiac metastasis\tOS\t\nKarabay 2012 [5]\t46\tM\tSCC\t*\t2M\techocardiogram\tMyocardium LA, LV\tVentricular fibrillation\t*\t*\t*\t*\t*\t\nYoun 2002 [6]\t65\tM\tSCC\teRT\tsimultaneous\tEchocardiogram, MRI, coronary angiography\tEndocardium RV \tHeart murmur\tEndomyocardial biopsy\teRT\t*\t*\t*\t\nTayama 2011 [7]\t48\tM\tSCC\tnone\tsimultaneous\techocardiogram\tEpicardium RV\tCardiac tamponade, dyspnea\tOpen excisium\tBSC\tRapid clinical deterioration\t1M\t1M\t\nCheng 2013 [8]\t58\tM\tSCC\tCCRT Surgery\t*\tEchocardiogram Chest CT scan\tMyocardium LV\tDyspnea, Chest tightness mimicking myocardial infarction\t*\tCTx\t*\t*\t*\t\nConsoli 2011 [9]\t67\tM\tSCC\tCCRT\t11M\tEchocardiogram, MRI\tEndocardium, pericardial effusion LV, RV\tDyspnea, palpitations, cardiac arrhythmia, hypotension\t*\tCTx\tNeoplastic effusion\t6M\t16M\t\nOliveira 2012 [10]\t81\tM\tSCC\tSurgery\t9M\tEchocardiogram, CT scan\tMyocardium, pericardium RV\tAcute stroke\tCT-guided needle aspiration biopsy\t \tpneumonia\t1M\t10M\t\nBasaran 2013 [11]\t80\tF\tSCC\tsurgery\t12M\techocardiogram\tMyocardium, LA, LV\tVentricular tachycardia\t*\tBSC\tRHF\t0M\t12M\t\nMaeda 2009 [12]\t62\tF\tSCC\tsurgery\t6M\tCT scan echocardiogram\tMyocardium LV\tnone\t*\tCTx\tcancer\t11M\t17M\t\nMoulin-Romsee 2007 [13]\t47\tF\tSCC\tCCRT Surgery\t*\tFDG-PET/TC\t* RA\tnone\t*\tBSC\tcancer\t*\t*\t\nAl-Mamgani 2007 [14]\t60\tM\t*\tCCRT\t11M\tCT scan ecocardiography\tMyocardium RV\tChest pain\t*\teRT\tpneumonia\t2M\t13M\t\nNakamura 2005 [15] (12)\n\t53\tF\tSCC\t*\tsimultaneous\tCT scan ecocardiography\t* Ball tumor in RA\tCardiac murmur Dyspnea on effort\tOpen excision\tSurgery CCRT\tcancer\t5M\t5M\t\nChello 1993 [16]\t75\tM\tmelanoma\tMedical therapy\tsimultaneous\tCT scan ecocardiography\t* LA\tDysphagia Weight loss Pericardial effusion\texperimental protocol with 99mTc labelled antimelanoma monoclonal Ab\tBSC\t*\t*\t*\t\nAbbate 2015 [17]\t49\tF\tSCC\tCTx CCRT Surgery\t20M\tCT scan MRI\t* LV\tnone\tsurgical debulking\tCTx\tischemic stroke\t12M\t44M\t\nTrocino 2015 [18]\t48\tF\tSCC\tSurgery\t36M\tCT scan Echocardiography MRI\tMyocardium LV\tnone\tmyocardial biopsy\tCTx\tmassive cardioembolic cerebral stroke\t10M\t46M\t\nOur case 2019\t73\tF\tSCC\tCCRT\t5M\tEchocardiography, MRI, CT scan, coronary angiography\tEndomyocardium RV\tnone\tEndomyocardial biopsy\tCTx\tRHF\t6M\t10M\t\n*no available data; CCRT, concurrent chemoradiotherapy; CT, computed tomography; CTx, chemotherapy; eRT, external radiotherapy; M, months; MRI, magnetic resonance imaging; RHF, right heart failure; SCC, squamous cell carcinoma; Tx, therapy.\t\nThe majority of these cases were not single metastases. Main characteristics of these cases were: median age 59.9 years (the incidence of CM reported from autopsies is variable ranging from 2.3% to 18.3%, predominantly in the sixth and seventh decade of life); prevalence of male (57.1%) (although the frequency of primary tumours was found to be different for men and women, 46% in men and 31.7% in women, no differences were detected in the incidence of CM from post-mortem examinations); the predominant histologic type was squamous cell carcinoma (92.3%); median time to the onset of this kind of metastases: 8.9 months; the method of choice to detect recurrence was echocardiography in 78.5% of cases; the right side of the heart was involved in the same way as the left (50%); the structure primarly affected was myocardium (70%) (unlike the cases diagnosed post-mortem in which the most common site was the epicardium); the main treatment with palliative purposes was surgery (36.3%), followed by concurrent chemo-radiation, chemo-radiation before surgery (18.1%), best supportive care, radiotherapy and chemotherapy followed by concurrent chemo-radiotherapy before surgery (9%); the median time to death from Cardiac metastases was 5.3 months with an overall survival of approximately 18.2 months [5-18]. Survival is determined by the inherent aggressiveness of the cancer manifested by tumor size, grade and distant metastasis at presentation. To date, our patient is the fifteenth case in the literature, with an uncommon presentation without symptoms or signs with a median time to death from cardiac recurrence and an overall survival respectively of six and 10 months.\n\nA variety of diagnostic imaging and hemodynamic techniques have been applied in the diagnostic process of all cases published, including echocardiography, CT, MRI, and even right heart catheterization. The method of choice to detect CM was two-dimensional echocardiography, the non-invasive imaging technique enabling clarification of the location, size, shape, number and mobility of the masses but it is usually limited in tissue characterization. Transesophageal echocardiography can give more information than the approach transthoracic and in the case of patients with specific physical habits, overcomes the disadvantage of poor acoustic window. However, echocardiography is usually limited in tissue characterization. Definite diagnosis requires pathological examination of tumor tissue. Electrocardiography is not specific. Localized and prolonged ST-segment elevation without Q waves appears to be pathognomonic for myocardial tumor invasion. Cardiac MRI could be the diagnostic tool of choice in the assessment of patients with esophageal cancer when CM are suspected; it offers improved resolution, a larger field of view and superior soft-tissue contrast, it is not invasive and does not require ionizing radiation or exposure to nephrotoxic contrast agents. Although there is overlap of the MRI characteristics of several cardiac masses, MRI is a reliable tool to identify necrosis, extra-cardiac spread, pericardial effusion and to exclude lipomas, fibromas and hemangiomas as well as thrombus or lipomatous hypertrophy. However, its inability to evaluate calcification constitutes an important limitation of MRI. Multidetector computed tomography is useful for the evaluation of calcification and fat content of a cardiac mass [19]. In descending order of frequency, epicardium (75.5%), followed by myocardium (38.2%) and endocardium (15.5%) are involved [20]. In our patient, hematogenous spread was a possible route for cardiac involvement, since the tumor was located on the ventricular septum and protruded into the right ventricular cavity. CM are usually bilateral, small and multiple; however, single large lesions are also observed. Valvular metastatic deposits, intracavitary or endocardial such as the one described in our case, occur in less than 6% of cases. Tachyarrhythmia is found often in these patients and may lead to syncope. Coronary occlusion or compression from tumor masses can lead to myocardial infarction, heart failure, and death. A typical clinical pattern of cardiac disease progression is characterized by a worsening performance status, exacerbation of cardiac symptoms, including tamponade, arrhythmia, obstruction, or dilated cardiomyopathy, representing one of the terminal events as in the case of the reported patient. CM are usually diagnosed in the setting of generalized carcinomatosis. At this stage, treatment must be with palliative intention to improve the quality of life, while in rare cases with a long life expectancy and a good performance status, when the heart is the only site of metastasis, it could be with curative intent.\n\nCurrent treatment options do little to encourage a positive outlook and are particularly limited in cases of CM. Because cardiac tissue involvement is frequently diffuse, the usefulness of chemotherapy or surgery is questionable. Chemotherapy is recommended in chemosensitive primary tumors. Surgery is the treatment of choice in highly selected patients with a long life expectancy and a good performance status and it is only indicated in exceptional cases of solitary intracavitary heart metastases leading to obliteration of the cardiac chambers or valve obstruction. Surgery offers the best chance of prolonged survival. Because patients suitable for surgery generally have a better prognosis than inoperable patients, postoperative chemotherapy and/or radiotherapy should be given to reduce the chance of local recurrence. In such patients, it is important to keep the treatment time as short as possible. Radiotherapy should be attempted to relieve symptoms, to produce local control, and to stabilize hemodynamic disturbances. Short-course radiotherapy may be suitable to achieve these objectives. Radiotherapy may lead to fibrosis of the lung or of the myocardium, and thus to disorders of the conduction system and also to pericarditis. Whatever the treatment selected, the clinical evolution is disappointing, and patients with heart metastases die within a year of the diagnosis. This poor prognosis makes it important to define the most appropriate therapeutic strategy may be taking the approach to surgery in cases where the latter is possible.\n\n(Abstract: Signorelli C, Chilelli MG, Pergolini A, Zampi G, Ruggeri EM. Ante Mortem Diagnosis of Intracardiac Metastases from Known Esophageal Cancer: A Case Report and Literature Review. 17th National Congress of Medical Oncology; October 23-25, 2015).\nhttps://academic.oup.com/annonc/article/26/suppl_6/vi/216104\n\nConclusions\nCM are unfavorable prognostic factors of survival and therapies are mostly palliative in order to ameliorate symptoms since cardiac dissemination mostly occurs in the setting of widespread metastatic disease. The therapeutic efficacy of an antineoplastic treatment must be balanced with its side effects and quality of life. The decision should involve a multi-disciplinary team. As heart metastases are often incurable, surgery is not an optimal option but in some patients can be useful for the relief of symptoms. Systemic chemotherapy is usually the most beneficial treatment. In patients who have known metastatic neoplasms and who present with cardiac manifestations, the clinician should be alert to the possibility of CM. However, treatment of all the metastatic cardiac tumors provides only palliation. Echocardiography performed periodically in patients with esophageal carcinoma could permit recognition of CM before the occurrence of overt cardiac signs leading to a chance for an aggressive surgical therapy. Accumulation of reports about treating cases of CM may help to clarify the natural course of this kind of lesions and how to treat them. After our review, we suggest that patients with a high risk of recurrence should be carefully evaluated using echocardiography for CM, even without symptoms. With the advent of modern diagnostic tools, better chemotherapy regimens, and better radiation techniques, and with the implementation of better perioperative care, patients with cancer have a somewhat improved survival. With increased longevity, a trend of increased incidence of CM has been shown in different studies. Because of the above-mentioned factors, together with the widespread use of modern imaging techniques, an increase in the frequency of the ante-mortem diagnosis of heart metastases is to be expected in the near future.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n\nMany thanks to Prof. Lucia Rosalba Grillo, Department of Pathology - S.Camillo-Forlanini Hospital - Rome, for performing histological analysis.\n==== Refs\nReferences\n1 Secondary cardiac tumor originating from laryngeal carcinoma: case report and review of the literature Acta Cardiol Renders F Vanderhyden M Andries E 57 60 60 2005 15779854 \n2 Cardiac metastases J Clin Pathol Bussani R De-Giorgio F Abbate A Silvestri F 27 34 60 2007 17098886 \n3 A 30-year analysis of cardiac neoplasms at autopsy Can J Cardiol Butany J Leong SW Carmichael K Komeda M 675 680 21 2005 https://www.ncbi.nlm.nih.gov/pubmed/16003450 16003450 \n4 Sudden death from metastatic esophageal cancer to the ventricular septum Jpn J Thorac Cardiovasc Surg Kataoka M Shigemitsu K Tanabe S Ohara T Takahata T Nose S 365 368 53 2005 16095236 \n5 Oesophageal cancer with myocardial metastasis complicated by ventricular fibrillation: the role of echocardiography Kardiol Pol Karabay CY Kocabay G Toprak C Kirma C 296 297 70 2012 https://www.ncbi.nlm.nih.gov/pubmed/22430418 22430418 \n6 Obstruction of right ventricular outflow tract by extended cardiac metastasis from esophageal cancer J Am Soc Echocardiogr Youn H-J Jung SE Chung WS 1541 1544 15 2002 12464926 \n7 Intracardiac metastasis of esophageal squamous cell carcinoma: report of a case Ann Thorac Cardiovasc Surg Tayama K Enomoto N Kohno M. Tobinaga S Otsuka H Kosuga K 166 169 17 2011 21597414 \n8 Left ventricle metastasis of esophageal cancer mimicking myocardial infarction in myocardial perfusion scintigraphy Int J Cardiol Cheng MF Huang TC Yen RF Tzen KY Wu YW 0 167 2013 \n9 Circulating tumor cells and cardiac metastasis from esophageal cancer: a case report Case Rep Oncol Consoli F Arcangeli G Ferrari V Grisanti S Almici C Bordonali T Simoncini E 299 303 4 2011 21734885 \n10 Cardiac metastasis from epidermoid esophageal cancer mimicking anterior myocardial infarction [Article in English, Portuguese] Rev Port Cardiol Oliveira SM Goncalves A Cruza C Almeida J Madureira AJ Amendoeirae I Macielab MJ 163 166 31 2012 22222060 \n11 Cardiac metastasis of an esophageal cancer: a rare cause of ventricular tachycardia and left ventricle outlet obstruction Arch Turk Soc Cardiol Başaran Ö Karabay CY Güler A Kirma C 670 41 2013 \n12 Myocardial metastasis from squamous cell carcinoma of the esophagus Gen Thorac Cardiovasc Surg Maeda M Goto T Harigai M Itoh T Moriki T Miyashita T 440 445 57 2009 19779796 \n13 Atrial Metastasis of esophageal carcinoma detected by follow-up FDG PET/CT Clin Nucl Med Moulin-Romsee G De Wever W Verbeken E Mortelmans L 393 395 32 2007 17452872 \n14 Cardiac metastases Int J Clin Oncol Al-Mamgani A Baartman L Baaijens M. de Pree I Incrocci L Levendag PC 369 13 2008 18704641 \n15 A metastatic ball tumor in the right atrium originating from esophageal cancer: report of a case Surg Today Nakamura Y Nakano K Gomi A Nakatani H Saegusa N Matsuya S Imai T 145 148 35 2005 15674497 \n16 Primary malignant melanoma of the oesophagus with a left atrial metastasis Thorax Chello M Marchese AR Panza A Mastroroberto P Di Lello F 185 186 48 1993 8493638 \n17 Isolated cardiac metastasis from squamous cell esophageal cancer Tumori Abbate MI Cicchiello F Canova S Cortinovis D Mariani S Maffini F Bidoli P 0 101 2015 \n18 Myocardial metastasis from oesophageal cancer J Cardiovasc Med Trocino G Fontana A Achilli F 0 16 2015 \n19 Multidetector CT and MR imaging of cardiac tumors Korean J Radiol Kim EY10.3348/kjr.2009.10.2.164 Choe YH Sung K Park SW Kim JH Ko YH 164 175 10 2009 19270863 \n20 Cardiac metastases Cancer Klatt EC Heitz DR 1456 1459 65 1990 2306690\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "11(12)",
"journal": "Cureus",
"keywords": "ante-mortem detection; cancer case report; cardiac imaging; cardiac metastases; esophageal cancer",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e6387",
"pmc": null,
"pmid": "31886099",
"pubdate": "2019-12-15",
"publication_types": "D002363:Case Reports",
"references": "21597414;15674497;15779854;23771169;22222060;2306690;21734885;8493638;22430418;23639460;17452872;26045127;12464926;19779796;17098886;16003450;24165006;18704641;19270863;16095236",
"title": "Asymptomatic Cardiac Metastases From Esophageal Cancer: A Case Report Of Ante-mortem Detection And Literature Review.",
"title_normalized": "asymptomatic cardiac metastases from esophageal cancer a case report of ante mortem detection and literature review"
} | [
{
"companynumb": "IT-MYLANLABS-2020M1022795",
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"abstract": "BACKGROUND\nPulmonary arterial hypertension (PAH) is a rare progressive disease of the pulmonary arterioles with an unfavourable prognosis.\n\n\nOBJECTIVE\nTo evaluate survival and prognostic factors in patients with PAH diagnosed and treated at a single centre in the years 2004–2013.\n\n\nMETHODS\nThe study included 55 children (33 girls; 66%, 22 boys; 33%), with an average age 6.2 ± 6.0 years, with idiopathic PAH — n = 23 (42%), PAH associated with systemic-to-pulmonary shunts — n = 17 (31%), and PAH after corrective cardiac surgery — n = 15 (27%). Forty-seven of them (87%) were treated with advanced therapy.\n\n\nRESULTS\nDuring the follow-up with an average time of 5.6 ± 4.7 years 15 (27.3%) children died. The one-, three-, five-, and ten-year survival was, respectively, 83.1%, 77.1%, 70.7%, and 65.2%. The analysis of the survival curves revealed a better prognosis in patients with baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) level < 605 pg/mL (p = 0.024) and a higher probability of survival of three and five years in children at baseline I/II World Health Organisation functional class (WHO-FC). The higher risk of death was associated with a higher pressure in the right atrium (HR 1.23, p < 0.01) and higher pulmonary resistance (HR 1.1, p < 0.01), whereas no history of syncope had a better prognosis (HR 0.31, p = 0.03).\n\n\nCONCLUSIONS\nSurvival in the study group was comparable to the currently published register data. Mortality risk factors were connected with the severity of the disease at diagnosis.",
"affiliations": "Department of Cardiology, The Children's Memorial Health Institute, Warsaw, Poland. m.zuk@czd.pl.",
"authors": "Żuk|Małgorzata|M|;Mazurkiewicz-Antoń|Katarzyna|K|;Migdał|Anna|A|;Jagiełłowicz-Kowalska|Dorota|D|;Turska-Kmieć|Anna|A|;Ziółkowska|Lidia|L|;Brzezińska-Rajszys|Grażyna|G|;Zubrzycka|Maria|M|;Kawalec|Wanda|W|",
"chemical_list": "D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain",
"country": "Poland",
"delete": false,
"doi": "10.5603/KP.a2015.0120",
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"issn_linking": "0022-9032",
"issue": "74(2)",
"journal": "Kardiologia polska",
"keywords": null,
"medline_ta": "Kardiol Pol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D007223:Infant; D008297:Male; D020097:Natriuretic Peptide, Brain; D010446:Peptide Fragments; D011379:Prognosis; D012307:Risk Factors",
"nlm_unique_id": "0376352",
"other_id": null,
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"pmc": null,
"pmid": "26101028",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Prognosis in children with pulmonary arterial hypertension: 10-year single-centre experience.",
"title_normalized": "prognosis in children with pulmonary arterial hypertension 10 year single centre experience"
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"companynumb": "PL-ACTELION-A-CH2019-192048",
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"activesubstancename": "BOSENTAN"
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"abstract": "mecA-positive Staphylococcus aureus isolates phenotypically susceptible to cefoxitin (mecA-methicillin-sensitive S. aureus [MSSA]) have been identified. We describe the treatment and outcomes among patients with mecA-MSSA bloodstream infections (BSI) and MRSA BSI matched 1:1 for age, BSI origin, and BSI type (n = 17 per group). Compared to MRSA BSI patients, mecA-MSSA BSI patients more often experienced clinical failure (58.8% and 11.8%, P = 0.010), driven largely by persistent bacteremia (35.3% and 11.8%). mecA-MSSA BSI patients may be at higher risk for poor clinical outcomes.",
"affiliations": "Ascension, Wheaton Franciscan-St. Francis Campus, Department of Pharmacy, Milwaukee, Wisconsin, USA.;Massachusetts General Hospital, Department of Pharmacy, Boston, Massachusetts, USA.;Marquette University, Milwaukee, Wisconsin, USA.;Aurora St. Luke's Medical Center, Department of Pharmacy Services, Milwaukee, Wisconsin, USA thomas.dilworth@aurora.org.",
"authors": "Jones|Dylan|D|;Elshaboury|Ramy H|RH|;Munson|Erik|E|;Dilworth|Thomas J|TJ|",
"chemical_list": "D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D046915:Penicillin-Binding Proteins; C487789:mecA protein, Staphylococcus aureus; D002440:Cefoxitin; D014640:Vancomycin; D010068:Oxacillin",
"country": "United States",
"delete": false,
"doi": "10.1128/AAC.01396-17",
"fulltext": null,
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"issn_linking": "0066-4804",
"issue": "62(1)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": "bacteremia; mecA PCR; mecA-positive methicillin-susceptible S. aureus; methicillin-resistant S. aureus; vancomycin",
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D001426:Bacterial Proteins; D002440:Cefoxitin; D005260:Female; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010068:Oxacillin; D046915:Penicillin-Binding Proteins; D012189:Retrospective Studies; D013203:Staphylococcal Infections; D016896:Treatment Outcome; D014640:Vancomycin; D055815:Young Adult",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29038267",
"pubdate": "2018-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "10770721;22993184;1892329;26503983;26373316;20147649;21208910;16914701;28373193;19873687;18171250;22491776;11600358",
"title": "A Retrospective Analysis of Treatment and Clinical Outcomes among Patients with Methicillin-Susceptible Staphylococcus aureus Bloodstream Isolates Possessing Detectable mecA by a Commercial PCR Assay Compared to Patients with Methicillin-Resistant Staphylococcus aureus Bloodstream Isolates.",
"title_normalized": "a retrospective analysis of treatment and clinical outcomes among patients with methicillin susceptible staphylococcus aureus bloodstream isolates possessing detectable meca by a commercial pcr assay compared to patients with methicillin resistant staphylococcus aureus bloodstream isolates"
} | [
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"companynumb": "US-PFIZER INC-2021194899",
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"actiondrug": "6",
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"activesubstancename": "DAPTOMYCIN"
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"abstract": "Kaposi`s sarcoma (KS) is a complication of immunosuppressive therapy for transplant recipients. Unlike adult recipients, KS in pediatric organ transplantation is quite rare. Treatment is usually withdrawal of immunosuppression; non-responders often receive chemotherapy.\n\n\n\nWe have reported a child with post-liver transplant visceral KS which has progressed despite withdrawal of immunosuppressive therapy, who has been treated with Paclitaxel for three weeks. KS has regressed completely after four cycles of Paclitaxel.\n\n\n\nPaclitaxel should be considered as an effective first line treatment option for patients with posttransplant KS.",
"affiliations": "Division of Pediatric Oncology, Health Sciences University, Okmeydanı Training and Research Hospital, İstanbul, Turkey.;Department of Pediatrics, Health Sciences University, Okmeydanı Training and Research Hospital, İstanbul, Turkey.;Department of Pediatrics, Health Sciences University, Okmeydanı Training and Research Hospital, İstanbul, Turkey.;Division of Pediatric Oncology, Health Sciences University, Okmeydanı Training and Research Hospital, İstanbul, Turkey.;Department of Pathology, Acıbadem University School of Medicine, İstanbul, Turkey.;Departments of Pediatric Gastroenterology, Memorial Şişli Hospital, İstanbul, Turkey.;Pediatric Surgery and Liver Transplantation Center, Memorial Şişli Hospital, İstanbul, Turkey.",
"authors": "Şen|Hilal Susam|HS|;Ateş|Belen Terlemez|BT|;Yılmazbaş|Pınar|P|;Ocak|Süheyla|S|;Kırımlıoğlu|Hale|H|;Gökçe|Selim|S|;Acarlı|Koray|K|",
"chemical_list": "D017239:Paclitaxel",
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-4301",
"issue": "62(5)",
"journal": "The Turkish journal of pediatrics",
"keywords": "Kaposi`s sarcoma; children; paclitaxel",
"medline_ta": "Turk J Pediatr",
"mesh_terms": "D000328:Adult; D002648:Child; D006801:Humans; D007165:Immunosuppression Therapy; D016031:Liver Transplantation; D017239:Paclitaxel; D012514:Sarcoma, Kaposi; D066027:Transplant Recipients",
"nlm_unique_id": "0417505",
"other_id": null,
"pages": "858-862",
"pmc": null,
"pmid": "33108091",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Successful treatment of pediatric post-liver transplant Kaposi`s sarcoma with paclitaxel.",
"title_normalized": "successful treatment of pediatric post liver transplant kaposi s sarcoma with paclitaxel"
} | [
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"companynumb": "NVSC2020TR309624",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
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"activesubstance": {
"activesubstancename": "TACROLIMUS"
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"drugadditional": "1",
"druga... |
{
"abstract": "Brevundimonas diminuta, a non-fermenting gram-negative bacterium, is emerging as an important multidrug resistant opportunistic pathogen. It has been described in cases of bacteremia, pleuritis, keratitis and peritoneal dialysis-associated peritonitis. We describe, for the first time, a case of pyogenic liver abscess caused by coinfection of B. diminuta and Streptococcus anginosus, and briefly review pyogenic liver abscesses and the literature regarding B. diminuta.",
"affiliations": "Internal Medicine Residency, Sparrow Hospital, Lansing, Michigan, USA jacob.burch@sparrow.org.;Internal Medicine Residency, Sparrow Hospital, Lansing, Michigan, USA.;Gastroenterology, Loyola University Medical Center, Chicago, Illinois, USA.;Internal Medicine, Michigan State University, East Lansing, Michigan, USA.",
"authors": "Burch|Jacob|J|http://orcid.org/0000-0002-7633-1725;Tatineni|Shilpa|S|;Enofe|Ikponmwosa|I|;Laird-Fick|Heather|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-236235",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(5)",
"journal": "BMJ case reports",
"keywords": "hepatitis and other GI infections; liver disease",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D042063:Caulobacteraceae; D060085:Coinfection; D006801:Humans; D046290:Liver Abscess, Pyogenic; D034366:Streptococcus anginosus",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33975829",
"pubdate": "2021-05-11",
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"abstract": "We present the case of 31-year-old man who developed hospital-acquired pneumonia in the intensive care unit. Pathogens were identified to be carbapenem-resistant isolates of Providencia stuartii and Klebsiella pneumoniae. The patient was treated with an extended infusion of double-dose meropenem (targeting the carbapenem-resistant P. stuartii) and colistin (targeting the carbapenem-resistant K. pneumoniae) for 2 weeks. The patient's disease responded well to the prescribed regimen; his chest X-ray became normal, and all other signs of infection subsided. To our knowledge, this is the first description of the emergence of carbapenem-resistant P. stuartii due to AmpC hyperproduction in Saudi Arabia.",
"affiliations": "Pharmaceutical Care Services, King Saud Medical City, Riyadh, Saudi Arabia.;Microbiology Department, King Saud Medical City, Riyadh, Saudi Arabia.;Prevention and Control of Infection Administration, King Saud Medical City, Riyadh, Saudi Arabia.;Pharmacy Department, Dr. Sulaiman Al Habib Hospital (As-Suwaidi), Riyadh, Saudi Arabia.;Intensive Care Unit, King Saud Medical City, Riyadh, Saudi Arabia.",
"authors": "Abdallah|M|M|;Alhababi|R|R|;Alqudah|N|N|;Aldyyat|B|B|;Alharthy|A|A|",
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"fulltext": "\n==== Front\nNew Microbes New InfectNew Microbes New InfectNew Microbes and New Infections2052-2975Elsevier S2052-2975(18)30087-810.1016/j.nmni.2018.09.007First Clinical Case in Emerging CountryFirst report of carbapenem-resistant Providencia stuartii in Saudi Arabia Abdallah M. mo.abdullah@ksmc.med.sa1∗Alhababi R. 2Alqudah N. 3Aldyyat B. 5Alharthy A. 41) Pharmaceutical Care Services, King Saud Medical City, Riyadh, Saudi Arabia2) Microbiology Department, King Saud Medical City, Riyadh, Saudi Arabia3) Prevention and Control of Infection Administration, King Saud Medical City, Riyadh, Saudi Arabia4) Intensive Care Unit, King Saud Medical City, Riyadh, Saudi Arabia5) Pharmacy Department, Dr. Sulaiman Al Habib Hospital (As-Suwaidi), Riyadh, Saudi Arabia∗ Corresponding author: M. Abdallah, Pharmaceutical Care Services, King Saud Medical City, Riyadh, Saudi Arabia. mo.abdullah@ksmc.med.sa20 9 2018 11 2018 20 9 2018 26 107 109 27 8 2018 10 9 2018 13 9 2018 © 2018 The Author(s)2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We present the case of 31-year-old man who developed hospital-acquired pneumonia in the intensive care unit. Pathogens were identified to be carbapenem-resistant isolates of Providencia stuartii and Klebsiella pneumoniae. The patient was treated with an extended infusion of double-dose meropenem (targeting the carbapenem-resistant P. stuartii) and colistin (targeting the carbapenem-resistant K. pneumoniae) for 2 weeks. The patient's disease responded well to the prescribed regimen; his chest X-ray became normal, and all other signs of infection subsided. To our knowledge, this is the first description of the emergence of carbapenem-resistant P. stuartii due to AmpC hyperproduction in Saudi Arabia.\n\nKeywords\nCarbapenem resistantextended infusionmeropenemProvidencia stuartii\n==== Body\nIntroduction\nProvidencia species are Gram-negative bacilli that belong to the Enterobacteriaceae family. The genus Providencia contains five species: P. stuartii, P. rettgeri, P. alcalifaciens, P. heimbachae and P. rustigianii\n[1]. Among the Providencia species, P. stuartii and P. rettgeri are the most common causes of nosocomial infections including urinary tract infections, pneumonia, and wound and bloodstream infections [1], [2]. Nosocomial infections with P. stuartii greatly affect patients' outcomes [3].\n\nWe present a case of a patient with hospital-acquired pneumonia caused by carbapenem-resistant isolates of P. stuartii and Klebsiella pneumoniae. To our knowledge, this is the first report of carbapenem-resistant P. stuartii due to AmpC hyperproduction in Saudi Arabia.\n\nCase presentation\nA 31-year-old man was admitted to our intensive care unit (ICU) from another hospital with postexploratory laparotomy and right thoracotomy for a gunshot wound to the abdomen and chest on February 2017. The patient had left arm injury with a left elbow fracture, for which he underwent open reduction internal fixation (ORIF). His condition was complicated by septic shock and acute kidney injury. At his arrival at hospital, the patient was found to have a chest infection and an infected laparotomy wound, for which empiric piperacillin/tazobactam therapy was provided. During his prolonged ICU stay (56 days), he received several antibiotics; the patient had continuous fever, leukocytosis and persistent source of infection (abdominal wound and left-hand ORIF site wound for which he underwent frequent dressing and debridement). Written informed consent was obtained from the patient's family for publication of this case report. The study was approved by our local institutional review board (H2RI-16-Apr17-01).\n\nP. stuartii isolates were identified using the VITEK 2 system (bioMérieux, Marcy l'Étoile, France). Susceptibility testing was determined by disc diffusion and interpreted by the Clinical and Laboratory Standards Institute criteria [4]. Phenotypic assay for detection of extended-spectrum β-lactamase, AmpC and carbapenamase production was performed as described previously [5].\n\nThe first carbapenem-resistant P. stuartii isolate was detected in the sputum on day 22 of ICU admission. The isolate was resistant to ciprofloxacin, trimethoprim/sulfamethoxazole, gentamicin, imipenem and meropenem; it was only sensitive to amikacin. We did not treat the patient according to the results of this culture because the chest X-ray was unremarkable at that time. The patient became highly febrile on day 30, so piperacillin/tazobactam 4.5 g was provided intravenously (iv) every 6 hours. On the third day of piperacillin/tazobactam therapy (day 32 of ICU admission), the fever was persistent and leukocytes were increasing, so the patient underwent septic screening (tracheal aspirate, urine, laparotomy site wound and blood), and piperacillin/tazobactam was changed to meropenem 1 g provided iv every 8 hours. Three days later (day 35), we received the results of the septic screening, which showed growth of P. stuartii and carbapenem-resistant K. pneumoniae in the urine, wound and blood. On day 37 we received the tracheal aspirate culture report, which revealed growth of carbapenem-resistant isolates of P. stuartii and K. pneumoniae. The carbapenem-resistant P. stuartii isolate was resistant to amikacin, ciprofloxacin, trimethoprim/sulfamethoxazole, gentamicin and imipenem, while it was intermediate to meropenem.\n\nBecause the patient's condition was not improving while receiving therapy with a conventional dose of meropenem (1 g provided iv every 8 hours), we changed the dosing regimen of meropenem to be 2 g delivered iv every 8 hours with extended infusion over 3 hours instead of 30 minutes. Also, we added colistin to treat the carbapenem-resistant K. pneumoniae. Colistin was prescribed as a loading dose of 9 million units iv followed by 3 million units iv every 8 hours. A follow-up septic screen was repeated on day 44. On day 47 the septic screen showed the positive growth of multidrug-resistant (MDR) Acinetobacter baumannii in the left-hand ORIF site wound and tracheal aspirate. A chest X-ray was ordered; it revealed nothing abnormal. Meropenem and colistin were discontinued after completing a course of 2 weeks. The patient was transferred to the ward after 56 days of ICU admission. He was stable with no signs and symptoms of infection.\n\nDiscussion\nAntimicrobial resistance in P. stuartii is uncommon in our ICU. However, the extensive consumption of colistin, tigecycline and carbapenems in our ICU because of high rates of MDR A. baumannii, carbapenem-resistant K. pneumoniae and extended-spectrum β-lactamase-producing Enterobacteriaceae might have played a role in the emergence of carbapenem-resistant P. stuartii. Our patient received multiple antibiotics before the isolation of the first carbapenem-resistant P. stuartii; he completed prolonged courses of colistin, tigecycline and imipenem. The use of colistin and tigecycline is associated with superinfections with P. stuartii and many MDR Gram-negative bacteria [6], [7].\n\nMany carbapenem-resistant P. stuartii cases have been reported [2]. Carbapenamase production (mainly New Delhi metallo-β-lactamase 1) is the main mechanism of carbapenem resistance in P. stuartii. Molecular typing helps in identifying the resistance genes in Providencia species. Unfortunately, our microbiology laboratory does not perform molecular typing. However, a phenotypic assay was performed and revealed AmpC production in carbapenem-resistant P. stuartii isolates recovered from our patient. Prolonged hospitalization before detection of carbapenem-resistant P. stuartii was present in one outbreak of carbapenem-resistant P. stuartii, ranging from 24 to 106 days [8]. In another outbreak of carbapenem-resistant P. stuartii\n[9], the median length of ICU stay was 39 days, while acquisition of carbapenem-resistant P. stuartii occurred in a median of 16 days after ICU admission. In our case, the first carbapenem-resistant P. stuartii was recovered on day 22 and the second on day 32. Both isolates were recovered from respiratory sites.\n\nNosocomial infections caused by carbapenem-resistant P. stuartii strains represent a challenging serious clinical threat because these strains are intrinsically resistant to last-resort agents, mainly colistin and tigecycline. Because reports of carbapenem-resistant P. stuartii are scarce, its treatment was rarely described. Our patient received a 2-week course of double-dose meropenem every 8 hours provided as an extended infusion over 3 hours. In addition, colistin was prescribed to treat the carbapenem-resistant K. pneumoniae coinfection. The use of extended infusion of meropenem for patients with hospital-acquired pneumonia has many advantages compared to a 30-minute infusion regimen; the severity of the disease can be reduced and the clinical efficacy can be improved, and organ failure recovery and long-term prognosis can be improved [10].\n\nConflict of interest\nThis report did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n==== Refs\nReferences\n1 O'Hara C.M. Brenner F.W. Miller J.M. Classification, identification, and clinical significance of Proteus, Providencia, and Morganella Clin Microbiol Rev 13 2000 534 546 11023955 \n2 Abdallah M. Balshi A. First literature review of carbapenem-resistant Providencia New Microbe New Infect 25 2018 16 23 \n3 Zavascki A.P. Carvalhaes C.G. da Silva G.L. Tavares Soares S.P. de Alcântara L.R. Elias L.S. Outbreak of carbapenem-resistant Providencia stuartii in an intensive care unit Infect Control Hosp Epidemiol 33 2012 627 630 22561721 \n4 Clinical and Laboratory Standards Institute Performance standards for antimicrobial susceptibility testing. Twenty-fourth informational supplement 2014 Clinical and Laboratory Standards Institute Wayne, PA \n5 Thomson K.S. Extended-spectrum-β-lactamase, AmpC, and carbapenemase issues J Clin Microbiol 48 2010 1019 1025 20181902 \n6 Katsiari M. Ntorlis K. Nteves I. Roussou Z. Platsouka E.D. Maguina A. Characteristics of superinfections during treatment with tigecycline J Chemother 28 2016 110 115 27077933 \n7 Hayakawa K. Marchaim D. Divine G.W. Pogue J.M. Kumar S. Lephart P. Growing prevalence of Providencia stuartii associated with the increased usage of colistin at a tertiary health care center Int J Infect Dis 16 2012 e646 e648 22818111 \n8 Oikonomou O. Liakopoulos A. Phee L.M. Betts J. Mevius D. Wareham D.W. Providencia stuartii isolates from Greece: co-carriage of cephalosporin (bla SHV-5 , bla VEB-1 ), carbapenem (bla VIM-1 ), and aminoglycoside (rmtB ) resistance determinants by a multidrug-resistant outbreak clone Microb Drug Resist 22 2016 379 386 27380549 \n9 Douka E. Perivolioti E. Kraniotaki E. Fountoulis K. Economidou F. Tsakris A. Emergence of a pandrug-resistant VIM-1 producing Providencia stuartii clonal strain causing an outbreak in a Greek intensive care unit Int J Antimicrob Agents 45 2015 533 536 25749199 \n10 Wang Z. Shan T. Liu Y. Ding S. Li C. Zhai Q. Comparison of 3-hour and 30-minute infusion regimens for meropenem in patients with hospital acquired pneumonia in intensive care unit: a randomized controlled clinical trial Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 26 2014 644 649 25230866\n\n",
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"keywords": "Carbapenem resistant; Providencia stuartii; extended infusion; meropenem",
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"title": "First report of carbapenem-resistant Providencia stuartii in Saudi Arabia.",
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"abstract": "BACKGROUND\nVery few cases of secondary peritonitis caused by Streptococcus pneumoniae have been described in the literature, and they have been found to occur mostly in patients with predisposing factors. Here, we report the case of an elderly patient who developed pneumococcal peritonitis secondary to perforation of gastroduodenal ulcer.\nAn 82-year-old man was admitted to intensive care unit (ICU) for septic shock with cardiac impairment 1 day after arriving in the Emergency Department.\nThe patient presented with pneumococcal bacteremia and pneumococcal antigenuria. No abdominal defense was found on examination. A computed tomography scan revealed pneumoperitoneum and peritoneal effusions.\n\n\nMETHODS\nThe patient was treated with effective empiric antibiotic therapy, and delayed surgery.\n\n\nRESULTS\nThe patient gradually improved and was discharged from ICU on day 14. The ultimate outcome was unfavorable, with death occurring on day 28.\n\n\nCONCLUSIONS\nThis rare infection can occur in elderly patients even in the absence of other predisposing factors. Secondary peritonitis may be suspected in patients with positive pneumococcal antigenuria or unexplained pneumococcal bacteremia, especially if an asthenic form is possible.",
"affiliations": "Service d'accueil des urgences Service de réanimation polyvalente Laboratoire de Bactériologie, Virologie, Parasitologie Service de chirurgie digestive, Centre hospitalier universitaire Félix-Guyon, Allée des Topazes, Saint Denis, France.",
"authors": "Allain-Jeannic|Gwenola|G|;Traversier|Nicolas|N|;Belmonte|Olivier|O|;Valance|Dorothée|D|;Bekkar|Sarah|S|;Allou|Nicolas|N|;Allyn|Jerome|J|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29995767MD-D-18-0157110.1097/MD.0000000000011323113233900Research ArticleClinical Case ReportDelayed surgery in a patient with pneumococcal peritonitis and bacteremia secondary to perforation of gastroduodenal ulcer A case reportAllain-Jeannic Gwenola MDabTraversier Nicolas MDcBelmonte Olivier MDcValance Dorothée MDbBekkar Sarah MDdAllou Nicolas MDbAllyn Jerome MDb∗NA. a Service d’accueil des urgencesb Service de réanimation polyvalentec Laboratoire de Bactériologie, Virologie, Parasitologied Service de chirurgie digestive, Centre hospitalier universitaire Félix-Guyon, Allée des Topazes, Saint Denis, France.∗ Correspondence: Jerome Allyn, Service de Réanimation polyvalente, Centre Hospitalier Universitaire Félix Guyon, Allée des Topazes, 97400 Saint Denis, France (e-mail: allyn.jer@gmail.com).7 2018 13 7 2018 97 28 e113238 3 2018 5 6 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nVery few cases of secondary peritonitis caused by Streptococcus pneumoniae have been described in the literature, and they have been found to occur mostly in patients with predisposing factors. Here, we report the case of an elderly patient who developed pneumococcal peritonitis secondary to perforation of gastroduodenal ulcer.\n\nPatient concerns:\nAn 82-year-old man was admitted to intensive care unit (ICU) for septic shock with cardiac impairment 1 day after arriving in the Emergency Department.\n\nDiagnoses:\nThe patient presented with pneumococcal bacteremia and pneumococcal antigenuria. No abdominal defense was found on examination. A computed tomography scan revealed pneumoperitoneum and peritoneal effusions.\n\nInterventions:\nThe patient was treated with effective empiric antibiotic therapy, and delayed surgery.\n\nOutcomes:\nThe patient gradually improved and was discharged from ICU on day 14. The ultimate outcome was unfavorable, with death occurring on day 28.\n\nLessons:\nThis rare infection can occur in elderly patients even in the absence of other predisposing factors. Secondary peritonitis may be suspected in patients with positive pneumococcal antigenuria or unexplained pneumococcal bacteremia, especially if an asthenic form is possible.\n\nKeywords\nbacteremiaperitonitisStreptococcus pneumoniaeOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nStreptococcus pneumoniae is usually responsible for spontaneous bacterial peritonitis in patients with cirrhosis or nephrotic syndrome, or in young healthy children.[1–3] It is rarely implicated in peritonitis secondary to organ perforation. Nevertheless, a few cases of secondary pneumococcal peritonitis have been reported, including in young women with an intrauterine device, in women after delivery, and in patients (especially children) with complicated appendicitis.[4–8] In addition, 2 studies have reported 5 cases of community peritonitis secondary to perforation of gastroduodenal ulcer in patients with predisposing factors.[8,9] Here, we report a misleading case of fatal peritonitis with pneumococcal bacteremia secondary to perforation of gastroduodenal ulcer which occurred in an octogenarian patient. The patient being deceased, informed consent for this publication was given by his wife. Ethical approval was not required given the methodology used.\n\n2 Case report\nAn 82-year-old man came to the Emergency Department after suffering for several days from epigastric discomfort triggered by physical effort. The patient had a history of high blood pressure, atrial flutter, nondialyzed chronic renal failure, and benign prostatic hypertrophy. He had been weaned from alcohol 20 years earlier. On admission, his treatment included losartan, hydrochlorothiazide, acetylsalicylic acid, and Serenoa repens extract. Clinical examination revealed a blood pressure of 115/70 mm Hg, a heart rate of 70 beats per minute, a normal temperature, tachypnea, and a bladder globe. The biology showed hepatic cytolysis 20 times the norm, a V factor of 22%, and lactate acidosis (5 mmol/L). Blood levels of paracetamol were low (6.9 mg/L). Abdominal ultrasonography showed normal hepatic parenchyma without abnormality of the bile ducts, right pleural effusions, and a bladder globe with bilateral hydronephrosis.\n\nTreatment with N-acetylcysteine was immediately initiated. The next day, the patient worsened clinically, and he presented with persisting hyperlactatemia of 4.7 mmol/L. Echocardiography showed a dilated left ventricle with an estimated ejection fraction of 20% and low cardiac output, prompting the initiation of dobutamine treatment. Coronary angiography was normal. The patient then developed fever and chills, which prompted investigation and that led to the introduction of antibiotic therapy with piperacillin and gentamicin.\n\nIn view of these developments, the patient was transferred to intensive care unit (ICU) on day 2. Clinical examination revealed apyrexia, satisfactory hemodynamic status, and epigastric pain without abdominal defense. A thoraco-abdominopelvic computed tomography scan (CT-scan) showed normal liver and spleen, pneumoperitoneum, and peritoneal and pleural effusions with no evidence of mesenteric ischemia, highlighting the presence of secondary peritonitis. In addition to symptomatic management of organ failure (including administration of dobutamine and norepinephrine, mechanical ventilation, and renal replacement therapy), antibiotic treatment with piperacillin-tazobactam, gentamicin, and fluconazole was conducted. Laparotomy was performed on the same day, revealing a perforation of the first duodenum with peritoneal effusions (1500 mL). The anatomopathological examination of operative biopsies concluded in a perforated ulcer.\n\nMicrobiological analysis was performed to identify the germ causing the infection. Pneumococcal antigenuria was positive. Blood cultures on admission to ICU became positive for S pneumoniae serotype 3 after 8 hours of incubation. Peritoneal fluid culture was positive for S pneumoniae, Klebsiella pneumoniae, Staphylococcus aureus, and Candida albicans. Alpha-hemolytic colonies of S pneumoniae on CNA Agar (Biomerieux, Marcy l’étoile, France) were identified using a sensitive OPTO-F optochin disk (Biomerieux, Marcy l’étoile, France) and a dryspot agglutination test (Oxoid, Basingstoke, UK). The antibiogram was performed on MHF with Biorad discs (Biorad, Marne la coquette, France). The strain showed a wild-type profile intermediate with ofloxacin, as defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST 2016). Minimum inhibitory concentrations (MICs) were measured using the E-test method (Biomerieux, Marcy l’étoile, France): Penicillin G. levels were 0.023 mg/L, amoxicillin levels were 0.023 mg/L, ceftriaxone levels were 0.016 mg/L, and cefotaxime levels were 0.012 mg/L. Typing was performed by the National Reference Center using the slide latex agglutination method. These results confirmed the diagnosis of pneumococcal peritonitis secondary to perforation of gastroduodenal ulcer.\n\nAdditional examinations were performed in the context of this pneumococcal bacteremia. Transesophageal echocardiography did not suggest endocarditis. The patient was not known to be cirrhotic, and the abdominal ultrasound performed showed normal liver parenchyma and vascularization, later confirmed by CT-scan. Plasma protein electrophoresis revealed a nonspecific inflammatory profile with hypogammaglobulinemia of 5.6 g/L. HIV and HCV serology were negative and HBV serology suggested immunity. Lumbar puncture was not performed given the absence of neurological signs. No other infectious foci (including otitis) were found.\n\nIn view of the above, antibiotic therapy was modified on day 4 to amoxicillin-clavulanic acid (2–4 g per day according to renal function) and fluconazole (400 mg per day) for a total duration of 7 days. As the patient gradually improved, he was weaned from dobutamine on day 3 and from norepinephrine on day 6. Renal replacement therapy was performed on day 6, and the patient was weaned from mechanical ventilation on day 8. There persisted biventricular dilatation and a left ventricular ejection fraction of 20%.\n\nWhile the outcome was initially favorable, the patient worsened after a few days. The presence of a suspicious liquid in an abdominal drain suggested nosocomial peritonitis, and antibiotic therapy was modified accordingly (to imipenem 3 g per day). However, additional examinations did not confirm this hypothesis. The patient eventually improved, and he was discharged from ICU on day 14. An episode of cardiac failure with thrombosis of the right atrium and right iliac vein resulted in patient death on day 28.\n\n3 Discussion\nWe thus report a case of peritonitis with pneumococcal bacteremia secondary to perforation of gastroduodenal ulcer. Studies have found that the incidence of perforation of gastroduodenal ulcer ranges from 7 to 10 cases per 100,000 persons and complicates less than 11% of gastroduodenal ulcers.[9,10] The 2 most commonly performed examinations for the diagnosis of intra-abdominal infection are ultrasonography and CT-scan. While CT-scan has higher sensitivity and specificity than ultrasonography, concerns about radiation exposure have recently prompted reappraisal of the roles of ultrasonography.[11] However, in the case of our patient, the secondary peritonitis could not be diagnosed with abdominal ultrasonography, but only with the CT-scan. This unfortunately caused a delay in surgery.\n\nThree different bacteria were found in the patient's abdomen, but only S pneumonia was detected in his blood. Moreover, other than age, the patient had no predisposing factor to infection with S pneumoniae. Given the absence of other infectious foci in the patient, we can conclude that S pneumonia played a predominant pathological role in the peritonitis.\n\nWhile management of perforated gastroduodenal ulcer is usually surgical, it may be conservative (nonoperative) under certain conditions.[12] In the case of our patient, a conservative, nonoperative strategy could not be implemented due to the presence of hemodynamic instability.[12] Unfortunately, delayed surgery after failure of conservative treatment in cases of perforated gastroduodenal ulcer is associated with a high mortality rate of around 50%.[13] By contrast, antibiotic treatment of pneumococcal peritonitis does not pose any particular problem. Indeed, a study of primary pneumococcal peritonitis has found no link between mortality and the resistance of S pneumoniae to penicillin.[14]\n\nVery few cases of pneumococcal peritonitis secondary to perforation of gastroduodenal ulcer have been reported in the literature. Rueda et al[15] reported a series of 136 cases of pneumococcal infection, which included 5 cases of primary peritonitis (3.7%) and no case of secondary peritonitis. The main pathophysiological hypothesis put forward to explain these is direct colonization from the oropharyngeal tract, which can be favored by low gastric acidity.[8] The advanced age of our patient seems to confirm this hypothesis.\n\n4 Conclusions\nOur case study confirms the existence of pneumococcal peritonitis secondary to perforation of gastroduodenal ulcer. This rare infection can occur in elderly patients even in the absence of other predisposing factors. Secondary peritonitis may be suspected in patients with positive pneumococcal antigenuria or unexplained pneumococcal bacteremia, especially if an asthenic form is possible.\n\nAuthor contributions\nConceptualization: Gwenola Allain-Jeannic, Nicolas Traversier, Olivier Bemonte, Dorothée Valance, Sarah Bekkar, Nicolas Allou, jerome allyn.\n\nData curation: Gwenola Allain-Jeannic, Nicolas Traversier, Olivier Bemonte, Dorothée Valance, Sarah Bekkar, Nicolas Allou, jerome allyn.\n\nFormal analysis: Gwenola Allain-Jeannic, Nicolas Traversier, Olivier Bemonte, Dorothée Valance, jerome allyn.\n\nInvestigation: Gwenola Allain-Jeannic, Nicolas Traversier, Olivier Bemonte, Dorothée Valance, Nicolas Allou, jerome allyn.\n\nMethodology: Gwenola Allain-Jeannic, Nicolas Traversier, Olivier Bemonte, Nicolas Allou, jerome allyn.\n\nValidation: Gwenola Allain-Jeannic, Olivier Bemonte, Dorothée Valance, Nicolas Allou, jerome allyn.\n\nVisualization: Gwenola Allain-Jeannic, Olivier Bemonte, jerome allyn.\n\nWriting – original draft: Gwenola Allain-Jeannic, Nicolas Traversier, jerome allyn.\n\nWriting – review & editing: Gwenola Allain-Jeannic, Nicolas Traversier, Olivier Bemonte, Dorothée Valance, Sarah Bekkar, Nicolas Allou, jerome allyn.\n\nResources: Sarah Bekkar.\n\nSupervision: Sarah Bekkar, Nicolas Allou.\n\nAbbreviations: ICU = intensive care unit, MIC = minimum inhibitory concentration.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Heo J Seo YS Yim HJ \nClinical features and prognosis of spontaneous bacterial peritonitis in korean patients with liver cirrhosis: a multicenter retrospective study . Gut Liver \n2009 ;3 :197–204 .20431746 \n[2] Bose B Keir WR Godberson CV \nPrimary pneumococcal peritonitis . Can Med Assoc J \n1974 ;110 : 305 passim .\n[3] Khilji MF \nPrimary peritonitis: a forgotten entity . Eur J Pediatr Surg Rep \n2015 ;3 :27–9 .\n[4] Bukovsky I Neuman M Ron-El R \nPneumococcal peritonitis in the presence of intra-uterine device—conservative treatment; a case report . Eur J Obstet Gynecol Reprod Biol \n1989 ;33 :79–82 .2806711 \n[5] Hemsley C Eykyn SJ \nPneumococcal peritonitis in previously healthy adults: case report and review . Clin Infect Dis \n1998 ;27 :376–9 .9709890 \n[6] Bucher A Müller F \nSpectrum of abdominal and pelvic infections caused by pneumococci in previously healthy adult women . Eur J Clin Microbiol Infect Dis \n2002 ;21 :474–7 .12111607 \n[7] Heltberg O Korner B Schouenborg P \nSix cases of acute appendicitis with secondary peritonitis caused by Streptococcus pneumoniae . Eur J Clin Microbiol \n1984 ;3 :141–3 .6723637 \n[8] Nielsen KR Ejlertsen T El-Batran S \nA five-year survey of pneumococcal peritonitis in two Danish counties—incidence, diagnosis and clinical entities . Clin Microbiol Infect \n2003 ;9 :738–40 .12925121 \n[9] Komen NA Bertleff MJ Van Doorn LJ \nHelicobacter genotyping and detection in peroperative lavage fluid in patients with perforated peptic ulcer . J Gastrintest Surg \n2008 ;12 :555–60 .\n[10] Behrman SW \nManagement of complicated peptic ulcer disease . Arch Surg \n2005 ;140 :201–8 .15724004 \n[11] Sartelli M Catena F Abu-Zidan FM \nManagement of intra-abdominal infections: recommendations by the WSES 2016 consensus conference . World J Emerg Surg \n2017 ;12 :22.28484510 \n[12] Mouly C Chati R Scotté M \nTherapeutic management of perforated gastroduodenal ulcer: literature review . J Visc Surg \n2013 ;150 :333–40 .24011662 \n[13] Marshall C Ramaswamy P Bergin FG \nEvaluation of a protocol for the non-operative management of perforated peptic ulcer . Br J Surg \n1999 ;86 :131–4 .10027376 \n[14] Capdevila O Pallares R Grau I \nPneumococcal peritonitis in adult patients . Arch Intern Med \n2001 ;161 :1742.11485507 \n[15] Rueda AM Serpa JA Matloobi M \nThe spectrum of invasive pneumococcal disease at an adult tertiary care hospital in the early 21st century . Medicine \n2010 ;89 :331–6 .20827110\n\n",
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"issn_linking": "0025-7974",
"issue": "97(28)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D013505:Digestive System Surgical Procedures; D006801:Humans; D008297:Male; D010437:Peptic Ulcer; D010439:Peptic Ulcer Perforation; D010538:Peritonitis; D011008:Pneumococcal Infections; D011027:Pneumoperitoneum; D012772:Shock, Septic; D013296:Streptococcus pneumoniae; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "2985248R",
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"pages": "e11323",
"pmc": null,
"pmid": "29995767",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12925121;20827110;24011662;9709890;11485507;4149584;6723637;26171311;12111607;28484510;2806711;10027376;20431746;17906908;15724004",
"title": "Delayed surgery in a patient with pneumococcal peritonitis and bacteremia secondary to perforation of gastroduodenal ulcer: A case report.",
"title_normalized": "delayed surgery in a patient with pneumococcal peritonitis and bacteremia secondary to perforation of gastroduodenal ulcer a case report"
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"abstract": "Next-generation sequencing (NGS) efforts have established catalogs of mutations relevant to cancer development. However, the clinical utility of this information remains largely unexplored. Here, we present the results of the first eight patients recruited into a clinical whole-genome sequencing (WGS) program in the United Kingdom. We performed PCR-free WGS of fresh frozen tumors and germline DNA at 75× and 30×, respectively, using the HiSeq2500 HTv4. Subtracted tumor VCFs and paired germlines were subjected to comprehensive analysis of coding and noncoding regions, integration of germline with somatically acquired variants, and global mutation signatures and pathway analyses. Results were classified into tiers and presented to a multidisciplinary tumor board. WGS results helped to clarify an uncertain histopathological diagnosis in one case, led to informed or supported prognosis in two cases, leading to de-escalation of therapy in one, and indicated potential treatments in all eight. Overall 26 different tier 1 potentially clinically actionable findings were identified using WGS compared with six SNVs/indels using routine targeted NGS. These initial results demonstrate the potential of WGS to inform future diagnosis, prognosis, and treatment choice in cancer and justify the systematic evaluation of the clinical utility of WGS in larger cohorts of patients with cancer.",
"affiliations": "Oxford Molecular Diagnostics Centre, Department of Oncology, University of Oxford, Oxford OX3 9DU, United Kingdom.;Oxford Molecular Diagnostics Centre, Department of Oncology, University of Oxford, Oxford OX3 9DU, United Kingdom.;Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, United Kingdom.;Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, United Kingdom.;Oxford Molecular Diagnostics Centre, Department of Oncology, University of Oxford, Oxford OX3 9DU, United Kingdom.;Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, United Kingdom.;Oxford Molecular Diagnostics Centre, Department of Oncology, University of Oxford, Oxford OX3 9DU, United Kingdom.;Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom.;Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, United Kingdom.;Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, United Kingdom.;Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, United Kingdom.;Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, United Kingdom.;Breast Unit, Royal Marsden NHS Foundation Trust and Kingston NHS Foundation Trust, London SW3 6JJ, United Kingdom.;Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, United Kingdom.;Breast Unit, Royal Marsden NHS Foundation Trust and Kingston NHS Foundation Trust, London SW3 6JJ, United Kingdom.;Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, United Kingdom.;Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.;University College London, Cancer Institute and Royal National Orthopaedic NHS Hospital, London WC1E 6BT, United Kingdom.;Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford OX3 9DU, United Kingdom.;Department of Ear Nose and Throat-Head and Neck Surgery, Oxford University Hospitals, Oxford OX3 9DU, United Kingdom.;Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom.;Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.;The Children's Cancer Research Institute (CCRI), 1090 Vienna, Austria.;Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.;Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, United Kingdom.",
"authors": "Schuh|Anna|A|0000-0001-5308-8753;Dreau|Helene|H|0000-0002-2532-4162;Knight|Samantha J L|SJL|0000-0002-6047-3462;Ridout|Kate|K|0000-0002-1170-2409;Mizani|Tuba|T|;Vavoulis|Dimitris|D|0000-0002-3984-1507;Colling|Richard|R|0000-0001-6344-9081;Antoniou|Pavlos|P|0000-0001-9074-9610;Kvikstad|Erika M|EM|0000-0002-2730-4472;Pentony|Melissa M|MM|0000-0001-6829-6678;Hamblin|Angela|A|;Protheroe|Andrew|A|0000-0001-9413-0575;Parton|Marina|M|;Shah|Ketan A|KA|0000-0001-6108-4103;Orosz|Zsolt|Z|;Athanasou|Nick|N|;Hassan|Bass|B|;Flanagan|Adrienne M|AM|;Ahmed|Ahmed|A|;Winter|Stuart|S|;Harris|Adrian|A|;Tomlinson|Ian|I|0000-0003-3037-1470;Popitsch|Niko|N|;Church|David|D|;Taylor|Jenny C|JC|",
"chemical_list": "D014408:Biomarkers, Tumor",
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"doi": "10.1101/mcs.a002279",
"fulltext": "\n==== Front\nCold Spring Harb Mol Case StudCold Spring Harb Mol Case StudcshmcscshmcscshmcsCold Spring Harbor Molecular Case Studies2373-2873Cold Spring Harbor Laboratory Press 10.1101/mcs.a002279MCS002279SchResearch ArticleClinically actionable mutation profiles in patients with cancer identified by whole-genome sequencing Clinical WGS in cancerClinical WGS in cancerhttp://orcid.org/0000-0001-5308-8753Schuh Anna 12http://orcid.org/0000-0002-2532-4162Dreau Helene 13http://orcid.org/0000-0002-6047-3462Knight Samantha J.L. 24http://orcid.org/0000-0002-1170-2409Ridout Kate 23Mizani Tuba 12http://orcid.org/0000-0002-3984-1507Vavoulis Dimitris 23http://orcid.org/0000-0001-6344-9081Colling Richard 13http://orcid.org/0000-0001-9074-9610Antoniou Pavlos 5http://orcid.org/0000-0002-2730-4472Kvikstad Erika M. 24http://orcid.org/0000-0001-6829-6678Pentony Melissa M. 24Hamblin Angela 6http://orcid.org/0000-0001-9413-0575Protheroe Andrew 7Parton Marina 8http://orcid.org/0000-0001-6108-4103Shah Ketan A. 9Orosz Zsolt 89Athanasou Nick 10Hassan Bass 11Flanagan Adrienne M. 12Ahmed Ahmed 13Winter Stuart 14Harris Adrian 15http://orcid.org/0000-0003-3037-1470Tomlinson Ian 4Popitsch Niko 16Church David 4Taylor Jenny C. 241 Oxford Molecular Diagnostics Centre, Department of Oncology, University of Oxford, Oxford OX3 9DU, United Kingdom;2 Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, United Kingdom;3 Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9DU, United Kingdom;4 Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom;5 Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom;6 Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, United Kingdom;7 Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, United Kingdom;8 Breast Unit, Royal Marsden NHS Foundation Trust and Kingston NHS Foundation Trust, London SW3 6JJ, United Kingdom;9 Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, United Kingdom;10 Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, United Kingdom;11 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom;12 University College London, Cancer Institute and Royal National Orthopaedic NHS Hospital, London WC1E 6BT, United Kingdom;13 Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford OX3 9DU, United Kingdom;14 Department of Ear Nose and Throat–Head and Neck Surgery, Oxford University Hospitals, Oxford OX3 9DU, United Kingdom;15 Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom;16 The Children's Cancer Research Institute (CCRI), 1090 Vienna, AustriaCorresponding author: jenny.taylor@well.ox.ac.uk4 2018 4 2 a00227930 8 2017 9 2 2018 © 2018 Schuh et al.; Published by Cold Spring Harbor Laboratory Press2018This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.Next-generation sequencing (NGS) efforts have established catalogs of mutations relevant to cancer development. However, the clinical utility of this information remains largely unexplored. Here, we present the results of the first eight patients recruited into a clinical whole-genome sequencing (WGS) program in the United Kingdom. We performed PCR-free WGS of fresh frozen tumors and germline DNA at 75× and 30×, respectively, using the HiSeq2500 HTv4. Subtracted tumor VCFs and paired germlines were subjected to comprehensive analysis of coding and noncoding regions, integration of germline with somatically acquired variants, and global mutation signatures and pathway analyses. Results were classified into tiers and presented to a multidisciplinary tumor board. WGS results helped to clarify an uncertain histopathological diagnosis in one case, led to informed or supported prognosis in two cases, leading to de-escalation of therapy in one, and indicated potential treatments in all eight. Overall 26 different tier 1 potentially clinically actionable findings were identified using WGS compared with six SNVs/indels using routine targeted NGS. These initial results demonstrate the potential of WGS to inform future diagnosis, prognosis, and treatment choice in cancer and justify the systematic evaluation of the clinical utility of WGS in larger cohorts of patients with cancer.\n\ncolon cancercutaneous leiomyosarcomaendometrial carcinomaneoplasm of the breastpharyngeal neoplasmprostate cancerNational Institute for Health Research (NIHR) 10.13039/501100000272Oxford Biomedical Research Centre (BRC)\n==== Body\nINTRODUCTION\nRecent international research programs have provided a comprehensive catalog of the genomic landscape of cancer and provided insights into the temporal and spatial heterogeneity of tumors. These studies used high-throughput next-generation sequencing technology (HTS) to reveal single-nucleotide variants (SNVs) and small indels (Pleasance et al. 2010a,b; Banerji et al. 2012; The Cancer Genome Atlas Network 2012; Curtis et al. 2012; Ellis et al. 2012; Shah et al. 2012; Stephens et al. 2012) in protein-coding regions that comprise <1% of the human genome. The clinical utility and cost-effectiveness of targeted next-generation sequencing (TGS) cancer panel testing to detect somatically acquired single gene mutations is now established in specific disease areas, such as lung and melanoma (Hamblin et al. 2017), and are illustrated by the efficacy of a number of therapeutics targeting the protein products of specific genes that are altered in human cancer. Molecular alterations have also been shown to have predictive and/or prognostic implications (Amado et al. 2008; Parsons et al. 2008).\n\nHowever, the breadth and significance of various mutation types across multiple genes affecting biological pathways relevant to cancer and their potential clinical significance are largely unexplored. Whole-genome sequencing (WGS) can provide a comprehensive assessment of the mutational spectra of cancers across the entire genome. Those that may be of particular clinical relevance can be divided into five broad, evidence-based areas of analysis.\n\nThe first comprises mutations in untranslated, intronic, and intergenic regions. Common inherited variants conferring susceptibility to human disease are found frequently in noncoding regulatory or intronic regions. The possibility that similar mechanisms operate somatically in cancer was highlighted by the discovery of potentially targetable somatic driver substitutions in the TERT gene promoter (Huang et al. 2013; Vinagre et al. 2013; Khurana et al. 2016; Smith et al. 2016) and more recently in NOTCH1 splice region and a PAX5 enhancer (Puente et al. 2015).\n\nThe second area (Lin et al. 2013) addresses complex types of mutations such as copy-number aberrations (CNAs) and translocations that have not been integrated systematically with SNV analyses and linked to clinical outcome or response to therapy such as CN losses and/or SNVs involving the TP53 locus at 17p13.1 in chronic lymphocytic leukemia (Zenz et al. 2010; Dreger et al. 2013; te Raa et al. 2013) and translocations (Manolov and Manolova 1972; Rowley 1973; Dalla-Favera et al. 1982; Larson et al. 1984; Shtivelman et al. 1985; Dreazen et al. 1987; Parker and Zhang 2013).\n\nThe third set of analyses includes the comprehensive investigation of molecular pathways such as DNA damage response (DDR) pathways. All cells rely on multiple DDR pathways specialized in the repair of specific forms of DNA damage. Genes involved in these DDR pathways are among the most frequently mutated genes in cancer. Whereas a defect in a single DDR pathway is compatible with cell viability, a combination of defects in two DDR pathways leads to cell death, a concept known as synthetic lethality. Synthetic lethality can be induced by small-molecule drugs, and exploitation of a tumor's defective DDR pathway has been shown to be an effective therapeutic strategy. For example, synthetic lethality of BRCA1/2 mutations causing defective homologous recombination repair (HRR) is induced by cisplatin or PARP inhibition and has been confirmed in clinical trials (Fong et al. 2009; Fong et al. 2010; Ledermann et al. 2012).\n\nComprehensive analysis of combinations of constitutional and/or somatically acquired base substitution, indels, rearrangements, and CN changes across all genes involved in HRR-based DNA double-strand break repair may yield better predictors of responsiveness to drugs targeting this pathway than BRCA1/2 mutations or promoter methylation alone (Waddell et al. 2015). Constitutional or somatically acquired biallelic mutations in a number of genes associated with DDR have been defined recently and evaluated prospectively in clinical trials (Mateo et al. 2015; Pritchard et al. 2016). In particular, somatic and germline mutations in ATM, ATR, PTEN, PALB2, RAD51C, RAD50, TP53, CHEK2, BRIP1, FANCA, HDAC2, MLH3, ERCC3, MRE11, and NBN have been associated with synthetic lethality after treatment with PARP inhibitors and other emerging potential therapeutics (Riabinska et al. 2013; Dietlein et al. 2014; Mateo et al. 2015; Kristeleit et al. 2016). Furthermore, in addition to HRR and MMR, other DDR key pathways are now being targeted in the clinic (Pritchard et al. 2016; Stover et al. 2016). The fourth area involves investigating global measures such as the absolute mutational burden and mutation signatures. These measures are not routinely investigated in the clinical setting yet but can point to particular subtypes of cancer with defective mismatch repair that are associated with favorable prognosis (Tan et al. 2008; Alexandrov et al. 2013a,b; Maccaroni et al. 2015; Nik-Zainal et al. 2016) and may benefit from immune checkpoint inhibition (Heemskerk et al. 2013; Chabanon et al. 2016). Recent studies have demonstrated a direct relationship between exonic mutational burden, durable sensitivity to PD-1 and CTLA-4 blockade, and overall survival (Santin et al. 2015; McGranahan et al. 2016; Strickland et al. 2016).\n\nThe fifth and final approach includes the systematic analysis of targetable germline variants and integration with somatic variant calling in all patients with cancer rather than limiting analysis to patients with a Mendelian pattern of inheritance and early onset. This avenue is important as (1) most targeted clinical cancer sequencing does not include analysis of the germline and (2) the “first hit” of cancer pathogenesis might be present in the germline and will be subtracted during routine whole-exome sequencing (WES) or WGS tumor bioinformatics analysis, so that biallelic mutations, such as those in DDR pathways described above, will be missed.\n\nAlthough WES can identify many of the mutation types described above, not all known cancer driver genes are captured by this technique and identification of complex rearrangements and copy-number abnormalities, particularly those involving noncoding regions, may not be detected. WGS allows the robust detection of all mutation types including complex somatically acquired changes. Although the feasibility of WGS in the clinical management of cancer patients has been described previously (Laskin et al. 2015), there are currently no published studies evaluating the utility of WGS in the clinical management of cancer patients beyond the detection of clinically actionable single gene variants. The aim of our study was to utilize WGS to comprehensively profile affected molecular pathways and global mutation signatures that would pinpoint clinically actionable events in patients with advanced cancers.\n\nRESULTS\nOverview\nThis study describes the clinically actionable mutations arising from WGS of the first eight consecutive patients recruited to a clinical genome sequencing program in the UK. The clinical characteristics of each case are described in Table 1 and the corresponding histology images are shown in Figure 1.\n\nFigure 1. Histology of each tumor sequenced. Histology images of tumors resected or biopsied from Cases 1–8; sections were obtained from formalin-fixed, paraffin-embedded tissue stained with hematoxylin and eosin (H&E). A–E and H were scanned at ×200, F and G were photographed at ×100 and ×40, respectively. (A) Case 1: Skin biopsy showing infiltration of the dermis (center) by a poorly defined tumor. (Inset) High magnification showing poorly differentiated carcinoma cells. (B) Case 2: Oral biopsy showing normal area of oral mucosa (upper right) with infiltration of the subepithelial tissue by tumor. (Inset) High magnification demonstrating a squamous cell carcinoma morphology with a lack of keratinization. (C) Case 3: Chest wall core biopsy showing skeletal muscle with widespread tumor invasion. (Inset) High magnification showing poorly differentiated carcinoma cells dissecting muscle bundles and infiltrating surrounding tissue. (D) Case 4: Cecal biopsy showing normal columnar epithelium (upper left) and an area of tumor (right). (Inset) High magnification showing poorly differentiated adenocarcinoma. (E) Case 5: Endometrial resection tissue demonstrating a large poloidal mass filling the uterine cavity with showing glandular and papillary areas. Background endometrium below. (Inset) High magnification showing the mixed appearance of the tumor. (F) Case 6: Rib biopsy at low magnification showing partially necrotic bone and cartilage (upper left) and cartilage infiltrated by a high grade tumor (central). (Inset) High magnification demonstrating neuroendocrine (small cell) differentiation. (G) Case 7: Left thigh core biopsy at low magnification showing inflamed and necrotic tissue with islands of poorly differentiated tumor. (Inset, left) High magnification demonstrating the dominant epithelioid appearance of the tumor. (Inset, right) High magnification of a spindle cell component also present. (H) Case 8: Cervical vertebral tumor biopsy at low magnification showing a highly cellular and poorly differentiated tumor. (Inset) High magnification showing the spindle cell morphology.\n\nTable 1. Clinical characteristics of patients referred for whole-genome sequencing\n\nCase\tSex\tAge\tPresentation\tPathological diagnosis\tTNM/Stage\tDistant metastasis site\tSurgical management\tMedical therapy\tResponse to therapy\tTissue for WGS\tTumor content estimates from pathology (bioinformatics)\tStatus January 2017\t\n1\tMale\t67\tThigh lesion\tMetastatic prostate adenocarcinoma\tcT3 cN1 cM1\npTX pNX pM1\tLeft thigh\tNonsurgical management of\tBicalutamide April to Nov 2014 radiotherapy 20 Gy 5 fractions completed Nov 2014, androgen blockade\tNot known\tFF biopsy\t50% (80%)\tDeceased\t\n2\tMale\t57\tNeck mass\tMetastatic (lymph node) squamous cell carcinoma, primary base of tongue non-keratinizing squamous cell carcinoma, oropharyngeal type\tcT4 cN2 cM0\npTX pN X pMX\tNone\tNo surgery\tRadical chemoradiotherapy 65 Gy in 30 fractions completed 05/08/2016. Cisplatin (stopped because of tinnitus). Concomitant cetuximab\tNot known\tFF biopsy\t70% (80%)\tLiving\t\n3\tMale\t42\tChest wall mass, widespread lymphadenopathy and bony disease\tMetastatic carcinoma (breast or sweat gland origin)\tcTX\ncN1(skin)/cN3(breast) pTX pNX pM1\tChest wall\tNo primary identified, skin lesion excised?\tSix cycles ECX-residual disease. Eribulin two cycles with rapid progression. Stable on paclitaxel and bicalutamide. Planned for taselisib (PI3Ka inhibitor) and palbociclib (CDK4/6 inhibitor) if progresses further.\tStable\tFF biopsy\t50% (80%)\tDeceased\t\n4\tFemale\t63\tIliac fossa pain, radiologically confirmed acystadenofibroma of right ovary\tColorectal adenocarcinoma (appendiceal orifice)\tcTX cNX cM1 pT4 pN2 pM1\tOvaries and peritoneum\tRight hemicolectomy, total hysterectomy and bilateral salpingo- oophorectomy\tHyperthermic intraperitoneal chemotherapy, mitomycin C and then oxaliplatin and capecitabine chemotherapy\tNot known\tFF resection\t95% (80%)\tLiving\t\n5\tFemale\t55\tPostmenopausal bleeding\tEndometrial endometrioid carcinoma\tClinically FIGO II, pathologically FIGO IA\tNone\tTotal hysterectomy and bilateral salpingo- oophorectomy\tVaginal brachytherapy\tResponse to adjuvant therapy\tFF resection\t80% (80%)\tLiving\t\n6\tMale\t63\tChest wall lesion\tMetastatic prostate adenocarcinoma (Gleason 4+4 on previous prostate biopsy)\tcT3 cN1 cM1\npTX pNX pM1\tWidespread bony sites\tNo surgery\tHormone therapy, docetaxel, etoposide, and carboplatin 6 cycles\tProgressive disease\tFF biopsy\t50% (95%)\tLiving\t\n7\tMale\t42\tThigh lesion, previous sarcoma of right axilla\tMetastatic sarcoma, undifferentiated\tN/A\tN/A\tN/A\tN/A\tN/A\tFF biopsy\t90% (60%)\tDeceased\t\n8\tMale\t7\tSoft tissue mass with subluxation at C4/C5 vertebrae\tSpindle cell tumor in keeping with a low-grade sarcoma\tN/A\tNone\tNone yet\tAwaiting treatment\tN/A\tFF biopsy\t95% (60%)\tLiving\t\nBaseline characteristics of patients, prior therapy, overall response, final outcome and preanalytical sample characteristics are presented.\n\nTNM, tumor, node, metastasis staging system; FF, fresh frozen; N/A, not applicable.\n\nA summary of the total number of somatic SNVs, CNAs, and SVs and a breakdown of these variants by the tier 1,2,3 classification system for each of the cases (1–8) is shown in Supplemental Table S1. These results show that the total number of somatic mutations per case is very variable, with two cases (Cases 5 and 7) demonstrating a hypermutated genotype as described below.\n\nThe actionable variants and the corresponding clinical implications are described in detail for Cases 1–8 below and summarized in Tables 2 and 3, respectively. It was particularly noticeable that the SNVs and CNAs in DDR genes provided future treatment options for four cases (Fig. 2).\n\nFigure 2. Identification of somatic and germline variants in genes from the DNA damage response (DDR) pathway from Cases 1–8. Graphical representation of the variants identified by WGS in 22 DDR pathway genes in cancer Cases 1–8. A and B show somatic and germline variants, respectively, for each cancer case. Each bar or track on the horizontal axis represents a different cancer case and the 22 individual DDR genes are represented on the vertical axis. CNAs, indels, and SNVs are represented by circles, squares, and diamonds, respectively. The color key indicates more detail about the type of variant (e.g., a red circle represents a homozygous copy-number loss). Only disruptive somatic or germline SNVs and indels are included, whereas for germline variants (B) only SNVs with minor allele frequency of <6% are included. Case 1 includes a somatic missense SNV and a cnLOH region involving TP53, as well as copy-number loss of PTEN and allelic imbalance of BRCA2. Case 2 presents copy-number aberrations overlapping various DDR genes, but no SNVs, indels, or copy-number events involving TP53. Case 3 includes TP53 mutations, an allelic imbalance involving TP53, BRCA1, BRIP1, RAD51C, and RAD51D, and a single loss involving FANCA. In Case 4, WGS detected a germline deleterious SNV in RAD51B, together with a somatic CN loss in the same locus. Case 5 includes somatic mutations in various DDR genes but no copy-number aberrations, whereas RAD54L and ATM in the germline are affected by a region of homozygosity and a missense mutation, respectively. Case 6 has a frameshift mutation and a CN loss involving TP53 and, importantly, a somatic homozygous CN loss encompassing BRCA2. In Case 7, most DDR genes are affected by a somatic CN loss or gain, whereas the germline includes missense mutations in FANCI, RAD54L, RAD51B, and PARP1. Finally, in Case 8, PTEN and BRCA2 are affected by somatic CN losses, and ATM includes a splice site mutation in the germline. See the main text for more details.\n\nTable 2. Summary of clinically actionable variants\n\nCase\tCancer type\tTier\tGene\tMutation type\tVAF (%)\tSomatic/germline mutation\tLocation\tDNA change\tProtein change\t\n1\tProstate\t1\tSETD2\tSNV\t23.33\tS\tChr 3:47129738\tNM 014159.6:c.5143-1 G>A\t\t\nPTEN\tCNA\t–\tS\tChr 10:89590587–90376982\tLoss\tN/A\t\nTP53\tSNV\ncnLOH\t36.89\n–\tS\nS\tChr 17:7577106\nChr 17:0–13533148\tNM_000546.5:c.832C>A\nAllelic Imbalance\tNP_000537.3:p.Pro278Thr\t\n2\tBRCA2\tcnLOH\t–\tS\tChr 13:18351244–115169878\tAllelic imbalance\tN/A\t\n2\tOral\t1\tTP53\tNone\t–\tN/A\tN/A\tN/A\tN/A\t\nEGFR\tNone\t–\tN/A\tN/A\tN/A\tN/A\t\n2\tMultiple\tCNA\t–\tS\tComplex molecular karyotype\tN/A\tN/A\t\nDDX3X\tSNV\t47.06\tS\tChr X:41198295\tNM_001356.3:c.107_108ins GC\tNP_001347.3:\np.Tyr38 AlafsTer 7\t\n3\tBreast/skin\t1\tPIK3CA\tSNV\t14.49\tS\tChr 3:178936091\tNM_006218.2:c.1633G>C\tNP_006209.2:p.Glu545Gln\t\nTP53\tIndel\nIndel\ncnLOH\t22.32\n11.76\n–\tS\nS\nS\tChr 17:7578211\nChr 17:7577085 \nChr 17:1–81195210\tNM_000546.5:c.638G>A\nNM_000546.5:c.853G>A\nAllelic imbalance\tNP_000537.3:p.Arg213Gln\nNP_000537.3:p.Glu285Lys N/A\nN/A\t\n2\tBRCA1\nBRIP1\nRAD51C\nRAD51D\tcnLOH\ncnLOH\ncnLOH\ncnLOH\t–\n–\n–\n–\tS\nS\nS\nS\tChr 17:1–81195210\nChr 17:1–81195210\nChr 17:1–81195210\nChr 17:1–81195210\tAllelic imbalance\nAllelic imbalance\nAllelic imbalance\nAllelic imbalance\tN/A\t\nFANCA\tCNA\t–\tS\tChr 16:46497599–90354753\tLoss\tN/A\t\n4\tColorectal\t1\tARID1A\tSNV\t24.36\tS\tChr 1:27101198\tNM 006015.4:c.4480C>T\tNP_006006.3.3:p.Gln1494Ter\t\nRAD51B\tSNV\nCNA\t28.57\n–\tGL\nS\tChr 14:69061259\nChr 14:68290373–69279891\tNM_133509.3.1:c.1094C>G\nLoss\tNP_598193.2:p.Pro365Arg N/A\nN/A\t\nTP53\tCNA\t–\tS\tChr 17:6934163–8217978\tLoss\tN/A\t\n2\tHDAC2\tCNA\t–\tS\tChr 6:112939290–132327952\tLoss\tN/A\t\nSMAD4\tSNV\t8.20\tS\tChr 18:48604788\tNM 005359.5:c.1610A>G\tNP_005350.1 :p.Asp537Gly\t\nNFE2L2\tSNV\t7.52\tS\tChr 2:178098954\tNM 006164.4:c.91G>A\tNP_6155.2: p.Gly31Arg\t\n5\tEndometrial\t1\tTP53\tNone\t–\tS\tN/A\tN/A\tN/A\t\nPOLE\tSNV\nSNV\t34.07\n37.50\tS\nS\tChr 12:133253184\nChr 12:133252045\tNM_006231.2:c.857C>G\nNM_006231.2:c.1165T>G\tNP_006222.2:p.Pro286Arg\nNP_006222.2:p.Phe389Val\t\nMultiple\tSNV\t–\tS\tTumor Mutation Burden\tHypermutated phenotype\tN/A\t\n6\tProstate\t1\tPTEN\tCNA\t–\tS\tChr 10:85557432–105804295\tLoss\tN/A\t\nCDKN2A\tCNA\t–\tS\tChr 9:10320113–26205565\tLoss\tN/A\t\nTP53\tSNV\nCNA\t58.82\n–\tS\nS\tChr 17:7573975\nChr 17:7506837–7671804\tNM_000546.5:c.1044_1051\ndelGGAACTCA\tNP_000537.3: p.Glu349GlyfsTer30\nN/A\t\nBRCA2\tCNA\t–\tS\tChr 13:32178877–33860144\tLoss (homozygous)\tN/A\t\n2\tFANCA\tCNA\t–\tS\tChr 16:46455960–90354753\tLoss\tN/A\t\nERCC3\tCNA\t–\tS\tChr 2:104172062–168223828\tLoss\tN/A\t\n7\tSarcoma\t1\tNRAS\tSNV\t96.49\tS\tChr 1:115256530\tNM 002524.4:c.181 C>A\tNP_002515.1:p.Gln61Lys\t\nCDKN2A\tCNA\t–\tS\tChr 9:21879074–22096083\tLoss (homozygous)\tN/A\t\nPTEN\tCNA\t–\tS\tChr 10:42347406–135534747\tLoss\tN/A\t\nMultiple\tSNV\t–\tS\tTumor Mutation Burden\tHypermutated phenotype\tN/A\t\nNF1\tCNA\t–\tS\tChr 17:25248166–30645676\tLoss\tN/A\t\n2\tMultiple\tCNA\t–\tS\tComplex molecular karyotype\tN/A\tN/A\t\n8\tSoft Tissue\t1\tCDKN2A\tCNA\t–\tS\tChr 9:21939408–22706613\tLoss (homozygous)\tN/A\t\nPTEN\tCNA\t–\tS\tChr 10:1–135534747\tLoss\tN/A\t\nTSC1\tCNA\t–\tS\tChr 9:135377559–141213431\tLoss\tN/A\t\n2\tBRCA2\tCNA\t–\tS\tChr 13:24080918–3436,992\tLoss\tN/A\t\nDetails of the tier 1 and tier 2 clinically actionable variants identified in Cases 1–8 are presented. The term allelic imbalance was ascribed when the BAF plots clearly revealed an acquired event, but interpretation of the Log2R plot was challenging (e.g., cnLOH vs. CN Loss). Such events were classified as “not clinically actionable.” For cases with a hypermutated genotype (Cases 5 and 7) only clearly actionable SNVs were included.\n\nSNV, small-nucleotide variant; indel, insertion/deletion; CNA, copy-number aberration; cnLOH, copy neutral loss of heterozygosity; SV, structural variant; S, somatic; GL, germline.\n\nTable 3. Clinical significance of actionable variants\n\nCase\tCancer type\tTier\tGene\tMutation Type\tSomatic/germline mutation\tPathway\tClinical significance of mutation\tPotential clinical trials\tMDT decision/Impact on clinical management\t\n1\tProstate\t1\tSETD2\tSNV\tS\tChromatin remodelling\tTherapy (WEE inhibitors)\tNCT01748825 (solid tumors)\nNCT02341456 (solid tumors)\nNCT02585973 (head and neck cancer)\tPatient died before WGS completed, but PARP/WEE inhibitors may have been an option.\t\nPTEN\tCNA\tS\tPTEN-AKT1- mTOR pathway\tPoor prognosis, therapy (mTOR, PARP inhibitors)\tNCT02145559 (solid tumors)\nNCT02465060 (NCI match)\t\nTP53\tSNV\ncnLOH\tS\nS\tDDR\nDDR\tPoor prognosis, therapy (PARP inhibitors)\tNCT02098343 (ovarian cancer)\t\n2\tBRCA2\tcnLOH\tS\tDDR\tTherapy (PARP inhibitors)\tNCT03040791\n(DDR-impaired prostate cancer) NCT03012321 (DDR-impaired prostate cancer)\t\n2\tOral\t1\tTP53\tNone\tN/A\tN/A\tTherapy\tN/A\tHPV +ve indicative of good prognosis. Standard of care was applied. Lack of DDR signature (please see text) and EGFR mutations supported cessation of cisplatin and commencement of cetuximab, respectively.\t\nEGFR\tNone\tN/A\tN/A\t\t\t\nMultiple\tCNA\tS\tMultiple\tPathological classification\tN/A\t\n2\tDDX3X\tSNV\tS\tRNA metabolism\tPathological classification, therapy (histone mthylation)\tN/A\t\n3\tBreast/Skin\t1\tPIK3CA\tSNV\tS\tPIK3CA signaling\tTherapy (PI3K inhibitors)\tNCT02389842 (breast and solid tumors)\nNCT01226316 (breast and solid tumors)\nNCT02437318 (breast cancer)\nNCT02423603 (breast cancer)\nNCT01872260 (breast cancer)\nNCT02088684 (breast cancer)\nNCT02465060 (NCI match)\tStandard of care was applied. Treatment with PI3K or PARP inhibitors proposed in event of disease progression. Patient died rapidly because of disease progression before such therapies initiated.\t\nTP53\tSNV\nSNV\ncnLOH\tS\nS\nS\tDDR\nDDR\nDDR\tPoor prognosis, therapy (PARP inhibitors)\tNCT02098343 (ovarian cancer)\nNCT01074970 (breast cancer)\t\n2\tBRCA1\nBRIP1\nRAD51C\nRAD51D\tcnLOH\ncnLOH\ncnLOH\ncnLOH\tS\nS\nS\nS\tDDR\nDDR\nDDR\nDDR\tTherapy (PARP inhibitors)\t\t\nFANCA\tCNA\tS\tDDR\tTherapy (PARP inhibitors)\tNCT03012321 (Prostate cancer)\t\n4\tColorectal\t1\tARID1A\tSNV\tS\tChromatin remodelling\tTherapy (Dasatinib; AKT inhibitor; EZH2 inhibitor)\tNCT02059265 (Ovarian cancer)\nNCT02576444 (solid tumors)\tStandard of care was applied. Excellent response to platinum therapy. PARP inhibition considered as an option at relapse.\t\nRAD51B\tSNV\nCNA\tGL\nS\tDDR\nDDR\tTherapy (PARP inhibitors)\tNCT02484404 (solid tumors)\nNCT00576654 (solid tumors)\nNCT02921256 (rectal cancer)\t\nTP53\tCNA\tS\tDDR\tPoor prognosis, therapy (PARP inhibitors)\tNCT02098343 (ovarian cancer)\t\n2\tHDAC2\tCNA\tS\tDDR\tTherapy (PARP inhibitors)\tNCT03012321 (prostate cancer)\t\nSMAD4\tSNV\tS\tTGF-β signaling\tBiological mechanism\tN/A\t\nNFE2L2\tSNV\tS\tAntioxidant metabolism\tBiological mechanism\tN/A\t\n5\tEndometrial\t1\tTP53\tNone\tS\tDDR\tPathological classification\tN/A\tResults from WGS clarified histopathological classification, confirming an endometrioid rather than serous tumor type with good prognosis. Patient declined chemotherapy on basis of confirmatory prognostic information from WGS. Option of checkpoint inhibitors in event of disease progression.\t\nPOLE\tSNV\tS\tPolymerase proofreading\nPolymerase proofreading\tTherapy (anti-PDL1)\tNCT02912572 (endometrial cancer)\t\nMultiple\tSNV\tS\tMultiple\tTherapy (anti-PDL1)\tNCT02912572 (endometrial cancer)\t\n6\tProstate\t1\tPTEN\tCNA\tS\tPTEN-AKT1- mTOR pathway\tPoor prognosis, therapy (mTOR inhibitors)\tNCT02145559 (solid tumors) NCT02465060 (NCI Match)\tCommenced treatment with PARP inhibitor rucaparib 24 months ago following results from WGS. Still alive. Clinical trial of anti-PD1 inhibitor might also be considered.\t\nCDKN2A\tCNA\tS\tCell cycle regulator of P53\tTherapy (Aurora /VEGF inhibitors)\tNCT02478320 (solid tumors)\t\nTP53\tSNV\nCNA\tS\nS\tDDR\nDDR\tPoor prognosis, therapy (PARP inhibitors)\tNCT03040791\n(DDR-impaired prostate cancer) NCT03012321 (DDR-impaired prostate cancer)\t\nBRCA2\tCNA\tS\tDDR\tTherapy (PARP inhibitors)\tNCT03040791\n(DDR-impaired prostate cancer) NCT03012321 (DDR-impaired prostate cancer)\t\n2\tFANCA\tCNA\tS\tDDR\tTherapy (PARP inhibitors)\tNCT03040791\n(DDR-impaired prostate cancer) NCT03012321 (DDR-impaired prostate cancer)\t\nERCC3\tCNA\tS\tDDR\tTherapy (PARP inhibitors)\tNCT03040791\n(DDR-impaired prostate cancer) NCT03012321 (DDR-impaired prostate cancer)\t\n7\tSarcoma\t1\tNRAS\tSNV\tS\tRAS pathway\tTherapy\t(Solid tumors and myeloma)\nNCT01449058\n(Solid tumors and hematology)\nNCT01763164 (melanoma)\nNCT02465060\n(NCI match)\tPatient died before WGS completed. Px had shown lack of reponse to anti-NCT02407509 EGFR antibody therapy MEK inhibitors.\t\nCDKN2A\tCNA\tS\tCell cycle regulator of P53\tTherapy (Aurora/VEGF inhibitors\tNCT02478320 (solid tumors)\t\nPTEN\tCNA\tS\tPTEN-AKT1- mTOR pathway\tTherapy (mTOR inhibitors)\tNCT02145559 (solid tumors)\nNCT02465060 (NCI match)\t\nMultiple\tSNV\tS\tMultiple\tTherapy (anti-PDL1)\tNCT02912572 (endometrial cancer)\t\nNF1\tCNA\tS\tRAS pathway\tTherapy (MEK inhibitor)\tNCT02465060 (NCI match)\t\n2\tMultiple\tCNA\tS\tMultiple\tPoor prognosis\tN/A\t\n8\tSoft tissue\t1\tCDKN2A\tCNA\tS\tCell cycle regulator of P53\tTherapy (Aurora/VEGF inhibitors)\tNCT02478320 (solid tumors)\tMDT recommendation of mTOR inhibition declined by clinician. Patient being prepared for surgical resection on disease progression.\t\nPTEN\tCNA\tS\tPTEN-AKT1- mTOR pathway\tTherapy (mTOR inhibitors)\tNCT02145559\t\nTSC1\tCNA\tS\tPTEN-AKT1- mTOR pathway\tTherapy (mTOR inhibitors PARP inhibitors)\tNCT02201212 (solid tumors)\nNCT02352844 (solid tumors)\nNCT02576444 (solid tumors)\t\n2\tBRCA2\tCNA\tS\tDDR\tTherapy (PARP inhibitors)\tNCT02465060 (NCI match)\t\nThe potential clinical implications of the tier 1 and tier 2 variants described in Table 2 are shown, including impact of the variant on diagnosis, prognosis, potential treatment, or clinical trials for which the patient might be eligible. Specifically, for defects in the DDR pathway, only inferred homozygous mutations were classified as clinically actionable (highlighted by shaded background).\n\nSNV, single-nucleotide variant; CAN, copy number aberration; cnLOH, copy neutral loss of heterozygosity; SV, structural variant; DDR, DNA damage response; S, somatic; GL, germline.\n\nAs expected, the mutation burden was found to be higher in introns than in exons (Supplemental Fig. 1). The somatic mutations derived from the WGS data allowed mutational signatures to be classified (Supplemental Table S2; Alexandrov et al. 2013a) and helped to identify the mutational processes operative in each patient (Fig. 3).\n\nFigure 3. The proportion of mutation signatures in Cases 1–8. Mutation signatures were obtained from the COSMIC mutation signatures consensus database (http://cancer.sanger.ac.uk/COSMIC /signatures), which were derived using published methods developed by Alexandrov et al. (2013a). Signatures represent genomic SNV distribution in a trinucleotide context. The contributions of each COSMIC signature found in the data were calculated using the deconstructSigs package (Rosenthal et al. 2016) in R. Stacked bars represent the proportion of each mutation signature found in each case across the whole genome, where all signatures found per case sum to 1. Mutation signature 1 is the most ubiquitous and represents aging. Signature 2: AID/APOBEC association. Signature 3: BRC1/2-associated and DNA double-strand break repair defect. Signature 4: smoking. Signature 5: unknown etiology. Signature 6: DNA mismatch repair defect. Signature 7: UV exposure. Signature 8: unknown. Signature 9: polymerase-associated mutation pattern. Signature 10: associated with altered POLE activity. Signature 11: alkylating agents. Signature 12: unknown. Signature 13: AID/APOBEC association. Signature 14: unknown. Signature 15: DNA mismatch repair defect. Signatures 16, 17, 18, 19: unknown. Signature 20: DNA mismatch repair defect. Signature 21: unknown. Signature 22: exposure to aristolochic acid. Signature 23. Unknown. Signature 24: exposure to aflatoxin. Signature 25: unknown. Signature 26: DNA mismatch repair defect. Signature 27,28: unknown. Signature 29: tobacco chewing. Signature 30: unknown. More details of signatures are described in Supplemental Table S2.\n\nThe majority of clinically actionable variants were somatic. Targeted in silico germline analysis of a predefined list of cancer predisposition genes (Supplemental Table S3) led to identification of multiple germline variants of uncertain significance (data not shown). One germline variant in RAD51B (Case 4) contributed to a homozygous impairment of a DDR locus and was therefore considered clinically actionable.\n\nOne anticipated advantage of using WGS is the ability to identify a spectrum of variants affecting noncoding regions. We used ENCODE databases (Supplemental Table S4) to annotate variants in regulatory regions (Supplemental Table S5), although none was considered to be clinically actionable on the basis of current knowledge.\n\nThe results for each patient are described in more detail below.\n\nCASE 1 (Prostate Cancer)\nA 67-yr-old man with a known history of prostate cancer was referred with an unusual cutaneous tumor of the left thigh (Table 1). The histology of this lesion showed a dermal infiltrate of poorly differentiated carcinoma cells (Fig. 1A) that demonstrated polyclonal prostate-specific antigen (PSA) and prostate-specific acid phosphatase (PSAP) expression by immunohistochemistry (IHC). CDX2, cytokeratin (CK) 7, and CK20 markers were negative. These findings were consistent with a prostatic origin.\n\nThe metastatic skin lesion was incompletely excised and the patient received bicalutamide from April to November 2014 combined with radiotherapy of 20 Gy in five fractions. Conventional androgen blockade commenced in January 2015. He received docetaxel chemotherapy from June to November 2015 and enzalutamide from January to February 2016.\n\nTGS of DNA derived from the metastasis showed a variant in TP53 (c.832C>A, p.Pro278Thr), indicative of poor prognosis. WGS of paired tumor and germline DNA confirmed the somatic tier 1 SNV in TP53 and additionally revealed a cnLOH region of Chromosome 17 (17p13.3-p12) involving TP53, as well as copy-number loss of PTEN and allelic imbalance of BRCA2 (Table 2; Fig. 2), all genes involved in the DDR. These events presented with allelic imbalance, which was most likely explained by germline contamination as the tumor content for biopsied tissue was estimated as 50% (Table 2; Supplemental Fig. S2). Mutation signature 5 associated with all cancer types (Alexandrov et al. 2013a) was the dominant signature from WGS data (Fig. 3). WGS also showed a SETD2 (tier 1) variant (c.5143-1G>A) (Table 2). Unfortunately, the patient died of progressive disease before the results of WGS were available.\n\nCASE 2 (Head and Neck Cancer)\nA 57-yr-old man presented with a large, left-sided base of tongue tumor and lymphadenopathy (Table 1). Biopsy from the oropharyngeal lesion revealed a nonkeratinizing squamous cell carcinoma (Fig. 1B). The tumor demonstrated positive staining with p16 IHC tests, in keeping with human papilloma virus (HPV) etiology and associated with a good prognosis for oropharyngeal cancer (Langendijk and Psyrri 2010).\n\nSNV and CNA analyses of WGS data did not show any somatically acquired clinically actionable mutations (Table 2). The genome exhibited a complex karyotype, a mutation in DDX3X, and absence of TP53 mutations, all in keeping with HPV-positive squamous cell carcinoma (Seiwert et al. 2015). We confirmed the presence of HPV-derived sequences in the whole-genome data and identified the viral subtype (Table 3; Supplemental Materials and Methods). Presence of mutation signature 2 is consistent with the viral etiology of the tumor (Fig. 3).\n\nThe patient started radical chemoradiotherapy at 65 Gy in 30 fractions in August 2016. Following one cycle of cisplatin, he developed intractable tinnitus. Cisplatin was stopped, a decision supported by the absence of a DDR mutation signature and good prognosis features, and the patient was started on concomitant cetuximab (Table 3). Reassuringly, WGS confirmed that there were no EGFR resistance mutations to this drug. Positron-emission and computed tomography (PET-CT) imaging at 3 mo indicated no residual disease.\n\nIn this case, WGS did not demonstrate any actionable mutations. However, it confirmed the presence of HPV, which, combined with absence of TP53 mutations, indicated a good prognosis for this patient. The absence of biallelic mutations in DDR genes or in the known cancer predisposition gene EGFR assisted in managing drug side effects and in confirming the choice of an alternative targeted therapy (Iida et al. 2014; Tajima and Koda 2015).\n\nCASE 3 (Breast Cancer and Melanoma)\nA 42-yr-old man with a previous history of malignant melanoma presented with a left chest wall mass and widespread lymphadenopathy (Table 1). Combined PET-CT scanning revealed disseminated disease with bony involvement. Biopsies from the chest wall lesion and overlying skin revealed a malignant tumor with an epithelioid morphology infiltrating into skeletal muscle. A bone marrow trephine biopsy (Fig. 1C) also revealed marrow space involvement. The tumor cells were immune-reactive for nonspecific epithelial markers (CAM 5.2, AE1/AE3) as well as CK7, CK19, GATA3, and GCDFP, suggesting a breast origin. The tumor did not express CK20 or CDX2 (colorectal), PSA, RCC (renal), TTF1 (lung), or melanoma markers. The suspicion was that it was of breast origin but ductal carcinoma in situ (DCIS) could not be identified in the chest wall biopsies, and a sweat gland tumor could not be excluded. Estrogen receptor (ER), progesterone receptor (PR), and Her-2/neu (ErbB-2) hormone markers were also negative by IHC tests. Based on these findings, the differential diagnosis was either a triple-negative breast (ductal) carcinoma or a malignant skin adnexal tumor. The patient commenced treatment with a standard carcinoma of unknown primary (CUP) schedule with six cycles of ECX (epirubicin, cisplatin, capecitabine/Xeloda) and showed a good clinical and radiological response. However, 3 mo later, when there was evidence of progressive chest wall disease, the patient entered a Phase II clinical trial of immunotherapy against standard of care chemotherapy. He was randomized to the control arm and received eribulin, a potent mitotic inhibitor. His disease rapidly progressed, leading to a switch to paclitaxel and bicalutamide because of strong androgen receptor expression identified by IHC tests. He achieved a complete clinical and radiological remission in the known sites of disease within 3 mo.\n\nBecause TGS and WGS showed an activating PIK3CA mutation (c.1633C>G, p.Glu545Gln), the proposed management was to proceed with the PIK3CA inhibitors, taselisib or pictilisib, at disease progression (Turner et al. 2015). In addition, WGS revealed two different acquired pathogenic TP53 mutations and an allelic imbalance reflecting either a CN loss or cnLOH involving TP53, BRCA1, BRIP1, RAD51C, and RAD51D (Fig. 2A) and a single loss of FANCA indicating PARP inhibition as a potential therapeutic avenue. Consistent with this, we identified mutation signature 3 (Fig. 3).\n\nSimilar to Case 1, this case illustrates that WGS can reveal all types of mutations in the DDR pathway. The dominant mutation signatures in this patient were signatures 16 (unknown significance), 2, and 13, whereas the DDR signature was also present. A germline deletion polymorphism involving APOBEC3A and APOBEC3B on Chromosome 22 is associated with the presence of large numbers of signature 2 and 13 mutations and with predisposition to breast cancer (Nik-Zainal et al. 2014), but this patient did not carry the germline polymorphism.\n\nCASE 4 (Colorectal Cancer)\nA 64-yr-old woman who presented with abdominal pain underwent excision of a radiologically nonsuspicious simple cyst of the right ovary (Table 1). At operation both ovaries were found to be infiltrated by solid tumor, there was a dilated right fallopian tube, and numerous widespread peritoneal deposits were observed. A bilateral salpingo-oophorectomy (BSO) was performed and the peritoneal lesions were biopsied. Histology of the ovaries and peritoneal lesions revealed a poorly differentiated carcinoma with areas of glandular and signet ring cell morphology, as well as focal neuroendocrine differentiation. The right fallopian tube was infiltrated by malignant cells and contained foci of endometriosis. The tumor cells were immune-reactive for carcinoembryonic antigen (CEA), CDX2, CK20, CK8/18, and CA19.9 IHC tests, suggesting a colorectal origin, and tested negative for markers of gynecological, breast, or other common tumors of epithelial origin (CK7, CA125, inhibin, p16, p53, WT1, PAX8, GCDPF, ER, and PR). Cytology of peritoneal washings also showed a malignant population of epithelial cells. The findings were consistent with a metastatic carcinoma of gastrointestinal (GI) origin. Endoscopic examination of the lower GI tract was carried out and revealed a tumor in the cecum at the appendiceal orifice. Biopsies from this area (Fig. 1D) revealed similar histological findings with tumor appearing to arise from overlying dysplastic mucosa. The overall findings were consistent with metastatic adenocarcinoma of colorectal origin. The patient underwent right hemicolectomy and hysterectomy. The surgery left her free of visible disease and she then opted for oxaliplatin-based adjuvant chemotherapy.\n\nTGS did not reveal any clinically actionable mutations. WGS identified a tier 1 germline deleterious SNV in RAD51B together with an acquired CN loss of this locus that could be regarded as a second hit and is consistent with impairment of the DDR signaling pathway function (Fig. 2A,B). Supporting these findings, mutation signature 3 was clearly present in this tumor (Fig. 3). Furthermore, WGS showed a tier 1 nonsense mutation in ARID1A (c.4480C>T, p.Gln1494Ter). A recent study demonstrated synthetic lethality by targeting EZH2 histone methyltransferase activity in ARID1A-mutated tumors using a clinically applicable small molecule inhibitor (Bitler et al. 2015a), and a clinical trial for patients with mutations in ARID1A is now recruiting and others are planned (Bitler et al. 2015b) for which the patient could be eligible.\n\nWGS also revealed tier 2 mutations in HDAC2, NFE2L2, and SMAD4 that are likely to have biological and prognostic significance (Table 2) but are not clinically actionable.\n\nImportantly, this case illustrates impairment of the DDR pathway because of a combination of a germline deleterious SNV with a second acquired hit affecting RAD51B. The patient may benefit from PARP-1 inhibition should she relapse after standard care. WGS, but not TGS, also revealed a tier 1 defect in the key chromatin-remodeling gene ARID1A, supporting eligibility to potentially efficacious therapy as part of a clinical trial.\n\nCASE 5 (Endometrial Cancer)\nA 55-yr-old woman presented with postmenopausal bleeding (Table 1). Ultrasound imaging of the pelvis revealed a uterine mass. Histolopathological review of the biopsy suggested a grade 3 mixed endometrioid/serous endometrial carcinoma. Total laparoscopic hysterectomy and bilateral salphingo-ophorectomy demonstrated a polypoidal tumor in the uterine cavity arising from the endometrium and extending to the lower segment. The results of histopathological analysis of the resected specimen (Fig. 1E) were similar to that of the biopsy. IHC tests were difficult to interpret; ER, PAX8, and vimentin showed positivity in some areas of the tumor (in keeping with endometrioid carcinoma) but occasional foci showed strong diffuse p16 staining (usually seen in serous carcinoma). PR (endometrioid) and WT1 (serous) markers were negative. The pattern of expression was therefore mixed (Kaspar and Crum 2015). This diagnostic uncertainty was highly clinically relevant, as uterine serous carcinoma is an aggressive tumor that is typically managed with intensive adjuvant therapy, whereas endometrioid histologies are associated with a more benign course. As uterine serous carcinoma is frequently associated with the presence of TP53 mutations, molecular testing was performed to identify these and other variants useful in guiding management (SGO Clinical Practice Endometrial Cancer Working Group et al. 2014a,b). Interestingly, although neither TGS nor WGS detected any TP53 mutation, WGS demonstrated a pathogenic mutation in the exonuclease domain of the replicative DNA polymerase POLE (c.857C>G, p.Pro286Arg) (Table 2), along with the characteristic ultramutated phenotype (Supplemental Fig. S1) and dominant mutational signature 10 this causes (Fig. 3; Prindle et al. 2010; Church et al. 2014; van Gool et al. 2015). Although unexpected, this result was not entirely surprising, as POLE mutations are often associated with high tumor grade and difficulty in pathological classification (Hussein et al. 2015; van Gool et al. 2018). Despite this association, endometrial cancers carrying POLE exonuclease domain mutations are recognized to have an excellent prognosis, possibly because they are more immunogenic than other cancers (Van Gool et al. 2015). In light of the molecular data, the initial pathological impression of an aggressive serous carcinoma was revised to a much more favorable prognosis (Tashiro et al. 1997; Bansal et al. 2009; Yemelyanova et al. 2011; Church et al. 2014; Stelloo et al. 2015). The patient elected to have post-operative brachytherapy only, and did not receive the adjuvant chemotherapy and external beam radiotherapy that is the standard of care for uterine serous carcinoma. This case illustrates that WGS results can assist with clinically relevant pathological differential diagnosis and can support de-escalation of therapy in line with the patient's choice (Table 3). Moreover, in the event of disease progression, POLE mutations may predict sensitivity to nivolumab or pebrolizumab (Santin et al. 2016).\n\nCASE 6 (Prostate Cancer)\nA 63-yr-old man presented with a PSA of 2900 µg/ml and was found to have a Gleeson 4+4 prostatic adenocarcinoma on biopsy (Table 1). Clinical imaging revealed pulmonary and bony metastases. Despite androgen deprivation treatment, the patient progressed and there was no response to docetaxel or radiotherapy. A biopsy from a rib metastasis at this time showed neuroendocrine differentiation (Fig. 1F), and it was concluded that a small-cell carcinoma component had developed following treatment (Miyoshi et al. 2001; Lipianskaya et al. 2014; Nadal et al. 2014).\n\nTGS performed on DNA obtained from the rib metastasis showed a pathogenic mutation in TP53. WGS confirmed the mutation and also showed a CN loss involving TP53 and, importantly, an acquired homozygous CN loss encompassing BRCA2 (Table 2; Fig. 2A). The patient had a dramatic clinical, radiological, and biochemical response following platinum-based chemotherapy (etoposide and carboplatin). At biochemical relapse, he obtained compassionate access to the PARP inhibitor rucaparib on the basis of the results from WGS showing a DDR pathway defect supported by the presence of mutation signature 3 (Fig. 3). He is alive 2 years following diagnosis of metastatic disease. WGS also showed loss of PTEN and CDKN2A. These offer further options for future therapeutic intervention with mTOR inhibitors and Aurora/VEGF inhibitors, respectively.\n\nThis case illustrates that WGS can reveal acquired alterations in DDR genes, including homozygous deletions and deleterious SNVs, leading to therapeutic intervention.\n\nCASE 7 (Sarcoma)\nA 42-yr-old man presented with a soft tissue mass in the right axilla, and a biopsy of this showed a high-grade malignant tumor with a mostly epithelioid appearance (Fig. 1G) and extensive necrosis (Table 1). The initial diagnosis made by the referring center was that of a cancer of unknown primary, but the possibility of a dedifferentiated metastatic malignant melanoma or sarcoma was raised at the time. The patient commenced conventional chemotherapy. Following transfer of care to a specialist orthopedic center, histology review noted focal spindle cell areas and suggested a mesenchymal tumor origin. The tumor was immune-reactive for S100 (nerve sheath marker) and INI1, focally positive for desmin and myogenin, and in some areas around necrotic foci, HIF1-α-positive (seen in neurofibromatosis 1). The tumor cells did not express CD45 (hematological), Melan A or HMB45 (differentiated melanoma markers), CD117 (GIST, dermatofibroma, angiosarcoma, Ewing's sarcoma), or phosphor-MET. FISH for the SS18 fusion gene (synovial sarcoma) was negative. The overall histopathological findings were most consistent with a malignant peripheral nerve sheath tumor (MPNST), showing rhabdomyosarcomatous differentiation (Triton tumor) as shown by desmin and myogenin immunopositivity. The absence of expression of H3K27me3 was also supportive of a histological diagnosis of MPNST (Lee et al. 2014; Prieto-Granada et al. 2016). An epithelioid MPNST was considered but thought to be unlikely because of INI1 IHC positivity. Furthermore, no CNA or cnLOH regions involving SMARCB1 were identified for this patient and no other inactivating mutations.\n\nShortly after initial presentation the patient developed metastatic disease in the left thigh. A biopsy showed similar histological findings and was subjected to WGS. TGS and WGS revealed a tier 1 mutation in NRAS (c.181C>A, p.Gln61Lys), which indicates lack of response to anti-EGFR antibody therapy or BRAF inhibition and points to MEK-inhibitor therapy. Similar to Case 5, WGS revealed a high number of SNVs/indels consistent with a hypermutator genotype (Supplemental Fig. S1); therefore, SNV analysis presented is limited to Tier 1 findings only.\n\nNo translocation events typical of sarcoma were identified. However, WGS showed a complex karyotype including an acquired homozygous CN loss of CDKN2A (Aurora/VEGF inhibitors), loss of PTEN (mTOR inhibitors), and a somatically acquired loss of NF1, again indicating potential response to MEK inhibition. CDKN2A loss is a common event in cancer, and there is preclinical evidence for efficacy of CDK4/6 inhibitors in tumors with CDKN2A loss (Gao et al. 2015; Elvin et al. 2017). Interestingly, in a phase 1 trial of abemaciclib, a selective CDK4 and 6 inhibitor, a patient with metastatic melanoma achieved a PR carrying similar molecular alterations (NRAS mutation and copy-number loss at the INK4 locus) to Case 7 (Patnaik et al. 2016).\n\nSurprisingly, the mutation signature strongly implied UV-light exposure (Fig. 3) as the underlying mutagenic mechanism, raising the possibility that the original suspected diagnosis of a dedifferentiated malignant melanoma was correct.\n\nWGS of the germline of this patient revealed no mutation in NF1. Genes related to PRC2 components were also investigated. For SUZ12, Case 7 showed an acquired CN loss (Chr 17:25,248,166–30,645,676) and for both EZH1 and EZH2, acquired subclonal CN losses were observed (Chr 7:98,693,981–159,138,663 and Chr 17:30,645,677–81,195,210, respectively). No CNAs or cnLOH events involving EED were identified. This made MPNST unlikely and highlights that the absence of H3K27me3 expression is not specific for this tumor type.\n\nShortly after submission of the sample for WGS, the patient developed widespread metastases and died. This case illustrates that even with extensive profiling, it is not always possible to provide a definite diagnosis.\n\nCASE 8 (Soft Tissue Tumor)\nA 7-yr-old boy presented with neck pain due to a soft tissue mass causing subluxation at the C4/C5 vertebral level. Histology of the mass (Fig. 1H) showed a cellular spindle cell lesion with focal nuclear atypia (Table 1). The tumor cells were immune-reactive for smooth muscle actin, but other soft tissue markers were negative. The proliferation index by Ki67 was 5%, indicative of a low-grade lesion. FISH showed no evidence of common translocation events including SS18, EWSR1, and MDM2, and there was no amplification by real-time PCR for the sarcoma-associated fusion genes ETV6-NTRK3 and SS18-SSX1/2/4. Taken together, these findings were not sufficient for a definitive diagnosis. The differential diagnosis included infantile myofibroma, myofibrosarcoma, and a low-grade spindle cell sarcoma. At the time of sequencing, histology and initial results of molecular genetic tests, taken together with imaging and clinical context, were consistent with a low-grade sarcoma, not otherwise specified (NOS). WGS analysis did not reveal any sarcoma-associated translocations. There were no clearly pathogenic SNVs, and the mutational burden of the tumor was low (Supplemental Fig. 1). There was an acquired homozygous loss of CDKN2A and heterozygous acquired losses of PTEN, TSC1, and BRCA2 (Table 2). The Cancer Genomics MDT recommended mTOR inhibition with temsirolimus, PARP inhibition, or aurora/VEGF inhibitors as potential treatment options as there was no standard of care for this patient.\n\nThe patient was subsequently offered conventional empirical chemotherapy at the local center (doxorubicin, ifosfamide, etoposide) followed by surgical resection when imaging postchemotherapy showed marked tumor progression despite concerns regarding positive resection margins and associated morbidity and risks. This case highlights the reluctance to use information from WGS for clinical decision-making even in a palliative setting and in situations where there is no standard of care.\n\nWGS versus In Silico WES: Clinical Implications\nIn summary, WGS led to identification of clinically actionable SNVs and CNAs for each case. Although exome sequencing can theoretically identify many of these changes, there are limitations to this approach. To explore whether the same results could have been obtained from WES, we applied an in silico filter to our WGS data using the SureSelect target regions and compared results obtained by the two different methods.\n\nAll clinically actionable SNVs detected by WGS in the eight patients were also detected when applying the in silico SureSelect filter on our data. However, for seven of the genes with actionable mutations in our cohort, 14 exons were not covered (Supplemental Table S6). Moreover, the SureSelect panel did not include 152 genes listed in the COSMIC Cancer Driver Gene List (Supplemental Table S7), and a further 2038 exons from remaining COSMIC genes are also not included in the panel (Supplemental Table S8). Furthermore, it is now well established that WES results will depend on the efficacy of capture and may miss up to 20% of targets. Unfortunately, it is not possible to predict which exonic regions these might be and therefore we could not simulate this in our analysis (Bamshad et al. 2011; Wang et al. 2017). For WGS of each cancer case, the average coverage across the entire genome is shown in Supplemental Table S9 and the percentage of COSMIC genes covered at ×75, averaged over the eight cancer cases in Supplemental Table S10.\n\nFor CNA and cnLOH events, we did not identify any differences that would affect the clinically actionable findings for the patients presented. However, we did identify events affecting noncoding regions that demonstrate the potential advantages of WGS over WES. These included (a) intergenic and intronic copy-number losses, (b) intergenic and intronic break-points, and (c) altered levels of allelic imbalance that would have been missed by WES (Supplemental Fig. S3).\n\nFor mutation analysis, we compared trinucleotide counts in our data to signatures from the COSMIC database (Supplemental Tables 11, 12 for WGS and WES, respectively). These signatures are based on whole-genome studies and are applicable to biological processes that affect the whole genome such as UV damage and smoking. Thus, the whole-genome data are more reflective of the true mutation signatures because we have more mutations and, therefore, more data to consider. We performed the signature analysis on regions defined by the SureSelect panel covering the whole exome and found that unless the samples contained an unusually large number of mutations (Cases 5 and 7) the signatures are not consistent with the WGS (Supplemental Fig. S4). We found that Case 5 is the only case with identical signatures in WGS and WES, though Cases 2 and 7 are similar.\n\nDISCUSSION\nTo our knowledge, this is the first study to evaluate the potential clinical utility of WGS in management of a consecutive series of patients with advanced cancer of varying tissue origin. Strikingly, for the first eight patients recruited and described here, WGS led to the identification of clinically actionable changes in all eight cases. WGS results helped to clarify an uncertain histopathological diagnosis in one case (Case 5), raised the possibility of an alternative diagnosis in a second case (Case 7), informed or supported prognosis in two cases (Cases 2 and 5), directly informed treatment changes in three patients (Cases 2, 5, and 6), leading to the joint clinicians’ and patients’ decision to de-escalate therapy in one case (Case 2), and indicated potential treatment options in all eight cases. Overall 26 different tier 1 clinically actionable somatic findings were identified from WGS compared with six SNVs/indels using the routine TGS approach. These provide exemplars of all of the five different analysis approaches described in the Introduction.\n\nIn four patients (Cases 1, 3, 4, and 6) WGS revealed a likely biallelic DDR mutation signature that would have been missed by conventional targeted cancer panel approaches, as it was defined by integration of SNVs, indels, and copy-number losses and analysis of global mutation signatures. These were in very different tumor types (prostate, male breast, and colorectal), yet all would be amenable to pharmacological intervention. Indeed, one patient (Case 6) obtained compassionate access to a PARP inhibitor and remains in remission at 24 mo.\n\nMutation burden is an important indicator of prognosis and indicates patients suitable for treatment with checkpoint inhibitors. In our study, a patient with endometrial cancer (Case 5) showed ultramutation because of a somatic POLE exonuclease domain mutation, findings associated with excellent prognosis of endometrial cancers, and the patient therefore opted to decline chemotherapy, thereby avoiding the associated toxicity (van Gool et al. 2016). Treatment with checkpoint inhibitors remains an option for this patient should she show clinical signs of relapse.\n\nIn contrast to conventional TGS, WGS provides information on both somatic and germline variants. This is important, as the same genes may underpin acquired or inherited cancers. For example, we identified acquired copy-number changes in BRCA1/2 that enabled synthetic lethal drugs to be used. Similarly, mutations in POLE were originally identified in inherited colorectal cancers but have since been recognized as somatic changes in both colorectal and endometrial cancers. Finally, Case 4 carried a deleterious germline variant in RAD51B and acquired loss of the other allele in the tumor. This information might be important for informing families of the genetic risk of cancer (Briggs and Tomlinson 2013) and also to pinpoint a homozygous impairment of the DDR pathway.\n\nSeveral cancers are known to be associated with viruses (Martin and Gutkind 2008). In our series, Case 2 (oropharyngeal cancer) had an HPV etiology indicated by p16 immunohistochemistry (a surrogate marker for HPV infection), which indicates a better prognosis than HPV-negative or smoking-related oral tumors (Duncan et al. 2013). IHC testing, however, has limitations, including a significant false-positive rate, and does not indicate viral subtype. WGS provided direct confirmation of the virus presence, as well as the subtype (Mahajan 2016). This is important as clinical trials relating to de-escalation of therapy in patients with good prognosis are underway. In addition to confirming the HPV status, WGS also informed the management of side effects leading to de-escalation and the choice of alternative therapy by confirming lack of DDR mutations and absence of EGFR mutations, which would have conferred resistance to cetuximab.\n\nWe did not find any clinically actionable mutations in noncoding regions or actionable translocations. Evidence of the clinical actionability of these types of events in solid tumors remains limited. For noncoding regions, mutations in the promoter of TERT2 gene are well-described (Huang et al. 2013), but these did not occur in our cohort. Clinically actionable or recurrent translocations have been described in lung and prostate cancer but were absent in our patients. Interestingly, sarcomas are characterized by frequent translocation events. However, the patient in our cohort who was referred with a possible sarcoma diagnosis but was found to have a UV light signature also did not carry any sarcoma-associated translocations, further strengthening the possibility that the primary tumor was not a sarcoma.\n\nThe turnaround time of WGS for cancer patients is critical. Two of the patients (Cases 1 and 7) died before WGS could be completed. Referral of patients for WGS should be encouraged at earlier stages in the disease course. Our fastest turnaround time for the whole process (including pathological assessment, release of tissue blocks, sequencing, and analysis stages) was 3 wk.\n\nIn the United Kingdom's National Health Service (NHS), we were limited by the availability of established funded therapies. Two treatment regimens emerge from this study as being of particular importance: PARP inhibitors for patients with defects in the DDR pathway and PDL1 checkpoint inhibitors for cancers showing hypermutation. These were made available through clinical trials or compassionate use. Clearly, this limited pilot study does not allow any conclusions regarding improvement in clinical outcome of patients undergoing the precision medicine approach presented herein. The challenges of testing physicians’ choice versus molecularly directed therapy in a randomized clinical trial setting highlighted by the SHIVA trial (Le Tourneau et al. 2015). Since then, major efforts using extensive targeted sequencing efforts systematically on thousands of patients with advanced cancer have demonstrated clinical utility in 35% of patients. Other similar studies have been initiated (Zehir et al. 2017).\n\nNonetheless, the results of this initial pilot study demonstrate that WGS can have an impact on informing diagnosis, prognosis, and potential treatment choice, including access to clinical trials, and justifies the systematic evaluation of the clinical utility of WGS in the management of patients with cancer in larger cohorts of patients.\n\nMETHODS\nPatients and Ethics\nThe first eight patients referred consecutively to the study are described (i.e., there was no preselection of cases). Patients were consented for analysis of tumor and constitutional DNA and feedback of somatic genetic testing results by a clinician. Feedback of clinically actionable germline variants was optional. Details of ethical approval are highlighted below.\n\nSample Preparation and DNA Extraction\nTumor Tissue Handling\nAll patients underwent biopsy of primary and/or metastatic cancer to obtain fresh tissue for sequencing. Fresh tissue samples were collected either by the clinician at the time of biopsy or from the resection specimen by the pathologist at dissection. Samples were snap-frozen in liquid nitrogen and an H&E frozen histology section was taken to confirm tissue content. Only samples with microscopically estimated tumor cell content of >40% were used for sequencing. Further formalin-fixed, paraffin-embedded (FFPE) tissue samples were collected for routine diagnostic histopathology, applying standard processing protocols such as H&E staining and IHC as appropriate. Frozen tissue was thawed rapidly for nucleic acid extraction. All samples underwent targeted sequencing using the 46 Gene Cancer Panel (as described in Hamblin et al. 2017) and WGS (methods described below and in Supplemental Information).\n\nDNA Extraction\nConstitutional DNA was isolated from 1.5 ml peripheral blood using the QIASymphony DSP DNA Midi kit (QIAGEN), according to the manufacturer's protocol. Tumor DNA was extracted from fresh frozen tissue using the All Prep Mini DNA Extraction kit (QIAGEN), as described in the manufacturer's protocol.\n\nWhole-Genome Sequencing\nLibraries of 350-bp fragments were generated from 1 µg sheared genomic DNA using the TruSeq PCR-Free library preparation kit (Illumina). Of note, 2 × 126 paired-end sequencing was performed using the HiSeq2500 HTv4 (Illumina). WGS was performed at a planned coverage of 30× for the constitutional DNA and of 75× for the tumor. The average coverage data across the entire genome per case, expressed as average number of reads, is shown in Supplemental Table 9 and the percentage of the genes covered at 75×, averaged over the eight tumor samples tested, in Supplemental Table 10.\n\nData Analysis\nFor a detailed description of alignment to the human reference genome, SNV, and structural variant calling, calculations of absolute exonic and intronic mutation burden, identification of previously described mutation signatures (Alexandrov et al. 2013a), the calculations of COSMIC signatures (Rosenthal et al. 2016), annotations of coding and noncoding variants, and detection of viral sequences, please refer to the Supplemental Materials and Methods.\n\nBriefly, analysis was performed using a bespoke, locked-down, and version-controlled bioinformatics pipeline according to the required specification for clinically accredited laboratories.\n\nPaired-end alignment of sequencing data against the reference genome hg19 (GRCh 37) was performed using the Whole-Genome Sequencing Application v2.0, based on Isaac Alignment Tool, within BaseSpace (Illumina). Somatic single nucleotide (SNV) and insertion/deletion (InDel) variant calling analysis was performed using the Tumour-Normal Application v1.0, based on Strelka, within BaseSpace. Calls were annotated using VariantStudio v2 (Illumina), a software using variant effect predictor (VEP) v2.8, COSMIC v77 and 1000 Genomes (v3). In a second approach, data were analyzed using QIAGEN's Ingenuity Variant Analysis software (QIAGEN Redwood City).\n\nFor copy-number and zygosity detection and analyses, Log2R values were generated from paired and unpaired tumor and germline data and these, together with B-allele frequency (BAF) outputs, were analyzed and events flagged and visualized using Nexus Discovery Edition 7.5 (BioDiscovery, Inc., El Segundo, CA).\n\nTranslocation events were investigated using BreakDancer (v1.4.5). Analysis was limited to a set of cancer-specific genes, as previously defined (Huret et al. 2013).\n\nPresence of HPV was determined by alignment of tumor sample reads using bwa (Li and Durbin 2009). HPV was confirmed and the HPV-35 subtype further classified by HPVDetector (Chandrani et al. 2015).\n\nIn Silico Whole-Exome Analysis\nTo explore whether we would have obtained similar or identical results from WES to those obtained by WGS, we applied an in silico filter using the Agilent SureSelect exome panel. SNVs, indels, and CNVs were then analyzed as in the WGS analyses described above and in the main text.\n\nInterpretation of Pathogenicity and Clinical Impact\nAll SNVs, indels, CNAs, and copy-neutral regions of homozygosity (cnLOHs) were classified with respect to their pathogenicity and clinical actionability (Futreal et al. 2004) (see Supplemental Information), information relating to germline and somatic changes at the respective locus was integrated. Analysis of germline changes was limited to a predefined in silico targeted panel of genes (Supplemental Table S3).\n\nSpecifically for defects in the DDR pathway, only inferred homozygous mutations were classified as clinically actionable. Allelic imbalance was not clinically actionable. For cases with hypermutated genotype (Cases 5 and 7) only clearly actionable mutations were included. A number of different sources, including COSMIC Cancer Genes Census (v77), “My Cancer Genome” (https://www.mycancergenome.org), and ClinicalTrials.gov (http:// clinicaltrials.gov) were used to determine whether genetic alterations were clinically relevant. Using this information, mutations were classified as tier 1, tier 2, or tier 3 (Li et al. 2017). Tier 1 variants were defined by strong prognostic or diagnostic relevance and/or clinically actionability based on the availability of either an FDA/EMA approved therapy or access to clinical trials relevant to the indication. Tier 2 variants were defined as those that might contribute to confirming the pathological diagnosis or have established biological relevance and/or those for which a clinical trial or approved therapy in a different tumor type was available. Tier 3 variants are those of unknown significance.\n\nAll variants showing annotations of potential clinical significance (tier 1 and 2 variants; see Table 2) were inspected manually using the integrative genomics viewer (IGV) (Robinson et al. 2011).\n\nAll results were fed back to clinicians in an integrated molecular and histopathological report overseen by the Genomics Tumour Board consisting of clinicians, senior clinical scientists, bioinformaticians, and histopathologists (Wagle et al. 2012; Dienstmann et al. 2014).\n\nADDITIONAL INFORMATION\nData Deposition and Access\nThe tier 1 and tier 2 variants identified in this study have been submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) and can be found under accession numbers SCV000493830 PTEN Chr 10:85557432–105804295 CN Loss; SCV000493831 BRCA2 Chr 13:32178877–33860144 CN Loss (Homozygous); and SCV000493829 TP53 Chr 17:7573975 NM_000546.5: c1044_1051 delGGAACTCA.\n\nEthics Statement\nWritten informed consent was obtained in line with the Declaration of Helsinki and local research ethics committees following the procedures outlined by the Oxford Radcliffe Biobank (South Central-Berkshire B Research Ethics Committee [REC no: 14/SC/1165]).\n\nAuthor Contributions\nA.S. and J.C.T. designed the study, interpreted results wrote the first draft, and edited the manuscript; H.D., S.J.L.K., T.M., P.A., D.V., K.R., E.M.K., M.M.P., and N.P. performed data analyses and contributed to Introduction, Methods, Results, and Discussion sections, R.C., A.H., A.P., M.P., K.A.S., Z.O., N.A., B.H., A.M.F., A.A., S.W., A.H., I.T., and D.C. contributed clinical and pathology data and assisted with the clinical interpretation of results.\n\nFunding\nThis publication presents independent research commissioned by the Health Innovation Challenge Fund (R6-388/WT 100127), a parallel funding partnership between the Wellcome Trust and the Department of Health. The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health. The authors also acknowledge a funding contribution from the Wellcome Trust Core award Grant Number 203141/Z/16/Z. This work was also funded and supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the National Health Service (NHS) or the NIHR.\n\nCompeting Interest Statement\nThe authors have declared no competing interest.\n\nReferees\nEdwin Cuppen\n\nAnonymous\n\nSupplementary Material\nSupplemental Material\n [Supplemental material is available for this article.]\n==== Refs\nREFERENCES\nAlexandrov LB , Nik-Zainal S , Wedge DC , Aparicio SA , Behjati S , Biankin AV , Bignell GR , Bolli N , Borg A , Borresen-Dale AL , \n2013a \nSignatures of mutational processes in human cancer . 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"fulltext_license": "CC BY-NC",
"issn_linking": "2373-2873",
"issue": "4(2)",
"journal": "Cold Spring Harbor molecular case studies",
"keywords": "colon cancer; cutaneous leiomyosarcoma; endometrial carcinoma; neoplasm of the breast; pharyngeal neoplasm; prostate cancer",
"medline_ta": "Cold Spring Harb Mol Case Stud",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D001706:Biopsy; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms; D006113:United Kingdom; D000073336:Whole Genome Sequencing; D055815:Young Adult",
"nlm_unique_id": "101660017",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29610388",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "20016485;2989692;20697090;27433846;27148575;20840072;26645727;4113130;18955455;26781813;27067784;21552211;23642549;25878334;25240281;20016488;18772396;23110309;27141333;23761041;18316791;26589277;23614766;3479997;24905773;28481359;23258224;26940869;28283584;22722193;24556366;27486176;19553641;27217383;24535589;9006334;26572163;26200345;20716626;26125128;27678458;23435461;19956178;23318258;27249731;28795426;25394778;25686104;21946919;22495314;24768039;23887589;6961453;6586073;25720322;24206917;21221095;24929052;11851626;26871470;23945592;24589459;26030518;22522925;25719666;23000897;22722201;23348506;19078924;20406929;26045862;4126434;25275081;23161685;26510020;24728294;28408746;26899170;22722202;27135926;19451168;25549143;23447401;25056374;25505230;27993330;26076146;26678200;22452356;27390348;26715889;22585170;26485756;14993899;28196074",
"title": "Clinically actionable mutation profiles in patients with cancer identified by whole-genome sequencing.",
"title_normalized": "clinically actionable mutation profiles in patients with cancer identified by whole genome sequencing"
} | [
{
"companynumb": "GB-TEVA-2018-GB-980149",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BICALUTAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nMutism/speech apraxia has been well documented as a toxic effect of cyclosporine after liver transplantation but has been reported only rarely with tacrolimus. Brain imaging with magnetic resonance or computed tomography has failed to demonstrate abnormalities in affected patients.\n\n\nMETHODS\nWe present the first example of an acute onset of loss of speech associated with a sudden elevation of serum tacrolimus level after successful orthotopic liver transplantation. We also describe the positron emission tomography (PET) scan of this patient's brain.\n\n\nRESULTS\nPET scan imaging of the brain was abnormal, demonstrating decreased metabolism in the posterior temporo-parieto-occipital regions. Statistical probability mapping revealed additional areas of hypometabolism in the cingulate gyrus.\n\n\nCONCLUSIONS\nPET scan revealed abnormalities of the brain in a patient with tacrolimus-induced mutism. The cingulate gyrus may play a role in the mutism/speech apraxia syndrome seen with cyclosporine/tacrolimus neurotoxicity.",
"affiliations": "Department of Neurology, Recanati/Miller Transplantation Institute, New York, New York, USA.",
"authors": "Bronster|D J|DJ|;Gurkan|A|A|;Buchsbaum|M S|MS|;Emre|S|S|",
"chemical_list": "D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1097/00007890-200009270-00017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "70(6)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D001921:Brain; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009155:Mutism; D016559:Tacrolimus; D014055:Tomography, Emission-Computed",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "979-82",
"pmc": null,
"pmid": "11014653",
"pubdate": "2000-09-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tacrolimus-associated mutism after orthotopic liver transplantation.",
"title_normalized": "tacrolimus associated mutism after orthotopic liver transplantation"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP018472",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional"... |
{
"abstract": "Multiple sclerosis is an inflammatory demyelinating disorder of the central nervous system. Its presentation is variable and its course and prognosis are unpredictable. Approximately 85% of individuals present a relapsing-remitting form of the disease, but some patients may evolve into a progressive course, accumulating irreversible neurological disability, defining its secondary progressive phase. Despite all the advances that had been reached in terms of diagnosis, many decisions are still taken based only on pure clinical skills. We present the case of a patient that, after being diagnosed with a clinically isolated syndrome many years ago, seemed to be entering in a secondary progressive course, developing a clinical picture dominated by a progressive gait disturbance. Nevertheless, multiple sclerosis heterogeneity asks for some clinical expertise, in order to exclude all other possible causes for patients' complaints. Here we present an important red flag in the differential diagnosis of secondary progressive multiple sclerosis.",
"affiliations": "Neurology-Neuroimmunology Department. Multiple Sclerosis Centre of Catalonia. Vall d'Hebron University Hospital. Barcelona. Spain.;Neurology-Neuroimmunology Department. Multiple Sclerosis Centre of Catalonia. Vall d'Hebron University Hospital. Barcelona. Spain.;Neurology-Neuroimmunology Department. Multiple Sclerosis Centre of Catalonia. Vall d'Hebron University Hospital. Barcelona. Spain.;Radiology Department. Magnetic Resonance Unit. Vall d'Hebron University Hospital. Barcelona. Spain.;Neurology-Neuroimmunology Department. Multiple Sclerosis Centre of Catalonia. Vall d'Hebron University Hospital. Barcelona. Spain.",
"authors": "Palavra|Filipe|F|;Tur|Carmen|C|;Tintoré|Mar|M|;Rovira|Àlex|À|;Montalban|Xavier|X|",
"chemical_list": null,
"country": "Portugal",
"delete": false,
"doi": "10.20344/amp.4322",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0870-399X",
"issue": "27(3)",
"journal": "Acta medica portuguesa",
"keywords": null,
"medline_ta": "Acta Med Port",
"mesh_terms": "D018450:Disease Progression; D005260:Female; D006801:Humans; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive",
"nlm_unique_id": "7906803",
"other_id": null,
"pages": "393-6",
"pmc": null,
"pmid": "25017353",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Secondary progression is not the only explanation.",
"title_normalized": "secondary progression is not the only explanation"
} | [
{
"companynumb": "2006BI005066",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOXETINE\\FLUOXETINE HYDROCHLORIDE"
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"drugadditional"... |
{
"abstract": "BACKGROUND\nAngiocentric glioma is a very uncommon low-grade tumor, predominantly occurring in pediatric patients, that was first described in 2005 and was codified 2 years later as a new central nervous system primary tumor. We herein report an exceptionally rare case of an elderly patient with angiocentric glioma. Only one additional case of angiocentric glioma in a patient older than 65 years has been hitherto reported.\n\n\nMETHODS\nAn 83-year-old male patient presented at our institution complaining of a 1-month history of progressive weakness of his right hand and difficulty performing fine movements. Magnetic resonance imaging of the brain was performed, and fluid-attenuated inversion recovery and T2-hyperintense diffuse cortico-subcortical lesion were reported. A neuronavigation-guided frontal craniotomy was performed to expose the premotor cortex, motor cortex, Rolandic sulcus, and postcentral gyrus. Intraoperative mapping showed that the tumor was close to the shoulder area. Therefore, only partial resection was safely feasible. Pathology report described astrocytic neoplastic cells affecting mainly the cortex and piamater with the classic finding of subpial palisading, with no endothelial invasion or atypia. Neoplastic cells were positive for glial fibrillary acidic protein, epithelial membrane antigen, Wilms tumor protein-1, P16, and P53. Low proliferative activity was seen (Ki-67 < 2%). Abundant gliovascular structures were also reported.\n\n\nCONCLUSIONS\nConsidering the morphologic and immunohistochemical data, the final pathologic diagnosis was angiocentric glioma. Furthermore, a thorough review of the literature was performed with the purpose of updating and summarizing the main clinical, radiologic, and pathologic features of this rare tumor.",
"affiliations": "Department of Neurosurgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain. Electronic address: lainhermesgq@gmail.com.;Department of Neurosurgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota, USA.;Department of Neurosurgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Department of Neurosurgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Department of Neuropathology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.",
"authors": "Gonzalez-Quarante|Lain Hermes|LH|;Fernández Carballal|Carlos|C|;Agarwal|Vijay|V|;Vargas Lopez|Antonio J|AJ|;Gil de Sagredo Del Corral|Oscar Lucas|OL|;Sola Vendrell|Emma|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2016.10.034",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "97()",
"journal": "World neurosurgery",
"keywords": "Angiocentric glioma; Elderly patient; Grade I glioma; Intractable seizures; Low-grade glioma",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000369:Aged, 80 and over; D001932:Brain Neoplasms; D003937:Diagnosis, Differential; D019317:Evidence-Based Medicine; D005910:Glioma; D006801:Humans; D008297:Male; D035583:Rare Diseases; D016896:Treatment Outcome",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "755.e5-755.e10",
"pmc": null,
"pmid": "27756673",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Angiocentric Glioma in an Elderly Patient: Case Report and Review of the Literature.",
"title_normalized": "angiocentric glioma in an elderly patient case report and review of the literature"
} | [
{
"companynumb": "ES-UCBSA-2017007370",
"fulfillexpeditecriteria": "1",
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"actiondrug": "4",
"activesubstance": {
"activesubstancename": "LACOSAMIDE"
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{
"abstract": "We report the initiation of CFTR modulator lumacaftor/ivacaftor combination (LUM/IVA) in two adolescents with cystic fibrosis who were treated with antifungal azoles (AZO) and tacrolimus (TCS) for liver transplantation. Despite multiple drug-drug interactions, maintaining therapeutic TCS levels was achievable. During the following year, LUM/IVA was well tolerated, providing clinical benefits.",
"affiliations": "Service de pédiatrie, Hôpital Mère Enfant Centre Hospitalier Universitaire, Hôpital Dupuytren Limoges France.;CRCM pédiatrique Marseille Hôpital Timone-Enfants, Assistance publique-Hôpitaux de Marseille Marseille France.;CRCM pédiatrique Lyon Hôpital Femme Mère Enfant, Hospices Civils de Lyon Lyon France.",
"authors": "Chouchane|Ikrame|I|;Stremler-Lebel|Nathalie|N|;Reix|Philippe|P|https://orcid.org/0000-0002-9192-8335",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.2053",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.2053CCR32053Case ReportCase ReportsLumacaftor/ivacaftor initiation in two liver transplantation patients under tacrolimus and antifungal azoles CHOUCHANE et al.Chouchane Ikrame \n1\nStremler‐Lebel Nathalie \n2\nReix Philippe https://orcid.org/0000-0002-9192-8335philippe.reix@chu-lyon.fr \n3\n\n4\n\n1 \nService de pédiatrie, Hôpital Mère Enfant\nCentre Hospitalier Universitaire, Hôpital Dupuytren\nLimoges\nFrance\n\n2 \nCRCM pédiatrique Marseille\nHôpital Timone‐Enfants, Assistance publique‐Hôpitaux de Marseille\nMarseille\nFrance\n\n3 \nCRCM pédiatrique Lyon\nHôpital Femme Mère Enfant, Hospices Civils de Lyon\nLyon\nFrance\n\n4 \nUMR 5558 (EMET), CNRS, LBBE\nUniversité de Lyon\nVilleurbanne\nFrance\n* Correspondence\n\nPhilippe Reix, Centre de ressources et de compétence pour la Mucoviscidose, Lyon, France.\n\nEmail: philippe.reix@chu-lyon.fr\n17 2 2019 4 2019 7 4 10.1002/ccr3.2019.7.issue-4616 618 04 10 2018 11 1 2019 26 1 2019 © 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Key Clinical Message\nWe report the initiation of CFTR modulator lumacaftor/ivacaftor combination (LUM/IVA) in two adolescents with cystic fibrosis who were treated with antifungal azoles (AZO) and tacrolimus (TCS) for liver transplantation. Despite multiple drug‐drug interactions, maintaining therapeutic TCS levels was achievable. During the following year, LUM/IVA was well tolerated, providing clinical benefits.\n\nazolescystic fibrosisivacaftorlumacaftortacrolimus source-schema-version-number2.0component-idccr32053cover-dateApril 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:08.04.2019\n\n\nChouchane \nI \n, \nStremler‐Lebel \nN \n, \nReix \nP \n. Lumacaftor/ivacaftor initiation in two liver transplantation patients under tacrolimus and antifungal azoles . Clin Case Rep . 2019 ;7 :616 –618 . 10.1002/ccr3.2053\n==== Body\n1 INTRODUCTION\nThe use of the CFTR modulator lumacaftor/ivacaftor combination (LUM/IVA) is part of the pharmacopeia for cystic fibrosis (CF) patients. However, it is not recommended for patients receiving tacrolimus (TCS) for solid organ transplantation because of the drug‐drug interaction.1 As a cytochrome P450/3A4 (CYP3A4) inducer, LUM/IVA decreases blood levels of the molecules that are substrates of CYP3A4 such as TCS.2\n\n\nAs recently underlined in a review paper by Mitchell et al, CFTR modulators should sooner or later become available for a large proportion of patients, some of which will likely require solid organ transplantation.3 Do patients receiving these medications should definitively be excluded from transplantation program is actually an open question.\n\nTo begin to answer this question, we report two cases of adolescents followed in different CF centers receiving TCS for liver transplantation (LT) in which LUM/IVA was initiated because of progressive respiratory status worsening.\n\n2 CASE 1\nA 17‐year‐old male patient underwent a LT in March 2014. In the year preceding LT, Aspergillus fumigatus (AF) and Scedosporium apiospermum (SAp) were recovered in his sputum cultures. Because of a high risk of post‐LT systemic scedosporiosis and/or invasive aspergillosis, he was put under voriconazole (VCZ). Before LT, his FEV1 was 76%. LT was performed using a deceased liver donor and was uncomplicated. He initially received TCS and mycophenolate mofetil, the latter being withdrawn in September 2014 because of hematological toxicity. VCZ was stopped because the patient's respiratory condition was good and both AF and SAp were no longer recovered. Unfortunately, his respiratory status gradually worsened, with repeated low‐volume hemoptysis and rapid lung function decline (at its nadir, FEV1 was measured at 60%). SAp was again recovered and VCZ was resumed. FEV1 stabilized at 60% but repeated low‐volume hemoptysis still occurred. Therefore, 11 months after LT, it was decided to introduce LUM/IVA in this patient receiving TCS (0.6 mg/d) and VCZ (400 mg/d). LUM/IVA (200 mg/125 mg) was introduced during hospitalization. It was started at one pill a day for 5 days, then one pill twice a day until reaching the final dose (two pills twice a day) at day 14. There was no immediate adverse event. Progression of TCS residual concentrations (C0) after LUM/IVA introduction is shown in Figure 1A. A relative increase of 130% of TCS was needed before reaching its therapeutic targets (4‐8 ng/mL). LUM/IVA introduction was also responsible for a steeper VCZ C0 decrease that remained below therapeutic targets despite a successive increase (Figure 1C). Liver function tests remained within normal ranges during the following year; clinical tolerance was good. A 13% absolute increase in FEV1 was observed at M1 and M6, which decreased thereafter (Figure 2).\n\nFigure 1 Residual concentrations ([C0]) of tacrolimus over time in case 1 (A) and case 2 (B) after lumacaftor/ivacaftor (250 mg/200 mg) initiation. Gray bands on panels A and B represent tacrolimus therapeutic targets after the 1st year of liver transplantation ([C0] of tacrolimus between 4 and 8 ng/mL). Vertical gray bars on panels A and B represent the gradual increase in the number of LUM/IVA pills administrated daily. Although not indicated on panels A and B, the progressive increase of LUM/IVA pills included a step to three pills (between D10 and D14 in case 1; between D7 and D10 in case 2). Time points given on the x‐axis of panels A and B do not exactly correspond to drug modification times or monitoring. These should be viewed as in between time points. Lower panels represent [C0] for voriconazole (C) and posaconazole (D)\n\nFigure 2 Patients FEV1 progression during the year following LUM/IVA initiation (arrow). M0 reports FEV1 value collected immediately before LUM/IVA initiation\n\n3 CASE 2\nAn 18‐year‐old female patient underwent a LT in January 2002. The LT was performed using a deceased liver donor. The clinical course was marked by an acute rejection in April 2002. The patient was chronically colonized by Pseudomonas aeruginosa with a mean need for two IVs a year, and she was also receiving posaconazole (PCZ) for a chronic AF airway colonization prior to LT. Because her respiratory status gradually deteriorated despite treatment, it was decided to introduce LUM/IVA (200 mg/125 mg) 15 years after LT (April 2017). Fifteen days before LUM/IVA initiation, the daily TCS dose was progressively increased from 0.4 mg to 0.8 mg. Her FEV1 was 78.5%. TCS was introduced during hospitalization. The patient received one pill a day of LUM/IVA for 6 days, then one pill twice a day for 4 days until the full daily dose was given at day 14. There were no short‐term safety concerns. TCS C0 decreased slightly after LUM/IVA introduction but then remained within therapeutic ranges (Figure 1B). The daily TCS dose was increased to 200% compared to the starting dose (Figure 1B). The drop in PCZ C0 was steeper and remained below therapeutic targets despite a gradual increase (Figure 1D). Liver function tests remained within normal ranges; clinical tolerance was good. A moderate increase in FEV1 was noted at M1 and M6, but did not continue beyond the 1st year (Figure 2).\n\n4 DISCUSSION\nWe report that introducing LUM/IVA in patients receiving TCS for LT was safe with a good tolerance both short‐ and mid‐term and some clinical benefit. We also shown that despite multiple drug‐drug interactions, it was possible to maintain achievable TCS blood levels in those patients.\n\nLUM/IVA was introduced in two different ways by different CF teams (100% increase of the daily dose of TCS 2 weeks before the first dose of LUM/IVA in case # 2; no pre‐LUM/IVA increase in case # 1). It seems that the “pre‐LUM/IVA increase” approach used in case # 2 was the most appropriate to initially maintain TCS levels within therapeutic ranges. In these two patients, whose immunosuppression was relatively low and with lower therapeutic ranges of TCS, the 100% pre‐LUM/IVA increase made it possible to maintain adequate TCS blood levels and avoided TCS under‐dosing as seen in patient # 1 after the second step of the LUM/IVA increase. The half‐life of tacrolimus varies greatly among healthy individuals and liver transplantation patients. After oral 0.3 mg/kg daily dose administration, steady‐state concentrations of TCS are reached at day 3.4 This means that a 100% pre‐LUM/IVA increase of TCS between 3 and 6 days before LUM/IVA introduction would be warranted to avoid TCS dropping below therapeutic targets in LT patients in the late phase of their immunosuppression. A different approach would be needed at the earliest phase of LTs that require maintenance of higher TCS blood levels.\n\nThe need for antifungal azoles in our patients was a matter of added complexity. On one hand, antifungal azoles are inhibitors of CYP3A4, 2C9, and 2C19 and are responsible for an increase in TCS blood levels.5 On the other hand, LUM/IVA is a strong inducer of CYP3A4 and therefore decreases blood levels of other CYP3A4 substrates such as VCZ and PCZ.2 The LUM/IVA induction effect was much steeper on both VCZ and PCZ than on TCS. Finally, the concomitant use of azoles in our cases can be seen as beneficial because it likely participated in maintaining adequate TCS levels. However, whenever possible, we would advise withdrawing azoles before LUM/IVA initiation, or using azoles not metabolized through CYP3A4 such as itraconazole.2\n\n\nIn conclusion, based on these two cases, we found that the initiation of LUM/IVA in patients who have received transplants with CF immunosuppressed with TCS and also receiving azoles may be safe and well tolerated with clinical benefits.\n\nAUTHORS CONTRIBUTION\nIC: collected the data and wrote the first draft of manuscript. NL‐S: obtained patient consent and reviewed manuscript edits. PR: obtained patient consent and reviewed manuscript edits.\n\nACKNOWLEDGMENTS\nThe authors would like to thank Heloise Petit, Alexandre Fabre, Sylvie Quaranta, Emmanuelle Sampol, from the Laboratoire de pharmacocinétique et de toxicologie of Faculté de Pharmacie of Assistance publique‐Hôpitaux de Marseille for their contribution.\n==== Refs\nREFERENCES\n1 \n(CHMP) CfMPfHU \n. Assessment report. Orkambi. International non‐property name: LUMACAFTOR/IVACAFTOR . Assessment report‐EMA/667775/2015. 24 september 2015 :616 ‐103 .\n2 \n\nJordan \nCL \n, \nNoah \nTL \n, \nHenry \nMM \n. Therapeutic challenges posed by critical drug‐drug interactions in cystic fibrosis . Pediatr Pulmonol . 2016 ;51 (S44 ):S61 ‐S70 .27662106 \n3 \n\nMitchell \nRM \n, \nJones \nAM \n, \nBarry \nPJ \n. CFTR modulator therapy in patients with cystic fibrosis and an organ transplant . Paediatr Respir Rev . 2018 ;27 :6 ‐8 .30158080 \n4 \n(CHMP) CfMPfHU \n. Summary information on referral opinion pursuant to article 30 of council directive 2001/83/EC for Prograf and associated names . Assessment report‐EMA/85997/2006. 10 April 2006 .\n5 \n\nVanhove \nT \n, \nBouwsma \nH \n, \nHilbrands \nL \n, et al. Determinants of the magnitude of interaction between tacrolimus and voriconazole/posaconazole in solid organ recipients . Am J Transplant . 2017 ;17 (9 ):2372 ‐2380 .28224698\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "7(4)",
"journal": "Clinical case reports",
"keywords": "azoles; cystic fibrosis; ivacaftor; lumacaftor; tacrolimus",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "616-618",
"pmc": null,
"pmid": "30997048",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports",
"references": "27662106;28224698;30158080",
"title": "Lumacaftor/ivacaftor initiation in two liver transplantation patients under tacrolimus and antifungal azoles.",
"title_normalized": "lumacaftor ivacaftor initiation in two liver transplantation patients under tacrolimus and antifungal azoles"
} | [
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"companynumb": "FR-VERTEX PHARMACEUTICALS-2019-003955",
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{
"abstract": "The primary central nervous system (CNS) presentation of lymphomatoid granulomatosis (LYG) is rare, and no standard therapy for LYG with primary CNS symptoms exists. CNS-LYG patients usually survive for only less than a year from diagnosis. This is the first report of high-grade primary CNS-LYG with monoclonality that was successfully treated with rituximab monotherapy, resulting in a durable remission for more than 1 year in a 66-year-old woman with pemphigus vulgaris who was also on immunosuppressive therapy.",
"affiliations": "Department of Hematology, Juntendo University School of Medicine, Japan.;Department of Hematology, Juntendo University School of Medicine, Japan.;Department of Hematology, Juntendo University School of Medicine, Japan.;Department of Hematology, Juntendo University School of Medicine, Japan.;Department of Hematology, Juntendo University School of Medicine, Japan.;Department of Dermatology, Juntendo University School of Medicine, Japan.;Department of Hematology, Juntendo University School of Medicine, Japan.;Department of Hematology, Juntendo University School of Medicine, Japan.;Department of Neurosurgery, Juntendo University School of Medicine, Japan.;Department of Pathology, School of Medicine, Kurume University, Japan.;Department of Hematology, Juntendo University School of Medicine, Japan.",
"authors": "Harada|Sakiko|S|;Ando|Jun|J|;Ando|Miki|M|;Nitta|Hideaki|H|;Inano|Tadaaki|T|;Hirasawa|Yusuke|Y|;Furukawa|Yoshiki|Y|;Kinoshita|Shintaro|S|;Kondo|Akihide|A|;Ohshima|Koichi|K|;Komatsu|Norio|N|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.7232-21",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n34121006\n10.2169/internalmedicine.7232-21\nCase Report\nHigh-grade Primary Central Nervous System Lymphomatoid Granulomatosis: Successful Rituximab Monotherapy\nHarada Sakiko 1\nAndo Jun 12\nAndo Miki 1\nNitta Hideaki 1\nInano Tadaaki 1\nHirasawa Yusuke 3\nFurukawa Yoshiki 1\nKinoshita Shintaro 1\nKondo Akihide 4\nOhshima Koichi 5\nKomatsu Norio 1\n1 Department of Hematology, Juntendo University School of Medicine, Japan\n2 Department of Transfusion Medicine and Stem Cell Regulation, Juntendo University School of Medicine, Japan\n3 Department of Dermatology, Juntendo University School of Medicine, Japan\n4 Department of Neurosurgery, Juntendo University School of Medicine, Japan\n5 Department of Pathology, School of Medicine, Kurume University, Japan\nCorrespondence to Dr. Miki Ando, m-ando@juntendo.ac.jp\n\n12 6 2021\n1 12 2021\n60 23 37953799\n2 2 2021\n16 4 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/).\nThe primary central nervous system (CNS) presentation of lymphomatoid granulomatosis (LYG) is rare, and no standard therapy for LYG with primary CNS symptoms exists. CNS-LYG patients usually survive for only less than a year from diagnosis. This is the first report of high-grade primary CNS-LYG with monoclonality that was successfully treated with rituximab monotherapy, resulting in a durable remission for more than 1 year in a 66-year-old woman with pemphigus vulgaris who was also on immunosuppressive therapy.\n\ncentral nervous system\nhigh-grade lymphomatoid granulomatosis\npemphigus vulgaris\nrituximab\n==== Body\npmcIntroduction\n\nLymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disease, which is angiocentric and angiodestructive involving extranodal sites [skin, lung, liver, kidney, central nervous system (CNS)] (1,2). Although CNS involvement is seen in around one-third of all LYG patients, the initial presentation of LYG with primary CNS symptoms (primary CNS-LYG) is very rare (3,4). However, since randomized treatment trials have not been conducted in primary CNS-LYG due to its scarcity - although it admittedly may be under-diagnosed owing to reluctance to conduct brain biopsies - no therapy for this form of LYG has yet been established (3,5,6).\n\nCase Report\n\nA 66-year-old woman was diagnosed with pemphigus vulgaris in May 2001. Initial treatment with corticosteroids and mycophenolate mofetil (MMF) was ineffective, and azathioprine, cyclosporine, and cyclophosphamide were sequentially substituted. None was fully effective. In April 2010, despite undergoing plasma exchange and prednisolone, the disease worsened, with buccal mucosal ulceration. In August 2010, supplemental intravenous immunoglobulin (IVIG) was initiated. Thereafter pemphigus vulgaris was controlled with prednisolone 20 mg/day, MMF 1,500 mg/day, and biweekly plasma exchange with IVIG 15 g/day for 4 days. Cytomegalovirus esophagitis was diagnosed in June 2018 and was satisfactorily controlled with ganciclovir 5 mg/kg twice a day for 2 weeks.\n\nIn September 2019, involuntary movements of both lower limbs and left lower limb pain while sleeping appeared. Physical examination revealed no new skin changes, no lymphoadenopathy, and no hepatosplenomegaly. Tendon reflexes could not be elicited in the lower limbs. Slight iliopsoas weakness was noted. Although her hemogram values were unremarkable (WBC 3,400/μL, RBC 350×104/μL, Hb 12.0 g/dL), the lymphocyte number clearly decreased to 210/μL. The lactate dehydrogenase activity in the patient's serum (255 U/L) increased (expected 124-222 U/L), the C-reactive protein value (0.20 mg/dL) was normal (<0.29 mg/dL), and the soluble interleukin-2 receptor value (235 IU/mL) was normal (157-474 IU/mL). A chemiluminescent enzyme immunoassay showed no evidence of human immunodeficiency virus (HIV)-1 and -2 infections. EBV infection was identified, with viral capsid antigen (VCA) IgG X320, VCA IgM <X10, and EBV nuclear antigen X20. A quantitative polymerase chain reaction assessment of whole-blood EBV DNA found 2.3×103 copies/μg. No abnormalities were found on urinalysis. Chest roentgenograms did not show any abnormality.\n\nBrain magnetic resonance imaging (MRI) revealed a mass lesion in her right frontal lobe in gadolinium-enhanced T1 weighted image (Fig. 1A). To make a precise diagnosis and control brain edema, neurosurgeons removed the mass completely. After surgery, her neurological disorders completely disappeared and no abnormal accumulations of fluorodeoxyglucose (FDG) were found on positron emission tomography-computed tomography (PET-CT) (Fig. 1B, C).\n\nFigure 1. Changes over time on magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT). (A) Hyperintense lesion, right frontal lobe, on presentation for evaluation of involuntary, painful lower-limb movement (MRI, gadolinium-enhanced T1 weighted image). (B, C) No abnormal accumulation of fluorodeoxyglucose (FDG) after surgical excision of the lesion (PET-CT). (D) New hyperintense lesion, left frontal lobe, 3 months after (A) and surgical excision (MRI, gadolinium-enhanced T1 weighted image). (E) Abnormal accumulation of FDG, left frontal lobe, 3 months after (A) and surgical excision (PET-CT). (F) No abnormal accumulation of fluorodeoxyglucose 2 months after (E) (PET-CT). (G) No lesion is observed 15 months after (A) (MRI, gadolinium-enhanced T1 weighted image).\n\nA neuropathologic examination found vascular-invasive infiltration by large to medium-sized atypical lymphocytes (Fig. 2A, B) that expressed the B-cell marker CD20 (Fig. 2C) as well as EBV nuclear antigen-2 (Fig. 2D) and EBV latent membrane protein 1 (Fig. 2E), exhibiting a type III latency pattern. T cell infiltration was not prominent. EBV-encoded small RNA (EBER) sequences were demonstrable by in situ hybridization, with >50 EBER-positive cells per high-power field (Fig. 2F). A southern blot analysis revealed clonality of immunoglobulin heavy chain (IgH) gene rearrangement and no clonality of T cell receptor. High-grade LYG (grade 3, World Health Organization 2016) was diagnosed, which was thought to have arisen as EBV-associated lymphoproliferative disease, with EBV reactivation caused by the long-term usage of immunosuppressants. MMF was discontinued and prednisolone was gradually reduced from October 2019. No other sites except for CNS were involved by LYG.\n\nFigure 2. Photomicrographs, histopathologic preparations of a brain right frontal lobe tumor-resection specimen. (A) Infiltration by large to medium-sized abnormal lymphoid cells with angiocentric distribution [Hematoxylin and Eosin (H&E) staining, original magnification (×) 40]. Scale bar, 200μm. (B). As above (H&E staining, ×400). Scale bar, 20μm. Immunohistochemical (C-E) and in situ hybridization studies (F), all ×600 with hematoxylin counterstain and diaminobenzidine chromogen: Tumor cells express the B-cell marker CD20 (C), EBV nuclear antigen-2 (D), and Epstein-Barr virus (EBV) latent membrane protein 1 (E). EBV-encoded small RNA in situ hybridization detects EBV sequences in >50 cells per high-power field (F). All 4 scale bars, 20μm.\n\nCNS-LYG recurrence was identified 3 months later (January, 2020) with a high-intensity lesion observed contralaterally on brain MRI (Fig. 1D). An abnormal accumulation of FDG was observed on PET-CT only in the left frontal lobe (Fig. 1E). We diagnosed the recurrence of LYG in the CNS. Patient fragility precluded the administration of combination immunochemotherapy such as DA-EPOCH-R (dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, and rituximab) or R-CHOP (cyclophosphamide, doxorubicin, vincristine and rituximab) (3); thus IV rituximab 375 mg/m2 every 7 days was initiated. In March 2020, after 4 rituximab treatments, FDG accumulation abnormalities were no longer found on PET-CT (Fig. 1F). Remission was diagnosed. Remission has continued for >12 months since the start of rituximab treatment, as established by brain MRI in December 2020 (Fig. 1G). The whole-blood EBV DNA copy number declined during therapy, then completely vanished after rituximab treatment. Involuntary movements of legs disappeared after surgery. At present (March 2021), she is clinically doing well (Fig. 3). Her primary skin disorder also has improved.\n\nFigure 3. Clinical course. An overview of the symptoms, treatments and time points of magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT). MMF: mycophenolate mofetil, PSL: prednisolone\n\nDiscussion\n\nImmunocompromise (iatrogenic, HIV-infection related, reflecting congenital immune deficiency, e.g.) makes it possible for the reactivation of EBV and the development of LYG (3,4,7). In our patient, HIV infection was not relevant and no repeated infection from childhood was observed, thus making congenital immune deficiency unlikely. We ascribe her immunocompromised status, manifested initially in chronic cytomegalovirus esophagitis and resulting in LYG, to the long-term use of immunosuppressants for pemphigus vulgaris.\n\nIn general, the prognosis of LYG is considered to be poor, with a median overall survival of only 14 months (4). B cell lymphoma develops in almost 13% of LYG patients (5,6). Prospective studies have established treatment protocols for LYG that require histopathologic grading, which is based on the number and density of large atypical EBV-positive B cells. The discontinuation of immunosuppressants, corticosteroids, or interferon-alpha is recommended for Grade 1 or 2 LYG, while immunochemotherapy is chosen for Grade 3 LYG because it is often monoclonal and should be treated as EBV-associated lymphoma (3,8-10). Rituximab has recently been used to treat LYG; in a retrospective study of 11 LYG patients treated with rituximab-based therapies, mainly R-CHOP, approximately two-thirds of patients responded. The median overall survival was ～1 y (3,11).\n\nAlthough systemic LYG with CNS involvement has a poor prognosis, with a mortality rate ranging from 65% to 90% at 14 months (5,6), rituximab was also reported to be to some extent effective (8,12,13). However, to the best of our knowledge, this is the first report of high-grade primary CNS-LYG with IgH monoclonality that was successfully treated with rituximab monotherapy, resulting in a durable remission for >12 months. Furthermore, our patient has survived for 17 months from diagnosis, whereas primary CNS-LYG patients usually survive only for <1 year from diagnosis (7). A case whereby rituximab and temozolomide immunochemotherapy was initiated on high-grade primary CNS-LYG with pulmonary involvement, the tumor progressed and the patient is reported to have died 2 months after the initial presentation (14). In our case, the fact that the tumor lesion was confined to the CNS, along with the discontinuation of immunosuppressants may have had the positive effect on the rituximab treatment outcome.\n\nSince the ratio of the cerebrospinal fluid concentration to the serum concentration of administered rituximab is only 0.1 to 4.4%, the rituximab molecule is therefore too large to cross the blood-brain barrier (BBB) readily (15). This is of potential concern in rituximab monotherapy for primary CNS-LYG (15,16). However, recent clinical trials demonstrate that chemotherapy with rituximab is more effective than chemotherapy alone for primary CNS lymphoma (16).\n\nThe malignant disease in our patient, treated with rituximab alone, responded well, with remission at this writing for >1 year. We did not measure rituximab in her CSF and can only speculate that angiodestruction in LYG may have allowed rituximab to cross the BBB. This question may warrant attention in rituximab treatment of other patients with LYG and CNS involvement. We note as of possible interest that rituximab is effective for several autoimmune diseases due to the suppression of antibody generation, including pemphigus vulgaris (17), and indeed in our patient rituximab monotherapy was also found to be associated with the clearance of her primary skin disorder.\n\nIn conclusion, primary CNS-LYG may recur even after complete resection. For cases with high-grade LYG with CNS involvement and monoclonality, aggressive rituximab-based chemotherapy is usually recommended. However, we experienced a case of high-grade primary CNS-LYG in which rituximab monotherapy proved to be effective with a successful 1 year remission.\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images.\n==== Refs\n1. Pittaluga SWW , Jaffe ES . Lymphomatoid granulomatosis. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised Fourth Edition. Swerdlow SH, Campo E, Harris NL et al , Eds. IARC, Lyon, 2017: 312.\n2. Liebow AA , Carrington CR , Friedman PJ . Lymphomatoid granulomatosis. Hum Pathol 3 : 457-558, 1972.4638966\n3. Melani C , Jaffe ES , Wilson WH . Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder. Blood 135 : 1344-1352, 2020.32107539\n4. Song JY , Pittaluga S , Dunleavy K , et al . Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations. Am J Surg Pathol 39 : 141-156, 2015.25321327\n5. Katzenstein AL , Carrington CB , Liebow AA . Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases. Cancer 43 : 360-373, 1979.761171\n6. Nishihara H , Tateishi U , Itoh T , Nagashima K , Tanaka S . Immunohistochemical and gene rearrangement studies of central nervous system lymphomatoid granulomatosis. Neuropathology 27 : 413-418, 2007.18018473\n7. Tanaka H , Furukawa S , Takeda Y , et al . Primary cerebral lymphomatoid granulomatosis progressing to methotrexate-associated lymphoproliferative disease under immunosuppressive therapy. Intern Med 54 : 503-507, 2015.25758078\n8. Lucantoni C , De Bonis P , Doglietto F , et al . Primary cerebral lymphomatoid granulomatosis: report of four cases and literature review. J Neurooncol 94 : 235-242, 2009.19322520\n9. Dunleavy K , Roschewski M , Wilson WH . Lymphomatoid granulomatosis and other Epstein-Barr virus associated lymphoproliferative processes. Curr Hematol Malig Rep 7 : 208-215, 2012.22814713\n10. Roschewski M , Wilson WH . Lymphomatoid granulomatosis. Cancer J 18 : 469-474, 2012.23006954\n11. Chavez JC , Sandoval-Sus J , Horna P , et al . Lymphomatoid granulomatosis: a single institution experience and review of the literature. Clin Lymphoma Myeloma Leuk 16 (Suppl ): S170-S174, 2016.27521314\n12. Zaidi A , Kampalath B , Peltier WL , Vesole DH . Successful treatment of systemic and central nervous system lymphomatoid granulomatosis with rituximab. Leuk Lymphoma 45 : 777-780, 2004.15160955\n13. Ishiura H , Morikawa M , Hamada M , et al . Lymphomatoid granulomatosis involving central nervous system successfully treated with rituximab alone. Arch Neurol 65 : 662-665, 2008.18474745\n14. Olmes DG , Agaimy A , Kloska S , Linker RA . Fatal lymphomatoid granulomatosis with primary CNS-involvement in an immunocompetent 80-year-old woman. BMJ Case Rep 2014 : bcr2014206825, 2014.\n15. Rubenstein JL , Combs D , Rosenberg J , et al . Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment. Blood 101 : 466-468, 2003.12393404\n16. Singh PK , Pan E . Review of rituximab in primary CNS lymphoma. J Neurol Sci 410 : 116649, 2020.31901591\n17. Randall KL . Rituximab in autoimmune diseases. Aust Prescr 39 : 131-134, 2016.27756976\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "60(23)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "central nervous system; high-grade lymphomatoid granulomatosis; pemphigus vulgaris; rituximab",
"medline_ta": "Intern Med",
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"nlm_unique_id": "9204241",
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"pages": "3795-3799",
"pmc": null,
"pmid": "34121006",
"pubdate": "2021-12-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "High-grade Primary Central Nervous System Lymphomatoid Granulomatosis: Successful Rituximab Monotherapy.",
"title_normalized": "high grade primary central nervous system lymphomatoid granulomatosis successful rituximab monotherapy"
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"abstract": "Patients with continuous-flow left ventricular assist devices have a high risk of gastrointestinal bleeding (GIB) and recurrent bleeding. Studies have shown octreotide can reduce the risk of GIB. This retrospective, case-crossover study, evaluated the efficacy of octreotide for the prevention of recurrent GIB in patients with left ventricular assist devices between August 2008 and October 2018. A total of 32 patients received octreotide and were included in the study. Hospital admission for GIB was evaluated before and after the initiation of octreotide. Each case served as his/her own control. Most patients were on a reduced aspirin dose (56.2%) and had a reduced international normalized ratio goal (59.4%) before starting monthly octreotide. The most common dose of long-acting octreotide was 30 mg every 28 days. Overall, octreotide decreased the frequency of GIB (4.3 vs. 0.9 events/year, p < 0.001). Nineteen (59.4%) patients did not have a subsequent gastrointestinal bleed. Of the 13 patients who rebled after initiation of octreotide, the frequency of events decreased by 2.6 bleeds per patient per year (4.8 vs. 2.2; p = 0.043). In high-risk patients who have failed conventional therapy, octreotide can be useful for the prevention of recurrent GIB.",
"affiliations": "From the Pharmacy Department, Sentara Norfolk General Hospital, Norfolk, Virginia.;Advanced Heart Failure Center, Sentara Norfolk General Hospital, Norfolk, Virginia.;Advanced Heart Failure Center, Sentara Norfolk General Hospital, Norfolk, Virginia.;From the Pharmacy Department, Sentara Norfolk General Hospital, Norfolk, Virginia.;Advanced Heart Failure Center, Sentara Norfolk General Hospital, Norfolk, Virginia.;From the Pharmacy Department, Sentara Norfolk General Hospital, Norfolk, Virginia.",
"authors": "Wilson|Tyler J|TJ|0000-0002-9133-633;Baran|David A|DA|0000-0002-7754-9953;Herre|John M|JM|0000-0002-5290-4541;Cameron|Chad M|CM|;Yehya|Amin|A|;Ingemi|Amanda I|AI|0000-0002-2834-8493",
"chemical_list": "D015282:Octreotide",
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"doi": "10.1097/MAT.0000000000001342",
"fulltext": "\n==== Front\nASAIO J\nASAIO J\nMAT\nAsaio Journal\n1058-2916\n1538-943X\nLippincott Williams & Wilkins Hagerstown, MD\n\n33369929\n00005\n10.1097/MAT.0000000000001342\nAdult Circulatory Support\nGastrointestinal Bleeding Rates in Left Ventricular Assist Device Population Reduced with Octreotide Utilization\nWilson Tyler J. tjwilso1@sentara.com\n*\nBaran David A. DABARAN@sentara.com\n†\nHerre John M. JMHERRE@sentara.com\n†\nCameron Chad M. CMCAMERO@sentara.com\n*\nYehya Amin AXYEHYA@sentara.com\n†\nIngemi Amanda I. AIINGEMI@sentara.com\n*\nFrom the * Pharmacy Department, Sentara Norfolk General Hospital, Norfolk, Virginia\n† Advanced Heart Failure Center, Sentara Norfolk General Hospital, Norfolk, Virginia.\nCorrespondence: Tyler J. Wilson, Pharmacy Department, Sentara Norfolk General Hospital, 600 Gresham Dr. Norfolk, VA 23507. Email: tjwilso1@sentara.com.\n18 12 2020\n9 2021\n67 9 989994\n4 2020\n10 2020\nCopyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASAIO.\n2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This 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\nPatients with continuous-flow left ventricular assist devices have a high risk of gastrointestinal bleeding (GIB) and recurrent bleeding. Studies have shown octreotide can reduce the risk of GIB. This retrospective, case-crossover study, evaluated the efficacy of octreotide for the prevention of recurrent GIB in patients with left ventricular assist devices between August 2008 and October 2018. A total of 32 patients received octreotide and were included in the study. Hospital admission for GIB was evaluated before and after the initiation of octreotide. Each case served as his/her own control. Most patients were on a reduced aspirin dose (56.2%) and had a reduced international normalized ratio goal (59.4%) before starting monthly octreotide. The most common dose of long-acting octreotide was 30 mg every 28 days. Overall, octreotide decreased the frequency of GIB (4.3 vs. 0.9 events/year, p < 0.001). Nineteen (59.4%) patients did not have a subsequent gastrointestinal bleed. Of the 13 patients who rebled after initiation of octreotide, the frequency of events decreased by 2.6 bleeds per patient per year (4.8 vs. 2.2; p = 0.043). In high-risk patients who have failed conventional therapy, octreotide can be useful for the prevention of recurrent GIB.\n\nleft ventricular assist device\ncontinuous-flow left ventricular assist device\ngastrointestinal bleed\noctreotide\nbleed\nOPEN-ACCESSTRUE\n==== Body\nGastrointestinal bleeding (GIB) is one of the most common complications in patients on continuous-flow left ventricular assist device (CF-LVAD) support and is associated with increased morbidity and mortality.1 The incidence of GIB after implantation of a CF-LVAD ranges between 15.4% and 61.0%.2,3\n\nThe pathophysiology of GIB in patients with CF-LVADs is multifactorial. The risk factors for increased likelihood of GIB in patients with CF-LVADs include chronic anticoagulation, antiplatelet agents, device physiology causing high shear stress resulting in acquired Von Willebrand disease, impaired platelet aggregation, formation of arteriovenous malformations, angiodysplastic lesions, and intestinal hypoperfusion.2–6 Various interventions to reduce the incidence of GIB include reduced antiplatelet dose, lower target international normalized ratio (INR) goals, decreased pump speed to allow for aortic valve opening, use of proton pump inhibitors or histamine-2 receptor antagonists, treatment with thalidomide, danazole, or octreotide.1,7–10\n\nOctreotide is a somatostatin analog, FDA approved for acromegaly, diarrhea associated with carcinoid tumors and vasoactive intestinal peptide (VIP) secreting neurogenic tumors. Octreotide is used off-label for treatment and secondary prevention of GIB. A few observational studies have shown a benefit with the use of long-acting release octreotide (LAR) for the prevention of recurrent GIB (Table 1).11–14 The largest of the studies included 51 patients with a 180 day follow-up in comparison to a historical cohort.12\n\nTable 1. Key Studies Utilizing LAR in CF-LVAD Patients\n\n\tDevices\tNumber of Patients\tOctreotide Regimen\tOutcomes\t\nJuricek et al.11\tHMII\t30\tIM LAR depot 20 mg every 4 weeks\tDecreased frequency of GIB 3.4 ± 3.1 to 0.7 ± 1.3 events/year; p < 0.001\t\nHVAD Heartassist\t\nShah et al.12\tHMII\t51\tIM LAR depot (37) or SQ daily (14) for 6 months\tIncreased freedom from rebleeding GIB for the octreotide group, 75 ± 6% vs 52 ± 8%, p < 0.01\t\nMalhotra et al.13\tHMII\t8\tIM LAR depot 20 mg every 4 weeks for 16 weeks\tNo episodes of GIB observed or reported\t\nSmallfield et al.14\tDevices not specified\t34\tIM LAR depot monthly or SQ daily (doses not specified)\tIM LAR depot monthly had lower rate of bleeding compared to SQ daily (29% vs. 42%)\t\nCF-LVAD, continuous-flow left ventricular assist device; GIB, gastrointestinal bleed; HMII, HeartMate II; HVAD, HeartWare HVAD System; LAR, long-acting release.\n\nWe conducted a retrospective cohort study evaluating the use of LAR at a single center over a 10 year period examining the incidence of GIB prior and following LAR therapy.\n\nMaterials and Methods\n\nPatient Population\n\nA retrospective, crossover study was conducted at Sentara Norfolk General Hospital. The study inclusion criteria included patients aged 18 years and older, CF-LVAD placement from August 2008 to October 2018, a GIB requiring hospital admission, standard-of-care treatment for secondary prophylaxis, and treatment with monthly LAR. Patients were excluded if they missed greater than two consecutive doses of LAR (Table 2). The study was approved by the Eastern Virginia Medical School Institutional Review Board.\n\nEndpoints\n\nEach patient served as their own control to compare GIB rates. The control period was time from CF-LVAD implant to initiation of LAR (pre-LAR), whereas the comparison period was time from the initiation of LAR (post-LAR) until the end of follow-up. The primary endpoint was bleeding events per patient per year pre-LAR in comparison with post-LAR. A bleeding event was defined as a GIB resulting in hospitalization. Although subject to clinical assessment, patients were generally admitted to the hospital for a decrease of 2 g/dl of hemoglobin or signs of a GIB, such as a positive fecal occult blood sample. After evidence of GIB, colonoscopies, and endoscopies were routinely performed. If no bleeding source was identified, additional invasive procedures such as spiral enteroscopy would be performed.\n\nInstitution-Specific Protocols\n\nPatients on CF-LVAD support were initially placed on aspirin 325 mg daily, warfarin with a goal INR of 2–3, and a proton pump inhibitor or histamine-2 receptor antagonist. Regimens after first bleed were then individualized per patient. Modifications to the INR goal, antiplatelet regimen, pump speed, or initiation of octreotide were considered before discharge at the discretion of the attending cardiologist. Per protocol, patients initiate octreotide when modifiable causes for bleeding (e.g., supratherapeutic INR or a lesion requiring cauterization) have been fixed. Patients started on octreotide continue monthly or more frequently until transplant or the patient expires.\n\nStatistical Analysis\n\nPaired categorical data were evaluated using the McNemar’s test. For continuous data, the paired t-test or Wilcoxon signed-rank test was utilized. We then performed a mixed effects analysis of variance (ANOVA) model and included a random effect for patient ID to account for correlation between pre and post measurements within the same patient. In this three-way full factorial ANOVA, we evaluated the impact of octreotide, a reduced INR goal, and reduced aspirin dose on the outcome of GIB frequency. A Kaplan–Meier analysis with a log rank test was utilized to determine the impact of LAR on the freedom from rebleeding. Statistical analysis was completed with IBM SPSS statistics software version 24.\n\nResults\n\nThirty-four patients out of 321 CF-LVAD implants during the study period developed a GIB and were initiated on LAR. Two of these patients were excluded, one due to receiving LAR for epistaxis and another due to missing greater than two consecutive doses of LAR. Pharmacokinetically when three consecutive doses are missed (3 months), the intramuscular drug is completely eliminated from the body. A total of 32 patients were included in the analysis, 15 (46.9%) had HeartMate II (Abbott, IL), 13 (40.7%) HVAD (Medtronic, MN), and 4 (12.4%) HeartMate III (Abbott, IL) (Figure 1).\n\nFigure 1. Patient selection.\n\nBaseline characteristics of the patients at the time of admission before the initiation of LAR are shown in Table 2. As this was a refractory patient population, most pre-LAR patients were on a reduced dose aspirin (56.2%), lower INR goal (59.4%), and were on a proton pump inhibitor (93.8%).\n\nTable 2. Patient Characteristics\n\nPatient Demographics\t\t\nGender: male, n (%)\t25 (78.1)\t\nAge at LVAD implantation, mean ± SE\t61.2 ± 1.2\t\nBody mass index, mean ± SE\t30.4 ± 0.91\t\nRace, n (%)\t\t\n Caucasian\t16 (50.0)\t\n African American\t16 (50.0)\t\nPast medical history, n (%)\t\t\n Hypertension\t26 (81.3)\t\n Ischemic etiology\t23 (71.9)\t\n Atrial fibrillation\t21 (65.6)\t\n History of ventricular tachycardia\t21 (65.6)\t\n Diabetes mellitus\t18 (56.3)\t\n History of prior bleeding events\t13 (40.6)\t\n History of prior thrombotic events\t9 (28.1)\t\n Current infection\t3 (9.4)\t\nLVAD, n (%)\t\t\n Heartmate II\t15 (46.9)\t\n HVAD\t13 (40.7)\t\n Heartmate III\t4 (12.4)\t\nCF-LVAD rotations per minute, mean ± SE\t\t\n Heartmate II\t9,211.3 ± 105.9\t\n HVAD\t2,821.5 ± 61.0\t\n Heartmate III\t5,550.0 ± 236.3\t\nDestination therapy, n (%)\t17 (53.1)\t\nINR at the time of the bleed before LAR, mean ± SE\t2.2 ± 0.094\t\nAspirin, n (%)\t\t\n None\t8 (25.0)\t\n 81 mg\t9 (28.1)\t\n 162 mg\t1 (3.1)\t\n 325 mg\t14 (43.8)\t\nAngiotensin-converting enzyme inhibitor/angiotensin II receptor antagonist use, n (%)\t19 (59.4)\t\nDigoxin use, n (%)\t4 (12.5)\t\nAcid suppression therapy, n (%)\t\t\n Proton pump inhibitor\t30 (93.8)\t\n Histamine-2 receptor antagonist\t2 (6.2)\t\nCF-LVAD, continuous-flow left ventricular assist device; HMII; HVAD; LAR, long-acting release.\n\nAll patients had a therapeutic INR at the time of GIB before LAR initiation. Characteristics related to GIB events and their management can be found in Table 3. Post-LAR there were more patients on a reduced aspirin dose (p = 0.04) and lower INR goal (p = 0.02). There was no difference between patient follow-up time pre-LAR and post-LAR (393.5 vs. 470.3 days, p = 0.4).\n\nTable 3. Patient Management Parameters Pre-LAR and Post-LAR\n\nInterventions\tPre-LAR\tPost-LAR\tp\t\nRecurrent bleeding management\t\nReduced aspirin dose (<325 mg), n (%)\t18 (56.2)\t25 (78.1)\t0.04\t\nAspirin, n (%)\t\t\t\t\n None\t8 (25.0)\t18 (56.2)\t0.04\t\n 81 mg\t9 (28.1)\t7 (21.9)\t\n 162 mg\t1 (3.1)\t0 (0)\t\n 325 mg\t14 (43.8)\t7 (21.9)\t\nReduced INR goal (INR range 2–3), n (%)\t19 (59.4)\t26 (81.3)\t0.02\t\nDose of LAR (mg), median, [interquartiles]\t\t30.0 [20.0–40.0]\t\t\nDose frequency of LAR (days), median, [interquartiles]\t\t28 [21–28]\t\t\nAngiotensin-converting enzyme inhibitor/angiotensin II receptor antagonist use, n (%)\t19 (59.4)\t15 (46.9)\t0.22\t\nDigoxin use, n (%)\t4 (12.5)\t5 (15.6)\t1.00\t\nCF-LVAD support parameters and durations\t\nReduced CF-LVAD rotations per minute, n (%)\t\t3 (9.4)\t\t\nPatient follow-up (days), mean ± SE\t393.5 ± 73.6\t470.3 ± 57.8\t0.4\t\nOutcome measures\t\nPatients with recurrent GIB, n (%)\t32 (100)\t13 (41)\t<0.01\t\nNumber of GIB median, [interquartiles]\t2.0 [1–3]\t0 [0–1]\t<0.01\t\nFrequency of GIB per year, median, [interquartiles]\t2.95 [1.2–5.7]\t0 [0–1.4]\t<0.001\t\nCF-LVAD, continuous-flow left ventricular assist device; GIB, gastrointestinal bleed; INR, international normalized ratio; LAR, long-acting release.\n\nBefore the initiation of LAR, patients had an average of 4.3 ± 3.8 GIB events per year (median 2.0 GIB events per year), whereas post-LAR patients had an average of 0.9 ± 1.4 GIB events per year (median 0 GIB events per year). Our study showed that LAR significantly reduced the frequency of GIB events per year, p <0.001 (Figure 2). Most patients (87.5%, 28/32) had a positive response to LAR with a decrease in admissions for GIB. After initiating LAR, 59.4% (19/32) did not have a subsequent GIB. Of the 13 patients that bled after the initiation of LAR, the frequency of events decreased by 2.6 bleeds per patient per year compared with pre-LAR (2.2 vs. 4.8; p = 0.043).\n\nFigure 2. Frequency of GIB pre-LAR and post-LAR. GIB, gastrointestinal bleed; INR, international normalized ratio.\n\nAmong the three devices studied, there was no difference in GIB frequency (p = 0.54) or effect of LAR (p = 0.28). A multivariate, mixed modeling analysis demonstrated that LAR significantly reduced GIB frequency (p < 0.01), whereas a reduced INR goal and reduced aspirin dose had no effect (p= 0.85, p = 0.54) (Tables 4 and 5). The Kaplan–Meier curves showed the time to first GIB for both pre-LAR and post-LAR. The 90 day freedom from GIB in pre-LAR was 50%, whereas in the same time frame, the post-LAR had 78% freedom from GIB (Figure 3).\n\nTable 4. Overall F-Tests From the Mixed Modeling Full Factorial ANOVA\n\nVariable\tF\tSig\t\nIntercept\t42.0\t1\t\nOctreotide\t24.47\t<0.01\t\nINR reduction (yes/no)\t0.04\t0.85\t\nAspirin reduction (yes/no)\t0.39\t0.54\t\nINR × aspirin\t0.07\t0.79\t\nOctreotide × INR\t1.77\t0.20\t\nOctreotide × aspirin\t0.02\t0.89\t\nOctreotide × INR × aspirin\t0.01\t0.93\t\nINR, international normalized ratio.\n\nTable 5. Estimated Magnitude of Main Effects\n\nVariable\tEstimate\t95% CI\tp\t\nOctreotide\t−0.31\t−0.43 to −0.18\t<0.01*\t\nINR reduction (yes/no)\t−0.014\t−0.16 to 0.14\t0.85\t\nAspirin reduction (yes/no)\t−0.046\t−0.20 to 0.10\t0.54\t\nINR, international normalized ratio.\n\nFigure 3. Kaplan–Meier graph displaying freedom from GIB. GIB, gastrointestinal bleed.\n\nOf the 32 patients included in this study, two patients developed a pump thrombosis. Patient 1 had a HeartMate II that had been on LAR for 4 months, had an INR of 1.7 (INR goal 1.5–2.0) and was on aspirin 325 mg daily at the time of admission. Patient 2 had a HeartMate II that had been on LAR over 2 years, had an INR of 3.20 (INR goal 2.0–3.0), and on aspirin 81 mg daily at the time of admission. Both patients had a reduction in their anticoagulant or antiplatelet, making it difficult to ascertain the cause of the pump thrombosis.\n\nDiscussion\n\nDespite improvements with CF-LVADs, GIB continues to be a vexing problem. This retrospective, case-crossover study aimed to evaluate the efficacy of LAR for prevention of recurrent GIB. Mehra et al.17 found that the incidence of GIB to be 0.31 and 0.49 GIB events per patient per year in HeartMate II and HeartMate III devices, respectfully. Our patients had a higher incidence of 4.3 ± 3.8 GIB events per patient per year. When analyzing the study’s incidence of GIB, we could consider that our patient population is higher risk for GIB compared with the average patient population. In our study, LAR prevented recurrent GIB in 59.4% of patients and showed an overall reduction of GIB in 87.5% of patients. Upon a multivariate analysis, only LAR significantly reduced the frequency of GIB, while reduced INR goal and reduced aspirin dose had no effect.\n\nPrevious studies have demonstrated the efficacy and safety of octreotide for recurrent GIB. Shah et al.12 used a historical cohort from the original HeartMate II trials and found that the use of octreotide in HeartMate II patients with or without prior GIB more than a 6 month period resulted in significantly fewer recurrent GIB (24% vs. 43%, p = 0.04) and increased freedom from rebleed (75% vs 52 ± 8%, p < 0.01). Our study mirrored these results at 6 months with fewer recurrent GIB (31% vs. 63%) and increased freedom from rebleed (67% vs. 38%). While on LAR, 13 patients had recurrent GIB and the majority of bleeds (10/13) occurred in the first 6 months. Despite this rebleeding, LAR decreased the frequency of GIB. Four patients did not respond to LAR and continued to have GIB.\n\nAnother study by Juricek et al.11 determined monthly LAR used in patients with HeartMate II, HVAD, and Heartassist CF-LVADs significantly reduced the frequency of GIB (3.0 ± 2.4 vs. 0.7 ± 1.3 GIB events/year, p < 0.05). Our study confirms these results with a similar decrease in GIB events/year (4.3 ± 3.8 vs. 0.9 ± 1.4, p < 0.001). Additionally, our study further elaborates on previous results evaluating outcomes with HeartMate III, continuing LAR longer than 12 months, and the impacts of adding LAR, adjusting aspirin dose, and INR goal on GIB. The use of octreotide resulted in reduction of GIB frequency and prevention of refractory GIB in patients with CF-LVADs.\n\nOctreotide is known to be associated with adverse effects such as hyperglycemia, bradycardia, hypertension, diarrhea, and injection site reactions. None of the patients in this study had side effects that were attributed to octreotide. Cost is another factor in the decision-making process as an average dose of octreotide of 20 mg is $5,117.69 USD per month, limiting use to patients with insurance coverage. At this time, most insurance plans that serve the patients around our center in the United States appear to cover LAR, although prior authorizations may take up to 14 days delaying initiation of therapy. The use of octreotide decreased frequency of hospitalization for GIB in 87.5% of patients. The costs of LAR may be offset with reduced hospitalizations and could be appropriate in patients with multiple admissions for GIB.\n\nModifications to patient regimens such as reduction in aspirin dose, reduction in goal INR, and changes in CF-LVAD settings have been utilized in an attempt to reduce the frequency of GIB; however, these treatments may increase the risk for thrombotic events.15,16 Use of octreotide in this population may decrease readmissions rates and increase days spent out of the hospital.11 There are several inherent limitations in this study. This was a retrospective single-center and relatively small study, including 32 patients that received LAR at our center. On average, these patients had at least 2 GIB before initiation of octreotide when adjustments in aspirin dose and target INR failed to prevent recurrent GIB. This leads to a selection bias, identifying only patients with the most frequent GIB who failed conventional therapies. Another limitation would include simultaneous medication interventions such as reduced aspirin doses or INR goals, which confounds the impact of LAR on our results. There were additional gastrointestinal interventions concurrently performed on these patients when a source of bleeding was found that could also impact the results. Additionally, the changes in clinical practice over the long study time frame cannot be taken into account. Our results should be considered in the context of the refractory population studied. Efforts were taken to identify and eliminate confounders to prevent impact on results.\n\nConclusion\n\nOverall, our study demonstrates that LAR is associated with a significant decrease in the frequency of GIB in high-risk patients with CF-LVADs. This study adds to prior literature and adds insight with additional follow-up time and the inclusion of the Heartmate III. Future prospective studies, including a randomized controlled trial, are needed to validate these findings.\n\nAcknowledgment\n\nDr. Trent Gaugler, PhD, Associate Professor of Mathematics at Lafayette University.\n\nDisclosure: Dr. Baran has consulting income from Abiomed, Getinge, Livanova, MC3, and speaking honoraria from Novartis and Pfizer. Dr. Herre has consulting income from LifeNet Health and receives grant support from Analytics 4 Life, Boston Scientific and DCRI. Dr. Yehya has speaking honoraria from Akcea therapeutics, CareDx, and Zoll. The other authors have no conflicts of interest to report.\n==== Refs\nReferences\n\n1. Guha A Eshelbrenner CL Richards DM Monsour HP Jr : Gastrointestinal bleeding after continuous-flow left ventricular device implantation: review of pathophysiology and management. Methodist Debakey Cardiovasc J 2015.11 : 24–27.25793026\n2. Harvey L Holley CT John R : Gastrointestinal bleed after left ventricular assist device implantation: Incidence, management, and prevention. Ann Cardiothorac Surg 2014.3 : 475–479.25452907\n3. Marsano J Desai J Chang S Chau M Pochapin M Gurvits GE : Characteristics of gastrointestinal bleeding after placement of continuous-flow left ventricular assist device: A case series. Dig Dis Sci 2015.60 : 1859–1867.25616611\n4. Aggarwal A Pant R Kumar S : Incidence and management of gastrointestinal bleeding with continuous flow assist devices. Ann Thorac Surg 2012.93 : 1534–1540.22541185\n5. Morgan JA Paone G Nemeh HW : Gastrointestinal bleeding with the HeartMate II left ventricular assist device. J Heart Lung Transplant 2012.31 : 715–718.22425231\n6. Goldstein DJ Aaronson KD Tatooles AJ : Gastrointestinal bleeding in recipients of the heartware ventricular assist system. JACC Heart Fail 2015.303–313.25770405\n7. Crow S John R Boyle A : Gastrointestinal bleeding rates in recipients of nonpulsatile and pulsatile left ventricular assist devices. J Thorac Cardiovasc Surg 2009.137 : 208–215.19154927\n8. Loyaga-Rendon RY Hashim T Tallaj JA : Octreotide in the management of recurrent gastrointestinal bleed in patients supported by continuous flow left ventricular assist devices. ASAIO J 2015.61 : 107–109.25232774\n9. Draper K Kale P Martin B Kelly Cordero R Ha R Banerjee D : Thalidomide for treatment of gastrointestinal angiodysplasia in patients with left ventricular assist devices: case series and treatment protocol. J Heart Lung Transplant 2015.34 : 132–134.25447569\n10. Schettle S Bawardy BA Asleh R : Danazol treatment of gastrointestinal bleeding in left ventricular assist device-supported patients. J Heart Lung Transplant 2018.37 : 1035–1037.29907501\n11. Juricek C Imamura T Nguyen A : Long-acting octreotide reduces the recurrence of gastrointestinal bleeding in patients with a continuous-flow left ventricular assist device. J Card Fail 2018.24 : 249–254.29427603\n12. Shah KB Gunda S Emani S : Multicenter evaluation of octreotide as secondary prophylaxis in patients with left ventricular assist devices and gastrointestinal bleeding. Circ Heart Fail 2017.10: e004500.29141860\n13. Malhotra R Shah KB Chawla R : Tolerability and biological effects of long-acting octreotide in patients with continuous flow left ventricular assist devices. ASAIO J 2017.63 : 367–370.27922890\n14. Smallfield GB Gunda S Emani S : A multicenter evaluation of octreotide for ventricular assist device related gastrointestinal bleeding. J Heart Lung Transplant 2016.35 : S245.\n15. Teuteberg JJ Slaughter MS Rogers JG ; ADVANCE Trial Investigators: The HVAD left ventricular assist device: risk factors for neurological events and risk mitigation strategies. JACC Heart Fail 2015.3 : 818–828.26450000\n16. Lea JC Floroff CK Ingemi AI Zeevi GR : Impact of time in therapeutic range after left ventricular assist device placement: a comparison between thrombus and thrombus-free periods. J Thromb Thrombolysis 2019.47 : 361–368.30739304\n17. Mehra MR Uriel N Naka Y ; MOMENTUM 3 Investigators: A fully magnetically levitated left ventricular assist device - final report. N Engl J Med 2019.380 : 1618–1627.30883052\n\n",
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"mesh_terms": "D018592:Cross-Over Studies; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006333:Heart Failure; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D015282:Octreotide; D012189:Retrospective Studies",
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"title": "Gastrointestinal Bleeding Rates in Left Ventricular Assist Device Population Reduced with Octreotide Utilization.",
"title_normalized": "gastrointestinal bleeding rates in left ventricular assist device population reduced with octreotide utilization"
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"abstract": "Tongue, skin and brain metastases of bladder cancer are very rare and few cases have been reported. We report a case of tongue, skin and brain metastases of bladder cancer. A 61-year-old woman was referred to our hospital with gross hematuria. Transurethral resection of the bladder (TURBT), tongue biopsy and skin biopsy were performed. Pathological findings showed urothelial carcinoma, G2, micro papillary variant, pT2＞ and tongue and skin metastases from urothelial carcinoma of bladder. After three cycles of chemotherapy (gemcitabine plus paclitaxel), tongue and skin metastases disappeared. Cystoscopy revealed no tumor of bladder. Eleven months later, she was admitted to our hospital because of disturbance of consciousness. Magnetic resonance imaging (MRI) showed multiple brain metastases. Rechallenge of chemotherapy (gemcitabine plus paclitaxel) restored from disturbance of consciousness and MRI showed partial response of brain metastases. We performed six additional courses of chemotherapy. Skin, tongue and brain metastases from bladder cancer indicate poor risk. Chemotherapy (gemcitabine plus paclitaxel)could be effective against these matastases.",
"affiliations": "The Department of Urology, Shiga Medical Center for Adults.;The Department of Urology, Shiga Medical Center for Adults.;The Department of Urology, Shiga Medical Center for Adults.;The Department of Urology, Shiga Medical Center for Adults.;The Department of Pathology, Shiga Medical Center for Adults.;The Department of Pathology, Shiga Medical Center for Adults.",
"authors": "Uemura|Yuichi|Y|;Ushida|Hiroshi|H|;Ishitoya|Satoshi|S|;Onishi|Hiroyuki|H|;Terashima|Tsuyoshi|T|;Takeuchi|Eiji|E|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D017239:Paclitaxel",
"country": "Japan",
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"issue": "61(10)",
"journal": "Hinyokika kiyo. Acta urologica Japonica",
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"medline_ta": "Hinyokika Kiyo",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D001932:Brain Neoplasms; D015653:Cystectomy; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D017239:Paclitaxel; D012878:Skin Neoplasms; D014062:Tongue Neoplasms; D001749:Urinary Bladder Neoplasms",
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"pages": "405-9",
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"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "The Combination Therapy of Gemcitabine Plus Paclitaxel Induced Complete Response in a Tongue Skin Brain Metastasis of Bladder Carcinoma: A Case Report.",
"title_normalized": "the combination therapy of gemcitabine plus paclitaxel induced complete response in a tongue skin brain metastasis of bladder carcinoma a case report"
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"abstract": "Helicobacter Pylori (HP) persistently colonizes the stomach in about 50% of the globe population and it is the main risk factor for peptic ulcer, as well as for gastric adenocarcinoma and MALT gastric lymphoma. The treatment for HP revolutionized the management of the peptic ulcer disease, providing permanent healing in many cases. Preventing colonization of HP would be the primary prevention of gastric malignancy and peptic ulceration. At the same time, the presence of HP provides protection for some diseases (gastroesophageal reflux disease and its complications, esophageal adenocarcinoma, asthma), the eradication of the microorganism having negative repercussions. HP has an increasingly recognized role in other extragastric pathologies. Thus, immune thrombocytopenic purpura has improved after treating HP infection. There are controversial association with ischemic heart disease and cerebrovascular disease. The current article highlights an important association between HP infection and a range of hepatobiliary disorders such as biliary lithiasis (where even an etiological role is involved), cholestatic syndromes (primary sclerosing cholangitis and primary biliary cholangitis), chronic hepatitis B virus, chronic hepatitis C virus, with an evolution towards cirrhosis and hepatocellular carcinoma.",
"affiliations": "Emergency Military Hospital, Focsani.;University of Medicine and Pharmacy \"Carol Davila\", Bucharest.;University of Oradea, Faculty of Medicine and Pharmacy.",
"authors": "Popescu|D|D|;Andronescu|D|D|;Babes|P A|PA|",
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"doi": "10.12865/CHSJ.44.02.16",
"fulltext": "\n==== Front\nCurr Health Sci JCurr Health Sci JCHSJCurrent Health Sciences Journal2067-06562069-4032Medical University Publishing House Craiova 2018.02.1610.12865/CHSJ.44.02.16Case ReportThe Association Between Helicobacter Pylori Infection and Liver and Biliary Tract Disorders POPESCU D. 1ANDRONESCU D. 2BABES P.A. 31 Emergency Military Hospital, Focsani 2 University of Medicine and Pharmacy „Carol Davila”, Bucharest 3 University of Oradea, Faculty of Medicine and Pharmacy Corresponding Author: Decebal Popescu,\nDepartment of Internal Medicine, Focsani Emergency Military HospitalCezar Bolliac Street, No. 3-5, FocsaniRomaniapopescudecebal7@yahoo.comApr-Jun 2018 27 3 2018 44 2 186 191 04 12 2017 27 3 2018 Copyright © 2018, Medical University Publishing House Craiova2018This is an open-access article distributed under the terms of a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International Public License, which permits unrestricted use, adaptation, distribution and reproduction in any medium, non-commercially, provided the new creations are licensed under identical terms as the original work and the original work is properly cited.Helicobacter Pylori (HP) persistently colonizes the stomach in about 50% of the globe population and it is the main risk factor for peptic ulcer, as well as for gastric adenocarcinoma and MALT gastric lymphoma. The treatment for HP revolutionized the management of the peptic ulcer disease, providing permanent healing in many cases. Preventing colonization of HP would be the primary prevention of gastric malignancy and peptic ulceration. At the same time, the presence of HP provides protection for some diseases (gastroesophageal reflux disease and its complications, esophageal adenocarcinoma, asthma), the eradication of the microorganism having negative repercussions. HP has an increasingly recognized role in other extragastric pathologies. Thus, immune thrombocytopenic purpura has improved after treating HP infection. There are controversial association with ischemic heart disease and cerebrovascular disease. The current article highlights an important association between HP infection and a range of hepatobiliary disorders such as biliary lithiasis (where even an etiological role is involved), cholestatic syndromes (primary sclerosing cholangitis and primary biliary cholangitis), chronic hepatitis B virus, chronic hepatitis C virus, with an evolution towards cirrhosis and hepatocellular carcinoma.\n\nhelicobacter Pylorihepatobiliary disorders primary sclerosing cholangitis primary biliary cholangitis biliary litiasis\n==== Body\nIntroduction\nHelicobacter pylori (HP), a bacterium discovered in 1982 by Warren and Marshall, infects over 50% of the world's population. It is a gram-negative bacterium, producing urease, located in the mucus covering the gastric mucosa or between the mucus layer and the gastric epithelium. There are multiple factors that allow it to adapt to hostile environments; an important role is the production of urease which causes alkalization of the pH in the environment [1,2].\n\nEpidemiology\nThe infection is contracted during childhood and over time it develops a typical, active gastritis that persists for the entire life without specific treatment [2].\n\nThe risk factors for those infected with HP include precarious socio-economic status, especially in numerous families living in agglomeration conditions, as well as the country of origin.\n\nThus, the prevalence differs depending on the country, being higher in the underdeveloped countries compared to the highly industrialized ones.\n\nMost infected individuals are asymptomatic; 10-15% make ulcerative peptic disease during life. In addition, HP is a proven factor in the etiology of gastric cancer and MALT lymphoma.\n\nIn 1994 it was declared a first grade carcinogen by the International Agency for Research on Cancer (IARC).\n\nHP infection increases 3-7 times the risk of peptic ulcer and gastrointestinal bleeding.\n\nHP is found in 70-90% of patients with duodenal ulcer and 30-60% of cases with gastric ulcer; eradication of the microbe reduces the risk of relapse below 10%, while patients receiving only acid suppression treatment have a 70% relapse risk. HP causes gastric mucosal lesions as well as other complications by releasing mediators of inflammation.\n\nPhysiopathology\nAlthough HP produces a systemic and mucosal humoral response, the production of antibodies does not lead to the eradication of infection.\n\nThe bacterium is very heterogeneous; the prognosis of HP infection depends on a combination of agent virulence and environmental factors that affect the distribution and severity of gastric inflammation and the level of acid secretion.\n\nThe virulence factors of HP that induce proinflammatory cytokine release or adhesion to epithelial cells explain the geographical differences in the incidence of the gastric cancer.\n\nSeveral of these virulence factors include: \n\n- Cag PAI (cytotoxin-associated gene pathogenicity island) [3];\n\n- Vac A (vacuolating cytotoxin A) [3];\n\n- Blood group antigen-binding adhesion (Bab A) an external protein of HP that contributes to severe gastric mucosal lesions [4];\n\nThey are recognized as having a more severe prognosis. Other virulence factors include:\n\n- HP neutrophil-activating protein (HP-NAP) is a neutrophil activating protein with a role in protecting against HP-DNA fragmentation by the oxidative stress [5];\n\n- Cell-wall polysaccharide.\n\nHP expressing the cytotoxin-associated gene A (Cag A) represents virulent strains having greater interaction with the human species.\n\nSeveral genes of a genomic fragment that cause the Cag pathogenic islet encode components of a type IV islet that translocates Cag A into the host cells and affects cell growth and cytokine production. Cag A is a potent antigenic protein that is an integral part of the Cag PAI, being associated with a prominent inflammatory response, increasing the production of IL8 [2,3,6].\n\nHP strains expressing active forms of Vac A or outer membrane-associated Bab A and Oip A (outer inflammatory protein A) proteins are similarly associated with increased disease risk compared to the strains lacking these proteins [6,7].\n\nIn addition to the local response, a systemic response is also induced in various extra gastric manifestations: haematological, cardiovascular, autoimmune diseases, respiratory disorders [8] and those of special interest in this work, liver and biliary tract diseases.\n\nCase presentation\nWe present the case of a 35-year-old male who was hospitalized at University Emergency Hospital Bucharest for epigastric pain with sudden onset at a post-prandial hour, accompanied by dyspnea, sweating and nausea. He presented a history of heredocolateral ischemic cardiopathy (father with myocardial infarction) and recent stress. Vital signs were normal except for respiratory rate=28/min; however, D-dimers were in normal range and saturation of oxygen in peripheral blood SaO2 was 100%. Electrocardiogram revealed ST depression (1-2mm) in DII, DIII and V3-V6. Chest x-ray was normal. The patient received aspirin, clopidogrel, morphine intravenous, heparin and intravenous nitroglycerin.\n\nIn differential diagnosis, acute coronary ischemia, pericarditis, acute aortic dissection, acute vascular disease (acute mesenteric ischemia, systemic vasculitis, pulmonary embolism) were considered. Troponin T was negative and transthoracic echocardiography did not reveal signs of pericarditis or left ventricular hypokinesia. The coronarography showed normal epicardial coronary arteries and ejection fraction 55-60% without kinetic abnormalities of the left ventricular wall.\n\nEvolving (after 24 hours), subxiphoid pain irradiated in the right hypochondrium, alkaline phosphatase increased by 50% and gamma-glutamyltransferase (GGT) increased five times, as well as total serum bilirubin. An abdominal ultrasound was performed to exclude acute cholecystitis or choledocholytiasis. This revealed gallstones without signs of acute cholecystitis (3mm thick wall, Murphy sign absent, no canalicular dilatation).\n\nOn day 3, Endoscopic Retrograde Cholangio-Pancreatography (ERCP) was performed, taking into account the signs of cholestasis, which did not detect dilatations of the ductus choledochus and intrahepatic bile ducts. The cystic channel was probably permeable by retrograde injection of biliary sludge by the contrast substance during ERCP. There was no biliary obstruction or choledocholithiasis. It was possible that a stone has passed spontaneously through the bile duct and the ultrasound and ERCP were normal, while GGT and serum bilirubin increased significantly. For this reason, laparoscopic cholecystectomy was decided to prevent another similar episode. During the intervention a very relaxed gallbladder, with a gangrenous wall, adherent to the epiploon (discordant with the ultrasound exam) was discovered. Surgical dissection was difficult and a drain was placed (unusual for laparoscopic cholecystectomy).\n\nCholesterol gallstones were found in the gallbladder, not pigment gallstones commonly found in hemolytic anemia or alcoholism. The patient did not have the usual clinical features in those with cholesterol lithiasis. This was a\n35-year-old man with a 25 kg/m2 BMI, non-obese or overweight, being known that cholesterol biliary lithiasis is found in 40-year-old, obese, fertile women.\n\nIt is known that HP may contribute to the formation of cholesterol. Since there is a growing literature on the association of cholelithiasis with HP and H. hepaticus infection, serological tests (Ac) have been performed to determine an old infection, thus confirming the possible infectious etiology of cholesterol. These were positive. The drain was removed the next day after the intervention. The patient evolved normally.\n\nThe main hepatobiliary diseases involving HP\nConsidering the large number of people infected with the hepatitis B virus (over\n350 million), 25-30% of whom develop to hepatic cirrhosis, hepatocellular carcinoma or death, and that 50% of the world's population is affected by HP, it is understood why more and more studies are being developed to demonstrate the association between HP infection and the evolution of chronic type B hepatitis. Thus, the studies of Fan et al. as well as Ponzetto et al. have shown that the percentage of HP infection is much higher in patients with chronic hepatitis B than in the healthy population [9]. The study of JuanWang et al., more complex, involving 4645 people, of which 2977 patients with chronic B-hepatitis and 1,688 healthy individuals (control group), had the purpose of demonstrating the role of HP infection in the evolution of hepatitis B and resulted in the recommendation of screening and HP eradication in these patients [9].\n\nThis study showed a series of associations: \n\n- the much higher prevalence of HP infection in those infected with hepatitis B than in the healthy group, suggesting a strong association between HP infection and viral hepatitis B;\n\n- the role of HP as a risk factor in the evolution of viral hepatitis B;\n\n- the role of HP in the progression of chronic hepatitis B to fibrosis;\n\n- increased prevalence of HP infection in patients with B virus cirrhosis and significantly higher in patients with severe cirrhosis with B-virus class C Child-Pugh Turcotte;\n\n- the role of HP as a risk factor for hepatocellular carcinoma [9].\n\nA multi-center, observer study, conducted over a two-year period and published in September 2015, from three Chinese hospitals that included 255 patients with hepatic cirrhosis compensated with B virus treated with nucleoside analogues (NA), showed the role of infection HP on thrombocytopenia in these patients. They were divided into three groups: the first group was that of the patients with compensated cirrhosis uninfected with HP who received only NA. The second group was that of patients with compensated cirrhosis and infected with HP who received NA and triple therapy to eradicate the bacterium. The third group was with patients infected with HP who received only NA.\n\nIt was found that, in those with HP infection, the platelet count was considerably lower than in non-infected patients with compensated cirrhosis, and during the two years of follow-up, by triple HP eradication therapy, the platelet count increased significantly in HP-cured patients than in the other two groups [10].\n\nIt can be concluded that the eradication of HP in patients with compensated cirrhosis with B virus and thrombocytopenic is beneficial and that a screening of HP infection should be performed in all cirrhotic B virus and thrombocytopenic patients.\n\nThe study by G. Esmat and collaborators in 2011 sought a link between hepatopathy caused by virus C (HVC) and HP infection. It was performed on 85 patients divided into five groups as follows: \n\n- group I (control group 1): 16 patients with chronic hepatitis C without histological activity;\n\n- group II: 25 patients with chronical active hepatitis C;\n\n- group III: 17 patients with HVC-associated cirrhosis;\n\n- group IV: 16 patients with HVC-associated cirrhosis and hepatocellular carcinoma;\n\n- group V (control group 2): 11 patients suffering from gastro-duodenal and gallbladder disease, but negative for HVC\n\nAll eighty-five patients were sampled liver tissue samples that were tested by the Polymerase Chain Reaction (PCR) for the presence of the HP DNA Cag A gene. Besides this method there were also used biochemical, radiological and RT-PCR methods for HP RNA (11).\n\nThe presence of the HP Cag A gene was highest in the 4th group (75%), 52.9% in the 3rd group, and 32% in the 2nd group compared to the control groups where the PCR positive for the Cag A gene was significantly lower [11].\n\nThe following differences were found in the METAVIR (F) staging: the HP Cag A gene was present in 28.2% of the cases of advanced fibrosis (F3 and F4) and only 5.9% in the cases of early fibrosis (F1 and F2) [11].\n\nIn the METAVIR staging activity (inflammation) score, the following differences were found: the presence of HP Cag A gene was in A1 cases of 15.3% and in A2 of 12.9% [11].\n\nThere were no percentage differences in the presence of the Cag A gene depending on the amount of viral RNA and the Child-Pugh Turcotte class in those with cirrhosis with C virus versus group IV where the presence of the Cag A gene was significantly elevated, but there may be a link between the presence of the Cag A gene and the evolution of the chronical hepatitis or cirrhosis in the presence or absence of hepatocellular carcinoma [11].\n\nAlthough it was not possible to cultivate HP microorganisms from the liver, bile or gall bladder, Nilsson et al. found Helicobacter DNA in the liver of patients with primary cholangiocarcinoma and hepatocellular carcinoma. Failure cultivation HP from liver could be explained by using the frozen bile as a sample and the highly inhibitory effects of bile acid or body transformation in an adverse and biliary inhibitory environment, from the normal spiral form to an unstable coccoid, incompatible with life [12,13]. Another explanation might be that the presence of Helicobacter DNA could be the result of its propagation through the enterohepatic portal circuit [12,13].\n\nIn the same study, in a 23-year-old patient with Wilson's disease manifested by cirrhosis and who, in the evolution of the disease, developed a fulminant hepatitis, subsequently remitted, subjected to an exploratory laparoscopy, a microbe could be isolated having the morphological and enzymatic characteristics of HP (spiral, scarring, urease secretion as well as oxidase, catalase, alkaline phosphatase and glutamyl transpeptidase), cagA-negative but positive vacA, having a sequence similarity of RNA of 99.38% to that of HP. It should be noted that the patient presented a positive ureic respiratory test, from which the conclusion of the intense colonization of the patient's stomach with HP can be concluded [13].\n\nMost likely, the bacterium has accessed the liver either retrograde from the duodenum or by haematogenic dissemination through the port system of the intestinal lumen [13].\n\nAlthough it cannot be ruled out that a random association exists between the two pathologies (HP infection and Wilson's disease), there is still the possibility that the presence of HP infection may aggravate a pre-existing liver disease [13].\n\nGallstones are an important medical problem in their frequency and cost, which is an economic burden especially in North American and European countries. At the age of 60, it affects 20% of women, 10% of men. In the US, 1.200.000 cholecystectomies are performed annually, with the cost of 24 billion USD in 2017 for the treatment of the disease and its complications [14].\n\nIn the United States, the complications of this disease cause approximately 3,000 deaths per year, accounting for 0.12% of all deaths [15].\n\nGallstones can form anywhere in the liver and the biliary tract, 70-80% being cholesterol gallstones.\n\nThe risk factors associated with lithiasis are: age, female sex, pregnancy, weight loss and bariatric surgery, biliary sludge, total parenteral nutrition, various medications (estrogen, etc.) [15,16].\n\nOf the systemic diseases that favor biliary litiasis, by far obesity occupies a prominent place (15).\n\nLately, more and more authors, on the basis of documented studies, have shown in patients with cholesterol lithiasis the more frequent discovery of HP and other Helicobacter species (H. bilis, H. hepaticus) both at the bile and bile tract level as well as at the level of calculus. On the basis of the latest studies, we can state that there is a series of evidence on the role of HP infection in the etiopathogenesis of cholesterol stones formation. Although some studies have not confirmed the association between HP and the formation of cholesterol stones, this may be explained by the precariousness of how they were performed. We can discuss three reasons for the failure to support these ideas: \n\n- lack of properly chosen control groups [12];\n\n- differences in the prevalence of HP infection from a geographic and socio-economic point of view in the countries where the studies were developed (30-50% in developed countries vs. 70-90% in poorly developed countries) [12,15];\n\n- non-standardization of Helicobacter infection detection methods. Thus researchers from Taiwan obtained DNA fragments of Helicobacter species from patients with biliary lithiasis by PCR while authors from Germany, using the same method, did not achieve any similar results [12].\n\nPrimary sclerosing cholangitis (PSC) is a chronic cholestatic liver characterized by inflammation and fibrosis of the intrahepatic and /or extrahepatic biliary tract. Male/female ratio is 2/1.\n\nThe PSC evolution causes biliary tract damage and ultimately causing cholestasis, biliary cirrhosis, hepatocellular insufficiency and cholangiocarcinoma. Long-term monitoring of PSC patients has highlighted an increase in the incidence of biliary tract cancer, gallbladder and colon cancer that may be related to chronical inflammation and exposure to bile acids. With the exception of liver transplantation, no medical, endoscopic or surgical therapy has determined improvement in survival [17].\n\nPSC occurs in association with intestinal inflammatory disease, usually ulcerative colitis [17].\n\nEtiology is unknown but genetic and immunological factors are probably involved. Of the other factors involved, the toxic bile can be remembered. This is manifested by the absence of phospholipids in the bile which not only causes bile acids toxicity but also the formation of an over-saturated cholesterol bile that facilitates the oxidation of bile epithelial cells.\n\nWhether this is a primary lesion event or a secondary factor that leads to disease progression, it is a problem in the debate.\n\nPrimary biliary cholangitis (PBC), originally known as primary biliary cirrhosis, is a chronic cholestatic liver disease that typically affects middle-aged women: the women-to-men ratio is 9:1 [15,18,19].\n\nIts pathogenesis includes a combination of environmental and genetic factors. Genetic studies suggest that human leukocyte antigen (HLA) and type 1 helper T cells (TH1/interleukin 12) are important in the destruction of bile ducts within this autoimmune cholangitis [20].\n\nFinally, a large percentage of patients progresses to cirrhosis and require monitoring for hepatocellular carcinoma.\n\nThe study by Hans-Olof Nilsson and his team aimed to determine the existence of an association between Helicobacter species and PSC by investigating the existence of Helicobacter gene sequences on liver biopsies taken from these patients [18]. \n\nNote that the study also included patients with primary biliary cirrhosis, non-cholestatic hepatic cirrhosis (NCHC) and patients with normal liver (18) grouped as follows:\n\n- 12 patients with primary sclerosing cholangitis of which 9 biopsies were positive for the Helicobacter genus;\n\n- 12 patients with primary biliary cholangitis of which 11 biopsies were positive for the Helicobacter genus;\n\n- 13 patients with non-cholestatic hepatic cirrhosis (6 with alcoholic cirrhosis, 4 with autoimmune hepatitis cirrhosis and 3 with cryptogenic cirrhosis) of which a single biopsy was positive for the Helicobacter genus;\n\n- 10 patients with normal liver of which no biopsy was positive for the Helicobacter genus.\n\nPCR analyses used primers for the following Helicobacter species: Helicobacter pylori (the gene encoding a 26-kDa specific protein and rRNA 16S), Helicobacter bilis, Helicobacter pullorum and Helicobacter hepaticus. It should be noted that no biopsy was compatible with the primers for H. bilis, H. pullorum or H. hepaticus.\n\nOf the 24 patients with cholestatic disease (PSC and PBC), 20 patients representing 80% were positive for HP and the positivity for those with non-cholestatic and normal liver disease was 4% (1 out of 23 patients).\n\nThus, it was found, on the one hand, that patients with Helicobacter DNA sequences present in biopsies had higher bases of alkaline phosphatase and prothrombin time compared to those without Helicobacter DNA sequences [18]. One patient in the non-cholestatic liver cirrhosis group, with the Helicobacter sequence present, had the highest value alkaline phosphatase in this group. Later, on a microscopic biopsy review it was found that the histological structural model was actually suggestive of primary sclerosing cholangitis [18].\n\nAlso from Nilsson's study it is noted that there is a higher prevalence of this sequence of HP in patients with PSC and ulcerative colitis [18].\n\nFrom this study there is no significant difference between the two cholestatic diseases (PSC and PBC) in relation to the frequency of this sequence of HP [18].\n\nIt is known HP vulnerability in vitro to the human bile free acids, such as deoxycholic and chenodeoxycholic acids. This explains the lack of hepatic colonization but does not explain the presence of HP in the faeces, nor the lack of reaction in terms of HP increase in antrum even under the conditions of a duodenal gastric reflux, the only justification in these situations being the adaptation of HP in vivo to bile acids [18].\n\nThe association of Helicobacter-positive patients with cholestatic liver disease is motivated by the higher alkaline phosphatase and prothrombin complex factors (consisting of coagulation factors II, VII, IX and X), and the lack of differences between serum bilirubin values in HP positive versus negative and differences in prothrombin complex factor levels in Helicobacter positive vs. Helicobacter negative, supports the association with cholestasis but not with severe hepatic impairment [18].\n\nAfter initially considered optimal for the study to be made only for the patients with primary sclerosing cholangitis and those with primary biliary cholangitis associated with cholestatic inflammatory disease represent the control group, it was a surprise finding the relatively equal proportion of Helicobacter positive with both sclerosing cholangitis as well as biliary cholangitis. This suggests the lack of an etiological role of HP and rather a triggering and favoring role in the two cholestatic diseases [18].\n\nIt is known that HP Ig G antibodies are found more frequently in cirrhotic patients compared to those without cirrhosis. More recently, it was found that those with primary biliary cholangitis without gastric infection present anti-HP antibody titers; probably infected patients have gone through HP infection or have had a\ncross-reaction of antibodies against other Helicobacter species [18].\n\nConclusions\nThis paper wants to be a review of medical research performed correctly in terms of clinical and statistical which showed an association between HP infection and hepatobiliary disease (viral hepatitis with known consequences-cirrhosis and hepatocellular carcinoma) cholestatic syndromes (PSC and PBC) and especially biliary lithiasis in which the microorganism would also have an etiopathogenical role.\n\nRegarding HP eradication only in patients with compensated cirrhosis with virus B and thrombocytopenia, triple therapy resulted in increased the number of platelets in patients cured of HP. In the case of the other hepatobiliary diseases associated with HP infection, further studies are needed to demonstrate the importance of finding and treating microorganism.\n==== Refs\nReferences\n1 Atherton JC Blaser MJ Helicobacter pylori Infections Longo Dl Fauci AS Kasper DL Hauser SL Jameson JL Loscalzo JL Harrison's Gastroenterology and Hepatology - 18th edition 2010 New York McGraw-Hill 253 259 \n2 Jemilohun AC Otegbayo JA Helicobacter pylori infection: past, present and future Pan Afr Med J 2016 23 21 21 27200126 \n3 Akopyanz N Clifton SW Kersulyte D Crabtree JE Youree BE Reece CA Bukanov NO Drazek ES Roe BA Berg DE Analyses of the cag pathogenicity island of Helicobacter pylori Mol Microbiol 1998 28 37 53 9593295 \n4 Ohno T Vallström A Rugge M Ota H Graham DY Arnqvist A Yamaoka Y Effects of Blood Group Antigen-Binding Adhesin Expression during Helicobacter Pylori Infection of Mongolian Gerbils J Infect Dis 2011 203 5 726 735 21227917 \n5 Fu H-W Helicobacter pylori neutrophil-activating protein: From molecular pathogenesis to clinical applications World J Gastroenterol 2014 20 18 5294 5301 24833859 \n6 Yamaoka Y Mechanisms of disease: Helicobacter pylori virulence factors Nat Rev Gastroenterol Hepatol 2010 7 11 629 641 20938460 \n7 Kalali B Mejías-Luque R Javaheri A Gerhard M H. pylori Virulence Factors: Influence on Immune System and Pathology Mediators Inflamm 2014 2014 426309 426309 24587595 \n8 Popescu D Andronescu D Babe? PA Association between helicobacter pylori infection and insulin resistance: a systematic review Rom J Diabetes Nutr Metab Dis 2017 24 2 149 154 \n9 Wang J Chen RC Zheng YX Zhao SS Li N Zhou RR Huang Y Huang ZB Fan XG Helicobacter pylori infection may increase the risk of progression of chronic hepatitis B disease among the Chinese population: a meta-analysis Int J Infect Dis 2016 50 30 37 27457918 \n10 Zhang XH He Y Feng R Xu LP Jiang Q Jiang H Lu J Fu HX Liu H Wang JW Wang QM Feng FE Zhu XL Xu LL Xie YD Ma H Wang H Liu KY Huang XJ Helicobacter pylori infection influences the severity of thrombocytopenia and its treatment response in chronic hepatitis B patients with compensatory cirrhosis: A multicenter, observational study Platelets 2016 27 3 223 229 26338255 \n11 Esmat G El-Bendary M Zakarya S Ela MA Zalata K Role of Helicobacter pylori in patients with HCV-related chronic hepatitis and cirrhosis with or without hepatocellular carcinoma: possible association with disease progression J Viral Hepat 2012 19 7 473 479 22676359 \n12 Zhou D Zhang Y Gong W Mohamed SO Ogbomo H Wang X Liu Y Quan Z Are Helicobacter Pylori and Other Helicobacter Species Infection Associated with Human Biliary Lithiasis? A Meta-Analysis PLoS One 2011 6 11 e27390 e27390 22087306 \n13 Magalhães Queiroz Santos A Isolation of a Helicobacter strain from the human liver Gastroenterology 2001 121 4 1023 1024 11665691 \n14 Morris S Gurusamy KS Patel N Davidson BR Cost-effectiveness of early laparoscopic cholecystectomy for mild acute gallstone pancreatitis Br J Surgm 2014 101 7 828 835 \n15 Sandblom G Videhult P Crona Guterstam Svenner A Sadr-Azodi O Mortality after a cholecystectomy: a population-based study HPB (Oxford) 2015 17 3 239 243 25363135 \n16 Njeze GE Gallstones Niger J Surg 2013 19 2 49 55 24497751 \n17 Marina G Lindor KD Primary sclerosing cholangitis Can J Gastroenterol 2008 22 8 689 698 18701947 \n18 Nilsson HO Taneera J Castedal M Glatz E Olsson R Wadström T Identification of Helicobacter pylori and other Helicobacter species by PCR, hybridization, and partial DNA sequencing in human liver samples from patients with primary sclerosing cholangitis or primary biliary cirrhosis J Clin Microbiol 2000 38 3 1072 1076 10698999 \n19 American Association for the Study of Liver Diseases A name change for PBC: cholangitis replacing cirrhosis 2014 Available from:\nwww.aasld.org/name-change-pbc-cholangitis-replacing-cirrhosis \n20 Juran BD Lazaridis KN Genetics and Genomics of PBC Clin Liver Dis 2008 12 2 349 ix 18456185\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": null,
"issue": "44(2)",
"journal": "Current health sciences journal",
"keywords": " biliary litiasis; primary biliary cholangitis; primary sclerosing cholangitis; helicobacter Pylori; hepatobiliary disorders",
"medline_ta": "Curr Health Sci J",
"mesh_terms": null,
"nlm_unique_id": "101597164",
"other_id": null,
"pages": "186-191",
"pmc": null,
"pmid": "30687530",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "10698999;11665691;18456185;18701947;20938460;21227917;22087306;22676359;24497751;24587595;24756933;24833859;25363135;26338255;27457918;9593295",
"title": "The Association Between Helicobacter Pylori Infection and Liver and Biliary Tract Disorders.",
"title_normalized": "the association between helicobacter pylori infection and liver and biliary tract disorders"
} | [
{
"companynumb": "RO-MYLANLABS-2019M1013500",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": "... |
{
"abstract": "Atrial fibrillation (AF) is a major risk factor for stroke in the elderly population. The use of anticoagulation in patients with AF greatly reduces the risk for stroke, but results in an increased risk of bleeding. Over the past several years, direct oral anticoagulants (DOACs, dabigatran, rivaroxaban, and apixaban) have been used in place of warfarin for stroke prevention in AF. We conducted a retrospective cohort study to assess the safety of DOACs in very elderly patients (75+) managed in a health care system encompassing both community and academic settings. We found that 36 % of patients had moderate to severe renal failure (estimated glomerular filtration rate <59 ml/min/1.73 m(2)) at the time of DOAC initiation. 142 patients were followed for a mean of 2.56 years, and five experienced a major bleeding episode while on anticoagulation, for a rate of 1.37 per 100 person years. All major bleeding episodes were associated with a decline in GFR compared to baseline. There were 12 non-major bleeding episodes reported. HAS-BLED scores were similar for those patients who experienced bleeding complications compared to those who did not. 21 % of patients were prescribed an inappropriately low dose of DOAC based on approved recommendations. DOACs appear to be a safe form of anticoagulation in very elderly patients with AF. However, the decline in GFR among patients with major bleeding highlights the importance of routine renal function monitoring.",
"affiliations": "Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, 420 Delaware St SE, MMC 480, Minneapolis, MN, 55455, USA.;Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.;Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, 420 Delaware St SE, MMC 480, Minneapolis, MN, 55455, USA. datta009@umn.edu.",
"authors": "Khan|Fatima|F|;Huang|Hans|H|;Datta|Yvonne H|YH|",
"chemical_list": "D000925:Anticoagulants",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11239-016-1410-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-5305",
"issue": "42(4)",
"journal": "Journal of thrombosis and thrombolysis",
"keywords": "Apixaban; Atrial fibrillation; Bleeding; Dabigatran; Direct oral anticoagulants; Elderly; Rivaroxaban",
"medline_ta": "J Thromb Thrombolysis",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D005260:Female; D006470:Hemorrhage; D006801:Humans; D015994:Incidence; D008297:Male; D012189:Retrospective Studies",
"nlm_unique_id": "9502018",
"other_id": null,
"pages": "573-8",
"pmc": null,
"pmid": "27520093",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": "26330425;24655742;26121536;24251359;23086966;21111555;21576658;22746356;25588595;19717844;15842354;25995317;17693178;25910928;26590293;24895454;21870978;26620417;26530138;24561548;21830957;11343485",
"title": "Direct oral anticoagulant use and the incidence of bleeding in the very elderly with atrial fibrillation.",
"title_normalized": "direct oral anticoagulant use and the incidence of bleeding in the very elderly with atrial fibrillation"
} | [
{
"companynumb": "US-BAYER-2016-166081",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "OBJECTIVE\nVenlafaxine use during pregnancy has increased over the past decade in concert with accumulating reproductive safety data; however, systematic data on venlafaxine during lactation remain sparse. The current study characterizes the level and determinants of venlafaxine and desvenlafaxine concentrations in breast milk and in nursing infant plasma.\n\n\nMETHODS\nWomen participating in a prospective investigation of perinatal pharmacokinetics from January 2001 through July 2006 who were treated with venlafaxine and who chose to continue venlafaxine during lactation were included in the analysis. Breast milk samples were collected via breast pump from foremilk to hindmilk from a single breast to determine the excretion gradient, and serial samples were collected over 24 hours to determine the time course of excretion. Paired maternal/infant plasma samples were also collected. Venlafaxine and desvenlafaxine concentrations were determined using high-performance liquid chromatography with ultraviolet detection. Statistical analyses of breast milk and infant plasma concentrations and their determinants were conducted.\n\n\nRESULTS\nThirteen women and their nursing infants participated, providing 106 breast milk samples. The mean milk/plasma ratio was 275.3% (95% CI = 144.8% to 405.7%). There were statistically significant time courses of excretion for venlafaxine (R = 0.36, F = 6.82, P < .02), desvenlafaxine (R = 0.48, F = 4.41, P < .009), and combined venlafaxine/desvenlafaxine (R = 0.51, F = 5.16, P < .004), with the highest venlafaxine and desvenlafaxine concentrations in the breast milk occurring 8 hours after maternal ingestion. Infant plasma concentrations for combined venlafaxine/desvenlafaxine were 37.1% of maternal plasma concentrations. The theoretical infant venlafaxine/desvenlafaxine dose was 0.208 mg/kg/d, and the relative infant venlafaxine/desvenlafaxine dose was 8.1%. The theoretical and relative infant doses for desvenlafaxine were 197% and 224% higher, respectively, than those for venlafaxine. No adverse events were observed or reported in the nursing infants.\n\n\nCONCLUSIONS\nConsistent with previous investigations of medications in breast milk, the venlafaxine and desvenlafaxine milk/plasma ratios were highly variable. The rate of venlafaxine/desvenlafaxine excretion into human breast milk is relatively higher than that observed for other antidepressants, largely due to higher desvenlafaxine excretion. These data expand the extant literature on venlafaxine and desvenlafaxine in lactation.",
"affiliations": "Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 1365 Clifton Road, N.E., Suite B6100, Atlanta, GA 30322, USA. jeff.newport@emory.edu",
"authors": "Newport|D Jeffrey|DJ|;Ritchie|James C|JC|;Knight|Bettina T|BT|;Glover|Bailey A|BA|;Zach|Elizabeth B|EB|;Stowe|Zachary N|ZN|",
"chemical_list": "D003511:Cyclohexanols; D003692:Delayed-Action Preparations; D014179:Neurotransmitter Uptake Inhibitors; D017367:Serotonin Uptake Inhibitors; D000069470:Venlafaxine Hydrochloride; D000069468:Desvenlafaxine Succinate",
"country": "United States",
"delete": false,
"doi": "10.4088/JCP.08m05001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-6689",
"issue": "70(9)",
"journal": "The Journal of clinical psychiatry",
"keywords": null,
"medline_ta": "J Clin Psychiatry",
"mesh_terms": "D000328:Adult; D001942:Breast Feeding; D002851:Chromatography, High Pressure Liquid; D003511:Cyclohexanols; D003692:Delayed-Action Preparations; D000069468:Desvenlafaxine Succinate; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007774:Lactation; D008895:Milk, Human; D014179:Neurotransmitter Uptake Inhibitors; D011247:Pregnancy; D017367:Serotonin Uptake Inhibitors; D000069470:Venlafaxine Hydrochloride",
"nlm_unique_id": "7801243",
"other_id": null,
"pages": "1304-10",
"pmc": null,
"pmid": "19607765",
"pubdate": "2009-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Venlafaxine in human breast milk and nursing infant plasma: determination of exposure.",
"title_normalized": "venlafaxine in human breast milk and nursing infant plasma determination of exposure"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2021-01654",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
... |
{
"abstract": "OBJECTIVE\nTo explore aspects of anorexia nervosa occurring in older populations, especially men, by reviewing the literature and presenting a case study of an elderly man with unexplained vomiting and weight loss.\n\n\nMETHODS\nThe literature is reviewed and an illustrative case study of an elderly man with unexplained vomiting and weight loss is described.\n\n\nCONCLUSIONS\nAnorexia nervosa is an uncommon cause of unexplained weight loss in the elderly, but may be under-recognized and associated with a high level of mortality.",
"affiliations": "Psychiatry registrar, Redcliffe-Caboolture Mental Health Service, Caboolture, QLD, Australia.;Psychiatry registrar, Redcliffe-Caboolture Mental Health Service, Caboolture, QLD, Australia.;Psychiatry registrar, Redcliffe-Caboolture Mental Health Service, Caboolture, QLD, AustraliaPsychiatry registrar, Redcliffe-Caboolture Mental Health Service, Caboolture, QLD, AustraliaVisiting medical officer, Redcliffe-Caboolture Mental Health Service, Caboolture Hospital, Mckean St, Caboolture, QLD, Australia George_Bruxner@health.qld.gov.au.",
"authors": "Malik|Fahd|F|;Wijayatunga|Uditha|U|;Bruxner|George M|GM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1039856214530174",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1039-8562",
"issue": "22(3)",
"journal": "Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists",
"keywords": "anorexia nervosa; anorexia tardive; elderly; male",
"medline_ta": "Australas Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "9613603",
"other_id": null,
"pages": "285-287",
"pmc": null,
"pmid": "24699190",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A case of anorexia nervosa in an elderly man.",
"title_normalized": "a case of anorexia nervosa in an elderly man"
} | [
{
"companynumb": "AU-JNJFOC-20141007531",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALBUTEROL"
},
"drugadditional": null,
... |
{
"abstract": "A 47-year-old male with a 5-year history of palatal myoclonus was found on magnetic resonance imaging (MRI) examination to have an ectatic dominant left vertebral artery that compressed the left inferior olive. Microvascular decompression effectively eliminated his symptoms. This case and a similar case presented here with an ectatic vertebral-basilar system illustrate the value of standard MRI in conjunction with magnetic resonance angiography (MRA) in evaluating palatal myoclonus, and they suggest a potential role for decompressive surgery when persistent, highly symptomatic inferior olivary ischemia or compression occurs.",
"affiliations": "Dept. Neurology, M741 HSC, Univ. Missouri School of Medicine, One Hospital Drive, Columbia, MO 65212, USA.",
"authors": "Meyer|M A|MA|;David|C E|CE|;Chahin|N S|NS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/jon2000104221",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1051-2284",
"issue": "10(4)",
"journal": "Journal of neuroimaging : official journal of the American Society of Neuroimaging",
"keywords": null,
"medline_ta": "J Neuroimaging",
"mesh_terms": "D001927:Brain Diseases; D019299:Decompression, Surgical; D006801:Humans; D007511:Ischemia; D018810:Magnetic Resonance Angiography; D008297:Male; D008866:Microsurgery; D008875:Middle Aged; D009207:Myoclonus; D009847:Olivary Nucleus; D013684:Telangiectasis; D014711:Vertebral Artery",
"nlm_unique_id": "9102705",
"other_id": null,
"pages": "221-3",
"pmc": null,
"pmid": "11147401",
"pubdate": "2000-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Palatal myoclonus secondary to vertebral artery compression of the inferior olive.",
"title_normalized": "palatal myoclonus secondary to vertebral artery compression of the inferior olive"
} | [
{
"companynumb": "US-ROCHE-1717463",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
},
"drugadditional": null,
"drug... |
{
"abstract": "There are fewer than 20 published case reports of bradycardia or asystole during intracranial embolisation procedures. These are well described in open neurosurgical procedures, particularly involving the skull base. We present a case of a 59-year-old male patient who presented for elective embolisation of a dural arteriovenous fistula. During the injection of Onyx, the patient experience sudden asystole, which recurred after a second Onyx injection. Following successful treatment, a third injection proceeded without incident.",
"affiliations": "Division of Neuroradiology, Joint Department of Medical Imaging, Toronto Western Hospital, Toronto, Canada.;Division of Neuroradiology, Joint Department of Medical Imaging, Toronto Western Hospital, Toronto, Canada.;Division of Neuroradiology, Joint Department of Medical Imaging, Toronto Western Hospital, Toronto, Canada.;Division of Neuroradiology, Joint Department of Medical Imaging, Toronto Western Hospital, Toronto, Canada.",
"authors": "Nicholson|Patrick|P|https://orcid.org/0000-0001-7182-5112;Hilditch|Christopher|C|;Brinjikji|Waleed|W|;Krings|Timo|T|",
"chemical_list": "C450660:Onyx copolymer; D011145:Polyvinyls; D004121:Dimethyl Sulfoxide",
"country": "United States",
"delete": false,
"doi": "10.1177/1591019918800801",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1591-0199",
"issue": "25(2)",
"journal": "Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences",
"keywords": "Cardiac arrest; Onyx; dAVF; embolisation; haemodynamic instability",
"medline_ta": "Interv Neuroradiol",
"mesh_terms": "D020785:Central Nervous System Vascular Malformations; D002533:Cerebral Angiography; D004121:Dimethyl Sulfoxide; D004621:Embolization, Therapeutic; D006323:Heart Arrest; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011145:Polyvinyls; D059230:Reflex, Trigeminocardiac",
"nlm_unique_id": "9602695",
"other_id": null,
"pages": "132-134",
"pmc": null,
"pmid": "30227807",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17885228;19468673;20377980;20465896;21994285;22526439;27436213",
"title": "Asystole during onyx embolisation of a dural AV fistula: The trigeminocardiac reflex.",
"title_normalized": "asystole during onyx embolisation of a dural av fistula the trigeminocardiac reflex"
} | [
{
"companynumb": "CA-MYLANLABS-2019M1078906",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIMETHYL SULFOXIDE"
},
"drugadditional": "3",... |
{
"abstract": "In environments in which opioids are increasingly abused for recreation, children are becoming more at risk for both accidental and nonaccidental intoxication. In toxic doses, opioids can cause potentially lethal acute leukoencephalopathy, which has a predilection for the cerebellum in young children. The authors present the case of a 2-year-old girl who suffered an accidental opioid overdose, presenting with altered mental status requiring cardiorespiratory support. She required emergency posterior fossa decompression, partial cerebellectomy, and CSF drainage due to cerebellar edema compressing the fourth ventricle. To the authors' knowledge, this is the first report of surgical decompression used to treat cerebellar edema associated with opioid overdose in a child.",
"affiliations": "Department of Neurosurgery, Emory University School of Medicine;;Department of Radiology, Children's Healthcare of Atlanta, Scottish Rite Hospital;;Department of Neurosurgery, Emory University School of Medicine;;Department of Neurosurgery, Emory University School of Medicine;;Department of Neurosurgery, Children's Hospitals and Clinics of Minnesota, St. Paul, Minnesota.;Georgia Poison Center;;Department of Neurosurgery, Emory University School of Medicine;;Department of Neurosurgery, Emory University School of Medicine;",
"authors": "Reisner|Andrew|A|;Hayes|Laura L|LL|;Holland|Christopher M|CM|;Wrubel|David M|DM|;Kebriaei|Meysam A|MA|;Geller|Robert J|RJ|;Baum|Griffin R|GR|;Chern|Joshua J|JJ|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "United States",
"delete": false,
"doi": "10.3171/2015.4.PEDS14667",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1933-0707",
"issue": "16(6)",
"journal": "Journal of neurosurgery. Pediatrics",
"keywords": "PICU = pediatric intensive care unit; acute leukoencephalopathy; cerebellitis; opioid toxicity; surgical treatment",
"medline_ta": "J Neurosurg Pediatr",
"mesh_terms": "D000701:Analgesics, Opioid; D002531:Cerebellum; D002557:Cerebrospinal Fluid Shunts; D002675:Child, Preschool; D003244:Consciousness Disorders; D003388:Cranial Fossa, Posterior; D019299:Decompression, Surgical; D062787:Drug Overdose; D004487:Edema; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D059906:Neuroimaging; D019635:Neurosurgical Procedures; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101463759",
"other_id": null,
"pages": "752-7",
"pmc": null,
"pmid": "26339960",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Opioid overdose in a child: case report and discussion with emphasis on neurosurgical implications.",
"title_normalized": "opioid overdose in a child case report and discussion with emphasis on neurosurgical implications"
} | [
{
"companynumb": "US-ZYDUS-011186",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MORPHINE\\MORPHINE HYDROCHLORIDE\\MORPHINE SULFATE\\MORPHINE TARTRATE"
... |
{
"abstract": "At present, the only specific medical treatment for acute ischaemic stroke is intravenous administration of recombinant tissue plasminogen activator within 4.5 hours of stroke onset. In the last year, two scores for risk stratification of intracranial haemorrhage have been derived from multicentric European trial groups, the Safe Implementation of Treatment in Stroke - Symptomatic IntraCerebral Haemorrhage risk score (SITS-SICH) and the SEDAN score. The aim of this study was to pilot their use in a cohort of patients treated at a South African tertiary hospital. Prospectively collected data were used from a cohort of 41 patients who underwent thrombolysis at Groote Schuur Hospital from 2000 to 2012. Computerised tomography brain imaging was available for review in 23 of these cases. The SITS-SICH and SEDAN scores were then applied and risk prediction was compared with outcomes. Two patients suffered symptomatic intracranial haemorrhage (SICH), representing 4.9% (95% CI: 0-11.5%) of the cohort. This was comparable to the SICH rate in both the SITS-SICH (5.1%) and SEDAN (6.5%) cohorts. Patient scores in the Groote Schuur Hospital cohort appeared similar to those of the validation cohorts of both SITS-SICH and SEDAN. With increasing use of thrombolysis in a resource-constrained setting, these scores represent a potentially useful tool in patient selection of those most likely to benefit from intravenous thrombolysis, reducing risk for SICH and with the added benefit of curtailing cost.",
"affiliations": "Division of Neurology, Department of Medicine, Groote Schuur Hospital and University of Cape Town, South Africa. alex.v.klemp@gmail.com.;Division of Neurology, Department of Medicine, Groote Schuur Hospital and University of Cape Town, South Africa.;Department of Radiology, Groote Schuur Hospital and University of Cape Town, South Africa.;Division of Neurology, Department of Medicine, Groote Schuur Hospital and University of Cape Town, South Africa.",
"authors": "von Klemperer|A|A|;Bateman|K|K|;Owen|J|J|;Bryer|A|A|",
"chemical_list": "D001786:Blood Glucose; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D010959:Tissue Plasminogen Activator; D013988:Ticlopidine; D001241:Aspirin",
"country": "South Africa",
"delete": false,
"doi": "10.5830/CVJA-2014-043",
"fulltext": "\n==== Front\nCardiovasc J AfrCardiovasc J AfrTBCCardiovascular Journal of Africa1995-18921680-0745Clinics Cardive Publishing 2562953810.5830/CVJA-2014-043Cardiovascular TopicsThrombolysis risk prediction: applying the SITS-SICH and SEDAN scores\nin South African patients von Klemperer A MB ChBalex.v.klemp@gmail.comDivision of Neurology, Department of Medicine, Groote Schuur Hospital and\nUniversity of Cape Town, South AfricaBateman K MB ChB, MRCP (UK), FC Neurol (SA)Division of Neurology, Department of Medicine, Groote Schuur Hospital and\nUniversity of Cape Town, South AfricaBryer A MB ChB, PhDDivision of Neurology, Department of Medicine, Groote Schuur Hospital and\nUniversity of Cape Town, South AfricaOwen J MB ChBDepartment of Radiology, Groote Schuur Hospital and University of Cape\nTown, South AfricaSep-Oct 2014 25 5 224 227 www.cvja.co.za24 11 2013 14 8 2014 Copyright © 2010 Clinics Cardive\nPublishing2010This is an open-access article distributed under the terms of the\nCreative Commons Attribution License, which permits unrestricted use,\ndistribution, and reproduction in any medium, provided the original work is\nproperly cited.Abstract\nAt present, the only specific medical treatment for acute ischaemic stroke is\nintravenous administration of recombinant tissue plasminogen activator\nwithin 4.5 hours of stroke onset. In the last year, two scores for risk\nstratification of intracranial haemorrhage have been derived from\nmulticentric European trial groups, the Safe Implementation of Treatment in\nStroke – Symptomatic IntraCerebral Haemorrhage risk score (SITS-SICH) and\nthe SEDAN score. The aim of this study was to pilot their use in a cohort of\npatients treated at a South African tertiary hospital.\n\nProspectively collected data were used from a cohort of 41 patients who\nunderwent thrombolysis at Groote Schuur Hospital from 2000 to 2012.\nComputerised tomography brain imaging was available for review in 23 of\nthese cases. The SITS-SICH and SEDAN scores were then applied and risk\nprediction was compared with outcomes.\n\nTwo patients suffered symptomatic intracranial haemorrhage (SICH),\nrepresenting 4.9% (95% CI: 0–11.5%) of the cohort. This was comparable to\nthe SICH rate in both the SITS-SICH (5.1%) and SEDAN (6.5%) cohorts. Patient\nscores in the Groote Schuur Hospital cohort appeared similar to those of the\nvalidation cohorts of both SITS-SICH and SEDAN.\n\nWith increasing use of thrombolysis in a resource-constrained setting, these\nscores represent a potentially useful tool in patient selection of those\nmost likely to benefit from intravenous thrombolysis, reducing risk for SICH\nand with the added benefit of curtailing cost.\n\nstrokeacute ischaemic strokethrombolysisintracranial haemorrhageriskSEDANSITS-MOSTrTPArecombinant tissue plasminogen activatorSafe Implementation of Treatment in Stroke – Symptomatic IntraCerebral\nHaemorrhage risk scoreSouth AfricaGroote Schuur Hospital\n==== Body\nAbstract\nStroke is the most common cause of death in people over the age of 50 years in South\nAfrica.1 It is estimated that there were\napproximately 75 000 new cases of stroke in South Africa in 2008. Of these,\napproximately 25 000 were fatal within the first 28 days. In 2007, there were 350\n000 people living with stroke in South Africa, of whom 35% had moderate to severe\ndisability as a result of their stroke. 2\n\nCurrently, intravenous (IV) administration of recombinant tissue plasminogen\nactivator (tPA) within 4.5 hours of symptom onset is the only medical therapy shown\nto improve outcomes in acute ischaemic stroke.3-5 It has become the standard of\ncare in many international stroke centres.\n\nHowever, it is still unclear which patients are most likely to benefit and in what\ntreatment time frame. Initial evidence demonstrated the benefit of thrombolysis in\nselected patients presenting within three hours. It has subsequently been shown that\nthe window of maximum beneficial effect extends to 4.5 hours.6,7\n\nCareful selection of patients suitable for thrombolysis treatment is required to\nmaximise the benefit obtained and offset the risk of clinical deterioration due to\nsymptomatic intracranial haemorrhage. Observational data from SITS-MOST show\nthrombolysis to be as safe and effective in real clinical practice as in clinical\ntrials; however, the rate of SICH remained between 1.7 and 4.6%.8 It has been estimated that of 100 patients\ntreated with tPA, one will have a severely disabling or fatal outcome due to\ntPA-related intracranial haemorrhage. 9\n\nIn 2011, Wasserman and Bryer published data on a cohort of 42 patients treated with\ntPA at a tertiary hospital in Cape Town, which showed comparable safety and early\noutcomes to similar cohorts in both developed and developing countries.10 Many clinicians however remain concerned\nabout the use of this treatment modality and the risk of SICH.11\n\nTwo scoring systems that attempt to stratify patients by their risk of developing\nSICH following thrombolysis have recently been derived from multicentre cohorts of\npatients – the Safe Implementation of Treatment in Stroke – Symptomatic\nIntraCerebral Haemorrhage risk score (SITS-SICH)12 and the SEDAN score.13 The\nSITS-SICH score is derived from the SITS-MOST patient cohort and was internally\nvalidated on a random sample of more than 15 000 patients; it incorporates primarily\nclinical variables which best predict the SICH following thrombolysis with tPA. The\nSEDAN score is based on both clinical and radiological findings on computerised\ntomography (CT) of the brain, and was externally validated in a smaller cohort of\n828 patients.\n\nBoth scores however have been validated in European populations in developed\ncountries and their utility in a different setting is not known. Accurate assessment\nof risk is necessary for clinicians to select patients who will most benefit from\nthrombolytic therapy, at the lowest risk of bleeding complications such as SICH. In\na resource-constrained setting in which the cost of thrombolytic therapy is\nsignificant, the inclusion of a risk-prediction score to the protocol used for\ntreatment may improve the cost–benefit ratio, and optimise the allocation of scarce\nresources.\n\nThe aim of this pilot study was to evaluate the performance of both the SITS-SICH and\nSEDAN scores in predicting the risk of SICH in a Groote Schuur thrombolysis stroke\ncohort.\n\nMethods\nData were extracted from a prospective cohort comprising all patients presenting to\nGroote Schuur Hospital (GSH) between 2000 and May 2012 with acute ischaemic stroke,\nwho received thrombolytic therapy with IV tPA according to the GSH Stroke Unit\nprotocol. Patients who received mechanical thrombolysis or intra-arterial tPA were\nexcluded.\n\nAge, gender, past medical history and prior medication were recorded. Admission data\nof vital signs, serum glucose levels, stroke severity according to the NIHSS,\ndisability according to the modified Rankin score, and details of tPA administration\n(time to onset and dose) were also recorded. For this study, all available CT brain\nscans performed on admission (pre-thrombolysis) were re-evaluated by a radiologist\nin training for signs of early infarct or the dense middle cerebral artery (MCA)\nsign. The SITS-SICH and SEDAN scores (see below) were calculated from these data and\npatients were risk-stratified accordingly.\n\nBoth the SITS-SICH and SEDAN scoring systems (see Tables 1, 2) were developed\nusing multiple regression analyses, and identified elevated serum glucose levels and\nhigh NIHSS scores on admission as poor prognostic indicators. The risk of SICH\nvaried according to the SICH definition used: by the SITS-MOST definition, the risk\nranged from 0.2% (score of 0) to 9.2% (score ≥ 9) while the risk of SICH by the\nECASS II definition ranged from 1.4% (score 0) to 23.2% (score ≥ 9). The SEDAN score\nrevealed an increasing risk of SICH in the external validation cohort, ranging from\n0.01% (score 0) to 27.8% (highest score 6). The single largest risk factor\nidentified for the development of SICH in the SITS-MOST study was dual antiplatelet\ntherapy with both aspirin and clopidogrel.12,13\n\nTable 1 Components of SITS score and overall risk level12\nCategory\tPoints (15)\t\nAspirin + clopidogrel therapy\t2\t\nAspirin monotherapy\t1\t\nNIHSS > 13\t2\t\nNIHSS 7–12\t1\t\nBlood glucose ≥ 180 mg/dl*\t2\t\nAge ≥ 72 years\t1\t\nSystolic BP ≥ 146 mmHg\t1\t\nWeight ≥ 95 kg Onset-to-treatment time ≥ 180 min\t1\t\nHistory of hypertension\t1\t\n*180 mg/dl ≈10 mmol/l\n\nTable 2 SEDAN score13\nCategory\tTotal\t6\t\nBlood sugar (glucose) on admission\t≤ 8 mmol/l\t0\t\n8.1–12 mmol/l\t1\t\n> 12 mmol/l\t2\t\nSigns of early infarction on admission\nCT*\tNo\t0\t\nYes\t1\t\nDense middle cerebral artery sign on\nadmission CT\tNo\t0\t\nYes\t1\t\nAge (years)\t≤ 75\t0\t\n> 75\t1\t\nNHSS score on admission\t0–9 points\t0\t\n≥ 10 points\t1\t\n*Signs of early infarction: hypo-attenuation of the middle cerebral\nartery territory (< 1/3), obscuration of the lentiform nucleus,\ncortical sulcal effacement, focal hypo-attenuation, loss of the insular\nribbon/obscuration of the Sylvian fissure, loss of grey–white\ndifferentiation in the basal ganglia, hypo-attenuation of the basal\nganglia.\n\nThe primary outcome was symptomatic intracranial haemorrhage according to either the\nSITS-MOST and/or ECASS II definitions. The SITS-MOST definition of SICH is a local\nor remote type II parenchymal haemorrhage within 22 to 36 hours after treatment (or\nsooner) associated with a ≥ fourpoint deterioration on the NIHSS score from baseline\nor from the lowest score from baseline to 24 hours, or leading to death.12\n\nThe ECASS II definition of SICH was any intracranial haemorrhage on any\npost-treatment image, within seven days of initiating treatment associated with a ≥\nfour-point deterioration on the NIHSS score from baseline or from the lowest score\nin seven days, or leading to death.14 Other\noutcomes reported were death, asymptomatic intracranial haemorrhage (AIH), and\nextracranial haemorrhage (EH).\n\nDuring most of the cohort period, the GSH Stroke Unit protocol required\npost-thrombolysis CT brain scans to be performed routinely within 48 hours of\nthrombolysis, or urgently with any suspicion of an intracerebral haemorrhage.\nPost-thrombolysis CT scans were reviewed for this study by a radiologist trainee\nblinded to clinical outcomes for evidence of intracranial haemorrhage.\n\nEthical approval was obtained from the UCT Groote Schuur Hospital human research\nethics committee (Ref: 499/2013).\n\nResults\nIn total, 45 patients underwent thrombolysis for acute ischaemic stroke at the GSH\nStroke Unit from January 2000 to May 2012. Four patients underwent mechanical\nthrombolysis with intraarterial tPA, and were excluded. The remaining 41 patients\nwho received IV tPA for acute ischaemic stroke were included (see Table 3).\n\nTable 3 Baseline characteristics\nBaseline characteristics (n =\n42)\t\nMedian age, years (IQ range)\t62 (50–66)\t\nWeight on admission, kg (IQ range)\t76 (67–80)\t\nPreceding history of hypertension, n\n(%)\t27 (66)\t\nMedian systolic BP on admission, mmHg (IQ range)\t149 (134–175)\t\nOn anti-platelet therapy at admission,\nn (%)\t11 (27)\t\nAbnormal serum glucose on admission, n\n(%)\t8 (20)\t\nMean time to thrombolysis (min)\t169\t\nMedian NIHSS score on admission, n (IQ\nrange)\t14 (11–17)\t\nCT brain scans (n =\n23)\t\nEarly signs of infarction, n\n(%)\t16 (70)\t\nHyperdense MCA, n (%)\t7 (30)\t\nFive patients were older than 72 years, and two patients were older than 75 years at\nstroke onset. Admission systolic blood pressures (SBP) were above 180 mmHg in five\npatients and greater than 220 mmHg in one patient. Of those taking antiplatelet\ntherapy at the time of admission, all were on aspirin monotherapy. Time to onset of\ntreatment with tPA was greater than 180 min in 13 patients and none of these were\ntreated more than 4.5 hours after onset of symptoms. Pre- and post-thrombolysis CT\nscans were available for review in 23 patients.\n\nTwo patients suffered SICH (ECASS II definition) postthrombolysis, comprising 4.9% of\nthe cohort. CT scans were available for review in one patient only and confirmed\nthat the haemorrhage fulfilled the SITS-MOST criteria (2.4%). Of the four patients\nwho died during their admission for stroke, one patient suffered a fatal SICH, while\nthree other patients died from causes unrelated to thrombolysis therapy: cardiogenic\nheart failure following an acute myocardial infarction, and recurrent cerebral\ninfarction and subsequent pneumonia. Eight patients had evidence of asymptomatic\nintracranial haemorrhage, attributed to haemorrhagic conversion of the ischaemic\ninfarct. In four of these patients, the CT scan was available to verify this\nfinding. Two patients had extracranial haemorrhage, including one patient with a hip\nhaematoma.\n\nThe median SITS-SICH score for our patient cohort was 4 (IQR 2–5). The patients were\nstratified into low, average, moderate and high risk (see Table 1). In the GSH cohort, the majority of patients had 3–5\npoints, or average risk, including the two patients who developed SICH. There were\nno patients who were scored as high risk (> 9). The distribution of patient risk in\nthe GSH cohort differed from the SITS-SICH cohort, with more patients classified as\nlow or average risk, and no high-risk patients (Table 4).\n\nTable 4 Comparison of SEDA N scores and risk of SICH by ECASS II definition for\nGSH and SEDAN validation cohorts\nScore\tTotal GSH cohort (n = 41) % (n)\tTotal SITS cohort (n = 15 814) %\n(n)\tSICH rate (GSH) %\tSICH rate (SITS) %\t\nLow (0–2 points)\t29 (12 /41)\t22.7\t0\t1.6\t\nAverage (3–5 points)\t53.7 (22/41)\t55\t9\t4.7\t\nModerate (6–8 points)\t17.1 (7/41)\t21.4\t0\t8.9\t\nHigh (> 9 points)\t0\t1.1\t0\t23.2\t\nOverall rate\t\t\t4.6 (2/41)\t5.1\t\nOne GSH patient who had a SEDAN score of 3 suffered a SICH (by both ECASS II and\nSITS-SICH criteria). There was one death in this group, due to complications related\nto pneumonia (Table 5).\n\nTable 5 Comparison of SEDA N scores and risk of SICH by ECASS II definition for\nGSH and SEDAN validation cohorts\nScore\tTotal GSH cohort (n = 23) % (n)\tTotal SEDAN cohort %\tSICH rate (GSH) (n = 2) % (n)\tSICH rate (SEDAN)* %\t\n0\t4.4 (1)\t12.4\t0\t0.9\t\n1\t30.4 (7)\t27.5\t0\t3.5\t\n2\t34.8 (8)\t28.3\t0\t5.1\t\n3\t26.1 (6)\t20.9\t16.7 (1)\t9.2\t\n4\t0 (0)\t8.6\t0\t16\t\n5\t4.4 (1)\t2.2\t0\t27\t\n6\t0\t0\t0\t0\t\nDiscussion\nUrgent thrombolysis with IV tPA is a priority in the emergency medical treatment of\nacute ischaemic stroke. Robust efficacy data exists for this therapeutic modality,\nparticularly when administered within the first 90 min, and the window of benefit\nhas widened since it was first introduced from three to 4.5 hours after onset of\nsymptoms. Published data from the GSH Stroke Unit reveal similar rates of SICH to\nthose from developed and several developing countries, which provide some\nreassurance to clinicians concerned about the safety profile of this modality in a\nSouth African setting. However, the risk of SICH remains, and care should be taken\nto select patients who are likely to have the most benefit at the lowest risk of\nSICH.\n\nTo be practical, the application of risk scores for SICH should include information\nthat is easily obtained in the emergency unit (EU). They should contain independent\nrisk factors for SICH and take into account the interplay between these factors in\nan individual patient.\n\nThe SITS-SICH score uses clinical variables that can be attained relatively quickly\nand easily at the bedside in a resource-constrained area. It has been validated in\nover 16 000 patients from multiple centres, many of whom did not have prior\nexperience in thrombolysis. The SEDAN score uses clinical information but it relies\non the assessment of brain CT imaging for subtle signs of stroke, which may be\noverlooked in a busy EU setting by inexperienced reviewers. Many South African\ncentres use older (fewer slice) scanners that would decrease the sensitivity in\ndetecting such signs.\n\nThe overall rates of SICH seen in the SITS-SICH validation cohort of 5.1% per ECASS\nII definition and 1.8% per SITSMOST definition compare with the GSH rates of 4.8 and\n2.4%, respectively. The SICH rate in the SEDAN score validation cohort was 6.5%.\nThere appeared to be a trend towards GSH patients being slightly lower risk than\neither of the SITS-MOST or SEDAN validation cohorts. This may reflect the more\ncautious approach in patient selection being used at our centre.\n\nThe main limitation of this pilot study was that of small sample size and low event\nrate in the GSH cohort. One is unable to comment on the ability of either score to\nreliably predict the risk of haemorrhage. However, the overall rate of SICH by the\nECASS II definitions was similar between the cohorts studied.\n\nA further limitation was that CT brain scans taken prior to 2003 were not available\nfor a review of the images, although reports were present. Therefore, signs of early\ninfarction and a dense middle cerebral artery sign could not be evaluated as is\nrequired for the SEDAN scoring system, nor could we confirm the presence of a type\nII parenchymal haemorrhage, required for the SITS-MOST definition of SICH.\n\nConclusion\nThe scores, in particular the SITS-SICH score, represent a potentially useful\nclinical tool to aid in patient selection for thrombolysis in ischaemic stroke. This\nstudy, piloting their use in a South African cohort, suggests that they may be\napplicable in our context but further research is required to validate their use.\nWith the increasing use of thrombolysis on a national level, such\nrisk-stratification tools might be considered for inclusion into a stroke unit\nprotocol.\n==== Refs\nReferences\n1 Statistics South Africa. Mortality and causes of death in South Africa, 2007: Findings\nfrom death notification. Statistical Release P0309.3. Pretoria Statistics South Africa 2007 \n2 Bertram MY Katzenellenbogen J Vos T Bradshaw D Hofman KJ The disability adjusted life years due to stroke in South Africa\nin 2008. Int J Stroke 2013 1 5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23295022. \n3 Wardlaw JM Murray V Berge E Del Zoppo GJ Thrombolysis for acute ischaemic stroke (Review\n). Cochrane Systematic Rev 2009 4 \n4 The National Institute of Neurological Disorders and Stroke rt-PA Stroke\nStudy Group. Tissue plasminogen activator for acute ischemic\nstroke. N Engl J Med 1995 333 24 1581 1587 7477192 \n5 Kwiatkowski TG Libman RB Frankel M Tilley BC Morgenstern LB Lu M et al. Effects of tissue plasminogen activator for acute ischemic stroke\nat one year. National Institute of Neurological Disorders and Stroke\nRecombinant Tissue Plasminogen Activator Stroke Study Group. New Engl J Med 1999 340 23 1781 1787 Available from: http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00008506-199910000-00011. 10362821 \n6 Hacke W Kaste M Bluhmki E Brozman M Dávalos A Guidetti D et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic\nstroke. New Engl J Med 2008 359 13 1317 1329 Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa0804656. 18815396 \n7 Ford G Freemantle N ECASS-II: intravenous alteplase in acute ischaemic\nstroke. Lancet 1999 353 9146 65 Available from: http://linkinghub.elsevier.com/retrieve/pii/S0140673698000051. 10023968 \n8 Wahlgren N Ahmed N Dávalos A Ford G a Grond M Hacke W et al. Thrombolysis with alteplase for acute ischaemic stroke in the\nSafe Implementation of Thrombolysis in Stroke-Monitoring Study (SITSMOST):\nan observational study. Lancet 2007 369 9558 275 282 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17258667. 17258667 \n9 Saver JL Hemorrhage after thrombolytic therapy for stroke: the clinically\nrelevant number needed to harm. Stroke 2007 38 8 2279 2283 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17641238. 17641238 \n10 Wasserman S Bryer A Early outcomes of thrombolysis for acute ischaemic stroke in a\nSouth African tertiary care centre. South Afr Med J 2012 102 6 541 544 Available from http://www.ncbi.nlm.nih.gov/pubmed/22668959. \n11 Lahri S Wallis L South African ischaemic stroke guideline, 2010. South Afr Med J 2011 101 1 7 author reply 7–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21626967. \n12 Mazya M Egido JA Ford GA Lees KR Mikulik R Toni D et al. Predicting the risk of symptomatic intracerebral hemorrhage in\nischemic stroke treated with intravenous alteplase: safe implementation of\ntreatments in stroke (SITS) symptomatic intracerebral hemorrhage risk\nscore. Stroke 2012 43 6 1524 1531 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22442178. 22442178 \n13 Strbian D Engelter S Michel P Meretoja A Sekoranja L Ahlhelm FJ et al. Symptomatic intracranial hemorrhage after stroke thrombolysis:\nThe SEDAN Score. Ann Neurol 2012 71 5 634 641 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22522478. 22522478 \n14 Hacke W Kaste M Fieschi C von Kummer R Davalos A Meier D et al. Randomised double-blind placebo-controlled trial of thrombolytic\ntherapy with intravenous alteplase in acute ischaemic stroke (ECASS\nII). Lancet 1998 352 9136 1245 1251 Available from: http://linkinghub.elsevier.com/retrieve/pii/S0140673698080209. 9788453\n\n",
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"abstract": "Cardiac pheochromocytoma is relatively rare. Few reports describe the intraoperative and postoperative progression of patients experiencing a life-threatening pheochromocytoma crisis treated with extracorporeal membrane oxygenation (ECMO).A 35-year-old man was referred to our facility for paroxysmal hypertension with a 10-year history of sweating, headaches, cardiac palpitations, and postexercise dyspnea. The patient initially underwent urine catecholamine measurement and an isotope scan, somatostatin receptor scintigraphy, and 18F-fluorodeoxyglucose positron emission tomography/computer tomography (CT), which indicated a multiple, cardiac pheochromocytoma. Echocardiography, cardiac magnetic resonance imaging (MRI), CT reconstruction, and a coronary CT angiography revealed several lesions at the aortic root and along the cardiac vasculature.Multifocal cardiac pheochromocytoma was diagnosed and pheochromocytoma crisis with severe cyclic blood pressure fluctuation occurred during surgery.Surgical resection of multiple pheochromocytomas in the right medial carotid sheath, mediastinum between the main and pulmonary arteries, and between the abdominal aorta and inferior vena artery was performed. To ensure cardiac perfusion and avoid severe circulatory fluctuation, the cardiac paraganglioma resection was prioritized. After resecting the cardiac pheochromocytoma, a severe pheochromocytoma crisis with rapid cyclic blood pressure fluctuation developed. ECMO and intraaortic balloon pump (IABP) were initiated to stabilize circulation and perfusion. Phenoxybenzamine, norepinephrine, epinephrine, and fluid resuscitation were administered to support cardiovascular function.The magnitude of blood pressure fluctuation steadily decreased with treatment. IABP was discontinued after 3 days, and ECMO was discontinued after 16 days. The patient was discharged 3 months postoperatively.This case indicates that mechanical life support with ECMO is a valuable option for pheochromocytoma-induced cardiac shock and should be considered as an effective therapeutic choice in patients with highly unstable hemodynamic function.",
"affiliations": "From the Department of Critical Care Medicine (XZ, DL, LS, YL, WD); Department of Cardiac Surgery (QM); Department of Nuclear Medicine (FL); Department of Radiology (ZJ); Department of Endocrinology (ZZ); and Department of Anesthesiology (AL, YH), Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.",
"authors": "Zhou|Xiang|X|;Liu|Dawei|D|;Su|Longxiang|L|;Long|Yun|Y|;Du|Wei|W|;Miao|Qi|Q|;Li|Fang|F|;Jin|Zhengyu|Z|;Zeng|Zhengpei|Z|;Luo|Ailun|A|;Huang|Yuguang|Y|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2592992910.1097/MD.0000000000000790007903900ArticleClinical Case ReportPheochromocytoma Crisis With Severe Cyclic Blood Pressure Fluctuations in a Cardiac Pheochromocytoma Patient Successfully Resuscitated by Extracorporeal Membrane Oxygenation A Case ReportZhou Xiang MDLiu Dawei MDSu Longxiang MD, PhDLong Yun MDDu Wei MDMiao Qi MDLi Fang MDJin Zhengyu MDZeng Zhengpei MDLuo Ailun MDHuang Yuguang MDDurante. Alessandro From the Department of Critical Care Medicine (XZ, DL, LS, YL, WD); Department of Cardiac Surgery (QM); Department of Nuclear Medicine (FL); Department of Radiology (ZJ); Department of Endocrinology (ZZ); and Department of Anesthesiology (AL, YH), Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.Correspondence: Prof. Dawei Liu, Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China (e-mail: dwliu98@163.com).5 2015 01 5 2015 94 17 e7906 1 2015 19 3 2015 29 3 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.2015This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nCardiac pheochromocytoma is relatively rare. Few reports describe the intraoperative and postoperative progression of patients experiencing a life-threatening pheochromocytoma crisis treated with extracorporeal membrane oxygenation (ECMO).\n\nA 35-year-old man was referred to our facility for paroxysmal hypertension with a 10-year history of sweating, headaches, cardiac palpitations, and postexercise dyspnea. The patient initially underwent urine catecholamine measurement and an isotope scan, somatostatin receptor scintigraphy, and 18F-fluorodeoxyglucose positron emission tomography/computer tomography (CT), which indicated a multiple, cardiac pheochromocytoma. Echocardiography, cardiac magnetic resonance imaging (MRI), CT reconstruction, and a coronary CT angiography revealed several lesions at the aortic root and along the cardiac vasculature.\n\nMultifocal cardiac pheochromocytoma was diagnosed and pheochromocytoma crisis with severe cyclic blood pressure fluctuation occurred during surgery.\n\nSurgical resection of multiple pheochromocytomas in the right medial carotid sheath, mediastinum between the main and pulmonary arteries, and between the abdominal aorta and inferior vena artery was performed. To ensure cardiac perfusion and avoid severe circulatory fluctuation, the cardiac paraganglioma resection was prioritized. After resecting the cardiac pheochromocytoma, a severe pheochromocytoma crisis with rapid cyclic blood pressure fluctuation developed. ECMO and intraaortic balloon pump (IABP) were initiated to stabilize circulation and perfusion. Phenoxybenzamine, norepinephrine, epinephrine, and fluid resuscitation were administered to support cardiovascular function.\n\nThe magnitude of blood pressure fluctuation steadily decreased with treatment. IABP was discontinued after 3 days, and ECMO was discontinued after 16 days. The patient was discharged 3 months postoperatively.\n\nThis case indicates that mechanical life support with ECMO is a valuable option for pheochromocytoma-induced cardiac shock and should be considered as an effective therapeutic choice in patients with highly unstable hemodynamic function.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nPheochromocytomas are catecholamine-secreting tumors originating from the stem cells of the neural crest. Approximately 1% of pheochromocytomas are intrathoracic in origin,1 and cases of multiple pheochromocytomas containing both adrenal and extraadrenal tissue are even rarer.2 Pheochromocytoma crisis is a life-threatening emergency with a high mortality despite aggressive treatment, mostly due to cardiovascular failure.3,4 The clinical manifestation of pheochromocytoma crisis ranges from severe hypertension to circulatory failure and shock, but the most severe, complex, difficult, and rare form of pheochromocytoma crisis is cyclic hypertension alternating with hypotension.5,6 Some studies have reported that extracorporeal membrane oxygenation (ECMO) was successfully used to reverse pheochromocytoma-induced, Takotsubo-like cardiomyopathy and global heart failure or cardiogenic shock.3,7–11 However, there are no known reports describing ECMO use in cases of life-threatening pheochromocytoma crisis with rapid cyclic blood pressure fluctuation. Herein, we report a rare case of pheochromocytoma crisis presenting as rapid cyclic blood pressure fluctuation caused by multiple, cardiac pheochromocytomas that was successfully treated by ECMO.\n\nCONSENT\nWritten informed consent was obtained from the patient before and after all procedures, and for the publication of this case report and accompanying images.\n\nCASE REPORT\nA 35-year-old man was referred to our facility for paroxysmal hypertension with a 10-year history of sweating, headaches, cardiac palpitations, and postexercise dyspnea. His blood pressure was 140/90 mm Hg with regular antihypertensive medication. Pheochromocytoma was preliminary diagnosed due to his significantly elevated urinary norepinephrine concentration at 259.2 μg/24 h (normal range 16.69–40.65 μg/24 h). Radionuclide examination comprising an isotope scan (iodine-131 metaiodobenzylguanidine), somatostatin receptor scintigraphy, and 18F-fluorodeoxyglucose positron emission tomography/computer tomography (CT) confirmed the diagnosis (Figure 1A–C). An echocardiography, cardiac magnetic resonance imaging (MRI), and CT reconstruction revealed several lesions at the aortic root, and a coronary CT angiography displayed coronary lesions (Figure 1D–F). The patient also had severe left ventricular (LV) dysfunction (ejection fraction 45.1%, end-diastolic/end-systolic dimension 67/51 mm), which was attributed to a suspected catecholamine-induced cardiomyopathy. His family history indicated that his mother was also diagnosed pheochromocytoma, and his sister died of pheochromocytoma. In addition, the serum total calcium (2.53 mmol/L), free calcium (1.20 mmol/L), phosphorus (1.34 mmol/L), parathyroid hormone (23.4 pg/mL), gastrin (80.9 pg/mL), calcitonin (3.96 pg/mL), and alkaline phosphatase (109 U/L) were also detected to exclude the multiple endocrine neoplasia. Finally, histopathological examination confirmed a diagnosis of pheochromocytoma, supported by AE1/AE3(−), CD56(NK-1)(+), CgA(+), Ki-67 (index 3%), S100(+), and Syn(+) results on immunohistochemistry.\n\nFIGURE 1 Radioisotope imaging, echocardiography, PET, CT, and MRI in a 35-year-old man. (A) Whole-body 131I-MIBG imaging 24 and 48 h after tracer injection. Radioactive accumulation was observed in the right neck. Heterogeneous radioactivity was also detected in the chest and in mid-abdomen. (B) Somatostatin receptor scintigraphy at 1 and 4 h. Somatostatin expression was detected at the right medial root of the cervical carotid sheath. Expression was also detected in the mediastinum between the main and pulmonary arteries, and in the mid-abdomen. (C) PET scan. Multiple metabolic abnormalities were observed in the medial right carotid sheath (C1, SUVmax 13.6), mediastinum between the main and pulmonary arteries (C2, SUV max14.5), and between the abdominal aorta and inferior vena artery (C3, SUVmax 43.6), suggesting malignant neoplasia or malignant paraganglioma. (D) Echocardiography. The left ventricle was enlarged and had reduced function (45.1% ejection fraction). A moderate echogenic mass measuring 31 × 30 mm was found at the aortic root and left main coronary artery. (E) Cardiac MRI. A lobulated mass was found between the aortic root and main pulmonary artery extending to the aortic arch (56 × 56 × 40 mm). (F) CT angiography of the coronary vasculature. Multiple punctate calcifications were observed in the coronary arteries. A mass lesion was observed in the pericardium surrounding the left and right coronary arteries, leading to severe stenosis of the left main coronary artery and multiple stenotic areas in the left anterior descending artery. 131I-MIBG = iodine-131 metaiodobenzylguanidine, CT = computed tomography, MRI = magnetic resonance imaging, PET = positron emission tomography, SUVmax = maximum standardized uptake value.\n\nAfter consulting with specialists across multiple disciplines, including a cardiologist, surgeon, anesthesiologist, and endocrinologist, the patient underwent a combined cardiac paraganglioma resection, coronary artery bypass grafting (CABG), aortic sinus reconstruction, main and pulmonary artery reconstruction, and main and pulmonary artery arthroplasty under cardiopulmonary bypass (CPB). Anesthesia was induced with midazolam (5 mg), fentanyl (0.05 mg), and propofol (60 mg). Following tracheal intubation with vecuronium bromide, the patient's blood pressure was 160/105 mm Hg and heart rate (HR) 82 beats/min (bpm). After beginning the CPB, his mean arterial pressure (MAP) was maintained at 80 mm Hg with norepinephrine infused at 0.8 to 1.0 μg/kg/min. The tumor was resected in 218 minutes during CPB. After the successful tumor removal, however, the patient could not be weaned from CPB. Even with aggressive fluid resuscitation (4928 mL of fluid administered, total positive fluid balance of 2650 mL, central venous pressure [CVP] of 14 mm Hg), the patient's blood pressure decreased dramatically during our attempt to discontinue CPB, dropping <60/45 mm Hg without any response to vasopressin, norepinephrine at 60 μg/kg/min, and epinephrine at 2.0 μg/kg/min. The patient also exhibited ventricular arrhythmia with a HR of 140 bpm and 3 episodes of ventricular fibrillation. The patient was successfully defibrillated and the HR restored to 50 to 60 bpm. However, myocardial contraction failed to fully recover, and thus, venoarterial (V-A)-ECMO and intraaortic balloon pump (IABP) circulatory support were initiated. With V-A-ECMO treatment, the MAP increased to 60 mm Hg, a sinus rhythm was restored, and the HR remained at 60 bpm. The patient was transferred to the intensive care unit (ICU) for further treatment. The entire surgical progression is shown in Figure 2.\n\nFIGURE 2 Dynamic changes in cardiac function during and after resection of multiple cardiac pheochromocytomas. The heart rate (HR), systolic blood pressure (SYS), and diastolic blood pressure (DIA), and dosages of norepinephrine (NE), epinephrine (E), amiodarone, phentolamine, and ECMO with IABP after CPB are indicated. The dramatic cyclic blood pressure fluctuation during the intraoperative and postoperative periods is particularly notable. CPB = cardiopulmonary bypass, ECMO = extracorporeal membrane oxygenation, IABP = intraaortic balloon pump, ICU = intensive care unit.\n\nUpon arriving to the ICU, the patient was still in severe cardiac shock and hypoperfusion despite receiving norepinephrine at 60 μg/kg/min and epinephrine at 2.0 μg/kg/min. The CVP, Gap mean central venous-to-arterial CO2-gap (Pvco2–Paco2), central venous oxygen saturation, and lactic acid concentration were 11 mm Hg, 10.9 mm Hg, 68.3%, and 22 mmol/L, respectively. Transthoracic echocardiography (Vivid 7; GE Medical Systems, Milwaukee, WI) showed severe LV systolic dysfunction (ejection fraction 20%), and the velocity time integral (VTI) was 7 cm with no evidence of abnormal regional wall motion, LV enlargement, or pericardial effusion. Hypothermia and dehydration therapy were initiated to protect the brain.\n\nThirty minutes after entering the ICU, the patient's blood pressure began fluctuating significantly despite full analgesia and sedation. At this point, norepinephrine and epinephrine were discontinued, but his blood pressure then increased rapidly, with the systolic blood pressure as high as 140 mm Hg. Phenoxybenzamine was administered to control blood pressure, but the blood pressure quickly plummeted once more, and norepinephrine and epinephrine were reinitiated at 0.98 and 0.294 μg/kg/min, respectively. His blood pressure began to exhibit an unusual rhythmic alternation between phases of relative hypertension and hypotension. This cyclic hemodynamic crisis continued for the next 10 days. However, the wave amplitude steadily decreased over time with continuous ECMO and other life support therapy; the progression of ECMO treatment and the infection index change are shown in Table 1. The VTI increased to 12 cm, and the LV rejection fraction increased to 45% on day 10. IABP was discontinued 3 days postoperatively. The patient's condition steadily improved, and ECMO was discontinued 16 days postoperatively. The tracheal cannula was extubated successfully, and the patient was transferred to the general ward 34 days postoperatively and discharged 3 months postoperatively.\n\nTABLE 1 Clinical Data Including Infection Indicators, Vasoactive Drug Use, and ECMO Parameters During and After Pheochromocytoma Resection\n\nDISCUSSION\nThe majority of pheochromocytomas are located in the adrenal glands. With <1% of tumors localized to the thoracic cavity, cardiac pheochromocytoma is extremely rare.1 There are no known reports of multiple pheochromocytomas at the paracarotid, heart, and intraabdominal cavity as in the present case. Surgical resection is the definitive treatment for pheochromocytoma11,12; however, in this case, resection of the cardiac pheochromocytoma required CPB and adequate anticoagulation. Tumor resection at 3 different locations in a single surgery is extremely difficult and presents several challenges including a long surgical duration, significant hemorrhage, significant surgical trauma, and violent circulation fluctuations, all of which dramatically increase the risk of death. In this case, both the coronary and pulmonary arteries were invaded by the pheochromocytoma. Prioritizing the coronary resection may ensure cardiac perfusion, restore heart function, and avoid severe circulation fluctuations; therefore, we decided to perform the surgery in stages. The first stage comprised the cardiac paraganglioma resection, CABG, aortic sinus reconstruction, main and pulmonary artery reconstruction, and main and pulmonary artery arthroplasty. The second stage comprised the surgical removal of the remaining 2 pheochromocytomas.\n\nMechanical life support with ECMO is an effective treatment for refractory cardiac shock, especially when heart failure is likely reversible.13 In the current case, the clinical progression occurred in 2 stages: severe refractory shock and hypoperfusion intraoperatively following resection of the cardiac pheochromocytoma; and severe cyclic blood pressure fluctuation postoperatively in the ICU. ECMO played a key role in addressing the hemodynamic instability during both the stages.\n\nThe acute refractory shock in this patient intraoperatively may have several causes. First, the abrupt decrease in catecholamine concentration after resecting the cardiac pheochromocytoma may have caused a catecholamine-resistant vasoplegia. The primary risk factor for this type of blood pressure abnormality is catecholamine secretion14,15; thus, the massive catecholamine secretion from the pheochromocytoma may have exaggerated the vasoplegia severity. Second, direct toxic effects of catecholamines on the myocardium and coronary artery may have caused catecholamine-mediated cardiomyopathy. The toxic effects of catecholamines are likely relevant in the pheochromocytoma crisis. The probable mechanisms underlying catecholamine-mediated cardiomyopathy include excess sympathetic stimulation, myocardial stunning, coronary arterial spasm, increased sarcolemmal permeability, elevated intracellular calcium concentration, and damage induced by oxygen-derived free radicals.10 Third, postoperative vasoplegic syndrome (PVS) has been shown to contribute to refractory shock after CPB.16–18 PVS does not usually decrease the cardiac output or trigger cyclical blood pressure fluctuations itself, but it instead causes persistent hypotension that is difficult to correct or triggers high blood pressure. Therefore, contribution from PVS cannot be excluded in the present case. Fourth, CPB performed after inducing hypothermia and CABG surgery both directly inhibit heart function. Finally, massive catecholamine release from multiple pheochromocytomas can cause peripheral vasodilation, severe cardiac depression, or distributive and cardiogenic shock.19\n\nThe complex mechanisms of acute refractory shock in this patient during surgery resulted in hemodynamic function characterized by extremely low cardiac output and peripheral vascular resistance unresponsive to catecholamines. In this life-threatening scenario, IABP and V-A ECMO were available as extracorporeal support systems. IABP provides only limited additional cardiac output, which is usually inadequate for acute refractory shock. V-A ECMO is an alternative option able to adequately perfuse all the organs irrespective of the lung condition. It can perform the functions of both ventricles and lungs, and can support a failing heart long term as needed. V-A ECMO can be started within 30 minutes and easily discontinued bedside in the ICU. In the present case, the MAP increased to 60 mm Hg immediately after initiating V-A-ECMO. IABP was also initiated to reduce cardiac afterload, ensure coronary artery perfusion, and maintain the pulse pressure early during V-A ECMO.\n\nAfter beginning V-A ECMO and IABP, organ perfusion improved, metabolic acidosis was corrected, and the response to vasoactive drugs was restored. However, as perfusion to the 2 remaining pheochromocytomas was restored, the blood pressure began to immediately cycle between hypertension and hypotension. The mechanism for this rapid blood pressure fluctuation is unclear, but baroreflex failure may be responsible. Baroreceptors are tonically active and can respond quickly to blood pressure changes.20,21 These patients may rapidly respond to α-blocker drugs such as phentolamine. In contrast to other cases of pheochromocytoma crisis with cyclic blood pressure fluctuation, however, the cardiac function in this patient was severely inhibited by the complex mechanisms as described. In this scenario of cyclic hemodynamic crisis, V-A ECMO can provide consistent perfusion and strengthen the cardiovascular tolerance for rapid cyclic blood pressure fluctuation and fluid resuscitation irrespective of poor cardiac function. Thus, V-A ECMO was not only key in successfully addressing the hemodynamic instability during the first refractory shock stage, but also the most important therapy ensuring adequate organ perfusion during the second stage comprising cyclic blood pressure fluctuation.\n\nPheochromocytoma crisis is rare but can cause refractory cardiovascular collapse and, occasionally, cyclic blood pressure fluctuation. ECMO can be used as valuable option for pheochromocytoma-induced cardiogenic shock, especially when highly unstable hemodynamics occurred. In patients experiencing a pheochromocytoma crisis with rapid cyclic blood pressure fluctuation, if acute heart failure also occurred, V-A ECMO is the most important mechanical life support to strengthen the cardiovascular tolerance for cyclic hemodynamic crisis and guarantee organs perfusion in such extreme hemodynamic status.\n\nAbbreviations: CABG = coronary artery bypass grafting, CPB = cardiopulmonary bypass, CVP = central venous pressure, ECMO = extracorporeal membrane oxygenation, IABP = intraaortic balloon pump, ICU = intensive care unit, MAP = mean arterial pressure, MRI = magnetic resonance imaging, PET = positron emission tomography, PVS = postoperative vasoplegic syndrome, VTI = velocity time integral.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nREFERENCES\n1. Jebara VA Uva MS Farge A \nCardiac pheochromocytomas . Ann Thorac Surg \n1992 ; 53 :356 –361 .1731689 \n2. Safwat AS Bissada NK Seyam RM \nThe clinical spectrum of phaeochromocytoma: analysis of 115 patients . BJU Int \n2008 ; 101 :1561 –1564 .18261156 \n3. Suh IW Lee CW Kim YH \nCatastrophic catecholamine-induced cardiomyopathy mimicking acute myocardial infarction, rescued by extracorporeal membrane oxygenation (ECMO) in pheochromocytoma . J Korean Med Sci \n2008 ; 23 :350 –354 .18437026 \n4. Guerrero MA Schreinemakers JM Vriens MR \nClinical spectrum of pheochromocytoma . J Am Coll Surg \n2009 ; 209 :727 –732 .19959041 \n5. Scholten A Cisco RM Vriens MR \nPheochromocytoma crisis is not a surgical emergency . J Clin Endocrinol Metab \n2013 ; 98 :581 –591 .23284003 \n6. Ganguly A Grim CE Weinberger MH \nRapid cyclic fluctuations of blood pressure associated with an adrenal pheochromocytoma . Hypertension \n1984 ; 6 \n(2 pt 1) :281 –284 .6724665 \n7. Sojod G Diana M Wall J \nSuccessful extracorporeal membrane oxygenation treatment for pheochromocytoma-induced acute cardiac failure . Am J Emerg Med \n2012 ; 30 :1017.e1 –1017.e3 .21741786 \n8. Noorani A Vuylsteke A Lewis C \nA moribund athlete . Lancet \n2012 ; 380 :74 .22770460 \n9. Banfi C Juthier F Ennezat PV \nCentral extracorporeal life support in pheochromocytoma crisis . Ann Thorac Surg \n2012 ; 93 :1303 –1305 .22450084 \n10. Flam B Broome M Frenckner B \nPheochromocytoma-induced inverted Takotsubo-like cardiomyopathy leading to cardiogenic shock successfully treated with extracorporeal membrane oxygenation . J Intensive Care Med \n2014 ; pii: 0885066614552992 .\n11. Pacak K Eisenhofer G Ahlman H \nPheochromocytoma: recommendations for clinical practice from the First International Symposium, October 2005 . Nat Clin Pract Endocrinol Metab \n2007 ; 3 :92 –102 .17237836 \n12. Lenders JW Eisenhofer G Mannelli M \nPhaeochromocytoma . Lancet \n2005 ; 366 :665 –675 .16112304 \n13. Hsu PS Chen JL Hong GJ \nExtracorporeal membrane oxygenation for refractory cardiogenic shock after cardiac surgery: predictors of early mortality and outcome from 51 adult patients . Eur J Cardiothorac Surg \n2010 ; 37 :328 –333 .19748279 \n14. Lentschener C Gaujoux S Thillois JM \nIncreased arterial pressure is not predictive of haemodynamic instability in patients undergoing adrenalectomy for phaeochromocytoma . Acta Anaesthesiol Scand \n2009 ; 53 :522 –527 .19239408 \n15. Kramer CK Leitao CB Azevedo MJ \nDegree of catecholamine hypersecretion is the most important determinant of intra-operative hemodynamic outcomes in pheochromocytoma . J Endocrinol Investig \n2009 ; 32 :234 –237 .19542740 \n16. Argenziano M Chen JM Choudhri AF \nManagement of vasodilatory shock after cardiac surgery: identification of predisposing factors and use of a novel pressor agent . J Thorac Cardiovasc Surg \n1998 ; 116 :973 –980 .9832689 \n17. Levin RL Degrange MA Bruno GF \nMethylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery . Ann Thorac Surg \n2004 ; 77 :496 –499 .14759425 \n18. Byrne JG Leacche M Paul S \nRisk factors and outcomes for ‘vasoplegia syndrome’ following cardiac transplantation . Eur J Cardiothorac Surg \n2004 ; 25 :327 –332 .15019656 \n19. Bergland BE \nPheochromocytoma presenting as shock . Am J Emerg Med \n1989 ; 7 :44 –48 .2643960 \n20. Cohn JN \nParoxysmal hypertension and hypovolemia . N Engl J Med \n1966 ; 275 :643 –646 .5918098 \n21. Hamada M Shigematsu Y Mukai M \nBlood pressure response to the Valsalva maneuver in pheochromocytoma and pseudopheochromocytoma . Hypertension \n1995 ; 25 :266 –271 .7843777\n\n",
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"mesh_terms": "D000310:Adrenal Gland Neoplasms; D000328:Adult; D001794:Blood Pressure; D003937:Diagnosis, Differential; D003952:Diagnostic Imaging; D015199:Extracorporeal Membrane Oxygenation; D005440:Fluid Therapy; D006338:Heart Neoplasms; D006801:Humans; D007423:Intra-Aortic Balloon Pumping; D008297:Male; D010673:Pheochromocytoma",
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"title": "Pheochromocytoma crisis with severe cyclic blood pressure fluctuations in a cardiac pheochromocytoma patient successfully resuscitated by extracorporeal membrane oxygenation: a case report.",
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"abstract": "Essential thrombocythemia (ET) represents a risk factor for ischemic stroke, although it is a rare cause. Chronic myeloproliferative disorder is associated with proliferation of megakaryocytes sustained increases circulating platelet count. Essential thrombocythemia cause is not known, yet, many patients suffering from this disease may have no symptoms for a long time. Early detection is necessary because it may recur frequently thrombosis if not treated properly. We present a case of a 72 year old man with a history of three stroke events. The clinical diagnostic procedure revealed an increased platelet count was 961000/ml, and these cerebrovascular events were the first manifestation of essential thrombocythemia.",
"affiliations": "Department of Neurology, Hospital of Neuropsychiatry Craiova, Romania.;Department of Histology, University of Medicine and Pharmacy of Craiova, Romania.",
"authors": "Pavaloiu|R M|RM|;Mogoanta|L|L|",
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"doi": "10.12865/CHSJ.43.01.16",
"fulltext": "\n==== Front\nCurr Health Sci JCurr Health Sci JCHSJCurrent Health Sciences Journal2067-06562069-4032Medical University Publishing House Craiova 2017.43.01.1610.12865/CHSJ.43.01.16Case ReportRepeated Events of Acute Ischemic Stroke in a Patient with Essential Thrombocythemia PAVALOIU R.M. 1MOGOANTA L. 21 Department of Neurology, Hospital of Neuropsychiatry Craiova, Romania1 Department of Histology, University of Medicine and Pharmacy of Craiova, RomaniaCorresponding Author: Pavaloiu Raluca Maria\nPhDUniversity of Medicine and Pharmacy of CraiovaRomaniapavaloiuraluca@yahoo.comJan-Mar 2017 27 9 2017 43 1 95 97 17 1 2017 19 3 2017 Copyright © 2017, Medical University Publishing House Craiova2017This is an open-access article distributed under the terms of a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International Public License, which permits unrestricted use, adaptation, distribution and reproduction in any medium, non-commercially, provided the new creations are licensed under identical terms as the original work and the original work is properly cited.Essential thrombocythemia (ET) represents a risk factor for ischemic stroke, although it is a rare cause. Chronic myeloproliferative disorder is associated with proliferation of megakaryocytes sustained increases circulating platelet count. Essential thrombocythemia cause is not known, yet, many patients suffering from this disease may have no symptoms for a long time. Early detection is necessary because it may recur frequently thrombosis if not treated properly. We present a case of a 72 year old man with a history of three stroke events. The clinical diagnostic procedure revealed an increased platelet count was 961000/ml, and these cerebrovascular events were the first manifestation of essential thrombocythemia. \n\nIschemic strokeessential thrombocythemia\n==== Body\nIntroduction\nThe diagnosis of acute stroke is frequently made, because a large number of patients show focal neurologic signs, evidence of damage to the cranial nerves, or sign of intracranial hypertension. Essential thrombocythemia (ET) is a myelodysplastic syndrome and it is a rare cause of ischemic stroke [1 ]. Not only the total number of platelets but also their function are essential elements which should be considered in cases of stroke associated with thrombocytemia. Such as antiplatelet agents and control of various risk factors are entitled to limit abnormal platelet activation of endothelial damage and thus limiting the risk of early recurrent accidents [2 ]. Treatment with hydroxyurea is effective in decreasing the incidence and prevention of high risk of thrombosis in patients with essential thrombocythemia [3 ].\n\nCase Report \nIn our study we present the case of a 72 years old man, of rural provenience, retired from the working field, with antecedents of arterial hypertension and three events of ischemic stroke, it is brought in Neurology Clinic on March 20, 2016 with the following symptoms: right side weakness and aphasia. Our patient had an ischemic episode on February 29 in left vertebrobasilar territory, and in history he had multiple cerebral ischemic event in bilateral carotid territory and in right vertebrobasilar territory. The habitual medication is: Clopidogrel 75mg, Candesartan 16mg, Indapamide 1,5mg, Nicergoline 30mg, Piracetam 800mg.\n\nAt the objective examination at hospital admission the patient had: facial asymmetry, right muscle weakness, rhythmic heart sounds, BP=180/90mmHg, PR=88b/min, without loss of consciousness.\n\nAt the neurological examination of the patient reveals: hemiparetic right attitude, without stiff neck, eyeballs deviation to the left, right central facial paralysis, without swallowing disorders for solids and liquids, walking impossible in the moment of examination, segmental muscle strength low in the right limbs, right muscle weakness, cutaneous plantar reflex bilateral present, language disorder type mixed aphasia.\n\nInvestigation: CBC: Hgb = 12,7g/dl, Hct = 40,3%, WBC = 16,600/mm3, PLT = 961000/ml, Ly = 12,4%, ESR = 2mm/hour, glycaemia = 111mg/dl, ALAT = 9U/L, ASAT = 17U/L, creatinine = 1.09mg/dl, ferritin = 47,18ng/ml.\n\nAt cardiology examination patient has also primary hypertension and ischemic heart disease.\n\nBased on laboratory tests we noticed an increased number of platelets what prompted us to ask for a hematological consult, because their number was obviously very high.\n\nAt another anamnesis, we also analyzed the patient history and found that the previous hospitalization which presented an ischemic event in the left vertebra-basilar territory, platelet count also had an increased value about 623000/ml.\n\nMeet the increased value in the table 1 of platelet which the patient he had on both ischemic events occurred at short time for which he was hospitalized in our clinic.\n\nTable 1 Platelet value on different ischemic events\n\n29 February 2016\t20 March 2016\t\nPLT = 623000/ml\tPLT = 961000/ml\t\nHematological examination: based on spinal puncture which showed marrow hypercelularity, hyperplasia of megakaryocytes, normal iron deposits in the bone marrow and myelofibrosis absence and laboratory investigations the diagnosis was essential thrombocythemia.\n\nIs explained in detail to patient and his family the medical status of where they are, therapeutic options, and the risks and benefits associated with each option.\n\nThe patient received a treatment with hydroxiurea 500mg x 2/day recommended by the hematologist.\n\nThe major goal of treatment is to prevent thrombosis and thromboembolic complications, as the leading cause of morbidity and mortality.\n\nIn the first week the patient presented a good response to treatment, as follows on March 29, the patient had a platelet value of 733000/ml.\n\nEvolution was still good and a few days later on April 6 exactly the platelet count have declined reaching a value of 719000/ml. \n\nOf course the patient continued treatment for stroke with platelet antiaggregating agents and neuroprotective, but also the treatment of cardiovascular risk factors with diuretics and antihypertensive drugs.\n\nComputerized tomography scan: the appearance sequel 4.7/1.8cm in the right cerebellar hemisphere, similar area with diameter of 7mm at the left ponto-mesencephalon region (Fig.1). \n\nSubcortical hypodensity with diameter of 13 mm in the left frontal region. Moderate cerebral atrophy, ventricular system on the midline (Fig. 2). \n\nDuring hospitalization, the patient was easily psychomotor agitated in the first days of stroke, no episodes of fever, bowel and urine output were normal, presented fluctuations in blood pressure and the heart rate, with gradual remission of motor deficits and the elements that constituted the clinical picture of ischemic stroke. \n\nAll this confirms the diagnosis of recent ischemic stroke and multiple sequels associated with essential thrombocythemia.\n\nFigure 1 The first CT scan on 29.02.2016, hypodense area with diameter of 7 mm at left ponto-mesencephalon region\n\nFigure 2 CT scan made on 20.03.2016, hypodensity with a diameter of 13mm in the left frontal region\n\nA platelet antiaggregating agent were also administered which is indicated to the patient witth intermediate risk.\n\nPatient evolution has been favorable, with progressive clinical improvement and also start neurological recover for the motor deficit. The patient was closely monitored for complications and received appropriate follow-up.\n\nDiscussion\nMultiple studies have shown that both the incidence and prevalence of stroke is increased due to the high frequency of risk factors.\n\nEssential thrombocythemia is recognized as a risk factor for cerebral ischemic events, but is meet more rarely.\n\nPathogenic mechanism was analyzed in several studies and has demonstrated a causal relationship between elevated platelet count and marked abnormalities of platelet function are associated with an increased risk of vascular occlusion [4 ,5 ].\n\nA small portion of patients diagnosed with essential thrombocythemia can develop later acute leukemia or myelofibrosis. Essential thrombocythemia patients may have a normal lifespan if they are closely monitored and treated appropriately, in particular to avoid its complications.\n\nClinical and laboratory data, hematological examination and the favorable response at the treatment may be arguments for the diagnosis of essential thrombocythemia. \n\nThe most frequent risk factors of the ischemic stroke are aterosclerosis and cardiac arrhythmias, but also are involved other factors as coagulation disorders. \n\nIn the present case, we considered that many recurrent infarction were secondary to platelet aggregation of several months, which causes gradual occlusion of vessels.\n\nRegarding the therapeutic protocol of patients with ischemic vascular events due to essential thrombocythemia, the recommended approach is a combination of chemotherapeutic agents with antiplatelet drugs [6 ].\n\nHydroxyurea is a non alkylating agent that has been proposed as a treatment of choice in patients with essential thrombocythemia who had at least one previous thrombotic event and aged over 60 years [7 ].\n\nHydroxyurea ability to reduce platelet counts in patients with essential thrombocythemia is well known, but its effectiveness in reducing thrombotic complications is not fully understood therfore the combination with antiplatelet medication is clearly indicated [3 ].\n\nConclusion\nIn the end we could affirm that in the clinical practice it is sometimes difficult to diagnose an essential thrombocythemia. Complete blood count should be read carefully and essential thrombocythemia can be suspected even if the platelet count is not increased greatly, especially in patients with ischemic stroke repeated. Hematologist must confirm the diagnosis as early and initiate appropriate treatment management.\n\nAcknowledgments\nAll authors equally contributed in the research and drafting of this paper.\n==== Refs\nReferences\n1 Mallada-Frechin J Abellán-Miralles I Medrano V Fernández-Izquierdo S Piqueras-Rodríguez L Ischemic stroke as a presentation of essential thrombocythemia Rev Neurol 2004 38 11 1032 1034 15202080 \n2 Alecu C Abraham P Ternisien C Enon B Saumet JL Essential thrombocythemia and cerebral ischemic accident J Mal Vasc 1999 24 4 300 302 10582180 \n3 Cortelazzo S Finazzi G Ruggeri M Vestri O Galli M Rodeghiero F Barbui T Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis N Engl J Med 1995 332 17 1132 1136 7700286 \n4 Zucker S Mielke CH Classification of thrombocytosis based on platelet function tests: Correlation with hemorrhagic and thrombotic complications Lab Clin Med 1972 80 3 385 394 \n5 Wu K-YK Platelet hyperaggregability and thrombosis in patients with thrombocythemia Ann Intern Med 1978 88 1 7 11 619762 \n6 Ross Russell RW Wade JPH Haematological causes of cerebrovascular disease Toole JF Handbook of Clinical Neurology: Vascular Diseases 1989 Amsterdam, Netherlands Elsevier Science Publishers BV 463 481 \n7 Cortelazzo S Viero P Finazzi G D’Emilio A Rodeghiero F Barbui T Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia J Clin Oncol 1990 8 3 556 562 2307991\n\n",
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"keywords": "Ischemic stroke; essential thrombocythemia",
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"title": "Repeated Events of Acute Ischemic Stroke in a Patient with Essential Thrombocythemia.",
"title_normalized": "repeated events of acute ischemic stroke in a patient with essential thrombocythemia"
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"abstract": "BACKGROUND\nFingolimod is the first oral agent used for treatment of relapsing-remitting multiple sclerosis. Macular edema, but not retinal hemorrhage, is a well-known adverse effect of fingolimod treatment. To the best of our knowledge, this is the first case report of extensive retinal hemorrhages following fingolimod treatment.\n\n\nMETHODS\nA 31-year-old male with relapsing-remitting multiple sclerosis developed macular edema and retinal hemorrhages in his left eye, 1 month after starting fingolimod treatment; treatment was then discontinued. The hemorrhages were flame-shaped, and were extensive along retinal arteries and veins. The hemorrhages started to decrease at 4 weeks and disappeared completely at 24 weeks after cessation of fingolimod treatment.\n\n\nCONCLUSIONS\nOccurrence of retinal hemorrhage warrants careful follow-up for multiple sclerosis patients treated with fingolimod.",
"affiliations": "Department of Ophthalmology, Kyoto Hakuaikai Hospital, 1 Keshiyama, Kamigamo, Kita-ku, Kyoto, 603-8041, Japan. naonao33k6ki@hotmail.co.jp.;Department of Neurology, Kyoto Hakuaikai Hospital, 1 Keshiyama, Kamigamo, Kita-ku, Kyoto, 603-8041, Japan. saidakyoko@yahoo.co.jp.",
"authors": "Ueda|Naoko|N|;Saida|Kyoko|K|",
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"fulltext": "\n==== Front\nBMC OphthalmolBMC OphthalmolBMC Ophthalmology1471-2415BioMed Central London 2648172812510.1186/s12886-015-0125-9Case ReportRetinal hemorrhages following fingolimod treatment for multiple sclerosis; a case report Ueda Naoko 81-72-672-8720naonao33k6ki@hotmail.co.jp Saida Kyoko saidakyoko@yahoo.co.jp Department of Ophthalmology, Kyoto Hakuaikai Hospital, 1 Keshiyama, Kamigamo, Kita-ku, Kyoto, 603-8041 Japan Department of Neurology, Kyoto Hakuaikai Hospital, 1 Keshiyama, Kamigamo, Kita-ku, Kyoto, 603-8041 Japan 19 10 2015 19 10 2015 2015 15 13522 6 2015 9 10 2015 © Ueda and Saida. 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nFingolimod is the first oral agent used for treatment of relapsing-remitting multiple sclerosis. Macular edema, but not retinal hemorrhage, is a well-known adverse effect of fingolimod treatment. To the best of our knowledge, this is the first case report of extensive retinal hemorrhages following fingolimod treatment.\n\nCase presentation\nA 31-year-old male with relapsing-remitting multiple sclerosis developed macular edema and retinal hemorrhages in his left eye, 1 month after starting fingolimod treatment; treatment was then discontinued. The hemorrhages were flame-shaped, and were extensive along retinal arteries and veins. The hemorrhages started to decrease at 4 weeks and disappeared completely at 24 weeks after cessation of fingolimod treatment.\n\nConclusions\nOccurrence of retinal hemorrhage warrants careful follow-up for multiple sclerosis patients treated with fingolimod.\n\nKeywords\nRetinal hemorrhagesFingolimodRelapsing-remitting multiple sclerosisSide effectMacular edemaissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nFingolimod (Gilenya®, Novartis, Emeryville, CA, USA) is the first oral agent used for treatment of relapsing-remitting multiple sclerosis (RRMS). Macular edema (ME) is a well-known adverse effect of fingolimod treatment, occurring in approximately 0.4 % of patients [fingolimod-associated macular edema (FAME)] [1]. However, retinal hemorrhage has been almost unrecognized as a side effect of fingolimod treatment. We therefore report a case of extensive flame-shaped retinal hemorrhages in a patient treated with fingolimod.\n\nCase presentation\nA 31-year-old male with a 13-year history of RRMS, after fingolimod treatment for 1 month, was diagnosed with ME and retinal hemorrhages in his left eye at a regular ophthalmic examination. His past history revealed that the onset of MS was accompanied by a visual disorder. He presented with several gadolinium-enhanced active lesions in his brain, despite therapies of steroid pulse, plasma exchanges, immunoglobulin, and interferon-beta (−β). Although interferon-β was used for a period of 6 months, 6 years prior, it was discontinued because of allergic skin reactions. The symptoms had improved after undergoing a course of five plasma exchanges 5 years prior but the patient refused further treatment. Over several years, the patient had developed paralysis in his right upper limb, both lower limbs, and had severe urinary incontinence and constipation. His Expanded Disability Score Scale (EDSS) was 8.5. Anti-aquaporin-4 antibody tested negative. Laboratory studies, including bleeding and coagulation tests, were within normal limits. He had no history of hypertension (blood pressure approximately 90–105/50–75 mmHg), diabetes mellitus, or hematological diseases. When retinal hemorrhages were recognized, the hemoglobin level was 15.0 g/dL and the platelet count was 210,000/μL (within the normal range). The patient had no history of uveitis and pars planitis.\n\nAt the first ophthalmological examination before taking fingolimod, his corrected visual acuity was 20/600 OD and 20/400 OS, optic disc color was pale, and spectral domain optical coherence tomography (SD-OCT) showed a thinner retina (particularly in the nerve fiber layer) without ME in both eyes (Fig. 1). This was regarded as the cause of decreased visual acuity. In all directions, the patient showed gaze-evoked nystagmus.Fig. 1 Spectral domain optical coherence tomography (SD-OCT) scans of both eyes before fingolimod treatment. The thinning of retinal nerve fiber layers was recognized, with (a) showing horizontal and (b) showing vertical images in the right eye, and (c) showing horizontal and (d) showing vertical images in the left eye. Because of the patient’s nystagmus, the precise averaging of multiple SD-OCT B-scans was not possible, so single B-scan images are shown\n\n\n\nFour weeks after fingolimod treatment, his left eye revealed extensive flame-shaped retinal hemorrhages along retinal arteries and veins (Fig. 2) as well as cystic ME, as measured by SD-OCT (Fig. 3). His visual acuity did not decrease considerably, with 20/600 OD and 20/500 OS. Most of the hemorrhages were found along both retinal arteries and veins beyond the mid-periphery involving all four quadrants of the retina. Deeper dot-blot hemorrhages, and a hemorrhage on the optic disc at the 12 to 1 o’clock position, were also recognized. The diameter and tortuosity of the retinal veins after the hemorrhages were the same as before the hemorrhages. Both eyes had no inflammatory signs in the anterior segment and vitreous, as assessed by slit lamp biomicroscopy examination. Fingolimod was discontinued. Because FAME remained for 13 weeks, topical treatment with 0.1 % betamethasone, four times daily, was started. FAME was resolved completely 4 weeks after starting topical steroid therapy; that was 17 weeks after the cessation of fingolimod. Retinal hemorrhages remained unchanged for 4 weeks after the cessation of fingolimod treatment, then started to decrease and disappeared completely at 24 weeks, indicating that the hemorrhages existed for 7 weeks longer than the FAME. During the treatments and follow-ups, neither retinal hemorrhages nor ME developed in the right eye. The patient’s visual acuity at the time of disappearance of retinal hemorrhages and FAME was 20/400 OD and 20/400 OS. Fluorescein angiography was not performed because the patient could not retain a sitting position.Fig. 2 Color fundus photography of the patient. Flame-shaped hemorrhages are seen along the retinal arteries and veins in the left eye 1 month after starting fingolimod treatment. Deeper dot-blot hemorrhages, and a hemorrhage on the disc at the 12 to 1 o’clock position, were also recognized. Moderate macular edema is also shown\n\nFig. 3 Spectral domain optical coherence tomography (SD-OCT) scans through the fovea. a Four weeks after starting fingolimod treatment, SD-OCT showed cystoid macular edema in the left eye. At that time, fingolimod was terminated. b Three weeks and (c) 13 weeks after cessation of fingolimod treatment, macular edema was still present. Topical betamethasone treatment began at 13 weeks. d Macular edema resolved 4 weeks after topical steroid treatment. Because of the patient’s nystagmus, the precise averaging of multiple SDOCT B-scans was not possible, and single B-scan images are shown\n\n\n\nDiscussion\nThis case study revealed extensive flame-shaped retinal hemorrhages in addition to ME, following fingolimod treatment. The retinal hemorrhages were mainly present at the mid-periphery. There were no differences of retinal vein dilatation and tortuosity before and after hemorrhaging. The hemorrhage pattern was considered to be different from that of central or branch retinal vein occlusion. The patient had no history of hypertension, diabetes mellitus, or hematological diseases. Eales disease and tuberculous vasculitis also cause uni/bilateral peripheral retinal hemorrhages. Although the purified protein derivative (PPD) skin test was not done, the hemorrhages gradually disappeared completely in 24 weeks without oral corticosteroid or anti-tuberculosis treatment after fingolimod was discontinued. There were no signs of vascular occlusion or retinal neovascularization that are often recognized in Eales disease.\n\nTo our knowledge, there has been only one report of a macular hemorrhage without apparent causes following treatment with fingolimod [2] that was completely resolved soon after discontinuation of fingolimod. This case report suggests that fingolimod may play a role in disrupting vascular integrity, because hemorrhages are not routinely seen in MS patients without other signs of uveitis.\n\nFAME is a well-known side effect of fingolimod. The sphingosine-1-phosphate (S1P) receptor plays a role in regulating vascular permeability, and enhancing endothelial barrier integrity. Fingolimod, a structural analog of S1P, inhibits this barrier action and leads to increased vascular permeability [3]. This may be the pathophysiological mechanism involving FAME.\n\nLightman et al. reported that cases of acute optic neuritis are characterized by retinal vascular abnormalities [4]. Their fluorescein angiograms showed multiple site leakage in the mid-peripheral retina. Optic neuritis patients with vascular abnormalities have a tendency to develop MS [4]. Recently, microcystic ME, predominantly affecting the inner nuclear layer, was reported in 4.7 % of patients with MS, and was more common in eyes with higher Multiple Sclerosis Severity Scores [5]. The presence of microcystic ME in MS suggests that there may be a breakdown of the blood-retinal barrier and tight junction integrity [5]. These observations suggest that the mid-peripheral retinal hemorrhages described in the present case report may have been associated with MS-associated uveitis, and could have introduced blood retinal barrier disruption.\n\nIn the present case, we found thinning of nerve fiber layers at the same level in both eyes, but it was only in the left eye that ME and retinal hemorrhages were developed. In FAME, 74 % of onset is the single eye onset type [6]. In microcystic edema in MS, two-thirds of the cases are reported as the single eye onset type [5]. The cause of symptom development in only a single eye is unclear, but MS patients are known to develop multiple and asymmetric symptoms.\n\nOur case report suggests that not only multiple sclerosis inflammatory disease, but also MS treatment with fingolimod, may lead to an increase in vascular permeability in some patients. Besides FAME, in severe cases of MS with persistent inflammation, fingolimod may also cause retinal hemorrhage.\n\nConclusions\nOccurrence of retinal hemorrhages warrants careful follow-up of MS patients treated with fingolimod.\n\nConsent\nBecause the patient could not move his hands smoothly, written informed consent was obtained from the patient’s mother for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nEthics approval\nApproval for this work was obtained from the Hakuaikai Ethics Committee of Kyoto, Japan.\n\nAbbreviations\nRRMSRelapsing-remitting multiple sclerosis\n\nMEMacular edema\n\nFAMEFingolimod-associated macular edema\n\nEDSSExpanded Disability Score Scale\n\nSD-OCTSpectral domain optical coherence tomography\n\nMSMultiple sclerosis\n\nS1PSphingosine-1-phospate\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nBoth authors, NU and KS, had full access to the data, and read and approved the final manuscript. Both authors were responsible for data collection. As the ophthalmologist, NU treated the patient, designed this study, drafted the manuscript and reviewed the literature. As the neurologist, KS also treated the patient and participated in the design of the study, review of the literature, and review of the manuscript.\n\nAcknowledgements\nThe authors thank Dr. Takahiko Saida and Dr. Masami Paku for assistance in the writing of the manuscript. We did not have any funding for this work.\n==== Refs\nReferences\n1. Melanie DW David EJ Myla DG Overview and safety of fingolimod hydrochloride use in patients with multiple sclerosis Expert Opin Drug Saf 2014 13 989 998 10.1517/14740338.2014.920820 24935480 \n2. Bhatti MT Freedman SM Mahmoud TH Fingolimod therapy and macular hemorrhage J Neuroophthalmol 2013 33 370 372 10.1097/WNO.0b013e31829b42e1 23845997 \n3. Jain N Bhatti MT Fingolimod-associated macular edema: incidence, detection and management Neurology 2012 78 672 680 10.1212/WNL.0b013e318248deea 22371414 \n4. Lightman S McDonald WI Bird AC Francis DA Hoskins A Batchelor JR Retinal venous sheathing in optic neuritis: its significance for the pathogenesis of multiple sclerosis Brain 1987 110 405 414 10.1093/brain/110.2.405 3567529 \n5. Gelfand JM Nolan R Schwartz DM Graves J Green AJ Microcystic macular oedema in multiple sclerosis is associated with disease severity Brain 2012 135 1786 1793 10.1093/brain/aws098 22539259 \n6. Zarbin MA Jampol LM Jager RD Reder AT Francis G Collins W Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis Ophthalmology 2013 120 1432 1439 10.1016/j.ophtha.2012.12.040 23531349\n\n",
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"mesh_terms": "D000328:Adult; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents; D008269:Macular Edema; D008297:Male; D009103:Multiple Sclerosis; D012166:Retinal Hemorrhage; D041623:Tomography, Optical Coherence",
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"title": "Retinal hemorrhages following fingolimod treatment for multiple sclerosis; a case report.",
"title_normalized": "retinal hemorrhages following fingolimod treatment for multiple sclerosis a case report"
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"abstract": "The standard treatment for advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer is the triple combination of pertuzumab, trastuzumab and docetaxel, but some patients cannot tolerate taxane. To explore a non-taxane triple therapy, we conducted a feasibility study of pertuzumab, trastuzumab and eribulin mesylate (PTE) therapy for previously treated advanced HER2-positive breast cancer with analyses of quality of life and biomarkers. Ten patients were enrolled, two of whom had a history of docetaxel allergy. The median number of prior regimens was 3. The most common Grade 3 toxicities were leukopenia (70%) and neutropenia (70%). Grade 4 or 5 adverse events were not observed. An improving trend for the Functional Assessment of Cancer Therapy-Breast (FACT-B) score at 3 months was observed. Eight cases were included in the biomarker analysis. The peripheral CD8+ T cell/ CD4+Foxp3+ regulatory T cells (Tregs) ratio was significantly increased (p = 0.039). The frequency of peripheral Tregs was associated with the trastuzumab trough concentration (p = 0.019). In a non-clinical analysis, Eribulin mesylate significantly inhibited Ser473 Akt phosphorylation in PIK3CA wild-type cells and mutated cells. These results suggest that PTE therapy is a feasible and promising option for advanced HER2-positive breast cancer. Further investigation is warranted.",
"affiliations": "Department of Hematology and Oncology, Mie University Graduate School of Medicine, 514-8507 Mie, Japan.;Department of Medical Oncology, Mie University Hospital, 514-8507 Mie, Japan.;Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, 514-8507 Mie, Japan.;Department of Medical Oncology, Mie University Hospital, 514-8507 Mie, Japan.;Department of Medical Oncology, Mie University Hospital, 514-8507 Mie, Japan.;Department of Medical Oncology, Mie University Hospital, 514-8507 Mie, Japan.;Department of Hematology and Oncology, Mie University Graduate School of Medicine, 514-8507 Mie, Japan.;Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, 514-8507 Mie, Japan.;Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, 514-8507 Mie, Japan.;Department of Medical Oncology, Mie University Hospital, 514-8507 Mie, Japan.;Department of Hematology and Oncology, Mie University Graduate School of Medicine, 514-8507 Mie, Japan.",
"authors": "Tono|Yasutaka|Y|;Ishihara|Mikiya|M|;Miyahara|Yoshihiro|Y|;Tamaru|Satoshi|S|;Oda|Hiroyasu|H|;Yamashita|Yoshiki|Y|;Tawara|Isao|I|;Ikeda|Hiroaki|H|;Shiku|Hiroshi|H|;Mizuno|Toshiro|T|;Katayama|Naoyuki|N|",
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"doi": "10.18632/oncotarget.24504",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 2450410.18632/oncotarget.24504Research PaperPertuzumab, trastuzumab and eribulin mesylate therapy for previously treated advanced HER2-positive breast cancer: a feasibility study with analysis of biomarkers Tono Yasutaka 12Ishihara Mikiya 2Miyahara Yoshihiro 3Tamaru Satoshi 2Oda Hiroyasu 2Yamashita Yoshiki 2Tawara Isao 1Ikeda Hiroaki 34Shiku Hiroshi 3Mizuno Toshiro 2Katayama Naoyuki 121 Department of Hematology and Oncology, Mie University Graduate School of Medicine, 514-8507 Mie, Japan2 Department of Medical Oncology, Mie University Hospital, 514-8507 Mie, Japan3 Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, 514-8507 Mie, Japan4 Department of Oncology, Nagasaki University Graduate School of Biomedical Sciences, 852-8523 Nagasaki, JapanCorrespondence to: Mikiya Ishihara,mishihara@clin.medic.mie-u.ac.jp13 3 2018 16 2 2018 9 19 14909 14921 9 5 2017 7 2 2018 Copyright: © 2018 Tono et al.2018This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.The standard treatment for advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer is the triple combination of pertuzumab, trastuzumab and docetaxel, but some patients cannot tolerate taxane. To explore a non-taxane triple therapy, we conducted a feasibility study of pertuzumab, trastuzumab and eribulin mesylate (PTE) therapy for previously treated advanced HER2-positive breast cancer with analyses of quality of life and biomarkers. Ten patients were enrolled, two of whom had a history of docetaxel allergy. The median number of prior regimens was 3. The most common Grade 3 toxicities were leukopenia (70%) and neutropenia (70%). Grade 4 or 5 adverse events were not observed. An improving trend for the Functional Assessment of Cancer Therapy-Breast (FACT-B) score at 3 months was observed. Eight cases were included in the biomarker analysis. The peripheral CD8+ T cell/ CD4+Foxp3+ regulatory T cells (Tregs) ratio was significantly increased (p = 0.039). The frequency of peripheral Tregs was associated with the trastuzumab trough concentration (p = 0.019). In a non-clinical analysis, Eribulin mesylate significantly inhibited Ser473 Akt phosphorylation in PIK3CA wild-type cells and mutated cells. These results suggest that PTE therapy is a feasible and promising option for advanced HER2-positive breast cancer. Further investigation is warranted.\n\nbreast cancereribulin mesylateHER2-positivetrastuzumabpertuzumab\n==== Body\nINTRODUCTION\nThe triple combination regimen of pertuzumab, trastuzumab and docetaxel is increasingly common because of its beneficial effects on human epidermal growth factor receptor 2 (HER2)-positive breast cancer [1–3]. However, this triple therapy is not appropriate for patients with a history of taxane allergy or those who are refractory to taxane. Thus, other safe and efficacious regimens combining a non-taxane with pertuzumab and trastuzumab are needed.\n\nEribulin mesylate is a non-taxane inhibitor of microtubule dynamics of the halichondrin class of antineoplastic drugs. This drug resulted in significant and clinically meaningful improvements in overall survival compared with the physician’s treatment of choice for patients with heavily pretreated metastatic breast cancer [4]. In a phase II study, the combination of trastuzumab and eribulin mesylate as a first-line therapy exhibited a 71.2% overall response rate (ORR), 11.6 months of progression-free survival (PFS) and an acceptable safety profile for locally recurrent or metastatic HER2-positive breast cancer [5]. Another study using an eribulin mesylate and trastuzumab combination reported a similar ORR and safety profile for HER2-positive breast cancer [6]. Eribulin mesylate and trastuzumab treatment is safe and yields a promising outcome for Japanese patients with HER2-positive breast cancer [7]. These data suggest that pertuzumab, trastuzumab and eribulin mesylate (PTE) could be promising as a treatment of advanced HER2-positive breast cancer.\n\nThe mechanism underlying prolonged overall survival in breast cancer patients treated with eribulin mesylate remains unclear. It is known that the serum HER2 extracellular domain (sHER) level, PIK3CA gene mutation status and trastuzumab concentration are associated with resistance to trastuzumab [8, 9]. The peripheral regulatory T cell (Treg) frequency is associated with a poor response [10], and tumor-infiltrating Tregs were correlated with decreased survival in breast cancer [11, 12].\n\nBased on these findings, we conducted a feasibility study of PTE chemotherapy for previously treated advanced HER2-positive breast cancer, including an analysis of quality of life (QOL) and concomitant analysis of biomarkers such as sHER levels, PIK3CA gene mutation status and circulating Treg levels.\n\nRESULTS\nPatient characteristics\nTen patients were enrolled from October 2013 to January 2015 (Supplementary Figure 1). The patient characteristics are presented in Table 1. The median age of the patients was 60 years (range: 35–75), and the median follow-up time was 14.7 months (range: 6.9–26.6). Two patients had a history of docetaxel allergy. The median number of prior regimens for metastatic disease was 3 (1–10). The median number of prior chemoregimens for metastatic disease was 3 (0–5). One patient developed lung and lymph metastases one year after adjuvant trastuzumab completion and under adjuvant tamoxifen.\n\nTable 1 Patient Characteristics\nNo. of patients, total\nMedian age, years (range)\t10\n60 (35–75)\t\n\tN\t%\t\nSex, female\t10\t100\t\nECOG PS\t\t\t\n 0\t5\t50\t\n 1\t5\t50\t\nHistory of chemotherapy\t\t\t\n Anthracycline\t5\t50\t\n Taxane*\t10\t100\t\n Trastuzumab\t10\t100\t\n (within 3 months of PTE)\t8\t80\t\n Lapatinib\t5\t50\t\n (within 3 months of PTE)\t2\t20\t\nHistology\t\t\t\n Invasive ductal carcinoma\t10\t100\t\nHormone receptor and HER2 status\t\t\t\n ER+ PgR+ HER2+\t4\t40\t\n ER+ PgR– HER2+\t2\t20\t\n ER– PgR– HER2+\t4\t40\t\nMedian No. of prior regimens\n for metastatic disease (range)\t3 (1–10)\t\nMedian No. of prior chemoregimens\n for metastatic disease (range)\t3 (0–5)\t\n*Two patients had a history of docetaxel allergy.\n\nAbbreviations: ER, estrogen receptor; PgR, progesterone receptor.\n\nDosage\nThe median number of PTE cycles was 6 (3–11). Eight patients reduced their eribulin mesylate doses from 1.4 mg/m2 to 1.1 mg/m2 due to adverse events (AEs) (two patients), skipped day 8 of eribulin mesylate therapy (four patients), or were treated with the physician’s treatment of choice (two patients). Five patients were administered ≤2.0 mg/body/day eribulin mesylate in the first cycle. Among these five patients, two required a dose reduction. All five patients whose eribulin mesylate dosage was >2.0 mg/body/day in the first cycle required a dose reduction. The dosages of pertuzumab and trastuzumab were not modified.\n\nAEs\nThe common (≥30%) treatment-related AEs included leukopenia, neutropenia, lymphopenia, diarrhea, hypokalemia, mucositis, dysgeusia, nausea, and skin disorder (Table 2). Grade 3 AEs included leukopenia (seven patients), neutropenia (eight patients), lymphopenia (two patients), febrile neutropenia (one patient), hypokalemia (one patient) and peripheral neuropathy (1 patient) (Table 2). Grade 4 or 5 AEs were not observed.\n\nTable 2 Treatment-Related Adverse Events (N = 10)\n\tAll grades (%)\tGrade 3 (%)\tGrade 4 (%)\t\nNon-hematologic toxicities\t\t\t\t\n Diarrhea\t7 (70)\t0\t0\t\n Hypokalemia\t7 (70)\t1 (10)\t0\t\n Hypertension\t2 (20)\t2 (20)\t0\t\n ALT increased\t4 (40)\t0\t0\t\n γ-GTP increased\t4 (40)\t0\t0\t\n AST increased\t3 (30)\t0\t0\t\n Mucositis\t3 (30)\t0\t0\t\n Dysgeusia\t3 (30)\t0\t0\t\n Nausea\t3 (30)\t0\t0\t\n Skin disorder\t3 (30)\t0\t0\t\n Hyperkalemia\t2 (20)\t0\t0\t\n Vomiting\t2 (20)\t0\t0\t\n Febrile neutropenia\t1 (10)\t1 (10)\t0\t\n Peripheral neuropathy\t1 (10)\t1 (10)\t0\t\n ALP increased\t1 (10)\t0\t0\t\n Malaise\t1 (10)\t0\t0\t\n Appetite loss\t1 (10)\t0\t0\t\n Stomach pain\t1 (10)\t0\t0\t\n Myalgia\t1 (10)\t0\t0\t\n QTc interval prolonged\t1 (10)\t0\t0\t\nHematologic toxicities\t\t\t\t\n Leukopenia\t8 (80)\t7 (70)\t0\t\n Neutropenia\t8 (80)\t7 (70)\t0\t\n Lymphopenia\t7 (70)\t2 (20)\t0\t\n Anemia\t2 (20)\t0\t0\t\n Platelet count decreased\t1 (10)\t0\t0\t\nSymptoms of cardiac failure were not observed. Left ventricular ejection fraction (LVEF) decreases below 50% were not observed. One patient had mild segmental hypokinesis. Her LVEF values at baseline and after treatment were 55% and 52%, respectively. She recovered 4 months after PTE discontinuation. One patient had a grade 2 corrected QT interval prolongation.\n\nQOL\nThe QOL of nine patients could be assessed. Scores at baseline and 3 months after the first PTE therapy were the Functional Assessment of Cancer Therapy-Breast (FACT-B) TOI (pre, 51.3; post, 58.3), FACT-G (pre, 65.3; post, 72.0) and FACT-B total score (pre, 84.7; post, 93.2). These scores exhibited an improving trend at 3 months, but this trend was not statistically significant (Figure 1).\n\nFigure 1 QOL assessment\nThe FACT-B Trial Outcome Index (TOI), FACT-G Total score and FACT-B Total score at baseline and 3 months after first PTE therapy are presented.\n\nEfficacy\nThe median PFS was 4.8 months (95% confidence interval: 3.7–5.9). One complete response (CR), one partial response (PR) and five cases of stable disease (SD) were observed (Table 3). Two patients (one CR and one SD) stopped eribulin mesylate and received trastuzumab and pertuzumab as maintenance therapy. These patients had a PFS of more than 2 years. At 3 months, all three patients with progressive disease (PD) developed brain metastasis. Of the three PD patients, two patients had extracranial progressive lesions, and the remaining patient had a PR for extracranial disease.\n\nTable 3 Response\n\tNo. of patients (%)\t95% CI (%)\t\nCR\t1 (10)\t\t\nPR\t1 (10)\t\t\nSD\t5 (50)\t\t\nPD\t3 (30)\t\t\nObjective response rate\t2 (20)\t2.5–55.6\t\nDisease control rate\t7 (70)\t34.8–93.3\t\nAbbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; CI, confidence interval.\n\nFlow cytometric analysis of PBMCs\nEight cases were available for flow cytometric analysis. At 3 months, the Treg frequency exhibited a tendency to decrease (p = 0.052) (Figure 2A and Supplementary Table 1). In addition, the CD8+ T cell/Treg ratio was significantly increased (p = 0.039) (Figure 2B). The frequencies of GITR-, CTLA-4- or PD-1-positive T cells were not altered (Supplementary Figure 2). The frequencies of naïve, CM, EM or TEMRA T cells were also unchanged (data not shown).\n\nFigure 2 Analysis of T cell subsets\nThe T cell subsets in peripheral blood from five healthy donors and eight patients before and 3 months after PTE therapy were assessed. (A) Frequency of Foxp3 expression in peripheral CD4+ T cells. (B) CD8+ T cells/CD4+Foxp3+ Treg ratio.\n\nCorrelation between trastuzumab trough concentration and Treg change\nAmong the 10 enrolled patients, eight serum samples were available. The average trastuzumab concentration of two cases who received a non-trastuzumab-containing regimen immediately before PTE therapy was less than 0.1 µg/mL before treatment. However, the average trastuzumab concentration of patients who received a trastuzumab-containing regimen immediately before PTE therapy was 1.26 µg/mL (range: 0.21–2.16). The average trastuzumab trough concentration at 3 months (immediately before the next cycle) was 1.99 µg/mL (range: 0.55–3.18). With the exception of one case, the concentration of each case at 3 months was increased compared with that at baseline. The sHER values were assessed in eight cases. At baseline, two cases had normal sHER values (upper normal limit; 15.2 µg/mL), and six cases had increased sHER values. At 3 months, all six cases exhibited decreased sHER values: four cases were in the normal range; one case exhibited extreme reduction from 314.0 µg/mL to 33.4 µg/mL; and one case exhibited a moderate decrease from 187.0 µg/mL to 159.0 µg/mL. A strong negative correlation was noted between the trastuzumab trough concentration at 3 months and the baseline sHER value (r = –0.798) (Figure 3A). No correlation between the trastuzumab trough concentration at 3 months and PFS was noted (r = 0.192) (Figure 3B).\n\nFigure 3 Correlation chart\n(A) Between the trastuzumab trough concentration at 3 months and sHER before treatment. (B) Between the trastuzumab trough concentration at 3 months and PFS.\n\nThe Treg change ratio and sHER change were not significantly correlated (p = 0.086) (Figure 4A). However, a strong negative correlation was noted between the trastuzumab trough concentration at 3 months and the Treg change (p = 0.019) (Figure 4B).\n\nFigure 4 Correlation chart\n(A) Between the Treg change ratio (3 months/baseline) and sHER change {(3 months - baseline)/baseline}. (B) Between the Treg change ratio (3 months/baseline) and the trastuzumab trough concentration at 3 months.\n\nInhibition of Akt signaling by eribulin mesylate\nA basic research study using breast cancer cell lines was conducted as a non-clinical collaborative study between Mie University and Eisai Co., Ltd. Paclitaxel exhibited an increased 50% inhibitory concentration (IC50) in PIK3CA mutant cell lines compared with the PIK3CA wild-type cell line. The IC50 of eribulin mesylate in the PIK3CA mutant cell line BT-474 was similar to that in the PIK3CA wild-type cell line SK-BR-3 (Figure 5). The IC50 of eribulin mesylate in another PIK3CA mutant cell line, namely, MDA-MB-361, was not assessable due to slow cell growth. Eribulin mesylate significantly inhibited Ser473 Akt phosphorylation in PIK3CA wild-type cells and mutated cells. In contrast, paclitaxel did not exhibit significant inhibition of Ser473 Akt phosphorylation (Figure 5 and Supplementary Figure 3).\n\nFigure 5 Phosphorylation of Akt\n(A) IC50 of SK-BR-3 (PIK3CA wild-type) and BT-474 (PIK3CA mutated-type). MDA-MB-361 (PIK3CA mutated-type) was not assessable. (B) Western blot assay assessing Akt phosphorylation. The cell lines were assayed after 24 hours of cultivation with eribulin mesylate or paclitaxel. The average of four experiments is presented. The data are the means + SEMs. *upper 95% CI < 1 in one-sample t-test.\n\nDISCUSSION\nIn the present study, we attempted to evaluate the feasibility of PTE chemotherapy for previously treated advanced HER2-positive breast cancer and to analyze QOL and biomarkers such as sHER levels, PIK3CA gene mutation status and circulating Tregs. Eribulin mesylate is an attractive cytotoxic agent because it offers overall survival benefits for previously treated patients with breast cancer [4]. The overall survival benefit of eribulin mesylate was reproduced in patients with advanced sarcoma [13]. Pertuzumab is a humanized anti-HER2 monoclonal antibody [14, 15] and acts as a complementary drug of trastuzumab [16]. In the CLEOPTRA trial, the addition of pertuzumab to trastuzumab and docetaxel resulted in superior overall survival [3]. These data suggest that PTE is a promising regimen for advanced HER2-positive breast cancer. In our study, manageable tolerability was found for PTE therapy (Table 2), and the QOL (Figure 1) of patients with advanced HER2-positive breast cancer was maintained. The most common grade 3 AEs were leukopenia and neutropenia, which were reported as frequent severe AEs in previous studies of eribulin monotherapy or in combination with trastuzumab [4–7]. A dose reduction of eribulin mesylate was needed due to neutropenia in our study, and the need for dose reduction might be influenced by prior chemotherapy. When PTE therapy is administered to heavily pretreated HER2-positive breast cancer patients, 1.1 mg/m2 or ≤2.0 mg/body eribulin mesylate might be a reasonable dosage. The common (≥30%) non-hematologic AEs were diarrhea, hypokalemia, mucositis, dysgeusia, nausea, and skin disorder. The incidence of diarrhea in PTE therapy was higher than that of eribulin mesylate monotherapy but comparable with that reported in the CLEOPATRA study, suggesting that diarrhea is not enhanced by eribulin mesylate. Although the sample size of our study is too small to assess efficacy, PTE therapy had one CR, one PR and five SD (Table 3), and two patients who received trastuzumab and pertuzumab as maintenance therapy had a PFS of more than 2 years. Araki et al. recently reported a phase II clinical study of the combination therapy of pertuzumab, trastuzumab and eribulin mesylate [17]. In their trial, the ORR was 34.8%, and the PFS was 42.6 weeks. Thus, PTE therapy might be an alternative for HER2-positive breast cancer patients who are not candidates for taxane treatment. A phase III clinical study comparing pertuzumab, trastuzumab and eribulin mesylate combination therapy with pertuzumab, trastuzumab and paclitaxel or docetaxel conducted by the Japan Breast Cancer Research Group is ongoing (UMIN000027938) in Japan. This clinical trial will answer whether the PTE therapy serves as an alternative to paclitaxel or docetaxel, pertuzumab and trastuzumab.\n\nThe majority of HER2-positive metastatic breast cancer patients who achieve an initial response to trastuzumab develop resistance within 1 year [18]. Elucidation of the mechanisms of trastuzumab resistance is needed to improve the survival of HER2-positive breast cancer patients. One of the mechanisms of resistance to trastuzumab is an insufficient trastuzumab concentration [9]. Zabrecky et al. reported that sHER competes against trastuzumab in binding to a HER2-positive breast cancer cell line in vitro [19]. A previous report demonstrated that high sHER levels correlate with worse prognosis in patients receiving trastuzumab. Pertuzumab binds to HER2 extracellular domain II, which might reduce the sHER levels and increase both the serum trastuzumab concentration and trastuzumab binding to HER2-positive cancer cells. However, a high sHER level was identified as a factor for poor prognosis in the CLEOPATRA trial [20]. Thus, we hypothesized that sHER competes with trastuzumab for binding to HER2-positive cancer cells under pertuzumab and trastuzumab therapy. As shown in Figure 3A, a strong relationship was noted between the baseline sHER and the serum trastuzumab trough concentration at 3 months. Unfortunately, no significant relationship was noted between the serum trastuzumab trough concentration at 3 months and PFS (Figure 3B). This finding might be affected by other factors, such as Fcγ receptor polymorphisms [21] and the ESR1 level [22].\n\nPIK3CA mutation is a poor prognostic factor in HER2-positive breast cancer [23, 24], and this finding was also confirmed in the CLEOPATRA trial [20]. Eribulin mesylate inhibited Akt signaling in PIK3CA-mutated cells, and this inhibition was comparable with that observed in PIK3CA wild-type cells (Figure 5). In this study, eight patients were assessed for PIK3CA status. Four patients had wild-type PIK3CA, and four patients had a mutant type. Of the four patients with PIK3CA mutations in our study, three had SD, and one had PD. One had a PFS of more than 3 years. These findings suggested that PTE triple agent therapy might be an effective treatment for HER2-positive breast cancer patients with either wild-type or mutated PIK3CA.\n\nWe observed a significant increase in the CD8+ T cells/Tregs ratio and a trend of reduced Tregs following PTE therapy. The cause of Treg reduction is an unresolved question. Perez et al. reported a strong positive correlation between Treg change and sHER change during trastuzumab therapy [10]. They hypothesized that sHER was eliminated from the circulation via antigen-trastuzumab complex formation and uptake by phagocytes through Fcγ receptor binding. Reduced circulating antigen subsequently reduces the expansion of antigen-specific Tregs [25, 26]. Trastuzumab and sHER complex formation could also lead to activation, maturation, and enhanced antigen cross-presentation by antigen-presenting cells [27, 28]. In our study, the correlation between Treg change and sHER change during PTE therapy was not confirmed (Figure 4A). Given that the response rate was 20%, the sHER level would not be affected by the tumor burden. Of the eight PBMC-assessable patients, six received a trastuzumab-containing regimen immediately before PTE therapy, suggesting that Treg reduction might be induced by eribulin mesylate. Eribulin mesylate could inhibit the transforming growth factor-beta (TGF-β) signaling pathway by decreasing TGF-β and/or Smad3 phosphorylation. TGF-β induced Foxp3 gene expression in T cell receptor-challenged CD4+CD25− naïve T cells, mediating their transition toward Tregs [29]. Ueda et al. reported that eribulin mesylate reduced the blood TGF-β concentrations in advanced breast cancer patients [30]. Eribulin mesylate could also reduce Smad2 and Smad3 phosphorylation [31]. Smad3 and/or Smad4 are required for TGF-β-mediated induction of Foxp3 in naïve CD4+ T cells [32]. These data supported the hypothesis that eribulin mesylate suppresses Treg induction via inhibition of the TGF-β/Smad pathway. Further investigation of this hypothesis is needed. The small sample size is a limitation of the Treg analysis. Further investigations are needed to confirm the increase in the CD8+ T cells/Tregs ratio after PTE therapy.\n\nAlthough Tregs were reduced during PTE therapy, we did not observe any indications of T cell activation, such as significant changes in T cell subsets (naïve, CM, EM and TEMRA) and checkpoint molecule expression (CTLA-4, GITR, and PD-1), in peripheral blood (Supplementary Figure 2 and Supplementary Table 1). Because PBMCs in our flow cytometric analysis were prepared by freeze-thawing under unstimulated conditions, the expression of checkpoint molecules might be underestimated. These data suggested that T cell activation mediated by the additions of checkpoint inhibitors to PTE therapy could enhance the anti-tumour effects. A strong negative correlation was noted between the trastuzumab trough concentration at 3 months and the Treg change (Figure 4B). Petricevic et al. reported that antibody-dependent cellular cytotoxicity activity was similar during trastuzumab treatment [33]. Increased trastuzumab concentrations could enhance Fcγ-mediated activation of tumour-associated macrophage cytotoxicity [34, 35] and induce tumour-specific CD8+ T cells [36]. Activated macrophages might also induce tumour-specific CD4+ helper T cells, resulting in a relative reduction in Tregs. Analysis of macrophages and T cells in the tumor microenvironment and regional lymph nodes is needed.\n\nAlthough the sample size of this study was small, this is the first report of QOL and Treg analyses in advanced HER2-positive breast cancer patients who received PTE therapy, and the results showed that PTE therapy maintained the QOL of patients with advanced HER2-positive breast cancer. PTE therapy might be a feasible option for advanced HER2-positive breast cancer patients, but further investigation is warranted.\n\nMATERIALS AND METHODS\nPatients and treatment\nThis was a single-institutional, open-label feasibility study of PTE for previously treated advanced HER2-positive breast cancer. Patients with a HER2-positive status [immunohistochemistry (IHC) 3+ or fluorescence in situ hybridization (FISH) ≥ 2.0]; aged 20–80 years; a performance status (PS) (ECOG scale) of 0–2; an LVEF ≥ 50%; a history of one or more cytotoxic agents and anti-HER2 therapy, including neo-adjuvant and adjuvant therapy; and adequate organ functions were enrolled. Patients with a history of eribulin mesylate use during the 6 months prior to consent or symptomatic brain metastasis were excluded.\n\nPatients were treated with pertuzumab (840 mg loading, then 420 mg, day 1), trastuzumab (8 mg/kg loading, then 6 mg/kg, day 1), and eribulin mesylate (1.4 mg/m2, day 1 and 8) every 3 weeks. A two-step dose reduction of eribulin mesylate (starting dose 1.4 mg/m2, to 1.1 mg/m2, then to 0.7 mg/m2) was performed, and this approach was based on the criteria of the Japanese user guide recommended by Eisai Inc. (http://onc.eisai.jp/halaven/halaven/). The dose of eribulin mesylate was reduced when the patients developed febrile neutropenia, grade 3–5 non-hematologic toxicity or skipped eribulin mesylate administration on day 8 due to a neutrophil count <1000/mm3.\n\nThe primary end point of this study was the safety of PTE therapy. Secondary end points were responses, PFS, and QOL (FACT-B). The projected sample size was 10 patients, as this was a feasibility study of a novel triple therapy for previously treated advanced HER2-positive breast cancer.\n\nThe protocol was reviewed and approved by the Institutional Review Board and conducted in accordance with the Declaration of Helsinki and applicable laws. All patients provided signed informed consent before registration [Clinical Trial Registration Number: UMIN000012018 (Registration Date: Oct 10, 2013)].\n\nAssessment\nAEs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. LVEF was assessed by cardiac ultrasonography every 3 months.\n\nQOL was assessed using the FACT-B [37] prior to treatment and 3 months after PTE therapy. Japanese FACT-B version 4 consists of 37 items that are divided into five subscales: physical well-being (PWB; seven items, 0–28 points), social/family well-being (SWB; seven items, 0–28 points), emotional well-being (EWB; six items, 0–24 points), functional well-being (FWB; seven items, 0–28 points), and a breast cancer subscale (BCS; 10 items, 0–36 points). The FACT-B Trial Outcome Index (TOI), FACT-G Total score and FACT-B Total score were calculated as follows:FACT-B TOI = (PWB score) + (FWB score) + (BCS score) (0–92 points)\n\nFACT-G Total score = (PWB score) + (SWB score) + (EWB score) + (FWB score) (0–108 points)\n\nFACT-B Total score = (PWB score) + (SWB score) + (EWB score) + (FWB score) + (BCS score) (0–144 points)\n\n\n\nHigh scores indicate a better QOL\nComputed tomography was performed every 3 months. Responses were assessed by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1.\n\nSample analysis\nPeripheral blood mononuclear cells (PBMCs) and serum were collected before and 3 months after the first PTE treatment (immediately before the next cycle). Separated serum was cryopreserved. We investigated the serum trastuzumab concentration, sHER value, and immune status. The serum trastuzumab concentration was measured by sandwich enzyme-linked immunosorbent assay as follows: anti-trastuzumab antibodies were coated onto immunoplates at a concentration of 0.1 µg/50 µl. The collected serum samples were diluted from 1:4,000 to 1:1,024,000. After the plates were washed, goat anti-human IgG (H + L chain) (MBL, Nagoya, Japan) and IgG-peroxidase (The Binding Site, San Diego, CA, USA) were added. After the TMB substrate (Pierce, Rockford, IL, USA) was added, the plate was assessed with a microplate reader (model 550; Bio-Rad, Hercules, CA USA). The trastuzumab concentration of each sample was measured thrice, and the average value was used for the analyses. The sHER value was determined using chemiluminescent immunoassays as described by SRL Inc. (Tokyo, Japan).\n\nPBMCs were isolated from peripheral blood by density gradient centrifugation and stored at ≤ –80° C. The immune status was assessed by flow cytometry analysis. After thawing of frozen PBMCs, aliquots containing 0.8–9.6 × 105 PBMCs were suspended in 100 μL of staining buffer (phosphate buffered saline containing 2% fetal bovine serum). Antibodies for surface markers were then added, and the plates were then incubated for 15 minutes on ice. For intracellular protein (CTLA-4 and FOXP3) staining, we used the True-Nuclear™ Transcription Factor Staining Procedure (BioLegend, San Diego, CA, USA). The following antibodies were used: CD3-Brilliant Violet 711, CD4–Alexa Fluor 700, CD8a-Brilliant Violet 785, CD45RA-FITC, FOXP3-PE, CTLA-4-PE-Cy7, GITR–APC, PD-1-Brilliant Violet 421, and CCR7-Brilliant Violet 605 (BioLegend, San Diego, CA, USA). Isotype controls included the appropriate fluorochrome-conjugated mouse IgG1/κ, IgG2a/κ, or IgG2b/κ. Stained cells were detected using an LSR II Fortessa with FACS Diva software (BD Biosciences). The data were analyzed using FlowJo software (Tree Star, Ashland, OR, USA). The Treg subset was defined as CD3+CD4+FOXP3+ cells. T cells were classified as naïve (CD45RA+CCR7+), central memory (CM; CD45RA-CCR7+), effector memory (EM; CD45RA-CCR7–), and terminally differentiated effector cells (TEMRA; CD45RA+CCR7–) [38]. Appropriate isotype controls served as the cut-off levels between positivity and negativity. A positive gate was set to include less than 0.1% of cells in each specimen with a matched isotype control.\n\nCell lines\nSK-BR-3, BT-474 and MDA-MB-361 breast cancer cell lines were purchased from American Type Culture Collection. SK-BR-3, BT-474 and MDA-MB-361 cells were grown in McCoy’s 5A Medium supplemented with 10% fetal bovine serum (FBS), Hybri-Care Medium supplemented with FBS and DMEM/F12 medium supplemented with FBS, respectively. In total, 100 units/ml penicillin and 100 μg/ml streptomycin were added to all culture media. The cultures were maintained at 37° C in a humidified atmosphere of 5% CO2 and 95% air.\n\nWestern blot assay\nBriefly, SK-BR-3, BT-474 and MDA-MB-361 cells were seeded in six-well plates or 10-cm dishes in complete culture media for overnight incubation. The cells were treated with DMSO or each concentration of eribulin mesylate or paclitaxel for 24 hours. The cells were then lysed with 1× cell lysis buffer (Cell Signaling Technology, Inc., Danvers, MA, USA) plus 1 mM PMSF or RIPA buffer containing protease inhibitor cocktail (Roche Diagnostics, Mannheim, Germany) and Halt phosphatase inhibitor cocktail (Thermo Fisher Scientific, Waltham, MA, USA). The cell lysates were cleared by centrifugation, and the protein concentration was measured using the Bio-Rad Protein Assay (Bio-Rad, Hercules, CA, USA) or BCA assay (Thermo Fisher Scientific Inc., Waltham, MA, USA). The proteins were denatured in 4× sample buffer (Thermo Fisher Scientific Inc., Waltham, MA, USA), separated by SDS-PAGE and transferred onto nitrocellulose membranes or PVDF membranes. After blocking, the membranes were incubated with anti-phospho-Akt (Ser473) (Cell Signaling Technologies), anti-Akt (Cell Signaling Technologies), and anti-β-actin antibodies (Santa Cruz or Cell Signaling Technologies) at the recommended concentration overnight. Anti-rabbit IgG (LI-COR, Inc., Lincoln, NE, USA or Santa Cruz) and anti-mouse IgG (LI-COR) were used as secondary antibodies. Immunoreactive bands were visualized with an image analyzer (LI-COR Odyssey Fc Imaging System; LI-COR, Inc., Lincoln, NE, USA or LAS 4000; Fuji Film, Tokyo, Japan).\n\nStatistical analysis\nThe data for patients who were alive or lost to follow-up were censored at the last date. The Kaplan–Meier method was used to estimate the PFS. The Wilcoxon signed-rank test was used to assess the QOL scores at baseline and 3 months after the first PTE treatment. Correlation coefficients for the serum trastuzumab concentration and the sHER value, the serum trastuzumab concentration and PFS, the serum trastuzumab concentration and Treg change ratio (3 months/baseline), and the Treg change ratio (3 months/baseline) and sHER change (3 months - baseline) *100/(baseline) were calculated. The paired t-test was used for comparisons of the immune statuses. All analyses were performed with IBM SPSS Statistics, version 23 (IBM Japan, Ltd.).\n\nSUPPLEMENTARY MATERIALS FIGURES AND TABLE\n Author contributions\n\nMI, ST and TM contributed to the design of the study. As members of the study steering committee, YT, MI, YM, ST, TM and NK oversaw the conduct of the study. MI, ST, HO, YY and TM contributed substantially to patient recruitment. YT, MI, YM, IT, HI, HS and NK contributed to data collection and analyses. YT, MI, TM and NK interpreted the data. YT performed the statistical analyses. YT and MI wrote the manuscript. MI conducted a non-clinical collaborative study between Mie University and Eisai Co., Ltd. All authors contributed to draft revisions, had full access to the data, attest to the accuracy and integrity of the data, and read and approved the final manuscript.\n\nWe thank Sahoko Sugino and Junko Nakamura for technical assistance, Toru Ogura for statistical support, and Taro Semba for a non-clinical collaborative study between Mie University and Eisai Co., Ltd.\n\nCONFLICTS OF INTEREST\n\nMI, ST, TM and NK received lecture fees from Eisai Co., Ltd. and Chugai Co., Ltd. The others have declared that no competing interests exist.\n\nWestern blot assays using breast cancer cell lines were conducted as a non-clinical collaborative study between Mie University and Eisai Co., Ltd., after completion of the PTE clinical trial.\n\nFUNDING\n\nThis study was supported by grants from Mie University School of Medicine. The funders had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.\n\nAbbreviations\nAEsadverse events\n\nCRcomplete response\n\nFACT-BFunctional Assessment of Cancer Therapy-Breast\n\nFBSfetal bovine serum\n\nFISHfluorescence in situ hybridization\n\nHER2human epidermal growth factor receptor 2\n\nIC5050% inhibitory concentration\n\nIHCimmunohistochemistry\n\nORRoverall response rate\n\nPBMCsperipheral blood mononuclear cells\n\nPDprogressive disease\n\nPFSprogression-free survival\n\nPRpartial response\n\nPSperformance status\n\nPTEpertuzumab, trastuzumab and eribulin mesylate\n\nQOLquality of life\n\nRECISTResponse Evaluation Criteria In Solid Tumors\n\nTGF-βtransforming growth factor-beta\n\nTOITrial Outcome Index\n\nTregsregulatory T cells\n\nSDstable disease\n\nsHERserum HER2 extracellular domain\n==== Refs\nREFERENCES\n1 Baselga J Cortés J Kim SB Im SA Hegg R Im YH Roman L Pedrini JL Pienkowski T Knott A Clark E Benyunes MC Ross G Swain SM CLEOPATRA Study Group Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer N Engl J Med 2012 366 109 19 https://doi.org/10.1056/NEJMoa1113216 22149875 \n2 Swain SM Kim SB Cortés J Ro J Semiglazov V Campone M Ciruelos E Ferrero JM Schneeweiss A Knott A Clark E Ross G Benyunes MC Baselga J Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study Lancet Oncol 2013 14 461 71 https://doi.org/10.1016/s1470-2045(13)70130-x 23602601 \n3 Swain SM Baselga J Kim SB Ro J Semiglazov V Campone M Ciruelos E Ferrero JM Schneeweiss A Heeson S Clark E Ross G Benyunes MC Cortés J CLEOPATRA Study Group Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer N Engl J Med 2015 372 724 34 https://doi.org/10.1056/NEJMoa1413513 25693012 \n4 Cortes J O’Shaughnessy J Loesch D Blum JL Vahdat LT Petrakova K Chollet P Manikas A Diéras V Delozier T Vladimirov V Cardoso F Koh H EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus E7389) investigators Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study Lancet 2011 377 914 23 https://doi.org/10.1016/S0140-6736(11)60070-6 21376385 \n5 Wilks S Puhalla S O’Shaughnessy J Schwartzberg L Berrak E Song J Cox D Vahdat L Phase 2, multicenter, single-arm study of eribulin mesylate with trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancer Clin Breast Cancer 2014 14 405 12 https://doi.org/10.1016/j.clbc.2014.04.004 25024001 \n6 O’Shaughnessy J McIntyre K Schwartzberg L Wilks S Puhalla S Berrak E Song J Vahdat L Impact of prior anthracycline or taxane use on eribulin effectiveness as first-line treatment for metastatic breast cancer: results from two phase 2, multicenter, single-arm studies Springerplus 2015 4 532 41 https://doi.org/10.1186/s40064-015-1322-y 26413438 \n7 Mukai H Saeki T Shimada K Naito Y Matsubara N Nakanishi T Obaishi H Namiki M Sasaki Y Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer Invest New Drugs 2015 33 119 27 https://doi.org/10.1007/s10637-014-0161-y 25242374 \n8 Morrow PK Zambrana F Esteva FJ Recent advances in systemic therapy: advances in systemic therapy for HER2-positive metastatic breast cancer Breast Cancer Res 2009 11 207 https://doi.org/10.1186/bcr2324 19664181 \n9 Nahta R Esteva FJ HER2 therapy: molecular mechanisms of trastuzumab resistance Breast Cancer Res 2006 8 215 22 https://doi.org/10.1186/bcr1612 17096862 \n10 Perez SA Karamouzis MV Skarlos DV Ardavanis A Sotiriadou NN Iliopoulou EG Salagianni ML Orphanos G Baxevanis CN Rigatos G Papamichail M CD4+CD25+ regulatory T-cell frequency in HER-2/neu (HER)-positive and HER-negative advanced-stage breast cancer patients Clin Cancer Res 2007 13 2714 21 https://doi.org/10.1158/1078-0432.CCR-06-2347 17473204 \n11 Shang B Liu Y Jiang SJ Liu Y Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis Sci Rep 2015 5 15179 https://doi.org/10.1038/srep15179 26462617 \n12 Wang Y Sun J Zheng R Shao Q Gao W Song B Chen X Qu X Regulatory T cells are an important prognostic factor in breast cancer: a systematic review and meta-analysis Neoplasma 2016 63 789 98 https://doi.org/10.4149/neo_2016_517 27468884 \n13 Schoffski P Chawla S Maki RG Italiano A Gelderblom H Choy E Grignani G Camargo V Bauer S Rha SY Blay JY Hohenberger P D’Adamo D Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial Lancet 2016 387 1629 37 https://doi.org/10.1016/S0140-6736(15)01283-0 26874885 \n14 Agus DB Gordon MS Taylor C Natale RB Karlan B Mendelson DS Press MF Allison DE Sliwkowski MX Lieberman G Kelsey SM Fyfe G Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer J Clin Oncol 2005 23 2534 43 https://doi.org/10.1200/JCO.2005.03.184 15699478 \n15 Nahta R Hung MC Esteva FJ The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells Cancer Res 2004 64 2343 6 15059883 \n16 Gianni L Pienkowski T Im YH Roman L Tseng LM Liu MC Lluch A Staroslawska E de la Haba-Rodriguez J Im SA Pedrini JL Poirier B Morandi P Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial Lancet Oncol 2012 13 25 32 https://doi.org/10.1016/S1470-2045(11)70336-9 22153890 \n17 Araki K Fukada I Yanagi H Kobayashi K Shibayama T Horii R Takahashi S Akiyama F Ohno S Ito Y First report of eribulin in combination with pertuzumab and trastuzumab for advanced HER2-positive breast cancer Breast 2017 35 78 84 https://doi.org/10.1016/j.breast.2017.06.015 28662406 \n18 Nahta R Yu D Hung MC Hortobagyi GN Esteva FJ Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer Nat Clin Pract Oncol 2006 3 269 80 https://doi.org/10.1038/ncponc0509 16683005 \n19 Zabrecky JR Lam T McKenzie SJ Carney W The extracellular domain of p185/neu is released from the surface of human breast carcinoma cells, SK-BR-3 J Biol Chem 1991 266 1716 20 1671042 \n20 Baselga J Cortes J Im SA Clark E Ross G Kiermaier A Swain SM Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive , first-line metastatic breast cancer J Clin Oncol 2014 32 3753 61 https://doi.org/10.1200/JCO.2013.54.5384 25332247 \n21 Tamura K Shimizu C Hojo T Akashi-Tanaka S Kinoshita T Yonemori K Kouno T Katsumata N Ando M Aogi K Koizumi F Nishio K Fujiwara Y FcgR2A and 3A polymorphisms predict clinical outcome of trastuzumab in both neoadjuvant and metastatic settings in patients with HER2-positive breast cancer Ann Oncol 2011 22 1302 7 https://doi.org/10.1093/annonc/mdq585 21109570 \n22 Loi S Dafni U Karlis D Polydoropoulou V Young BM Willis S Long B de Azambuja E Sotiriou C Viale G Ruschoff J Piccart MJ Dowsett M Effects of estrogen receptor and human epidermal growth factor receptor-2 levels on the efficacy of trastuzumab: a secondary analysis of the HERA trial JAMA Oncol 2016 2 1040 7 https://doi.org/10.1001/jamaoncol.2016.0339 27100299 \n23 Cizkova M Dujaric ME Lehmann-Che J Scott V Tembo O Asselain B Pierga JY Marty M de Cremoux P Spyratos F Bieche I Outcome impact of PIK3CA mutations in HER2-positive breast cancer patients treated with trastuzumab Br J Cancer 2013 108 1807 9 https://doi.org/10.1038/bjc.2013.164 23612454 \n24 Jensen JD Knoop A Laenkholm AV Grauslund M Jensen MB Santoni-Rugiu E Andersson M Ewertz M PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab Ann Oncol 2012 23 2034 42 https://doi.org/10.1093/annonc/mdr546 22172323 \n25 Knoechel B Lohr J Kahn E Bluestone JA Abbas AK Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen J Exp Med 2005 202 1375 86 https://doi.org/10.1084/jem.20050855 16287710 \n26 Lohr J Knoechel B Abbas AK Regulatory T cells in the periphery Immunol Rev 2006 212 149 62 https://doi.org/10.1111/j.0105-2896.2006.00414.x 16903912 \n27 Rafiq K Bergtold A Clynes R Immune complex-mediated antigen presentation induces tumor immunity J Clin Invest 2002 110 71 9 https://doi.org/10.1172/JCI15640 12093890 \n28 Schuurhuis DH van Montfoort N Ioan-Facsinay A Jiawan R Camps M Nouta J Melief CJM Verbeek JS Ossendorp F Immune complex-loaded dendritic cells are superior to soluble immune complexes as antitumor vaccine J Immunol 2006 176 4573 80 https://doi.org/10.4049/jimmunol.176.8.4573 16585547 \n29 Chen W Jin W Hardegen N Lei KJ Li L Marinos N McGrady G Wahl SM Conversion of peripheral CD4+CD25– naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3 J Exp Med 2003 198 1875 86 https://doi.org/10.1084/jem.20030152 14676299 \n30 Ueda S Saeki T Takeuchi H Shigekawa T Yamane T Kuji I Osaki A In vivo imaging of eribulin-induced reoxygenation in advanced breast cancer patients: a comparison to bevacizumab Br J Cancer 2016 114 1212 8 https://doi.org/10.1038/bjc.2016.122 27140309 \n31 Yoshida T Ozawa Y Kimura T Sato Y Kuznetsov G Xu S Uesugi M Agoulnik S Taylor N Funahashi Y Matsui J Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states Br J Cancer 2014 110 1497 505 https://doi.org/10.1038/bjc.2014.80 24569463 \n32 Chen W Konkel JE TGF-beta and ‘adaptive’ Foxp3(+) regulatory T cells J Mol Cell Biol 2010 2 30 6 https://doi.org/10.1093/jmcb/mjp004 19648226 \n33 Petricevic B Laengle J Singer J Sachet M Fazekas J Steger G Bartsch R Jensen-Jarolim E Bergmann M Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity and phagocytosis to the same extent in both adjuvant and metastatic HER2/neu breast cancer patients J Transl Med 2013 11 307 https://doi.org/10.1186/1479-5876-11-307 24330813 \n34 Clynes RA Towers TL Presta LG Ravetch JV Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets Nat Med 2000 6 443 6 10742152 \n35 De Palma M Lewis CE Macrophage regulation of tumor responses to anticancer therapies Cancer Cell 2013 23 277 86 https://doi.org/10.1016/j.ccr.2013.02.013 23518347 \n36 Park S Jiang Z Mortenson ED Deng L Radkevich-Brown O Yang X Sattar H Wang Y Brown NK Greene M Liu Y Tang J Wang S Fu YX The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity Cancer Cell 2010 18 160 70 https://doi.org/10.1016/j.ccr.2010.06.014 20708157 \n37 Brady MJ Cella DF Mo F Bonomi AE Tulsky DS Lloyd SR Deasy S Cobleigh M Shiomoto G Reliability and validity of the functional assessment of cancer therapy-breast quality-of-life instrument J Clin Oncol 1997 15 974 86 https://doi.org/10.1200/JCO.1997.15.3.974 9060536 \n38 Sallusto F Geginat J Lanzavecchia A Central memory and effector memory T cell subsets: function, generation, and maintenance Annu Rev Immunol 2004 22 745 63 https://doi.org/10.1146/annurev.immunol.22.012703.104702 15032595\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "9(19)",
"journal": "Oncotarget",
"keywords": "HER2-positive; breast cancer; eribulin mesylate; pertuzumab; trastuzumab",
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"title": "Pertuzumab, trastuzumab and eribulin mesylate therapy for previously treated advanced HER2-positive breast cancer: a feasibility study with analysis of biomarkers.",
"title_normalized": "pertuzumab trastuzumab and eribulin mesylate therapy for previously treated advanced her2 positive breast cancer a feasibility study with analysis of biomarkers"
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"abstract": "Pregabalin is an anticonvulsant and analgesic designed to treat neuropathic pain and partial seizure disorders and has been available in Australia as a prescription medication since 2005. Studies have found high rates of polydrug use associated with pregabalin and it is reportedly used recreationally for its euphoric and relaxing effects as well as to self-manage opioid withdrawal symptoms. A robust analytical method for the analysis of pregabalin using protein precipitation and LC/MS/MS was developed, validated and employed in routine case work. In recent years a substantial increase in pregabalin detections in coronial case submissions had been noted. This study examines the case characteristics and outcomes of 332 coronial cases submitted to the laboratory and analyzed for pregabalin between 2015 and 2017. Pregabalin was identified in approximately 5% of all coronial cases submitted during this time. A high rate of concurrent drug use with pregabalin was evident with the predominant classes being opioids, benzodiazepines and anti-depressants. Post-mortem blood pregabalin concentrations ranged from <0.05 to 140 mg/kg (median 5.5 mg/kg); however, limited interpretation of levels could be achieved as the drug was rarely identified in the absence of other drugs. Cause of death (COD) was found to be drug related in 58% of all cases, with mixed drug toxicity specifically mentioned as related to COD in 40% of cases.",
"affiliations": "Forensic & Scientific Services, Health Support Queensland, Australia.;Forensic & Scientific Services, Health Support Queensland, Australia.;Forensic & Scientific Services, Health Support Queensland, Australia.",
"authors": "Thompson|Amanda|A|;Morey|Sarah|S|;Griffiths|Andrew|A|",
"chemical_list": "D000700:Analgesics; D000927:Anticonvulsants; D000069583:Pregabalin",
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"title": "Pregabalin and Its Involvement in Coronial Cases.",
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"abstract": "Severe decompression illness (DCI) is an uncommon medical issue affecting divers and results mainly from rapid surfacing using inadequate decompression protocols. Massive gas embolism with central nervous system involvement often leads to a poor prognosis, with permanent residual neurologic defects. Moreover, DCI complicated with multiple organ dysfunction syndrome (MODS) is tremendously rare and difficult to cure, although hyperbaric oxygen (HBO2) therapy following the U.S. Navy Treatment Tables is a consensus. We report a case of severe DCI with profound shock and MODS after an initial treatment with HBO2 therapy using U.S. Navy Treatment Table 6A. Following the Surviving Sepsis Campaign Guidelines, low-dose hydrocortisone was administered. Although this treatment went against recommendation of the U.S. Navy Diving Manual, it resulted in a dramatic clinical improvement. After a second round of HBO2 treatments, the patient was discharged from hospital two weeks after the diving accident.",
"affiliations": "Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.;Hyperbaric Oxygen Therapy Center, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.;Hyperbaric Oxygen Therapy Center, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.;Hyperbaric Oxygen Therapy Center, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.;Hyperbaric Oxygen Therapy Center, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.",
"authors": "Lee|Cho-Hao|CH|;Peng|Chung-Kan|CK|;Chang|Shan-Yueh|SY|;Shen|Chih-Hao|CH|;Huang|Kun-Lun|KL|",
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"keywords": " decompression illness ; glucocorticoids ; hyperbaric oxygen therapy ; multiple organ dysfunction ; shock ",
"medline_ta": "Undersea Hyperb Med",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D003665:Decompression Sickness; D004242:Diving; D006801:Humans; D006854:Hydrocortisone; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure; D017410:Practice Guidelines as Topic; D012016:Reference Values; D017582:Renal Replacement Therapy; D012769:Shock; D016896:Treatment Outcome",
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"title": "Surviving Sepsis Campaign guidelines for a diver with DCI: case report.",
"title_normalized": "surviving sepsis campaign guidelines for a diver with dci case report"
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"abstract": "The number of older adult patients with rheumatoid arthritis(RA)is increasing. As older adult patients tend to have multiple diseases requiringmedications, they are likely to experience side effects from the decline in their physiological functioning. In addition, suppression of disease activity leads to a decline in ADL in the case of patients livingalone, even leadingto difficulties in livingat home. In the 3-years clinical course on older adult RA patients livingalone with multiple diseases, we show the mindset that community pharmacists must have for three events(namely, hypoalbuminemia, chronic heart failure, and dehydration)in which inflammation influences medicinal or side effects.",
"affiliations": "Cocokarafine Healthcare, Inc., Cocokarafine Pharmacy Kinuta.",
"authors": "Kawana|Michiyo|M|;Hatsuta|Minoru|M|;Hirohara|Masayoshi|M|;Kushida|Kazuki|K|",
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"mesh_terms": "D001172:Arthritis, Rheumatoid; D006333:Heart Failure; D006699:Home Care Services; D006801:Humans; D007249:Inflammation; D010595:Pharmacists",
"nlm_unique_id": "7810034",
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"title": "Mindset for Pharmacists as an Expert of Pharmacotherapy-Case of Home-Care Rheumatoid Arthritis Patients with Multiple Diseases.",
"title_normalized": "mindset for pharmacists as an expert of pharmacotherapy case of home care rheumatoid arthritis patients with multiple diseases"
} | [
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"companynumb": "JP-PFIZER INC-2019265963",
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"abstract": "The incidence of headaches during pregnancy is 35%. Although ruling out pre-eclampsia as a possible cause for headache is important in the pregnant population, acute sinusitis should remain on the differential as it occurs six times more frequently in pregnant women. Untreated disease can lead to rare intracranial complications such as a subdural empyema.Case presentation: 21-year-old female with recurring headaches at 33 weeks of gestation was diagnosed with pre-eclampsia with severe features requiring emergent caesarean section. The woman continued to have altered mental status and focal neurologic deficits after delivery. Computerized tomography head imaging demonstrated a subdural collection discovered to be an empyema due to unilateral acute sinusitis of odontogenic origin.\nMaintaining a clinical suspicion for acute sinusitis as a cause of headache in a pregnant woman is important for prompt diagnosis and treatment before it develops into a rare intracranial complication.",
"affiliations": "Department of Otolaryngology Head and Neck Surgery, Loyola University Medical Center, Maywood, IL, USA.;Stritch School of Medicine, Loyola University, Maywood, IL, USA.;Department of Otolaryngology Head and Neck Surgery, Loyola University Medical Center, Maywood, IL, USA.",
"authors": "Yang|Sara|S|https://orcid.org/0000-0001-8949-1421;Han|Jane J|JJ|;Patadia|Monica|M|",
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"doi": "10.1177/1753495X20970095",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1753-495X",
"issue": "14(4)",
"journal": "Obstetric medicine",
"keywords": "Pregnancy; empyema; headache; pre-eclampsia; sinusitis",
"medline_ta": "Obstet Med",
"mesh_terms": null,
"nlm_unique_id": "101464191",
"other_id": null,
"pages": "257-259",
"pmc": null,
"pmid": "34880941",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports",
"references": "29052046;19464507;16175681;29404826;22892137;17420130;26889651;16443148;7403786;23983844;15547546;29285572;25638394",
"title": "Sinusitis as a cause of insidious headache in a pregnant woman: A case report.",
"title_normalized": "sinusitis as a cause of insidious headache in a pregnant woman a case report"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-342521",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID"
... |
{
"abstract": "OBJECTIVE\nThe effect of therapeutic plasma exchange (TPE) on antifactor Xa activity in a patient treated with enoxaparin and levetiracetam is reported.\n\n\nCONCLUSIONS\nA 52-year-old woman was treated with levetiracetam and prophylactic enoxaparin while receiving TPE to manage respiratory failure due to anti-MDA5 antibody-associated interstitial lung disease (ILD) with dermatomyositis. Due to a scant amount of evidence regarding the management of these medications in TPE, therapeutic monitoring principles were used to assess the effect TPE had on these medications. A pre-TPE antifactor Xa activity level and levetiracetam serum assay, a post-TPE antifactor Xa activity level and levetiracetam serum assay, levetiracetam serum assays at 1 and 6 hours after the patient received her next dose, and a levetiracetam assay of the waste plasma from the TPE were collected for therapeutic drug monitoring and pharmacokinetic calculations. Utilizing standard population pharmacokinetic data, the expected antifactor Xa activity without TPE was 0.14 IU/mL. This concentration was significantly higher than the undetectable concentration (<0.1 IU/mL) that was drawn immediately after TPE, suggesting significant removal of antifactor Xa activity. The measured levetiracetam level did not significantly differ from the expected post-TPE levetiracetam level that was calculated using patient-specific pharmacokinetic data.\n\n\nCONCLUSIONS\nIn a patient receiving TPE to manage anti-MDA5 antibody ILD associated with dermatomyositis and a prior seizure, TPE significantly altered enoxaparin antifactor Xa activity as evidenced by the undetectable antifactor Xa activity level drawn after TPE. Alternatively, TPE had a minimal effect on the clearance of levetiracetam as evidenced by the post-TPE level and fraction elimination of only 5% of total body stores.",
"affiliations": "Department of Pharmacy, Mayo Clinic Rochester, Rochester, MN peters.bradley@mayo.edu.;previously Pharm.D. student, University of Minnesota, College of Pharmacy, Minneapolis, MN.;Department of Pulmonary and Critical Care Medicine, Mayo Clinic Rochester, Rochester, MN.;Department of Laboratory Medicine and Pathology, Division of Transfusion Medicine, Mayo Clinic Rochester, Rochester, MN.",
"authors": "Peters|Bradley J|BJ|;Hofer|Mikaela|M|;Daniels|Craig E|CE|;Winters|Jeffrey L|JL|",
"chemical_list": "D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D000077287:Levetiracetam",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp170885",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "75(23)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": "Apheresis; enoxaparin; levetiracetam; plasma exchange; plasmapheresis",
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D000077287:Levetiracetam; D017563:Lung Diseases, Interstitial; D008875:Middle Aged; D010951:Plasma Exchange; D012131:Respiratory Insufficiency",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "1883-1888",
"pmc": null,
"pmid": "30463865",
"pubdate": "2018-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Effect of plasma exchange on antifactor Xa activity of enoxaparin and serum levetiracetam levels.",
"title_normalized": "effect of plasma exchange on antifactor xa activity of enoxaparin and serum levetiracetam levels"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/19/0106681",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": null,... |
{
"abstract": "Major depressive disorder (MDD) is a common, debilitating disorder with substantial socioeconomic burden. Many patients with MDD experience symptoms that impair functioning and productivity, often negatively affecting work or educational pursuits. This Phase 3b open-label study evaluated adjunctive brexpiprazole in young adults with MDD, who were in work or study.\n\n\n\nYoung patients (18-35 years) with MDD (inadequate responders to 1-3 antidepressant treatments [ADT] for their current episode) received brexpiprazole 1-3mg/day (target dose, 2mg/day) adjunctive to the same stable dose of ADT for 12 weeks.\n\n\n\nDepressive symptoms improved during treatment with adjunctive brexpiprazole (primary endpoint, least squares [LS] mean change from baseline in Montgomery-Åsberg Depression Rating Scale [MADRS] total score, -18.1 [p<0.0001]). Reductions from baseline in Sheehan Disability Scale Score (SDS; LS mean change -11.2 [p<0.0001]) and Work Limitations Questionnaire (WLQ; p<0.0001) indicated improvements in the effects of patients' symptoms on functioning (work/school, social life, and home responsibilities). Changes from baseline in additional measures supported improvements in patient functioning and depression symptoms. The most common adverse events were headache (21.3%), weight increase (17.0%), and somnolence (17.0%); reported rates of akathisia were low (6.4%). Clinically relevant increases in weight (≥7%) occurred in 10.5% of patients.\n\n\n\nOpen-label design; absence of comparator.\n\n\n\nBrexpiprazole may represent an effective therapy for adjunctive treatment strategy of young adults with MDD who are working or studying. The observed improvements in work/school functioning in patients with MDD, whose depression was treated with ADT+brexpiprazole, suggests potential to reduce socioeconomic burden.",
"affiliations": "Duke University Medical Center Durham, University of North Carolina, Chapel Hill, NC, USA; Richard H Weisler Md And Association, MD, PA, Raleigh, NC, USA. Electronic address: rweisler@aol.com.;Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan.;Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan.;Otsuka Pharmaceutical Development and Commercialization Inc., Princeton, NJ 08540, USA.;H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.;Otsuka Pharmaceutical Development and Commercialization Inc., Princeton, NJ 08540, USA.;University of South Florida College of Medicine, Tampa, FL, USA.",
"authors": "Weisler|Richard H|RH|;Ota|Ai|A|;Tsuneyoshi|Kana|K|;Perry|Pamela|P|;Weiller|Emmanuelle|E|;Baker|Ross A|RA|;Sheehan|David V|DV|",
"chemical_list": "D000928:Antidepressive Agents; D015363:Quinolones; D013876:Thiophenes; C000591922:brexpiprazole",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-0327",
"issue": "204()",
"journal": "Journal of affective disorders",
"keywords": "Brexpiprazole; Functioning; Major depressive disorder; Work; Young adults",
"medline_ta": "J Affect Disord",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000928:Antidepressive Agents; D003865:Depressive Disorder, Major; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004651:Employment; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D011569:Psychiatric Status Rating Scales; D015363:Quinolones; D013334:Students; D013876:Thiophenes; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7906073",
"other_id": null,
"pages": "40-7",
"pmc": null,
"pmid": "27322768",
"pubdate": "2016-11-01",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Brexpiprazole as an adjunctive treatment in young adults with major depressive disorder who are in a school or work environment.",
"title_normalized": "brexpiprazole as an adjunctive treatment in young adults with major depressive disorder who are in a school or work environment"
} | [
{
"companynumb": "US-OTSUKA-2016_016536",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BREXPIPRAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "We report the outcomes of 30 patients with juvenile myelomonocytic leukemia (JMML) who received unmanipulated hematopoietic stem cell transplantation (HSCT) with oral or intravenous busulfan, fludarabine, and melphalan between 2001 and 2011. Mutations in PTPN11 were detected in 15 patients. Six patients received human leukocyte antigen (HLA)-matched HSCT from related donors, and 24 patients received HSCT from alternative donors, including 13 HLA-mismatched donors. Primary engraftment failed in five patients, all of whom had received allografts from HLA-mismatched donors. HLA-mismatched HSCT resulted in poorer event-free survival than HLA-matched HSCT (28.8 vs. 70.6 %). Three patients died of transplantation-related causes, and eight patients experienced hematological relapse (including five patients who died due to disease progression). Eight patients received a second HSCT, and four of these patients have survived. The 5-year estimated overall survival for all patients was 72.4: 88.9 % for the patients without a mutation in PTPN11 (n = 10) and 58.3 % for the patients with a mutation in PTPN11 (n = 15) (P = 0.092). The conditioning regimen reported in the present study achieved hematological and clinical remission in >50 % of patients with JMML who received HSCT from alternative donors, and may also be effective for JMML patients with PTPN11 mutation.",
"affiliations": "Department of Cell Transplantation and Regenerative Medicine, Tokai University Hospital, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan, miharu@is.icc.u-tokai.ac.jp.",
"authors": "Yabe|Miharu|M|;Ohtsuka|Yoshitoshi|Y|;Watanabe|Kenichiro|K|;Inagaki|Jiro|J|;Yoshida|Nao|N|;Sakashita|Kazuo|K|;Kakuda|Harumi|H|;Yabe|Hiromasa|H|;Kurosawa|Hidemitsu|H|;Kudo|Kazuko|K|;Manabe|Atsushi|A|;|||",
"chemical_list": "D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine; D008558:Melphalan",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-014-1715-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "101(2)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002066:Busulfan; D002648:Child; D002675:Child, Preschool; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D054429:Leukemia, Myelomonocytic, Juvenile; D008297:Male; D008558:Melphalan; D019233:Retreatment; D012189:Retrospective Studies; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014740:Vidarabine",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "184-90",
"pmc": null,
"pmid": "25504334",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article",
"references": "9160658;23926304;15800672;22348520;18302710;23702913;22847790;19047918;11960345;19743300;18397212;12592323;23832011;17268527;15353481;15877738",
"title": "Transplantation for juvenile myelomonocytic leukemia: a retrospective study of 30 children treated with a regimen of busulfan, fludarabine, and melphalan.",
"title_normalized": "transplantation for juvenile myelomonocytic leukemia a retrospective study of 30 children treated with a regimen of busulfan fludarabine and melphalan"
} | [
{
"companynumb": "JP-MYLANLABS-2015M1030476",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": n... |
{
"abstract": "BACKGROUND\nOverall survival of adolescents with relapsed T-cell lymphoblastic lymphoma (T-LL) remains poor with limited options for salvage therapy. The BCL-2 inhibitor venetoclax combined with hypomethylating agents like decitabine, has shown favorable responses in elderly patients with acute myeloid leukemia.\n\n\nMETHODS\nWe present the case of a 19-year-old adolescent with stage III relapsed and refractory T-LL who did not respond to 3 lines of salvage therapy. The patient was treated with venetoclax and decitabine and achieved a dramatic response.\n\n\nCONCLUSIONS\nThis case highlights the potential clinical activity of venetoclax and decitabine in relapsed T-LL.",
"affiliations": "Departments of Pediatrics.;Departments of Pediatrics.;Departments of Pediatrics.;Nuclear Medicine.;Departments of Pediatrics.;Hematopathology.;Departments of Pediatrics.",
"authors": "Baig|Muhammad U|MU|;Rytting|Michael|M|;Roth|Michael|M|;Morani|Ajaykumar C|AC|;Nunez|Cesar|C|;Lin|Pei|P|;Cuglievan|Branko|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000002050",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "43(7)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": null,
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e991-e996",
"pmc": null,
"pmid": "33480649",
"pubdate": "2021-10-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Venetoclax and Decitabine in Pediatric Refractory T-cell Lymphoblastic Lymphoma.",
"title_normalized": "venetoclax and decitabine in pediatric refractory t cell lymphoblastic lymphoma"
} | [
{
"companynumb": "US-TEVA-2022-US-2016831",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "4",
... |
{
"abstract": "Cytomegalovirus (CMV) infection is a common cause of morbidity and mortality in immunocompromised hosts. Tissue-invasive CMV disease causing ulcerative skin disease or esophageal necrosis is rare. We herein describe two cases: a 47-year-old renal and pancreas transplant recipient who presented with skin ulcerations on his elbow and a 50-year-old renal transplant recipient who presented with acute esophageal necrosis. In both, tissue biopsy revealed CMV inclusion bodies by immunohistochemical staining of infected endothelial and mucosal cells. Ganciclovir was given to both cases and full remission occurred. Due to the varying presentations of acute CMV infection in immunosuppressed hosts, high suspicion and early tissue biopsy are vital for proper diagnosis and treatment when any suspicious cutaneous or mucosal manifestations are present.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.;School of Medicine, Ross University, Miramar, FL, USA.;School of Medicine, Ross University, Miramar, FL, USA.;Division of Infectious Diseases, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.",
"authors": "Mena Lora|Alfredo|A|0000-0002-8337-757X;Khine|Justin|J|;Khosrodad|Nadia|N|;Yeldandi|Vijay|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2017/4916973",
"fulltext": "\n==== Front\nCase Rep TransplantCase Rep TransplantCRITCase Reports in Transplantation2090-69432090-6951Hindawi 10.1155/2017/4916973Case ReportUnusual Manifestations of Acute Cytomegalovirus Infection in Solid Organ Transplant Hosts: A Report of Two Cases http://orcid.org/0000-0002-8337-757XMena Lora Alfredo amenalor@uic.edu\n1\nKhine Justin \n2\nKhosrodad Nadia \n2\nYeldandi Vijay \n1\n\n1Division of Infectious Diseases, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA\n2School of Medicine, Ross University, Miramar, FL, USAAcademic Editor: Marian Klinger\n\n2017 11 9 2017 2017 491697311 6 2017 27 7 2017 6 8 2017 Copyright © 2017 Alfredo Mena Lora et al.2017This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Cytomegalovirus (CMV) infection is a common cause of morbidity and mortality in immunocompromised hosts. Tissue-invasive CMV disease causing ulcerative skin disease or esophageal necrosis is rare. We herein describe two cases: a 47-year-old renal and pancreas transplant recipient who presented with skin ulcerations on his elbow and a 50-year-old renal transplant recipient who presented with acute esophageal necrosis. In both, tissue biopsy revealed CMV inclusion bodies by immunohistochemical staining of infected endothelial and mucosal cells. Ganciclovir was given to both cases and full remission occurred. Due to the varying presentations of acute CMV infection in immunosuppressed hosts, high suspicion and early tissue biopsy are vital for proper diagnosis and treatment when any suspicious cutaneous or mucosal manifestations are present.\n==== Body\n1. Introduction\nCytomegalovirus (CMV) is a Herpesviridae with high seroprevalence, estimated between 30 and 97% [1–3]. Primary infection in an immunocompetent host can be asymptomatic or only self-limiting disease [1]. CMV establishes life-long latency in the host and can then be reactivated under immunocompromised states or cause a carrier-state [1, 4, 5]. CMV can affect immunocompromised hosts aggressively and is a significant cause of morbidity and mortality in solid organ transplant (SOT) recipients [1, 6]. SOT recipients are at highest risk in the first month after transplantation [6]. Serologic status of the donor, recipient, and the type of transplanted organ play a key role, as CMV disease is more likely in SOT recipients with no preexisting CMV-specific immunity [1, 6].\n\nClinical manifestations of CMV infection in SOT recipients include fever, malaise, leukopenia, and thrombocytopenia. CMV can also cause end-organ damage involving kidneys, pancreas, colon, lung, and CNS disease [1, 6]. Cutaneous CMV involvement is rare but when present can be rapidly fatal if not diagnosed quickly [7–10]. CMV cutaneous lesions can precede systemic disease. Thus, a high index of suspicion and early biopsy is needed for timely management to decrease morbidity and mortality [11]. Gastrointestinal (GI) tract CMV infections can cause colonic ulcerations, bleeding, and perforations with colitis and esophagitis as the two most common manifestations [12, 13]. We describe two atypical cases of CMV infection in immunocompromised hosts following successful organ transplantation.\n\n2. Case 1: CMV Skin Lesion\nA 47-year-old male presented with a two-week history of back pain, generalized muscle aches, nausea, vomiting, diarrhea, and pain in his right elbow (Figure 1). Medical history included hypertension, hyperlipidemia, end-stage renal disease, renal transplant five years earlier, and pancreas transplant one year earlier. Medications included mycophenolic acid and tacrolimus for immunosuppression. Patient had not recently been on corticosteroids and had adequate allograft function with a baseline serum creatinine range of 1.7–1.9 mg/dL. Pretransplant studies revealed negative CMV IgG in the recipient and positive serology in the donor, but no additional risk factors for CMV infection were present. Patient was on trimethoprim-sulfamethoxazole for prophylaxis for the past 12 months and CMV prophylaxis with valganciclovir was taken for 6 months after transplantation and discontinued 6 months before presentation.\n\nAt presentation, the patient was febrile to 38 degrees Celsius. Physical exam was remarkable for tenderness in right costovertebral region and a tender, edematous, and erythematous scab on the right elbow with minimal drainage present. Labs revealed leukopenia with total white blood cell count of 3,000 mm3, hemoglobin of 10.2 g/dL, platelets of 184,000 mm3, and normal transaminases. Electrolytes were unremarkable with creatinine at baseline (1.9 mg/dL). Chest imaging was normal. He was admitted to the hospital and received empiric antimicrobials for a possible bacterial cellulitis.\n\nHis condition did not improve despite broad antibacterial coverage. A punch biopsy was performed on the lesion. The tissue was found to have multiple viral cytopathic inclusion bodies and a lymphocytic vasculitis concerning CMV infection. Further histopathologic studies confirmed the diagnosis (Figure 2). Serum PCR for CMV was reported at 21,000 copies. The patient was started on valganciclovir 900 mg every 12 hours. Antibacterials were stopped and patient was eventually discharged on a three-week course. The patient tolerated therapy and the lesions resolved.\n\n3. Case 2: CMV Esophageal Lesion\nA 50-year-old male presented with a one-day history of shortness of breath. Medical history included peripheral vascular disease, hyperlipidemia, diabetes, hypertension, end-stage renal disease, and cadaveric renal transplant 11 days prior to presentation. His immediate postoperative course was complicated by acute tubular necrosis and delayed graft function. The patient received IV methylprednisolone on the day of surgery followed by a 7-day prednisone taper. He received basiliximab and was subsequently switched to anti-thymocyte globulin (ATG) for induction therapy. Pretransplant studies revealed negative CMV IgG in the recipient and positive serology in the donor. He was started on valganciclovir and trimethoprim-sulfamethoxazole for prophylaxis on postoperative day 0, along with tacrolimus and mycophenolic acid for immunosuppression. He required two sessions of hemodialysis postoperatively. Allograft function recovered, with serum creatinine improving from 9.3 to 7.2 mg/dL by postoperative day 5. He was discharged home on day 7.\n\nAt presentation, the patient developed respiratory failure and cardiopulmonary arrest. Return of spontaneous circulation was achieved after five minutes of cardiopulmonary resuscitation. Laboratory values were remarkable for white blood cell count of 16.5 mm3, platelet count of 166,000 mm3, and a hemoglobin level of 6.8 g/dL. Serum creatinine was 4.0 mg/dL. Liver function tests were normal. Chest imaging and renal ultrasound revealed no abnormalities. The patient was extubated five days later. He developed epigastric discomfort. Esophagogastroduodenoscopic (EGD) examination showed duodenal ulcerations with adherent clots and a blackened middle and lower esophagus thought to be secondary to ischemia (Figure 3). Serum CMV PCR detected no viral copies. Biopsies revealed viral inclusions throughout these lesions consistent with CMV (Figure 4). The patient was started on ganciclovir and clinically improved. He was transitioned to PO valganciclovir after one week and treated for a total of 21 days. Valganciclovir was subsequently changed to prophylactic doses and continued for 12 months.\n\n4. Discussion\nCMV infections have been recognized as a significant cause of morbidity and mortality in immunocompromised patients such as in solid organ transplant patients [7]. Skin ulcerations in immunocompromised patients merit a broad differential diagnosis including infectious and noninfectious causes. CMV involvement of skin has been described in the literature, but this condition remains rare. To our knowledge, there are fewer than 200 cases reported in the medical literature in the English language. Skin manifestations can include petechiae, nodules, ulcers, erosions, purpura, morbilliform eruptions, vesiculobullous lesions, papules, and verrucous lesions [9, 14–19]. There does not seem to be a predilection for the location of these lesions. The anogenital, perineum, heel, scrotum, axilla, or penile regions have all been reported to be involved [12, 20–22]. Painful ulceration of the tongue with CMV infection in renal transplant patients has also been reported [12]. Though these skin manifestations are heterogeneous, they all exhibit a typical histological appearance that includes vascular endothelial cytopathic changes and intranuclear inclusion bodies [11, 23]. Prior to advent of antiviral therapy, cutaneous CMV disease was associated with high mortality and was often diagnosed postmortem [23]. Early biopsy is imperative for reaching the diagnosis without delay, initiating appropriate therapy, and preventing further morbidity or mortality.\n\nGastrointestinal CMV disease is common in the first 6–12 months after transplantation and causes significant morbidity and mortality [24, 25]. The GI tract is the most common site of tissue-invasive CMV infection with colitis as the first most common site and esophagitis as the second most common [12, 13]. Failure to identify early stage CMV infection can cause further viremia, end-organ damage at other sites, and further damage to the GI microvasculature causing ulcerations, bleeding, and perforation [12]. Typical endoscopic findings of tissue-invasive CMV of the GI tract include shallow, erythematous erosions or localized ulcers [25]. Histopathology may show CMV inclusion bodies. Serum CMV PCR studies may yield negative results in patients with tissue-invasive disease; thus early biopsy for suspected tissue-invasive disease is recommended [1].\n\nIn the second case study, the patient presented 10 days after transplantation and had received ATG therapy as part of his induction therapy. ATG therapy increases the risk of CMV disease and is considered an independent risk factor [26, 27]. This likely contributed to his severe tissue-invasive disease. EGD revealed classic duodenal and esophageal ulcerations and immunohistochemical stains of the biopsy specimens revealed viral inclusion bodies consistent with CMV. Other rare gastrointestinal presentations of CMV infections include GI obstruction, perforation, thrombosis of large venous structures, splenic artery thrombosis, and pancreatitis [12]. Renal-allograft ureteral strictures have also been described [12].\n\nWe herein describe two rare manifestations of CMV disease in SOT transplant recipients. Despite being a well-recognized cause of morbidity and mortality in SOT recipients, CMV infection can present in atypical forms and pose a diagnostic challenge. High index of suspicion and early tissue biopsy are key for proper diagnosis and treatment.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this paper.\n\nFigure 1 Cutaneous CMV ulceration of right elbow.\n\nFigure 2 Histocytology stain showing CMV inclusion bodies from elbow biopsy.\n\nFigure 3 Esophagogastroduodenoscopy showing (a) duodenal ulcerations with adherent clots and (b) blackened middle and lower esophagus.\n\nFigure 4 Histocytology stain indicating CMV inclusion bodies from esophageal biopsy.\n==== Refs\n1 Razonable R. R. Humar A. Cytomegalovirus in solid organ transplantation American Journal of Transplantation 2013 13 s4 93 106 10.1111/ajt.12103 2-s2.0-84874828991 23465003 \n2 Cannon M. J. Schmid D. S. Hyde T. B. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection Reviews in Medical Virology 2010 20 4 202 213 2-s2.0-77954170594 10.1002/rmv.655 20564615 \n3 Staras S. A. S. Dollard S. C. Radford K. W. Flanders W. D. Pass R. F. Cannon M. J. Seroprevalence of cytomegalovirus infection in the United States, 1988–1994 Clinical Infectious Diseases 2006 43 9 1143 1151 10.1086/508173 2-s2.0-33750128821 17029132 \n4 Manuel O. Pang X. L. Humar A. Kumar D. Doucette K. Preiksaitis J. K. An assessment of donor-to-recipient transmission patterns of human cytomegalovirus by analysis of viral genomic variants Journal of Infectious Diseases 2009 199 11 1621 1628 2-s2.0-67650671190 10.1086/598952 19385736 \n5 Razonable R. R. Epidemiology of cytomegalovirus disease in solid organ and hematopoietic stem cell transplant recipients American Journal of Health-System Pharmacy 2005 62 8 supplement 1 S7 S13 \n6 Trimarchi H. Casas G. Jordan R. Cytomegalovirus maculopapular eruption in a kidney transplant patient Transplant Infectious Disease 2001 3 1 47 50 10.1034/j.1399-3062.2001.003001047.x 11429041 \n7 Colsky A. S. Jegasothy S. M. Leonardi C. Kirsner R. S. Kerdel F. A. Diagnosis and treatment of a case of cutaneous cytomegalovirus infection with a dramatic clinical presentation Journal of the American Academy of Dermatology 1998 38 2 349 351 2-s2.0-0031943044 10.1016/S0190-9622(98)70581-X 9486714 \n8 Swanson S. Feldman P. S. Cytomegalovirus infection initially diagnosed by skin biopsy American Journal of Clinical Pathology 1987 87 1 113 116 2-s2.0-0023205195 10.1093/ajcp/87.1.113 3026168 \n9 Evans D. J. Williams E. D. Cytomegalic inclusion disease in the adult Journal of Clinical Pathology 1968 21 3 311 316 10.1136/jcp.21.3.311 2-s2.0-0014282084 4301686 \n10 Toome B. K. Bowers K. E. Scott G. A. Diagnosis of cutaneous cytomegalovirus infection: a review and report of a case Journal of the American Academy of Dermatology 1991 24 5 860 867 10.1016/0190-9622(91)70134-N 2-s2.0-0025898741 1646834 \n11 Pariser R. J. Histologically specific skin lesions in disseminated cytomegalovirus infection Journal of the American Academy of Dermatology 1983 9 6 937 946 2-s2.0-0021077113 10.1016/S0190-9622(83)70212-4 6315790 \n12 Ardalan M. Rare presentations of cytomegalovirus infection in renal allograft recipients Nephro-Urology Monthly 2012 4 2 431 436 2-s2.0-84858398941 10.5812/numonthly.1844 23573461 \n13 Kotton C. N. Kumar D. Caliendo A. M. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation Transplantation 2013 96 4 333 360 2-s2.0-84883455574 10.1097/TP.0b013e31829df29d 23896556 \n14 Penneys N. S. Hicks B. Unusual cutaneous lesions associated with acquired immunodeficiency syndrome Journal of the American Academy of Dermatology 1985 13 5 I 845 852 2-s2.0-0022356131 10.1016/S0190-9622(85)70228-9 3001157 \n15 Feldman P. S. Walker A. N. Baker R. Cutaneous lesions heralding disseminated cytomegalovirus infection Journal of the American Academy of Dermatology 1982 7 4 545 548 2-s2.0-0019955590 10.1016/S0190-9622(82)80255-7 6292265 \n16 Robson G. Mackay I. Generalized cytomegalovirus infection in a patient with lupoid hepatitis Australasian Annals of Medicine 1969 18 147 150 4183285 \n17 Minars N. Silverman J. F. Escobar M. R. Martinez A. J. Fatal cytomegalic inclusion disease: associated skin manifestations in a renal transplant patient Archives of Dermatology 1977 113 11 1569 1571 10.1001/archderm.1977.01640110089015 2-s2.0-0017642797 201217 \n18 Meyers J. D. Flournoy N. Thomas E. D. Cytomegalovirus infection and specific cell-mediated immunity after marrow transplant Journal of Infectious Diseases 1980 142 6 816 824 2-s2.0-0019275086 10.1093/infdis/142.6.816 6257800 \n19 Guo R. F. Gebreab F. H. Tang E. H. Piao Z. Lee S. S. Perez M. L. Cutaneous ulcer as leading symptom of systemic cytomegalovirus infection Case Reports in Infectious Diseases 2015 2015 4 723962 10.1155/2015/723962 \n20 Lambert E. M. Strasswimmer J. Lazova R. Antaya R. J. Cytomegalovirus ulcer: successful treatment with valganciclovir Archives of Dermatology 2004 140 10 1199 1201 10.1001/archderm.140.10.1199 2-s2.0-5444254879 15492181 \n21 Drago F. Aragone M. G. Lugani C. Rebora A. Cytomegalovirus infection in normal and immunocompromised humans: a review Dermatology 2000 200 3 189 195 10.1159/000018381 2-s2.0-0034103277 10828625 \n22 Prasad N. Jain M. Gupta A. Sharma R. K. Agarwal V. An unusual case of CMV cutaneous ulcers in a renal transplant recipient and review of literature NDT Plus 2010 3 4 379 382 10.1093/ndtplus/sfq082 2-s2.0-77956035828 25949436 \n23 Golden M. P. Hammer S. M. Wanke C. A. Albrecht M. A. Cytomegalovirus vasculitis. Case reports and review of the literature Medicine 1994 73 5 246 255 10.1097/00005792-199409000-00003 7934809 \n24 Silva M. Silva R. Macedo G. Extensive esophageal ulceration in a renal transplant patient GE Portuguese Journal of Gastroenterology 2016 23 2 116 118 10.1016/j.jpge.2015.08.005 28868444 \n25 Helderman J. H. Goral S. Gastrointestinal complications of transplant immunosuppression Journal of the American Society of Nephrology 2002 13 1 277 287 2-s2.0-0036138550 11752050 \n26 Taherimahmoudi M. Ahmadi H. Baradaran N. Cytomegalovirus infection and disease following renal transplantation: preliminary report of incidence and potential risk factors Transplantation Proceedings 2009 41 7 2841 2844 10.1016/j.transproceed.2009.07.027 2-s2.0-70149101109 19765452 \n27 Low C. Y. Hosseini-Moghaddam S. M. Rotstein C. Renner E. L. Husain S. The effect of different immunoprophylaxis regimens on post-transplant cytomegalovirus (CMV) infection in CMV-seropositive liver transplant recipients Transplant Infectious Disease 2017 10.1111/tid.12736\n\n",
"fulltext_license": "CC BY",
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"issue": "2017()",
"journal": "Case reports in transplantation",
"keywords": null,
"medline_ta": "Case Rep Transplant",
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"pubdate": "2017",
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"title": "Unusual Manifestations of Acute Cytomegalovirus Infection in Solid Organ Transplant Hosts: A Report of Two Cases.",
"title_normalized": "unusual manifestations of acute cytomegalovirus infection in solid organ transplant hosts a report of two cases"
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"abstract": "OBJECTIVE\nThe elderly accounts for a large proportion of patients with metastatic colorectal cancer (mCRC). This study reviews patterns of care and outcomes for elderly patients with mCRC in the community setting.\n\n\nMETHODS\nElderly patients (≥ 65 years) with mCRC on the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) registry were identified. Treatment, bevacizumab-related adverse events, and overall survival (OS) were analysed by age cohorts, comparing those aged 65-74 vs. 75-84 vs. ≥ 85 years and correlated with potential prognostic factors. Factors affecting chemotherapy and bevacizumab administration were analysed using logistic regression analysis.\n\n\nRESULTS\nOf 1439 patients, 363, 352, and 106 were aged 65-74, 75-84, and ≥ 85 years, respectively. 584 (71%) patients received first-line chemotherapy, with chemotherapy use declining with advancing age (84%, 69%, and 34% in 65-74-, 75-84- and ≥ 85-year-olds, respectively). Seven (10%) patients aged ≥ 85 years were not treated with chemotherapy on the basis of age alone. Only 10 of 36 very elderly patients who received chemotherapy also received bevacizumab. Factors affecting bevacizumab administration included age, treatment location, and comorbidities. There was no impact of age on bevacizumab-related adverse events. Resection of metastatic disease occurred in 173 (21%) patients overall, with rates declining with age (26% vs. 21% vs. 6%).\n\n\nCONCLUSIONS\nChemotherapy usage and resection of metastatic disease decline with advancing age. A minority of patients are not treated with systemic therapy due to advanced age alone. Our cohort suggests underutilisation of bevacizumab in older patients, but where given, toxicity rates did not increase with age.",
"affiliations": "Department of Medical Oncology, The Canberra Hospital, Canberra, Australia.;Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia; Department of Medical Oncology, The Royal Melbourne Hospital, Melbourne, Australia.;Department of Medical Oncology, The Canberra Hospital, Canberra, Australia.;Department of Medical Oncology, The Canberra Hospital, Canberra, Australia; ANU Medical School, Australian National University, Acton, Australia.;Department of Medical Oncology, The Royal Melbourne Hospital, Melbourne, Australia.;Department of Medical Oncology, Cabrini Health, Melbourne, Australia.;Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia; Department of Medical Oncology, Eastern Health, Melbourne, Australia; Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia.;Department of Medical Oncology, Royal Hobart Hospital, Hobart, Australia.;Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia; Department of Medical Oncology, The Royal Melbourne Hospital, Melbourne, Australia; Department of Medical Oncology, Western Hospital, Melbourne, Australia.;Department of Medical Oncology, The Canberra Hospital, Canberra, Australia; ANU Medical School, Australian National University, Acton, Australia. Electronic address: desmond.yip@anu.edu.au.",
"authors": "Parakh|Sagun|S|;Wong|Hui-Li|HL|;Rai|Rajat|R|;Ali|Sayed|S|;Field|Kathryn|K|;Shapiro|Jeremy|J|;Wong|Rachel|R|;Nott|Louise|L|;Gibbs|Peter|P|;Yip|Desmond|D|",
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"issue": "6(5)",
"journal": "Journal of geriatric oncology",
"keywords": "Bevacizumab; Chemotherapy; Colorectal; Elderly; Outcomes; Surgery",
"medline_ta": "J Geriatr Oncol",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D015179:Colorectal Neoplasms; D003131:Combined Modality Therapy; D003695:Delivery of Health Care; D018572:Disease-Free Survival; D005260:Female; D015577:Geriatric Assessment; D006801:Humans; D008297:Male; D009017:Morbidity; D009362:Neoplasm Metastasis; D011379:Prognosis; D011446:Prospective Studies; D012042:Registries; D015996:Survival Rate",
"nlm_unique_id": "101534770",
"other_id": null,
"pages": "387-94",
"pmc": null,
"pmid": "26190441",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Patterns of care and outcomes for elderly patients with metastatic colorectal cancer in Australia.",
"title_normalized": "patterns of care and outcomes for elderly patients with metastatic colorectal cancer in australia"
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"companynumb": "AU-ROCHE-1444748",
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"abstract": "We report the cases of two patients who developed worsening behavioural and psychological symptoms of dementia (BPSD), coinciding with starting the factor Xa inhibitor direct oral anticoagulant medications apixaban and rivaroxaban, respectively. Both patients required detaining under the Mental Health Act. Their symptoms improved significantly, within 2 weeks, on switching to alternative anticoagulant therapies and they were both discharged from the acute psychiatric ward. Front-line staff should partake in postmarketing surveillance of medications, completing the Medicines and Healthcare products Regulatory Agency yellow cards for example (UK). There is increasing evidence for an aetiological role of cerebral mitochondrial dysfunction in neuropsychiatric disorders. Development of a rating scale of drugs that are potentially less toxic to cerebral mitochondria could inform national prescribing guidelines and enable safer treatments to be offered to older people, reducing the likely hood of them experiencing apparent BPSD.",
"affiliations": "Older Peoples Community Mental Health Team, Somerset NHS Foundation Trust, Frome, Somerset, UK.;Department of Molecular Neuroscience, UCL Queen Square Institute of Neurology, National Hospital, London, UK i.hargreaves@ucl.ac.uk.;Older Peoples Psychiatric Inpatient Unit, Somerset NHS Foundation Trust, Taunton, Somerset, UK.;Complex Treatment and Intervention Team, Avon and Wiltshire Mental Health Partnership NHS Trust, Midsomer Norton, Somerset, UK.",
"authors": "Porter|Kim Maria Frances|KMF|;Hargreaves|Iain Parry|IP|;De Souza|Stephen|S|;Goddard|Rebecca|R|",
"chemical_list": "D000925:Anticoagulants; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D000069552:Rivaroxaban; D000069604:Dabigatran",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-240059",
"fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\nbcr-2020-240059\n10.1136/bcr-2020-240059\nCase Report\n1506\n1560\n1375\n200\n208\n1561\n382\n432\n1347\n454\nTreatment with the direct oral anticoagulants (DOACs) apixaban and rivaroxaban associated with significant worsening of behavioural and psychological symptoms of dementia (BPSD)\nPorter Kim Maria Frances 1\nHargreaves Iain Parry 2\nDe Souza Stephen 3\nGoddard Rebecca 4\n1 Older Peoples Community Mental Health Team, Somerset NHS Foundation Trust, Frome, Somerset, UK\n2 Department of Molecular Neuroscience, UCL Queen Square Institute of Neurology, National Hospital, London, UK\n3 Older Peoples Psychiatric Inpatient Unit, Somerset NHS Foundation Trust, Taunton, Somerset, UK\n4 Complex Treatment and Intervention Team, Avon and Wiltshire Mental Health Partnership NHS Trust, Midsomer Norton, Somerset, UK\nCorrespondence to Dr Iain Parry Hargreaves; i.hargreaves@ucl.ac.uk\n2021\n8 3 2021\n8 3 2021\n14 3 e24005913 1 2021\n© BMJ Publishing Group Limited 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttp://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nWe report the cases of two patients who developed worsening behavioural and psychological symptoms of dementia (BPSD), coinciding with starting the factor Xa inhibitor direct oral anticoagulant medications apixaban and rivaroxaban, respectively. Both patients required detaining under the Mental Health Act. Their symptoms improved significantly, within 2 weeks, on switching to alternative anticoagulant therapies and they were both discharged from the acute psychiatric ward. Front-line staff should partake in postmarketing surveillance of medications, completing the Medicines and Healthcare products Regulatory Agency yellow cards for example (UK). There is increasing evidence for an aetiological role of cerebral mitochondrial dysfunction in neuropsychiatric disorders. Development of a rating scale of drugs that are potentially less toxic to cerebral mitochondria could inform national prescribing guidelines and enable safer treatments to be offered to older people, reducing the likely hood of them experiencing apparent BPSD.\n\npsychiatry (drugs and medicines)\ndrugs: CNS (not psychiatric)\nunwanted effects / adverse reactions\nmemory disorders (psychiatry)\npsychiatry of old age\nspecial-featureunlocked\n==== Body\nBackground\n\nGlobally, the estimated proportion of the general population aged 60 and over with dementia is between 5% and 8% equating to around 50 million people. There are nearly 10 million new cases every year.1 Ischaemic heart disease and stroke are the biggest cause of death worldwide.2 Factor Xa inhibitor direct oral anticoagulants (DOACs) have become widely prescribed over recent years in the UK, being included as drugs recommended by the National Institute for Health and Care Excellence as achieving anticoagulation in prevention of systemic emboli in patients in atrial fibrillation (AF) or with deep vein thrombosis. A significant proportion of the population with mild cognitive impairment or dementia are, therefore, also treated with DOAC’s for these coexistent diagnoses. In our experience locally, reflecting changing practice throughout the developed world, many patients are being switched from warfarin to factor Xa inhibitor DOACs, which do not require close monitoring of blood levels. Despite no listed neuropsychiatric side effects in the British National Formulary (BNF) for these, we suspected that these two patients were experiencing iatrogenic worsening of their behavioural and psychological symptoms of dementia (BPSD). We hypothesise that similar factor Xa inhibitor side effects are experienced by many older people to a varying degree and wrongly attributed to BPSD.\n\nCase presentation 1\n\nA woman in her early 80s was admitted to her local District General Hospital (DGH) following a fall. She was found to have a pulmonary embolus (PE) and to be in AF. She was commenced on apixaban. During this admission, staff raised concerns about her memory and on discharge, referred her to the local memory assessment service (MAS). Following initial MAS assessment approximately 3 weeks later, the patient was commenced on the antidepressant mirtazapine for low mood and poor sleep. However, after a further 3 weeks, she was brought to the liaison department at the DGH following physically assaulting police officers and paramedics. Her husband confirmed a deterioration in his wife’s memory over 6 months with her becoming repetitive in conversation and forgetting who some of the neighbours were. She had also started to accuse him of having an affair and steeling her money over these months. He denied this saying that they spent nearly all their time together. However, he indicated that there had been a noticeable worsening of her presentation following her hospital admission 6 weeks before with a PE, with her becoming physically aggressive since, assaulting him on multiple occasions and calling the police frequently. He explained that he had had to lock himself in the bathroom that day for his own safety. At interview, the patient reported low mood and poor sleep since the alleged affair, saying that she had seen this person and found a slip in her husband’s pocket. Her mood was labile, alternating between irritability and tearfulness. She was noted to be repetitive in conversation with poor recall of recent events. Her insight was poor although she was aware of recent memory difficulties. She was assessed and admitted under section 2 of the Mental Health Act (MHA) with a provisional diagnosis of delusional jealousy in the context of likely dementia.\n\nInvestigations\n\nPhysical examination was unremarkable. Medications included apixaban (5 mg two times per day), bisoprolol (2.5 mg two times per day), digoxin (125 μg one time per day) and glyceryl trinitrate spray as required. A dementia blood screen was normal. An MRI head scan showed minor generalised cerebral atrophy with a few foci within the supratentorial white matter reported as likely age related ischaemic phenomena. The patient scored 70/100 on the Addenbrooke’s cognitive examination, losing marks in the memory domain and suggestive of at least mild dementia.\n\nManagement\n\nMirtazapine was stopped as the patient’s agitation and aggression had only worsened. Subsequent trials of medication to manage this included intramuscular lorazepam (0.5–1.0 mg), required on several occasions; quetiapine (125 mg daily) combined with citalopram (20 mg daily), both subsequently stopped as not effective; replaced by aripiprazole (15 mg daily), also ineffective and replaced by oral zuclopenthixol, (increased to 18 mg daily). After 2 weeks on this dose of zuclopenthixol and nearly 4 months on the acute psychiatric ward, although the patient was no longer expressing delusion ideas regarding, her husband having an affair her presentation had, if anything, worsened with regard to her agitation and aggression, throwing a chair, banging on the doors, hitting out at staff and asking for her mother. The decision was made to switch apixaban to dabigatran as an alternative DOAC. The rationale was that there had been no other obvious precipitating factors that might explain the relatively sudden and persistent deterioration in the patient’s mental state and the temporal relationship with starting apixaban. She became markedly more settled over the next 2 weeks, no longer banging on doors or wanting to leave. She acknowledged feeling more calm and relaxed. There were no longer concerns regarding her mood or sleep. This was in the absence of any other behavioural approach, medication or management changes.\n\nOutcome and follow-up\n\nThe patient was discharged to a local care home, which would not have been considered possible prior to her switching anticoagulant medication and appearing far less agitated and aggressive. She was significantly more settled and her presentation was of mild dementia. Treatment with antipsychotic medication had been effective for her delusional beliefs throughout her admission and she continued treatment with clopixol (18 mg daily). The management plan was to reduce this while monitoring her mental state for any re-emergence of BPSD agitation and aggression. After a month, both she and her husband were enquiring about the possibility of her returning home.\n\nCase presentation 2\n\nThe second case is of a man in his early 70s, described by his family as having some mild memory problems and confusion at times although managing his activities of daily living well enough. He did not think it severe enough to bother his general practitioner (GP). However, approximately a month after commencing rivaroxaban for AF, he became agitated and more confused. So much so that not only did he present to his GP, who referred him to our MAS, he was in turn referred to our older persons community mental health team, as his apparent BPSD had worsened rapidly. He had become physically threatening and aggressive towards his wife and daughters. He was assessed and admitted under the MHA and received a working diagnosis of advanced dementia. This led to trials of treatment with a variety of psychotropic medications. His apparent BPSD appeared to be treatment resistant and his presentation worsened.\n\nAt the time, in 2016, there were no side effects listed for rivaroxaban in the BNF which might have suggested the potential for worsening of mental state or cognition. However, in the absence of any other identifiable psychosocial or pathophysiological causes or changes to medication, we switched rivaroxaban to warfarin. We saw a significant improvement in the patient’s presentation within 2 weeks. Importantly, further improvements were noted on gradually reducing and discontinuing the psychotropic medications that were being prescribed in an attempt to manage his change in behaviour. This patient had also became settled sufficiently to be discharged. He caught the bus home, a fact he was able to recount to us in clinic a month later when his clinical presentation was also of mild dementia.\n\nDiscussion\n\nFront-line healthcare staff in acute settings and the community manage a heavy workload. It is all too easy to overlook potential neuropsychiatric drug side effects, especially if they are not clearly listed. They may be easily missed among older patients and wrongly attributed to dementia.\n\nRivaroxaban is structurally related to the antibiotic linezolid, which has been reported to cause mitochondrial toxicity.3 Premarketing in vitro studies concluded the risk of mitochondrial toxicity associated with this anticoagulant to be low.4 However, a more recent in vitro study, using rat kidney mitochondria, reported evidence of mitochondrial swelling and a collapse of the membrane potential following exposure to low doses of rivaroxaban.5 The effect of apixaban, which is structurally related to rivaroxaban, has yet to be investigated on mitochondrial function.6\n\nRecent research supports not only an association between reduced cerebral mitochondrial function and neuropsychiatric symptoms and disorders, but also the aetiological role it may play.7\n\nThere is a need for a far greater awareness and understanding of the potential cerebral mitochondrial toxicity of drugs commonly prescribed to our older populations. These are numerous and include, for example, some of the drugs prescribed for diabetes (metformin) and raised cholesterol (statins) as well as many of those prescribed for neuropsychiatric symptoms such as trazadone and sodium valproate.8\n\nAsthenia (abnormal physical weakness or lack of energy) has more recently become listed as a common/very common side effect of rivaroxaban in the BNF. This is presumably as a result of the medicines and healthcare products regulatory agency (MHRA) yellow card reporting of suspected adverse reactions being submitted. This clinical symptom may be associated with mitochondrial toxicity.9 Interestingly, Karlsvik et al reported no increase in the level of fatigue after initiation of treatment with rivaroxaban.10\n\nFurther research could enable the compiling of a cerebral mitochondrial toxicity burden scale of drugs, similar to that as already exists for anticholinergic burden on cognitive functioning.11 There are research techniques that can assess cerebral mitochondrial dysfunction using non-invasive brain scanning of lactate levels, which are considered to be a good correlate of mitochondrial function.12 Such a scale could inform clinical decision making, switching patients to drugs that are potentially less toxic to cerebral mitochondria, when appropriate.\n\nWe may then be able to significantly improve quality of life and reduce the burden and cost for patients, their carers, psychiatric services and the social care system by potentially avoiding psychiatric admission and placement in dementia care homes with fees, in the UK of between £34 000 (residential) and £47 000 (nursing) per annum.13\n\nPatient’s perspective\n\nSomething changed when I was in hospital after my fall, something wasn’t right. I feel calmer and much better now, ready to go back home with my husband.\n\nLearning points\n\nConsider drug-induced neuropsychiatric symptoms in older patients with suspected behavioural and psychological symptoms of dementia (BPSD). Avoid assuming that their worsening presentation is necessarily secondary to cerebral emboli because they have a degree of vascular pathology on brain imaging and are in atrial fibrillation.\n\nOlder patients are particularly prone to experiencing neuropsychiatric side effects of drugs that may not have been apparent during preclinical trials. Polypharmacy and associated drug interactions are also more common. All front-line staff should be encouraged to discuss with colleagues any medicine safety concerns, which can be particularly hard to unpick from BPSD, and to report these via the medicines and healthcare products regulatory agency yellow card system, for example.\n\nNeuropsychiatric symptoms and disorders are known to be associated with reduced cerebral mitochondrial function. There is an increasing body of research supporting that this relationship is aetiological. If so, any further drug-induced impairment of cerebral mitochondrial function could, therefore, be expected to precipitate or exacerbate such symptoms or disorders already present potentially.\n\nAn increased awareness of which drugs are less toxic to cerebral mitochondria, with the development of a rating scale for example, could inform prescribing guidelines (National Institute for Health and Care Excellence) and safer treatments being offered to older people, reducing the likely hood of them experiencing apparent BPSD and requiring psychiatric detention.\n\nContributors: IPH, KMFP, SDS and RG conceived the case review article. KMFP, SDS and RG where directly involved in the clinical management of the two cases cited. IPH shared his expert knowledge of the potential mitochondrial toxicity of drugs. KMFP carried out the literature search. RG and KMFP drafted the first manuscript. All authors contributed to revising and approving the final manuscript.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n\n1 World Health Organisation. 2020. Dementia. key facts (online) September.\n2 World Health Organisation. 2020. The top 10 causes of death (online) December.\n3 Soriano A, Miró O, Mensa J. Mitochondrial toxicity associated with linezolid. N Engl J Med 2005;353 :2305–6. 10.1056/NEJM200511243532123 16306535\n4 European Medicines Agency. CHP assessment report for Xarelto (EMEA/543519/2008, 2008.\n5 Samiei F, Sajjadi H, Jamshidzadeh A, et al . Contrasting role of concentration in rivaroxaban induced toxicity and oxidative stress in isolated kidney mitochondria. Drug Res 2019;69 :523–7. 10.1055/a-1001-2154\n6 Bridoux A. Chemical characteristics of direct FXa inhibitors registered for atrial fibrillation. Ann Cardiol Cardiovasc Med 2019;3 :1028.\n7 Pei L, Wallace DC. Mitochondrial etiology of neuropsychiatric disorders. Biol Psychiatry 2018;83 :722–30. 10.1016/j.biopsych.2017.11.018 29290371\n8 Hargreaves IP, Al Shahrani M, Wainwright L, et al . Drug-induced mitochondrial toxicity. Drug Saf 2016;39 :661–74. 10.1007/s40264-016-0417-x 26992920\n9 Filler K, Lyon D, Bennett J, et al . Association of mitochondrial dysfunction and fatigue: a review of the literature. BBA Clin 2014;1 :12–23. 10.1016/j.bbacli.2014.04.001 25147756\n10 Karlsvik TM, Borgenvik TL, Aadalen M, et al . Fatigue after initiating rivaroxaban for venous thromboembolism. Res Pract Thromb Haemost 2020;4 :582–5. 10.1002/rth2.12312 32548556\n11 PrescQIPP NHS. Anticholinergic drugs. Available: www.prescqipp.info\n12 Rowland LM, Pradhan S, Korenic S, et al . Elevated brain lactate in schizophrenia: a 7 T magnetic resonance spectroscopy study. Transl Psychiatry 2016;6 :e967. 10.1038/tp.2016.239 27898072\n13 Paying For Care LTD. England and Wales (payingforcare.org), 2019.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1757-790X",
"issue": "14(3)",
"journal": "BMJ case reports",
"keywords": "drugs: CNS (not psychiatric); memory disorders (psychiatry); psychiatry (drugs and medicines); psychiatry of old age; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D000069604:Dabigatran; D003704:Dementia; D006801:Humans; D011720:Pyrazoles; D011728:Pyridones; D000069552:Rivaroxaban",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33685912",
"pubdate": "2021-03-08",
"publication_types": "D016428:Journal Article",
"references": "16306535;26992920;31499543;25147756;27898072;32548556;29290371",
"title": "Treatment with the direct oral anticoagulants (DOACs) apixaban and rivaroxaban associated with significant worsening of behavioural and psychological symptoms of dementia (BPSD).",
"title_normalized": "treatment with the direct oral anticoagulants doacs apixaban and rivaroxaban associated with significant worsening of behavioural and psychological symptoms of dementia bpsd"
} | [
{
"companynumb": "GB-JNJFOC-20210327000",
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"occurcountry": "GB",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": "1",
... |
{
"abstract": "The oral fluoropyrimidine, capecitabine is attracting great interest in the context of tumour-selective therapy and rationally designed combination regimens. Agents such as taxanes upregulate thymidine phosphorylase (TP), and there is therefore a clear rationale for their combination with capecitabine. Preclinical studies of capecitabine/taxane combination therapy demonstrated synergistic antitumour activity and phase I studies showed encouraging efficacy. Therefore, a randomised, phase III trial (docetaxel versus docetaxel/capecitabine) has been initiated in anthracycline-refractory metastatic breast cancer patients. Recruitment is complete. In colorectal cancer, capecitabine/oxaliplatin combination therapy is promising and a phase I, dose-finding trial has been conducted in patients with refractory metastatic solid tumours. A similar trial has evaluated capecitabine/irinotecan combination treatment. Capecitabine is also being investigated as adjuvant therapy for colorectal and breast cancers. The primary objective of the ongoing X-ACT trial in almost 2000 Dukes' C colon cancer patients is to demonstrate at least equivalent disease-free survival between capecitabine and the Mayo Clinic regimen. In addition, the CALGB is planning a randomised, phase III trial of capecitabine versus doxorubicin/cyclophosphamide or cyclophosphamide/methotrexate/5-fluorouracil (CMF) as adjuvant treatment in high-risk, node-negative breast cancer patients aged >65 years.",
"affiliations": "Department of Internal Medicine and Oncology/Hematology, Kliniken Essen-Mitte, Germany. hwilke@kem.telba.de",
"authors": "Wilke|H|H|",
"chemical_list": "D009944:Organoplatinum Compounds; D043823:Taxoids; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000077143:Docetaxel; D000069287:Capecitabine; D000077146:Irinotecan; D017239:Paclitaxel; D005472:Fluorouracil; D002166:Camptothecin",
"country": "England",
"delete": false,
"doi": "10.1016/s0959-8049(01)00417-8",
"fulltext": null,
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"issn_linking": "0959-8049",
"issue": "38 Suppl 2()",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": null,
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D000069287:Capecitabine; D017024:Chemotherapy, Adjuvant; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003131:Combined Modality Therapy; D003841:Deoxycytidine; D000077143:Docetaxel; D005472:Fluorouracil; D005544:Forecasting; D006801:Humans; D000077146:Irinotecan; D009369:Neoplasms; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D017239:Paclitaxel; D043823:Taxoids",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "21-5",
"pmc": null,
"pmid": "11841932",
"pubdate": "2002-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Future treatment options with capecitabine in solid tumours.",
"title_normalized": "future treatment options with capecitabine in solid tumours"
} | [
{
"companynumb": "NL-ROCHE-1916035",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Intravenous immunoglobulin (IVIg) treatment for acute exacerbations of Myasthenia Gravis (MG) was shown in several open-label studies. There are only two studies demonstrating the efficiency of regular intermittent IVIg therapy on MG patients who are not in their acute attack periods. Thirteen patients who had displayed an inadequate clinical response to immunosuppressive treatments, or who were not appropriate for immunosuppressive treatment due to the age factor and thus were given regular IVIg therapy, were retrospectively investigated. Moreover, the pre- and post-treatment attack frequencies were also evaluated. The mean number of attacks was 0.0960 attacks/year before IVIg therapy, and 0.0056 attacks/year after IVIg therapy (p = 0.002). The number and severity of the attacks were decreased in all patients. Eight patients (62 %) had used steroids; among them, steroid was completely stopped in two patients following the regular IVIg therapy, and the dose was decreased by 50 % in the other six patients. The requirement for pyridostigmine did not decrease in four patients, whereas this need decreased by 20-50 % in nine patients. IVIg can produce repeated beneficial effects in patients with MG and may be useful as an adjunct in the management of MG. IVIg has minimal adverse effects and ability to reduce corticosteroid dose. These results suggest that intravenous immunoglobulin maintenance therapy is a valid modality in patients with resistant treatment MG.",
"affiliations": "Department of Neurology, Ankara University School of Medicine, İbni Sina Hospital, Samanpazarı, Ankara, Turkey, drmsorgun79@yahoo.com.tr.",
"authors": "Sorgun|Mine Hayriye|MH|;Sener|Huseyin Ozden|HO|;Yucesan|Canan|C|;Yucemen|Nezih|N|",
"chemical_list": "D016756:Immunoglobulins, Intravenous",
"country": "Italy",
"delete": false,
"doi": "10.1007/s10072-013-1621-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-1874",
"issue": "35(6)",
"journal": "Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology",
"keywords": null,
"medline_ta": "Neurol Sci",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007116:Immunization, Passive; D016756:Immunoglobulins, Intravenous; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis",
"nlm_unique_id": "100959175",
"other_id": null,
"pages": "891-6",
"pmc": null,
"pmid": "24399309",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article",
"references": "4941403;11391130;2635936;3718134;22007295;21061395;6198570;6721451;3376987;10716766;20402760;18254004;1950455;20081745",
"title": "Intravenous immunoglobulin for prophylaxis of acute exacerbation in Myasthenia Gravis.",
"title_normalized": "intravenous immunoglobulin for prophylaxis of acute exacerbation in myasthenia gravis"
} | [
{
"companynumb": "TR-BAXTER-2014BAX040309",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": n... |
{
"abstract": "We present results obtained in five patients with advanced thyroid cancer, derived from the follicular epithelium, treated with Sorafenib used off-label. The median age at the time Sorafenib was started was 61 years. Only one patient tolerated the standard dose of 400 mg twice daily. The most severe adverse events were.",
"affiliations": "Endocrinology Service, Portuguese Institute of Oncology Francisco Gentil EPE; NOVA Medical School/NOVA Medical School, Lisbon, Portugal.",
"authors": "Bugalho|Maria João|MJ|",
"chemical_list": "D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib",
"country": "India",
"delete": false,
"doi": "10.4103/0973-1482.154011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1998-4138",
"issue": "12(2)",
"journal": "Journal of cancer research and therapeutics",
"keywords": null,
"medline_ta": "J Cancer Res Ther",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009536:Niacinamide; D056687:Off-Label Use; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011878:Radiotherapy; D000077157:Sorafenib; D013964:Thyroid Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "101249598",
"other_id": null,
"pages": "1084-7",
"pmc": null,
"pmid": "27461704",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Off-label use of Sorafenib in patients with advanced thyroid carcinoma: Retrospective analysis of five cases.",
"title_normalized": "off label use of sorafenib in patients with advanced thyroid carcinoma retrospective analysis of five cases"
} | [
{
"companynumb": "PT-BAYER-2016-153750",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": "1",
"dr... |
{
"abstract": "OBJECTIVE\nThe purpose of this study was to investigate the prevalence of prescribed combinations of interacting drugs in the Swedish population.\n\n\nMETHODS\nThis study design was retrospective and cross-sectional, based on a national register of dispensed prescription drugs during the period from January 1 to April 30, 2010. Prescription data was linked to the drug-drug interaction database SFINX to yield the prevalence of interacting combinations dispensed in the population. The study focused in particular on C- (clinically relevant interactions that can be handled, e.g. by dose adjustments), and D-interactions (clinically relevant interactions that should be avoided).\n\n\nRESULTS\nThirty-eight and 3.8 % of the population were dispensed combinations of drugs classified as C- or D- interactions, respectively, i.e. clinically relevant, involving all therapeutic areas. Half of the D-interactions were associated with increased risk of adverse drug reactions whereas the other half were considered interactions with a potential to cause therapeutic failure. We identified a top 15 list of D-interactions that included 80 % of the total number of interacting drug combinations. Regarding individual drugs, a group of only ten drugs was involved in as much as 94 % of all D-interactions.\n\n\nCONCLUSIONS\nThis study reveals that the majority of prescribed interacting drug combinations in Sweden involve a limited number of drugs. The findings may increase the awareness among prescribers of these most common drug interactions in clinical practice and highlight an area for pharmacological education. It may also serve as an inventory of potential interactions within different therapeutic areas for further research.",
"affiliations": "Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.",
"authors": "Holm|Johan|J|;Eiermann|Birgit|B|;Eliasson|Erik|E|;Mannheimer|Buster|B|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00228-014-1745-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-6970",
"issue": "70(11)",
"journal": "European journal of clinical pharmacology",
"keywords": null,
"medline_ta": "Eur J Clin Pharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D016208:Databases, Factual; D004347:Drug Interactions; D011307:Drug Prescriptions; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D012189:Retrospective Studies; D013548:Sweden; D055815:Young Adult",
"nlm_unique_id": "1256165",
"other_id": null,
"pages": "1375-83",
"pmc": null,
"pmid": "25190295",
"pubdate": "2014-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19081411;15659000;11673748;11520839;12875612;20406225;21437429;12672733;11998554;16898956;9002493;23940522;2610502;23621352;2751276;17805522;19176635;18303127;1782973;8513845;2286594;21091806;19350116;18584194;9180655;17154346;17867728;2249379;21122160;22198703;22464478;19779704;18257601;24038765;16858720;14531506;18665660;19205683;22752671;15231615;20653354;2873348;16268469;22111719;678924;9555760;8988065;16897791;9010701",
"title": "A limited number of prescribed drugs account for the great majority of drug-drug interactions.",
"title_normalized": "a limited number of prescribed drugs account for the great majority of drug drug interactions"
} | [
{
"companynumb": "SE-JNJFOC-20150114729",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "HER2-positive breast cancers usually contain large amounts of T-cell infiltrate. We hypothesised that trastuzumab resistance in HER2-positive breast cancer could be mediated by immune mechanisms. We assessed the safety and anti-tumour activity of pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, added to trastuzumab in trastuzumab-resistant, advanced HER2-positive breast cancer.\n\n\n\nWe did this single-arm, multicentre, phase 1b-2 trial in 11 centres based in five countries. Eligible participants were women aged 18 years or older, who had advanced, histologically confirmed, HER2-positive breast cancer; documented progression during previous trastuzumab-based therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; and a formalin-fixed, paraffin-embedded metastatic tumour biopsy for central assessment of programmed cell death 1 ligand 1 (PD-L1) status. In phase 1b, we enrolled patients with PD-L1-positive tumours in a 3 + 3 dose-escalation of intravenous pembrolizumab (2 mg/kg and 10 mg/kg, every 3 weeks) plus 6 mg/kg of intravenous trastuzumab. The primary endpoint of the phase 1b study was the incidence of dose-limiting toxicity and recommended phase 2 dose; however, a protocol amendment on Aug 28, 2015, stipulated a flat dose of pembrolizumab of 200 mg every 3 weeks in all Merck-sponsored trials. In phase 2, patients with PD-L1-positive and PD-L1-negative tumours were enrolled in parallel cohorts and received the flat dose of pembrolizumab plus standard trastuzumab. The primary endpoint of the phase 2 study was the proportion of PD-L1-positive patients achieving an objective response. This trial is registered in ClinicalTrials.gov, number NCT02129556, and with EudraCT, number 2013-004770-10, and is closed.\n\n\n\nBetween Feb 2, 2015, and April 5, 2017, six patients were enrolled in phase 1b (n=3 received 2 mg/kg pembrolizumab, n=3 received 10 mg/kg pembrolizumab) and 52 patients in phase 2 (n=40 had PD-L1-positive tumours, n=12 had PD-L1-negative tumours). The data cutoff for this analysis was Aug 7, 2017. During phase 1b, there were no dose-limiting toxicities in the dose cohorts tested. Median follow-up for the phase 2 cohort was 13·6 months (IQR 11·6-18·4) for patients with PD-L1-positive tumours, and 12·2 months (7·9-12·2) for patients with PD-L1-negative tumours. Six (15%, 90% CI 7-29) of 40 PD-L1-positive patients achieved an objective response. There were no objective responders among the PD-L1-negative patients. The most common treatment-related adverse event of any grade was fatigue (12 [21%] of 58 patients). Grade 3-5 adverse events occurred in 29 (50%) of patients, treatment-related grade 3-5 adverse events occurred in 17 (29%), and serious adverse events occurred in 29 (50%) patients. The most commonly occurring serious adverse events were dyspnoea (n=3 [5%]), pneumonitis (n=3 [5%]), pericardial effusion (n=2 [3%]), and upper respiratory infection (n=2 [3%]). There was one treatment-related death due to Lambert-Eaton syndrome in a PD-L1-negative patient during phase 2.\n\n\n\nPembrolizumab plus trastuzumab was safe and showed activity and durable clinical benefit in patients with PD-L1-positive, trastuzumab-resistant, advanced, HER2-positive breast cancer. Further studies in this breast cancer subtype should focus on a PD-L1-positive population and be done in less heavily pretreated patients.\n\n\n\nMerck, International Breast Cancer Study Group.",
"affiliations": "Division of Research and Clinical Medicine, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia. Electronic address: sherene.loi@petermac.org.;IBCSG Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.;Institute Jules Bordet, Brussels, Belgium.;Centre Léon Bérard, Lyon, France.;Westmead Hospital and the University of Sydney, Sydney, NSW, Australia.;University of Milano, Milan, Italy; IEO, European Institute of Oncology IRCCS, Milan, Italy.;Institut de Cancérologie de l'Ouest, Saint-Herblain, Nantes, France.;Ospedale di Prato-AUSL Toscana Centro, Prato, Italy.;Institut Bergonié Comprehensive Cancer Center, Université de Bordeaux, Bordeaux, France.;International Breast Cancer Study Group, CHU Liège, Liège University, Liège, Belgium.;Medical University of Vienna, Vienna, Austria.;University Hospital Inselspital, Bern, Switzerland; International Breast Cancer Study Group Coordinating Center, Bern, Switzerland.;International Breast Cancer Study Group Coordinating Center, Bern, Switzerland; International Breast Cancer Study Group and Central Pathology Office, Bern, Switzerland.;International Breast Cancer Study Group Coordinating Center, Bern, Switzerland.;QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.;International Breast Cancer Study Group and Ospedale di Prato-AUSL Toscana Centro, Prato, Italy.;International Breast Cancer Study Group and Division of Medical Senology, IEO, European Institute of Oncology IRCCS, Milan, Italy.;University of Milano, Milan, Italy; IEO, European Institute of Oncology IRCCS, Milan, Italy; International Breast Cancer Study Group and Central Pathology Office, Bern, Switzerland.;IBCSG Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.;Institut Gustave Roussy, Université Paris Sud, INSERM U981, Villejuif, France.",
"authors": "Loi|Sherene|S|;Giobbie-Hurder|Anita|A|;Gombos|Andrea|A|;Bachelot|Thomas|T|;Hui|Rina|R|;Curigliano|Giuseppe|G|;Campone|Mario|M|;Biganzoli|Laura|L|;Bonnefoi|Hervé|H|;Jerusalem|Guy|G|;Bartsch|Rupert|R|;Rabaglio-Poretti|Manuela|M|;Kammler|Roswitha|R|;Maibach|Rudolf|R|;Smyth|Mark J|MJ|;Di Leo|Angelo|A|;Colleoni|Marco|M|;Viale|Giuseppe|G|;Regan|Meredith M|MM|;André|Fabrice|F|;|||",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"country": "England",
"delete": false,
"doi": "10.1016/S1470-2045(18)30812-X",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "20(3)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen; D001943:Breast Neoplasms; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D016896:Treatment Outcome",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "371-382",
"pmc": null,
"pmid": "30765258",
"pubdate": "2019-03",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial.",
"title_normalized": "pembrolizumab plus trastuzumab in trastuzumab resistant advanced her2 positive breast cancer panacea a single arm multicentre phase 1b 2 trial"
} | [
{
"companynumb": "AU-MYLANLABS-2019M1032621",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo evaluate if magnesium sulfate (MgSO4 ) titration following fetoscopic spina bifida closure is associated with fewer maternal complications than the Management of Myelomeningocele Study (MOMS) tocolytic regimen.\n\n\nMETHODS\nThis prospective cohort study included 73 consecutive patients undergoing fetoscopic closure of spina bifida between 2015 and 2020. A policy of using the MgSO4 regimen per the MOMS trial was changed to a flexible one in which MgSO4 was titrated according to the frequency of the uterine contractions following surgery. The frequency of maternal pulmonary edema, low maternal oxygen saturation requiring oxygen supplementation, atelectasis, hypocalcemia, and preterm delivery was compared before and after the policy was changed.\n\n\nRESULTS\nA higher proportion of women in the group that used the MOMS MgSO4 regimen had pulmonary edema compared to those in the flexible one (26.1% [6/23] vs. 6% [3/50]; p = 0.024). Multivariate analysis showed that the MOMS tocolytic regimen was independently associated with a higher risk of pulmonary edema (adjusted odds ratio: 8.57; 95% confidence interval: 1.54-47.7; p = 0.014) than a flexible one. There was no difference in the rate of preterm delivery.\n\n\nCONCLUSIONS\nFollowing fetoscopic closure of spina bifida, the MOMS MgSO4 regimen is associated with an increased risk of pulmonary edema than a more flexible regimen.",
"affiliations": "Division of Fetal Therapy and Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital Fetal Center, Houston, Texas, USA.;Division of Fetal Therapy and Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital Fetal Center, Houston, Texas, USA.;Division of Fetal Therapy and Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital Fetal Center, Houston, Texas, USA.;Division of Fetal Therapy and Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital Fetal Center, Houston, Texas, USA.;Division of Fetal Therapy and Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital Fetal Center, Houston, Texas, USA.;Division of Fetal Therapy and Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital Fetal Center, Houston, Texas, USA.;Division of Fetal Therapy and Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital Fetal Center, Houston, Texas, USA.;Division of Fetal Therapy and Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital Fetal Center, Houston, Texas, USA.;Division of Fetal Therapy and Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital Fetal Center, Houston, Texas, USA.;Department of Neurosurgery, Baylor College of Medicine and Texas Children's Hospital Fetal Center, Houston, Texas, USA.;Division of Fetal Therapy and Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital Fetal Center, Houston, Texas, USA.;Division of Fetal Therapy and Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital Fetal Center, Houston, Texas, USA.;Division of Fetal Therapy and Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital Fetal Center, Houston, Texas, USA.",
"authors": "Lehoczky|Lucy|L|;Southworth|Annie B|AB|;Martinez|Gabriela Z|GZ|https://orcid.org/0000-0001-9404-0430;Belfort|Michael A|MA|;Shamshirsaz|Alireza A|AA|;Shamshirsaz|Amir|A|;Sanz Cortes|Magdalena|M|https://orcid.org/0000-0002-0265-9859;Nassr|Ahmed A|AA|https://orcid.org/0000-0001-6333-3177;Donepudi|Roopali|R|;Whitehead|William E|WE|;Johnson|Rebecca|R|https://orcid.org/0000-0003-0517-5769;Meshinchi|Nazli|N|;Espinoza|Jimmy|J|https://orcid.org/0000-0002-9830-2212",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/pd.5923",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0197-3851",
"issue": "41(8)",
"journal": "Prenatal diagnosis",
"keywords": "closure; fetoscopic; flexible; magnesium sulfate; regimen; spina bifida",
"medline_ta": "Prenat Diagn",
"mesh_terms": null,
"nlm_unique_id": "8106540",
"other_id": null,
"pages": "983-988",
"pmc": null,
"pmid": "33591585",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Magnesium sulfate titration reduces maternal complications following fetoscopic closure of spina bifida.",
"title_normalized": "magnesium sulfate titration reduces maternal complications following fetoscopic closure of spina bifida"
} | [
{
"companynumb": "US-EXELA PHARMA SCIENCES, LLC-2021EXL00038",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MAGNESIUM SULFATE"
},
"druga... |
{
"abstract": "Systemic reactions from local tetracaine use are often an anomaly - not only is tetracaine short-acting and quickly metabolized by the pseudocholinesterase system leading to very limited systemic uptake, but most adverse reactions are usually associated with dental or spinal anesthesia. Furthermore, reactions to local anesthetics manifest in standard allergy-type reactions. When local anesthetics lead to nervous or cardiac system abnormalities, it is termed a local anesthetic systemic toxicity - an event with an incidence currently estimated to be 0.03%.\n\n\n\nWe present a case of a 56-year-old female who experienced a systemic reaction to tetracaine 1% while undergoing a fine needle biopsy of a thyroid nodule. The patient had previous allergic reactions to lidocaine. Upon conclusion of the procedure, the patient began convulsing and became rigid and non-verbal. She was able to move all extremities, had no respiratory distress, no swelling, hives, or redness, and was swallowing without difficulty. After about 5 min, the patient began to improve and experienced reversal of all previous symptoms. Her physical exam and labs were otherwise normal, she returned to her baseline functioning, and was discharged without any medical interventions.\n\n\n\nThis case illustrates a case of LAST in a patient with previous Lidocaine allergy without any other obvious risk factors. There have been no cases of cross-reaction between lidocaine and tetracaine so it explores the possibility of patients having cross reaction to those two different kinds of local anesthetic.",
"affiliations": "Loyola University Chicago, Stritch School of Medicine, United States of America.;Loyola University Chicago, Stritch School of Medicine, Department of Emergency Medicine, United States of America.;Loyola University Chicago, Stritch School of Medicine, Department of Emergency Medicine, United States of America; Loyola University Health System, Department of Pharmacy, United States of America. Electronic address: mrech@lumc.edu.",
"authors": "Adeleye|Ayomide|A|;Sharp|Lydia|L|;Rech|Megan A|MA|",
"chemical_list": "D000779:Anesthetics, Local; D013748:Tetracaine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2020.05.026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "38(9)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000772:Anesthesia, Local; D000779:Anesthetics, Local; D001707:Biopsy, Needle; D005260:Female; D006801:Humans; D008875:Middle Aged; D012640:Seizures; D013748:Tetracaine; D016606:Thyroid Nodule",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "1984.e1-1984.e3",
"pmc": null,
"pmid": "32505475",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Neurotoxicity secondary to local tetracaine use.",
"title_normalized": "neurotoxicity secondary to local tetracaine use"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-51613",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"dru... |
{
"abstract": "BACKGROUND\nThe rarity of Ewing's sarcoma (ES) in the maxillofacial region of children, coupled with the technical challenge of resection and associated functional and cosmetic impairment has resulted in deficient data regarding the optimal local control of the disease.\n\n\nOBJECTIVE\nTo describe our experience in the management of primary maxillofacial ES in children, focusing on the therapeutic modalities for local control of the disease.\n\n\nMETHODS\nSingle institution observational study.\n\n\nMETHODS\nThis is a single institution review of patients, treated between 2007 and 2016.\n\n\nRESULTS\nSix primary maxillofacial ES were treated according to the EURO-EWING 99 protocol, consisting of a uniform chemotherapy regimen, combined selectively with surgery and radiotherapy as local treatment. Patients' mean age was 9.42 years (range 6-12.5 years). One patient initially suffered from metastasis and succumbed to the disease; another refused further treatment following chemotherapy and was lost to follow-up. Four patients underwent surgery and adjuvant radiotherapy successfully. At a mean follow-up of 3.78 years relapse-free and overall survival rates were 60% and 80% respectively. The aesthetic and functional outcome was satisfactory in all treated patients.\n\n\nCONCLUSIONS\nIn eligible cases the combination of chemotherapy with surgery and adjuvant radiotherapy results in optimal oncological and functional outcome for children with ES of the maxillofacial region. Metastasis and poor response to chemotherapy are the most important adverse prognostic factors.",
"affiliations": "University Department of Oral and Maxillofacial Surgery at 'A. & P. Kyriakou' Children's Hospital of Athens (Head: Professor Ioannis Iatrou), Dental School, University of Athens, Thivon and Levadias Str, 11527, Ampelokipi, Athens, Greece.;University Department of Oral and Maxillofacial Surgery at 'A. & P. Kyriakou' Children's Hospital of Athens (Head: Professor Ioannis Iatrou), Dental School, University of Athens, Thivon and Levadias Str, 11527, Ampelokipi, Athens, Greece.;University Department of Oral and Maxillofacial Surgery at 'A. & P. Kyriakou' Children's Hospital of Athens (Head: Professor Ioannis Iatrou), Dental School, University of Athens, Thivon and Levadias Str, 11527, Ampelokipi, Athens, Greece. Electronic address: our_schoinohoriti@yahoo.com.;University Department of Oral and Maxillofacial Surgery at 'A. & P. Kyriakou' Children's Hospital of Athens (Head: Professor Ioannis Iatrou), Dental School, University of Athens, Thivon and Levadias Str, 11527, Ampelokipi, Athens, Greece.;University Department of Oral and Maxillofacial Surgery at 'A. & P. Kyriakou' Children's Hospital of Athens (Head: Professor Ioannis Iatrou), Dental School, University of Athens, Thivon and Levadias Str, 11527, Ampelokipi, Athens, Greece.",
"authors": "Iatrou|Ioannis|I|;Theologie-Lygidakis|Nadia|N|;Schoinohoriti|Ourania|O|;Tzermpos|Fotios|F|;Mylonas|Anastassios I|AI|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jcms.2017.12.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1010-5182",
"issue": "46(2)",
"journal": "Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery",
"keywords": "Children; Ewing's sarcoma (ES); Maxillofacial region; Radiotherapy; Surgical treatment",
"medline_ta": "J Craniomaxillofac Surg",
"mesh_terms": "D002648:Child; D003131:Combined Modality Therapy; D005153:Facial Neoplasms; D005260:Female; D006115:Greece; D006801:Humans; D008297:Male; D008339:Mandibular Neoplasms; D008441:Maxillary Neoplasms; D011862:Radiography, Panoramic; D012512:Sarcoma, Ewing; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8704309",
"other_id": null,
"pages": "213-221",
"pmc": null,
"pmid": "29287925",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Ewing's sarcoma of the maxillofacial region in Greek children: Report of 6 cases and literature review.",
"title_normalized": "ewing s sarcoma of the maxillofacial region in greek children report of 6 cases and literature review"
} | [
{
"companynumb": "GR-TEVA-2018-GR-866387",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
... |
{
"abstract": "The availability of video electroencephalography monitoring (VEEGM) in neurological intensive care units has allowed the recognition and treatment of nonconvulsive status epilepticus (NCSE). However, little is known about characteristics, management, and outcomes in patients with NCSE in developing countries. We retrospectively reviewed the video-EEG reports of 120 patients who were monitored from November 2009 to March 2013. Indications for video-EEG were mostly unexplained alterations of consciousness or witnessed convulsive seizures. We identified the clinical characteristics, treatment regimes, and outcomes of patients with NCSE and tried to determine which parameters were associated with prognosis. NCSE was detected in 12/120 (10%) patients (3 females, 9 males; age 24-86 years). Admission diagnoses were: stroke (3), epilepsy (3), autoimmune limbic encephalitis (3), herpes encephalitis (1), presumed encephalitis-cardiac arrest (1), and malignancy (1). Eight patients had witnessed convulsive seizures before video-EEG. Interictal periodic epileptiform discharges were detected in 9 patients. In one-third of patients, ≥2 EEG recordings were required to capture seizures. In addition to anticonvulsants, 3 patients received immunosuppressive therapy, while intravenous anesthetics were given to 7 patients. Four patients (33.3%; 1 female, 3 males; age 51-67 years; etiology: stroke, autoimmune encephalitis, encephalitis-cardiac arrest, and malignancy; Glasgow coma scale (GCS) score <8 in 3 patients; all had periodic discharges; intravenous anesthetics were used) died in the intensive care unit. NCSE is not an infrequent finding in neurological intensive care units, thus necessitating prolonged video-EEG monitoring in patients at risk. Witnessed convulsions may indicate the presence of nonconvulsive seizures in patients with altered consciousness. Repeated recordings may increase the detection of ictal events. Periodic epileptiform discharges are commonly observed and may predict poor prognosis. Mortality seems to be influenced mostly by the underlying etiology.",
"affiliations": "Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey nesedericioglu@yahoo.com.;Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.;Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.",
"authors": "Dericioglu|Nese|N|;Arsava|Ethem Murat|EM|;Topcuoglu|Mehmet Akif|MA|",
"chemical_list": "D000927:Anticonvulsants",
"country": "United States",
"delete": false,
"doi": "10.1177/1550059413503639",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1550-0594",
"issue": "45(4)",
"journal": "Clinical EEG and neuroscience",
"keywords": "neurological intensive care unit; nonconvulsive status epilepticus; outcome; video-EEG monitoring",
"medline_ta": "Clin EEG Neurosci",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants; D004569:Electroencephalography; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D008991:Monitoring, Physiologic; D011379:Prognosis; D012189:Retrospective Studies; D012640:Seizures; D013226:Status Epilepticus; D062606:Tertiary Care Centers",
"nlm_unique_id": "101213033",
"other_id": null,
"pages": "293-298",
"pmc": null,
"pmid": "24293162",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The Clinical Features and Prognosis of Patients With Nonconvulsive Status Epilepticus in the Neurological Intensive Care Unit of a Tertiary Referral Center in Turkey.",
"title_normalized": "the clinical features and prognosis of patients with nonconvulsive status epilepticus in the neurological intensive care unit of a tertiary referral center in turkey"
} | [
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-141226",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"druga... |
{
"abstract": "We report four cases of fatal pulmonary embolism confirmed by autopsy among inpatients in a Hong Kong psychiatric hospital from 2010 to 2014. None of the four patients had a medical or premorbid condition associated with vascular thromboembolism or causing prolonged immobilisation. Only two patients were taking long-term antipsychotic medication, but all were physically restrained shortly before the event.",
"affiliations": "Department of Psychiatry, Kwai Chung Hospital, Hong Kong.;Department of Psychiatry, Kwai Chung Hospital, Hong Kong.;Department of Psychiatry, Kwai Chung Hospital, Hong Kong.;Department of Psychiatry, Kwai Chung Hospital, Hong Kong.",
"authors": "Lee|C C|CC|;Fung|R|R|;Pang|S W|SW|;Lo|T L|TL|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.12809/eaap1837",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2078-9947",
"issue": "29(4)",
"journal": "East Asian archives of psychiatry : official journal of the Hong Kong College of Psychiatrists = Dong Ya jing shen ke xue zhi : Xianggang jing shen ke yi xue yuan qi kan",
"keywords": null,
"medline_ta": "East Asian Arch Psychiatry",
"mesh_terms": "D000328:Adult; D000369:Aged, 80 and over; D001344:Autopsy; D017809:Fatal Outcome; D005260:Female; D006723:Hong Kong; D006778:Hospitals, Psychiatric; D006801:Humans; D007297:Inpatients; D008297:Male; D008875:Middle Aged; D011655:Pulmonary Embolism; D012149:Restraint, Physical",
"nlm_unique_id": "101536416",
"other_id": null,
"pages": "136-137",
"pmc": null,
"pmid": "31871311",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Pulmonary Embolism as a Cause of Death in Psychiatric Inpatients: a Case Series.",
"title_normalized": "pulmonary embolism as a cause of death in psychiatric inpatients a case series"
} | [
{
"companynumb": "HK-MYLANLABS-2020M1029938",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nParaneoplastic neurological syndromes (PNSs) are broad-spectrum disorders that can affect any part of the nervous system varying in core symptoms. Onconeural antibodies, including Hu, Yo, Ri, anti-CV2, amphiphysin, Ma2, and Tr are well-characterized and commonly used for the diagnosis of definite PNS. Generally, anti-CV2 antibodies have usually been associated with cerebellar ataxia, chorea, peripheral and autonomic neuropathies, myelopathy, optic neuritis, and retinitis. However, Parkinsonism has not been reported as the core symptom in patients with anti-CV2 antibodies.\n\n\nMETHODS\nWe report a patient with anti-CV2 antibody manifested as Parkinsonism and autonomic dysfunction, which may lead to the diagnosis of multiple system atrophy with predominant Parkinsonism (MSA-P). A lumbar puncture examination was undergone to find a positive anti-CV2 antibody in cerebrospinal fluid. PET-CT showed no tumor. Immunotherapy was adopted and the symptoms were relieved for 5 months. However, with no evidence of tumor, he died after 8 months.\n\n\nCONCLUSIONS\nOur findings indicate that PNS with anti-CV2 antibody can be shown as MSA-P mimic. Considering that MSA is a neurodegenerative disease with a poor prognosis, screening for other treatable or controllable factors like PNS presented in this case is necessary when encountering a rapid progressive MSA-mimic patient.",
"affiliations": "Department of Neurology, Jilin University First Hospital, Xinmin Street 1, Changchun, Jilin, China.;Department of Neurology, Jilin University First Hospital, Xinmin Street 1, Changchun, Jilin, China.;Department of Neurology, Jilin University First Hospital, Xinmin Street 1, Changchun, Jilin, China.;Department of Neurology, Jilin University First Hospital, Xinmin Street 1, Changchun, Jilin, China.;Department of Neurology, Jilin University First Hospital, Xinmin Street 1, Changchun, Jilin, China.;Department of Neurology, Jilin University First Hospital, Xinmin Street 1, Changchun, Jilin, China. lcui@jlu.edu.cn.",
"authors": "Song|Jia|J|;Zhang|Ying|Y|;Lang|Yue|Y|;Wang|Yi-Heng|YH|;Shao|Jie|J|;Cui|Li|L|http://orcid.org/0000-0002-4254-6736",
"chemical_list": "D001323:Autoantibodies",
"country": "England",
"delete": false,
"doi": "10.1186/s12883-021-02448-6",
"fulltext": "\n==== Front\nBMC Neurol\nBMC Neurol\nBMC Neurology\n1471-2377\nBioMed Central London\n\n2448\n10.1186/s12883-021-02448-6\nCase Report\nParkinsonism and dysautonomia with anti-CV2/CRMP5 associated paraneoplastic neurological syndromes mimicking multiple system atrophy: a case report\nSong Jia songjia19@mails.jlu.edu.cn\n\nZhang Ying zhang_ying99@jlu.edu.cn\n\nLang Yue langyue@jlu.edu.cn\n\nWang Yi-Heng yhwang18@mails.jlu.edu.cn\n\nShao Jie 15948396172@163.com\n\nhttp://orcid.org/0000-0002-4254-6736\nCui Li lcui@jlu.edu.cn\n\ngrid.430605.4 0000 0004 1758 4110 Department of Neurology, Jilin University First Hospital, Xinmin Street 1, Changchun, Jilin China\n26 10 2021\n26 10 2021\n2021\n21 40824 5 2021\n18 10 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nParaneoplastic neurological syndromes (PNSs) are broad-spectrum disorders that can affect any part of the nervous system varying in core symptoms. Onconeural antibodies, including Hu, Yo, Ri, anti-CV2, amphiphysin, Ma2, and Tr are well-characterized and commonly used for the diagnosis of definite PNS. Generally, anti-CV2 antibodies have usually been associated with cerebellar ataxia, chorea, peripheral and autonomic neuropathies, myelopathy, optic neuritis, and retinitis. However, Parkinsonism has not been reported as the core symptom in patients with anti-CV2 antibodies.\n\nCase presentation\n\nWe report a patient with anti-CV2 antibody manifested as Parkinsonism and autonomic dysfunction, which may lead to the diagnosis of multiple system atrophy with predominant Parkinsonism (MSA-P). A lumbar puncture examination was undergone to find a positive anti-CV2 antibody in cerebrospinal fluid. PET-CT showed no tumor. Immunotherapy was adopted and the symptoms were relieved for 5 months. However, with no evidence of tumor, he died after 8 months.\n\nConclusions\n\nOur findings indicate that PNS with anti-CV2 antibody can be shown as MSA-P mimic. Considering that MSA is a neurodegenerative disease with a poor prognosis, screening for other treatable or controllable factors like PNS presented in this case is necessary when encountering a rapid progressive MSA-mimic patient.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1186/s12883-021-02448-6.\n\nKeywords\n\nParaneoplastic syndrome\nAnti-CV2 antibody\nMultiple system atrophy\nCollapsin response mediated protein 5\nDysautonomia\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nPNS represents the remote effects of tumors on the nervous system, which is not associated with invasion or compression of the tumor but by activation of the immune system. Antibodies produced by the body against the tumor antigen may damage the nervous system. These antibodies are divided into 1) antibodies against neuronal nuclear and cytoplasmic antigens and 2) antibodies against cell surface and synaptic proteins. As a member of the former first identified as a biomarker of PNS in 2001 [1], collapsin response mediated protein 5 (CRMP5) is a neuronal cytoplasmic protein recognized by anti-CV2 antibody expressed in the cerebellum, hippocampus, thalamus, peripheral neurons, spinal cord, retina, and in SCLCs [1, 2]. Accordingly, the clinical presentations associated with anti-CV2 antibody include cerebellar ataxia, chorea, peripheral and autonomic neuropathies, myelopathy, optic neuritis, and retinitis [1, 3, 4]. Anti-CV2 antibody related PNS is closely related to small cell lung cancer and thymoma [1, 3]. The symptoms can be significantly alleviated after tumor-targeted treatment. Here, we report a case with anti-CV2 associated PNS mimicking MSA without tumor. It reminds physicians of the possibilities for diseases that present as MSA, especially tumor related PNS.\n\nCase presentation\n\nA 70-year-old man presented to hospital with a 6-month history of slow movements with leaning forward and postural instability. Erectile dysfunction also occurred for more than half a year, before the motor symptoms. A month ago, the symptoms worsened. Meanwhile, he suffered from severe dizziness while standing, constipation and urinary incontinence in this month.. He was a heavy smoker previously without subjective loss of smell, seizures, or changes in body weight. He had no diabetes, family history of genetic diseases or exposure to toxic substances.\n\nHis supine blood pressure (BP) was 106/76 mmHg with heart rate (HR) 82 beats/ min, while it could not be measured accurately when standing. He showed hypophonia and reduced facial expression. The muscle strength score in extremities was 5/5. He also showed bradykinesia, bilateral reduced arm swing and right upper limbs and both lower limbs rigidity without tremor. The deep tendon reflexes were normal and plantar reflex was flexor bilaterally.\n\nThe values of thyroid function test, tumor markers were within the normal range. Results of serum anti-HIV antibody and hepatitis C antibody were negative. Urinary ultrasound showed 130 mL of post-void residual urine. Midbrain sonography and thymus computed tomography (CT) were normal. Multi-detector row CT scan of the lungs showed nodules with no thickening of bronchial wall, enlargement of hilar and mediastinal lymph nodes or atelectasis. Brain magnetic resonance imaging (MRI) showed no brain stem or cerebellar atrophy (Fig. 1A). The 11C-CFTPET/CT scan showed reduced uptake of 11C-CFT in the left caudate nucleus and bilateral putamen (Fig. 1B), and 18F-FDGPET/CT scan showed symmetrical hypometabolism of bilateral frontal-parietal lobes (Fig. 1C).Fig. 1 A Images of the patient’s MRI. Brain MRI showed multiple ischemic foci without brain stem or cerebellar atrophy. B Images of the patient’s 11C-CFTPET/CT. 11C-CFTPET/CT scan showed low metabolism of the left caudate nucleus and bilateral putamen. C Images of the patient’s 18F-FDGPET/CT. 18F-FDGPET/CT scan showed symmetrical low metabolism of bilateral frontal-parietal lobes\n\nBased on his clinical information, he developed dysautonomia accompanied by Parkinsonism, which led to the diagnosis of MSA-P. According to the second consensus statement on the diagnosis of multiple system atrophy, he met the criteria of probable MSA [5]. Considering his hypotension, levodopa-benserazide 12.5 mg /3.125 mg were given orally three times a day. A week later, the dose was doubled. However, he showed no improvement in bradykinesia and instability posture, and the stiffness in the limbs prevented him from moving around at will. What’s worse, he suffered from a severe drop in BP, which set him free from a levodopa trial. Meanwhile, he was recommended to wear elastic socks, raise head 30° when lying, use abdominal straps when standing and drink adequate water. At the same time, droxidopa 100 mg was given orally once a day. However, his BP did not improve significantly. In case of supine hypertension, the dose was not increased and midodrine was not used.\n\nMeanwhile, his dysautonomia progressed relatively rapidly. There was no supportive imaging evidence for MSA. Considering that MSA is a neurodegenerative disorder with no effective treatment and poor prognosis, we checked for other treatable or controllable factors. He underwent a lumbar puncture examination. In the cerebrospinal fluid (CSF), protein was 460 mg / L and total leukocyte count was 4.00 × 106 / L. The anti-CV2 antibody was positive in the CSF and negative in the serum. Then a whole-body PET-CT scan was done and no tumor was detected. Based on the recommended diagnostic criteria for PNS [3], we diagnosed the patient as definite PNS with the nonclassical neurological syndrome, well-characterized onconeural antibodies, and no cancer.\n\nIntravenous immunoglobulin was given at 0.4 g/kg/day. After 5 days of immunotherapy, his dizziness was significantly improved and he could walk independently. His supine BP was 130/83 mmHg with HR 79 beats/min. When standing, his BP was 123/75 mmHg with HR 82 beats/min at 1 min and 115/66 mmHg with HR 85 beats/min at 3 min. The BP was higher than that on admission with the absence of orthostatic hypotension. He received active hydration and medication every day since admission. However, the BP did not improve until the use of immunoglobulin, suggesting that it was the immunotherapy that worked. Moreover, there was no post-void residual urine in reexamination. As the symptoms relieved, intravenous immunoglobulin was stopped after 10 days. In consideration of the age and side effects, immunotherapy was refused by his relatives in the follow-up therapy. Considering that neurological symptoms may appear before the discovery of tumor in some PNS patients, we a followed him up dynamically.\n\nFive months later, his symptoms worsened characterized by frequent falls, inability to walk independently, dysphagia and unintelligible speech. His limbs were too tense to be bent. Likewise, no positive results were found in tumor screening. The BP was 140/89 mmHg, and levodopa-benserazide 50 mg /12.5 mg were given orally three times a day for months. However, it did not work. Unfortunately, he died after 8 months. We also organized the patient’s clinical manifestations and treatment options as a timeline (Fig. 2).Fig. 2 Clinical manifestations and treatment options organized as a timeline. The clinical manifestations and treatment options was consolidated as a timeline\n\nDiscussion and conclusions\n\nThe patient’s clinical presentation was classified as “non-classical neurological syndrome”, indeed, the presentations of dysautonomia and Parkinsonism in anti-CV2 antibody related PNS are rare. Although autonomic neuropathy is taken as common signs, only seven patients showed Parkinsonism without severe and rapidly progressive dysautonomia [1, 6–9]. Here, we summarized the clinical characteristics of these 7 patients in tabular form (Additional Table 1).\n\nAmong the 7 patients (excluding this case), the ratio of male: female was approximately equal (42.9%). The mean age of onset was 60.3 (range 45-72 years old) during the 4 patients whose ages were recorded. Clinical manifestations were described in detail in 4 patients, with concomitant symptoms including: dysarthria (n = 1,25%) hoarse voice (n = 1,25%), autonomic nerve damage (n = 2,50%, one constipation, the other urinary urgency), sleep disturbance (n = 1, 25%, core symptom), and loss of taste (n = 1,25%). Basal ganglia changes were found in all the 4 patients (100%) whose brain MRI results were described, which could account for Parkinsonism. One case was combined with the thalamus and brainstem changes (25%). Two cases of MRS examination showed a reduction of NAA peak located in bilateral basal ganglia (n = 1,50%) and bilateral lateral ventricles (n = 1,50%). Lumbar puncture results were shown in 4 cases, 2 patients had elevated CSF protein levels (50%), with a maximum CSF protein of 629 mg/L. Three patients underwent EEG examination, and 2 showed abnormal results (66.7%) with slow waves in the temporal region. Four cases described the sites of antibody in detection, 2 in both blood and cerebrospinal fluid (50%), and 2 merely in blood (50%). Four cases gave the information about complicated tumor, treatment and prognosis. Two patients suffered from SCLC (50%), and radiotherapy (1 case, 50%) and chemotherapy (2 cases, 100%) were adopted to perform clinical improvements. One patient diagnosed with breast cancer (25%) got improvements in life quality after surgery. No tumor was found in one patient (25%) who received hormone treatment: dexamethasone 10 mg for 3 days and 15 mg for 30 days by intravenous drip, then 6 mg orally once a day with 0.75 mg reduced every 7 days. During the following up, the patient suffered from originally uncontrollable tremors and new onset of seizure. In all, patients achieved cancer treatment when tumors were found are more related to better outcomes than patients accessed to immunotherapy with no tumor.\n\nHere, we report the first case of anti-CV2 antibody-positive PNS mimicking MSA-P. We speculate antibodies damage CRMP5 distributed in the basal ganglia and autonomic nervous system. However, the mechanism remains unknown. PNS treatments consist of tumor-targeted therapy, immunotherapy, and symptomatic treatment. Immunotherapy is indicated in patients with positive anti-CV2 antibody acting as pain, gross or fine motor skills, impairment in speech function. However, in general, immunotherapy is not effective in PNS patients with intracellular antibodies such as anti-CV2 antibody [4]. Instead, the symptoms can be significantly alleviated after targeted treatment. The prognosis of PNS has a great relationship with the type of primary tumor and onconeural antibody. Dubey et al. [4] found that patients with CRMP5 have a better 5-year survival rate than patients with ANNA1.\n\nIn addition to PNS, many diseases exhibit Parkinsonism and dysautonomia simultaneously (Additional Table 2). Physicians should make a comprehensive differential diagnosis as follows especially treatable diseases: 1) Neurodegenerative diseases: MSA-P, Parkinson’s Disease, Dementia with Lewy bodies. They are mostly shown as slow onset with old age and rare family history. Parkinsonism and autonomic dysautonomia can occur with different core symptoms. Neuroimaging shows characteristic features. There is no effective treatment with poor prognosis, so it is necessary to exclude other treatable diseases. 2) Hereditary degeneration diseases: fragile X-associated tremor ataxia syndrome (FXTAS), spinocerebellar ataxia (SCA), Perry syndrome. SCA and Perry syndrome are autosomal dominant, while FXTAS X chromosome dominant. The patients suffering from hereditary degeneration diseases are younger than those of neurodegenerative diseases with slow progression. Cerebellar ataxia often acts as the core symptom and some patients may display Parkinsonism and autonomic dysfunction. Genetic testing is reliable. Likewise, there is no effective treatment requiring to be carefully identified. 3) Hereditary metabolic diseases: Wilson’s disease, Gaucher’s disease-related to Parkinsonism. They are genetically related disorders at a young age and slow onset of abnormal cellular metabolism inherited as an autosomal recessive pattern. Wilson’s disease is a copper accumulation disorder, while Gaucher’s disease is a lysosomal metabolism disorder. Multiple organs are involved, and the nervous system tends to be one part. Genetic or laboratory testing can help with the confirmation of diagnosis. As for treatment, dietary changes and replacement therapy with enzymes have a positive effect on patients. We need to take this kind of disease into consideration as the treatment can alleviate the symptoms. 4) Infection and autoimmune diseases: Sjogren’s syndrome, acquired immune deficiency syndrome [10]. Patients have histories of infection or autoimmune diseases. Symptoms can deteriorate rapidly. Etiological examination or pathological biopsy is probative for diagnosis. It has to be emphasized that immunotherapy leads to a better prognosis, thereby the possibility of such diseases should be considered preferentially. 5) PNS [11]. Older patients showed rapid progression and risk factors associated with tumors. Generally, clinical manifestations are closely related to the type of antibody. Examination of paraneoplastic antibodies in the blood and CSF and the screening for tumors is required. Treatment aiming at tumors can relieve symptoms. Even with no tumor found, immunotherapy can relieve symptoms for some time as is described in this report. Therefore, we should actively detect PNS-related antibodies and the presence of primary tumors in patients with MSA symptoms. 6) Systemic light chain amyloidosis [12]. It’s a rare disease caused by extracellular deposition of amyloid with rapid progression. Symptoms are related to organs where amyloid is deposited (such as the heart, liver, kidney, and peripheral nerves) with a case report showing MSA-mimic. Tissue biopsy or abdominal liposuction is convincing. Patients are commonly treated with chemotherapy, but the prognosis is generally poor for organ complications. Given that, it is of great significance to check for treatable factors.\n\nIn this study, we report a case of anti-CV-2-associated Parkinsonism and rapidly progressive dysautonomia. The characteristics are as follows: 1) PNS patients with anti-CV-2 antibody have been reported to be associated with Parkinsonism (Additional Table 1), yet no dysautonomia or mild dysautonomia were described in these cases. Here, we reported a patient associated with anti-CV-2 antibody with rapid progression (compared with MSA-P patients) of severe autonomic nervous symptom impairment and Parkinsonism, which is difficult to differentiate from MSA-P in clinical manifestations. We speculate that CRMP5 is expressed in both autonomic nervous system and basal ganglia, as evidenced by reduced uptake of 11C-CFT in the left caudate nucleus. 2) Tumor-specific treatment is beneficial to clinical outcomes in patients with PNS. However, our patient was repeatedly screened for tumors to show negative results, and immunotherapy is a valuable treatment for temporary relief of symptoms. Therefore, on the one hand, screening for tumors should be carried out throughout the course of the disease, on the other hand, immunotherapy can be taken as an alternative as early as possible when no tumor is found.\n\nHowever, there are limitations in this case: 1) Considering the absence of evidence of tumors and economic reasons, the patient did not recheck PET-CT and the antibody after immunotherapy and during his follow-up. 2) Autopsy was not performed after death, so the exact cause of death could not be determined, nor could it be determined whether the patients had antigen-antibody complex deposition and pathological changes in basal ganglia and autonomic nervous system in the brain tissue, so as to explore the mechanism of anti-CV-2 antibody in cerebrospinal fluid causing Parkinsonism and autonomic nervous dysfunction. 3) Due to limited conditions, the titer of anti-CV-2 antibody in cerebrospinal fluid and the specific binding ratio of dopamine were unknown. This study reminds physicians of the differential diagnosis of MSA-P, especially PNS when encountering patients with Parkinsonism and rapidly progressing autonomic failure.\n\nSupplementary Information\n\nAdditional file 1: Table 1. Clinical characteristics of anti-CV-2 related PNS presenting with Parkinsonism.\n\nAdditional file 2: Table 2. Summary of diseases manifested as Parkinsonism and dysautonomia.\n\nAbbreviations\n\nAIDS Acquired immune deficiency syndrome\n\nBP Blood pressure\n\nCRMP5 Collapsin response mediated protein 5\n\nCSF Cerebrospinal fluid\n\nCT Computed tomography\n\nDLB Dementia with Lewy bodies\n\nED Erectile dysfunction\n\nEEG Electroencephalography\n\nFDG PET Fluorodeoxyglucose positron emission tomography\n\nFLAIR Fluid-attenuated inversion recovery\n\nFXTAS Fragile X-associated tremor ataxia syndrome\n\nHIV Human immunodeficiency virus\n\nHR Heart rate\n\nMIBG Meta-iodobenzylguanidine\n\nMRI Magnetic resonance imaging\n\nMRS Magnetic resonance spectroscopy\n\nMSA-P Multiple system atrophy predominant Parkinsonism\n\nNAA N-acetylaspartate\n\nOH Orthostatic hypotension\n\nPD Parkinson’s disease\n\nPET Positron emission tomography\n\nPNS Paraneoplastic neurological syndromes\n\nREM Rapid eye movement\n\nSCA Spinocerebellar ataxia\n\nSCLC Small-cell lung carcinoma\n\nThe authors acknowledge the contribution of the patient and his agreement to have his case published.\n\nAuthors’ contributions\n\nJSo, YZ: Study concept and design, acquisition of data, drafting the article. YL, Y-HW, JSh: acquisition of data, analysis and interpretation. LC: critical revision of the manuscript for important intellectual content. All authors have read and approved the manuscript.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nAvailability of data and materials\n\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient’s next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\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\nJia Song and Ying Zhang contributed equally to this work and share first authorship.\n==== Refs\nReferences\n\n1. Yu Z Kryzer TJ Griesmann GE Kim KK Benarroch EE Lennon VA CRMP-5 neuronal autoantibody: Marker of lung cancer and thymoma-related autoimmunity Ann Neurol 2001 49 146 154 10.1002/1531-8249(20010201)49:2<146::AID-ANA34>3.0.CO;2-E 11220734\n2. Ricard D Rogemond V Charrier E Aguera M Bagnard D Belin MF Isolation and expression pattern of human Unc-33-like phosphoprotein 6/collapsin response mediator protein 5 (Ulip6/CRMP5): Coexistence with Ulip2/CRMP2 in Sema3A-sensitive oligodendrocytes J Neurosci 2001 21 7203 7214 10.1523/JNEUROSCI.21-18-07203.2001 11549731\n3. Graus F Delattre JY Antoine JC Dalmau J Giometto B Grisold W Recommended diagnostic criteria for paraneoplastic neurological syndromes J Neurol Neurosurg Psychiatry 2004 75 1135 1140 10.1136/jnnp.2003.034447 15258215\n4. Dubey D Lennon VA Gadoth A Pittock SJ Flanagan EP Schmeling JE Autoimmune CRMP5 neuropathy phenotype and outcome defined from 105 cases Neurology 2018 90 e103 e110 10.1212/WNL.0000000000004803 29222126\n5. Gilman S Wenning GK Low PA Brooks DJ Mathias CJ Trojanowski JQ Second consensus statement on the diagnosis of multiple system atrophy Neurology 2008 71 670 676 10.1212/01.wnl.0000324625.00404.15 18725592\n6. Tada S Furuta M Fukada K Hirozawa D Matsui M Aoike F Severe parkinsonism associated with anti-CRMP5 antibody-positive paraneoplastic neurological syndrome and abnormal signal intensity in the bilateral basal ganglia J Neurol Neurosurg Psychiatry 2016 87 907 910 10.1136/jnnp-2015-311569 26374701\n7. Yap SM Lynch T MacMahon P Murray B Paraneoplastic Atypical Parkinsonism with Anti-CRMP5 Antibodies and Severe Caudate and Putaminal Hypometabolism on 18-Fluorodeoxyglucose Positron Emission Tomography of the Brain Mov Disord Clin Pract 2017 4 263 265 10.1002/mdc3.12370 30838264\n8. Cheng Y Liu K Liu S Meng H Zheng X Zhang Y Anti-CV2 autoimmune encephalitis: a case report and review of the literatures Chin J Neurol 2018 51 5 376 381 10.3760/cma.j.issn.1006-7876.2018.05.009\n9. Wu X Wang H Xu G Lin Y Anti-CV2 Autoimmune Encephalitis With Parkinson-Like Symptoms and Bilateral Leukoencephalopathy—A Case Report Front Neurol 2019 10 October 1 5 30761061\n10. Kurihara M Sasaki T Ishiura H Tsuji S HIV dementia with a decreased cardiac 123 i-metaiodobenzylguanidine uptake masquerading as dementia with lewy bodies Intern Med. 2018 57 3007 3010 10.2169/internalmedicine.0876-18 29780124\n11. Ricigliano VAG Fossati B Saraceno L Cavalli M Bazzigaluppi E Meola G MSA mimic? Rare occurrence of anti-hu autonomic failure and thymoma in a patient with parkinsonism: Case report and literature review Front Neurosci 2018 12 JAN 1 6 29403346\n12. Albanese A Cocco A Milani P Lalli S Palladini G Parkinsonism and dysautonomia: Multiple system atrophy? Parkinsonism Relat Disord 2020 77 146 149 10.1016/j.parkreldis.2019.05.005 31097298\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2377",
"issue": "21(1)",
"journal": "BMC neurology",
"keywords": "Anti-CV2 antibody; Collapsin response mediated protein 5; Dysautonomia; Multiple system atrophy; Paraneoplastic syndrome",
"medline_ta": "BMC Neurol",
"mesh_terms": "D001323:Autoantibodies; D006801:Humans; D008297:Male; D019578:Multiple System Atrophy; D020361:Paraneoplastic Syndromes, Nervous System; D020734:Parkinsonian Disorders; D000072078:Positron Emission Tomography Computed Tomography; D054969:Primary Dysautonomias",
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"pubdate": "2021-10-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Parkinsonism and dysautonomia with anti-CV2/CRMP5 associated paraneoplastic neurological syndromes mimicking multiple system atrophy: a case report.",
"title_normalized": "parkinsonism and dysautonomia with anti cv2 crmp5 associated paraneoplastic neurological syndromes mimicking multiple system atrophy a case report"
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"abstract": "BACKGROUND\nBrain MRI plays an essential role in both diagnosis and follow-up of the JC virus infection of the brain. Recently, MR studies with susceptibility-weighted imaging (SWI) sequences have shown hypointensities in U-fibers adjacent to white matter (WM) lesions of progressive multifocal leukoencephalopathy (PML). This finding has been confirmed with the use of quantitative susceptibility mapping (QSM), allowing to hypothesize a paramagnetic effect in these regions. Here, we report the first longitudinal assessment of QSM and R2* maps in natalizumab-associated PML to evaluate serial changes in susceptibility contrast images and their role in PML diagnosis and follow-up.\n\n\nMETHODS\nWe report the case of a 42-year-old woman with multiple sclerosis (MS) who eventually developed, after the 28th natalizumab infusion, subacute cognitive decline and received a laboratory-confirmed diagnosis of PML, leading to immediate drug discontinuation. Three months later, she suffered a new clinical exacerbation, with a brain scan revealing significant inflammatory activity compatible with the radiological diagnosis of an Immune Reconstitution Inflammatory Syndrome (IRIS). She was then treated with corticosteroids until the clinico-radiological spectrum became stable, with the final outcome of a severe functional impairment. Quantitative maps obtained in the early symptomatic stage clearly showed increased QSM and R2* values in the juxtacortical WM adjacent to PML lesions, which persisted during the subsequent disease course.\n\n\nCONCLUSIONS\nHigh QSM and R2* values in U-fibers adjacent to WM lesions were early and seemingly time-independent radiological findings in the presented PML case. This, coupled to the known absence of significant paramagnetic effect of new active MS lesions, could support the use of quantitative MRI as an additional tool in the diagnosis and follow-up of natalizumab-related PML in MS.",
"affiliations": "Department of Advanced Biomedical Sciences, University \"Federico II\", Naples, Italy.;Department of Advanced Biomedical Sciences, University \"Federico II\", Naples, Italy.;Department of Neurosciences, Reproductive and Odontostomatological Sciences, University \"Federico II\", Naples, Italy.;IRCCS SDN, Naples, Italy.;Department of Neurosciences, Reproductive and Odontostomatological Sciences, University \"Federico II\", Naples, Italy.;Department of Neurosciences, Reproductive and Odontostomatological Sciences, University \"Federico II\", Naples, Italy.;Department of Advanced Biomedical Sciences, University \"Federico II\", Naples, Italy.;Institute of Biostructure and Bioimaging, National Research Council, Naples, Italy.",
"authors": "Pontillo|Giuseppe|G|;Cocozza|Sirio|S|;Lanzillo|Roberta|R|;Borrelli|Pasquale|P|;De Rosa|Anna|A|;Brescia Morra|Vincenzo|V|;Tedeschi|Enrico|E|;Palma|Giuseppe|G|",
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"doi": "10.3389/fneur.2017.00294",
"fulltext": "\n==== Front\nFront NeurolFront NeurolFront. Neurol.Frontiers in Neurology1664-2295Frontiers Media S.A. 10.3389/fneur.2017.00294NeuroscienceCase ReportBrain Susceptibility Changes in a Patient with Natalizumab-Related Progressive Multifocal Leukoencephalopathy: A Longitudinal Quantitative Susceptibility Mapping and Relaxometry Study Pontillo Giuseppe 1†Cocozza Sirio 1*†Lanzillo Roberta 2Borrelli Pasquale 3De Rosa Anna 2Brescia Morra Vincenzo 2Tedeschi Enrico 1Palma Giuseppe 41Department of Advanced Biomedical Sciences, University “Federico II”, Naples, Italy2Department of Neurosciences, Reproductive and Odontostomatological Sciences, University “Federico II”, Naples, Italy3IRCCS SDN, Naples, Italy4Institute of Biostructure and Bioimaging, National Research Council, Naples, ItalyEdited by: Mike P. Wattjes, VU University Medical Center, Netherlands\n\nReviewed by: Jérôme Hodel, American Printing House for the Blind, United States; Friedemann Paul, Charité Universitätsmedizin Berlin, Germany\n\n*Correspondence: Sirio Cocozza, siriococozza@hotmail.it†These authors have contributed equally to this work.\n\nSpecialty section: This article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Neurology\n\n19 6 2017 2017 8 29424 3 2017 07 6 2017 Copyright © 2017 Pontillo, Cocozza, Lanzillo, Borrelli, De Rosa, Brescia Morra, Tedeschi and Palma.2017Pontillo, Cocozza, Lanzillo, Borrelli, De Rosa, Brescia Morra, Tedeschi and PalmaThis 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) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Background\nBrain MRI plays an essential role in both diagnosis and follow-up of the JC virus infection of the brain. Recently, MR studies with susceptibility-weighted imaging (SWI) sequences have shown hypointensities in U-fibers adjacent to white matter (WM) lesions of progressive multifocal leukoencephalopathy (PML). This finding has been confirmed with the use of quantitative susceptibility mapping (QSM), allowing to hypothesize a paramagnetic effect in these regions. Here, we report the first longitudinal assessment of QSM and R2* maps in natalizumab-associated PML to evaluate serial changes in susceptibility contrast images and their role in PML diagnosis and follow-up.\n\nCase presentation\nWe report the case of a 42-year-old woman with multiple sclerosis (MS) who eventually developed, after the 28th natalizumab infusion, subacute cognitive decline and received a laboratory-confirmed diagnosis of PML, leading to immediate drug discontinuation. Three months later, she suffered a new clinical exacerbation, with a brain scan revealing significant inflammatory activity compatible with the radiological diagnosis of an Immune Reconstitution Inflammatory Syndrome (IRIS). She was then treated with corticosteroids until the clinico-radiological spectrum became stable, with the final outcome of a severe functional impairment. Quantitative maps obtained in the early symptomatic stage clearly showed increased QSM and R2* values in the juxtacortical WM adjacent to PML lesions, which persisted during the subsequent disease course.\n\nDiscussion and conclusion\nHigh QSM and R2* values in U-fibers adjacent to WM lesions were early and seemingly time-independent radiological findings in the presented PML case. This, coupled to the known absence of significant paramagnetic effect of new active MS lesions, could support the use of quantitative MRI as an additional tool in the diagnosis and follow-up of natalizumab-related PML in MS.\n\nmultiple sclerosisprogressive multifocal leukoencephalopathyneuroinflammationneuroimmunologyMRIsusceptibility-weighted imaging\n==== Body\nBackground\nProgressive multifocal leukoencephalopathy (PML) is a rare and severe demyelinating disease of the central nervous system caused by the reactivation of JC virus (JCV) in immunosuppressed patients (1).\n\nIn recent years, PML has gained increasing attention due to its association with natalizumab treatment in multiple sclerosis (MS) (2–4) and its prognosis, once regarded as invariably poor, seemingly ameliorates with early diagnosis and adequate treatment (5).\n\nNeuroimaging plays a pivotal role in both diagnosis and follow-up of JCV infection and brain MRI has been included in PML diagnostic workflow, due to its high-sensitivity in the screening of suspected patients, even in a presymptomatic stage (6, 7).\n\nConventional MRI findings of PML are relatively well-known (8–11). Recently, some authors investigated brain magnetic susceptibility changes in PML, proposing the use of susceptibility contrast [namely, susceptibility-weighted imaging (SWI)] as an additional diagnostic tool (12–14). However, to date, no data are available on the quantitative longitudinal assessment of susceptibility changes in PML and their possible use as a biomarker of disease progression.\n\nIn contrast to SWI, quantitative susceptibility mapping (QSM) and R2* mapping offer the possibility of a quantitative, and therefore more consistent, evaluation of brain susceptibility changes. Here, we describe the first longitudinal use of QSM and relaxometry maps in a patient with MS who developed a natalizumab-related PML.\n\nCase Presentation\nWe report the case of a 42-year-old woman with a 10-year history of relapsing remitting-MS, treated with natalizumab in the last 2 years. She was JCV antibody-positive and had previously received another disease modifying therapy (interferon beta-1a/Rebif 44).\n\nAfter the 28th infusion of natalizumab, she eventually developed subacute cognitive decline, confirmed by neuropsychological tests. Approximately 2 weeks after this clinical onset, a brain MRI scan revealed the presence of multiple new lesions, highly suggestive of PML. Natalizumab was immediately discontinued, she was hospitalized and JCV DNA copies were found in cerebrospinal fluid (2,322 copies/mL), leading to a definite diagnosis of PML (6).\n\nThree months later, prompted by further cognitive deterioration and subacute right hemiplegia, another brain MRI scan revealed significant inflammatory activity, compatible with the clinico-radiological diagnosis of an Immune Reconstitution Inflammatory Syndrome (IRIS).\n\nShe subsequently received corticosteroids (several 3–5 days cycles of 1 g/die i.v. bolus of methylprednisolone, alternating with 25 mg/die of prednisone per os), until the clinico-radiological spectrum became stable, and she was moved to a neuro-rehabilitation center.\n\nThe final clinical outcome was a severe functional impairment, with impossibility of independent ambulation, right hemiplegia, incoordination, mixed aphasia, cognitive decline, and an overall Expanded Disability Status Scale score of 7.0, compared with the baseline value of 2.5.\n\nSince the clinical onset, the patient was closely followed-up in our center with several brain MRI scans, three of them with contrast administration, respectively at 35, 91, and 280 days from the first diagnostic examination.\n\nWritten informed consent was obtained from the patient for the publication of this case report.\n\nMR data were collected on a 3-T scanner (Trio, Siemens Medical Systems, Erlangen, Germany).\n\nIn all scans, along with the routine clinical sequences, an unenhanced 3D double-echo FLASH sequence (TR = 28 ms; TE1 = 7.63 ms; TE2 = 22.14 ms; voxel size = 0.65 mm × 0.65 mm × 1.3 mm; 128 axial slices) was acquired with a flip angle of 20° to provide QSM and R2* maps, as already described in detail (15–17).\n\nA complete depiction of the evolution of MRI findings during the disease course is shown in Figure 1, where four MRI scans are displayed, in comparison with a pre-PML baseline examination, performed after 14 natalizumab infusions, while the patient was asymptomatic (Figure 1A).\n\nFigure 1 Evolution of MRI findings in our case of natalizumab-related progressive multifocal leukoencephalopathy (PML). Axial fluid-attenuated inversion recovery (FLAIR, first column), contrast-enhanced T1-weighted images (second column), R2* maps (third column), and quantitative susceptibility maps (QSM, fourth column), of two levels (ventricular bodies and basal ganglia planes) from brain MRI scans performed in a phase of multiple sclerosis stability (A), in the early symptomatic PML phase (B), at a PML follow-up (C), when Immune Reconstitution Inflammatory Syndrome (IRIS)-PML ensued (D), and at a chronic stage (E). (A) Multiple periventricular and juxtacortical FLAIR-hyperintense demyelinating lesions, non-enhancing after i.v. gadolinium administration, and without significant susceptibility modifications on R2* or QSM maps. (B) Evidence of new FLAIR-hyperintense bilateral parieto-occipital subcortical lesions, with mild contrast enhancement and clearly increased values of R2* and QSM in the adjacent U-fibers (arrows). Furthermore, a small non-enhancing, FLAIR-hyperintense lesion in the left globus pallidus is present, showing mildly decreased values on R2* and QSM maps (arrowheads). (C) Progressive extension of the previously described lesions showing lack of significant contrast-enhancement and constantly high R2* and QSM values in adjacent U-fibers. The left pallidal lesion now shows a mild increase in susceptibility on R2* and QSM maps. (D) Further extension of FLAIR-hyperintensities with most of the lesions vividly enhancing after contrast administration. U-fibers high values on R2* and QSM maps are still present, whereas the susceptibility changes in the left globus pallidus become more evident. (E) Reduction of the lesion load with significantly increased values on R2* and QSM maps of adjacent U-fibers, associated with brain atrophy. The left globus pallidus’ lesion shows a punctate hypointense signal on FLAIR images, corresponding to a significant increase of R2* and QSM values. (F) Plots showing the time evolution of QSM and R2* values in the U-fibers adjacent to the left parieto-occipital subcortical lesion, with reference to the baseline (dotted line). The three colored bands represent different phases of the disease (PML, PML–IRIS, and chronic stage).\n\nIn summary, the first brain MRI performed shortly after clinical onset revealed new bilateral parieto-occipital subcortical lesions, with mild contrast-enhancement and clearly increased susceptibility and R2* values in the adjacent U-fibers. Moreover, a new fluid-attenuated inversion recovery (FLAIR)-hyperintense lesion was present in the left globus pallidus, with no significant paramagnetic effect (Figure 1B).\n\nDespite natalizumab discontinuation, a follow-up MRI scan, performed 35 days later, revealed progressive extension of the subcortical white matter (WM) lesions with persistently high QSM and R2* values in the adjacent U-fibers. Besides, the left pallidal lesion showed a mild increase of both susceptibility and R2*, reflecting a more marked paramagnetic effect (Figure 1C).\n\nFollowing a clinical exacerbation, another brain MRI scan performed 91 days after the first diagnostic examination showed further increase in the multifocal extension, with changes in the contrast-enhancement pattern, suggestive of intense inflammatory activity due to IRIS. QSM anomalies of U-fibers adjacent to WM lesions were still present, even if more blurred, while susceptibility changes in the left globus pallidus became more evident (Figure 1D).\n\nFinally, in a chronic stage, 280 days after the first examination, a follow-up brain MRI (Figure 1E) revealed partial regression of the lesions, associated to a moderate parieto-occipital atrophy, and even higher QSM and R2* values in the affected U-fibers. Furthermore, the left pallidal lesion showed a punctate hypointense focus on FLAIR images, corresponding to a significant increase in susceptibility on QSM and R2* maps.\n\nPlots showing the time evolution of QSM and R2* values in the U-fibers adjacent to the left parieto-occipital subcortical lesion are shown in Figure 1F.\n\nDiscussion\nBrain MRI is essential for the diagnosis and monitoring of PML, and several conventional MRI features have been reported as characteristics of this condition, including multifocal WM lesions involving U-fibers, punctate and/or rim-like enhancement after gadolinium injection, and minimal/absent mass effect (8, 9).\n\nFurthermore, some non-conventional MRI techniques (e.g., MR-spectroscopy and ultra-high field MRI) have been proposed as an additional diagnostic tool in this condition (18–20), and the role of susceptibility contrast imaging has been recently investigated.\n\nIn particular, previous studies have reported the presence, on SWI sequences, of hypointensities in U-fibers adjacent to the WM lesions of PML (13, 14). This finding has been confirmed by the observation of clearly increased values in U-fibers on QSM maps, allowing to hypothesize a paramagnetic effect in the juxtacortical regions adjacent to PML lesions (12). However, these findings have only been reported in cross-sectional reports, evaluating imaging findings at a specific time point.\n\nTo the best of our knowledge, no studies have been performed using a quantitative MRI method at different time points, covering the entire history of the disease to evaluate possible susceptibility changes that may help in the diagnosis or in monitoring the clinical evolution of these patients.\n\nIn our case, increased QSM values in U-fibers adjacent to WM lesions, suggesting a paramagnetic effect, were a constant finding. This feature was independent from the clinical course of the disease, being already present in the early phase, when the appearance of new lesions could mimic MS recurrence rather than the occurrence of a PML, and persisting in chronic stages. This finding, coupled with the known absence of significant paramagnetic effect of new active MS lesion (21, 22), allows us to encourage the inclusion of susceptibility contrast imaging, and in particular of QSM, in clinical routine examination, since the presence of a clear paramagnetic effect could further help in differentiating PML lesions from MS progression.\n\nThe meaning of these susceptibility changes has not yet been fully understood. Indeed, high amounts of iron have been reported within oligodendrocytes and myelin sheaths at the cortical–subcortical junction, in both healthy and MS patients’ brains (23). In MS plaques, iron is released by oligodendrocytes and myelin destruction and, in the chronic course of the plaque, it accumulates within activated macrophages and microglia, with an increasing paramagnetic effect (21, 22). Our findings support the hypothesis that a similar mechanism of iron accumulation could occur in PML, in which however a different inflammatory pattern, characterized by more pronounced myelin degeneration, could lead to an increase in intracellular iron deposition with stronger and earlier detectable susceptibility changes (14). During the PML–IRIS phase, a slight descent of QSM values (which however were still markedly higher than baseline), was most likely due to macrophages dilution in the abundant inflammatory edema (as suggested by the conspicuous R2* drop).\n\nIn addition, we reported the presence of a lesion in the left globus pallidus, characterized by slowly progressive increase of QSM and R2* values. Previous studies have described susceptibility changes in basal ganglia of PML patients, characterized mainly by a diffuse, although asymmetrical, low signal on SWI typically attributed to iron deposition (13, 14). In our case, no significant global susceptibility changes were present in deep gray matter nuclei. These apparently conflicting results may be related to the absence, in our patient, of an extensive involvement of the deep WM adjacent to the basal ganglia. Instead, susceptibility changes in the left globus pallidus are more likely attributable to an intralesional microhemorrage, also reported as a rare finding in PML (1, 24), rather than to a focal iron accumulation within the lesion.\n\nFinally, some limitations should be considered in the present report. In particular, histopathological confirmation is lacking in our case, which would have allowed to directly verify our hypotheses. Furthermore, this is a single-subject evaluation, although studied at several time points, with all the associated limits. For this reason, future longitudinal studies including a group of PML patients are warranted, to further corroborate our findings.\n\nConclusion\nWe support the hypothesis that susceptibility contrast imaging could represent a valid aid in the diagnosis of natalizumab-related PML in MS, even at an early stage, and therefore should be included in the MRI evaluation of patients with such clinical suspicion, or even in the routine imaging surveillance in this population.\n\nEthics Statement\nThis study was carried out in accordance with the recommendations of “name of guidelines, name of committee” with written informed consent from the subject. The subject gave written informed consent in accordance with the Declaration of Helsinki. Since this was an observational case study, a formal review by the local Institutional Review Board was not required.\n\nAuthor Contributions\nGPontillo and SC: study concept and design; analysis and interpretation. RL, AR, and VM: acquisition of data. PB: analysis and interpretation. ET: critical revision; study supervision. GPalma: analysis and interpretation; critical revision; and study supervision.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1 Bag AK Cure JK Chapman PR Roberson GH Shah R \nJC virus infection of the brain . AJNR Am J Neuroradiol (2010 ) 31 :1564 –76 .10.3174/ajnr.A2035 20299430 \n2 Bloomgren G Richman S Hotermans C Subramanyam M Goelz S Natarajan A \nRisk of natalizumab-associated progressive multifocal leukoencephalopathy . N Engl J Med (2012 ) 366 :1870 –80 .10.1056/NEJMoa1107829 22591293 \n3 Meira M Sievers C Hoffmann F Haghikia A Rasenack M Décard BF \nNatalizumab-induced POU2AF1/Spi-B upregulation: a possible route for PML development . Neurol Neuroimmunol Neuroinflamm (2016 ) 3 :e223 .10.1212/NXI.0000000000000223 27088119 \n4 Schwab N Schneider-Hohendorf T Pignolet B Breuer J Gross CC Göbel K \nTherapy with natalizumab is associated with high JCV seroconversion and rising JCV index values . Neurol Neuroimmunol Neuroinflamm (2016 ) 3 :e195 .10.1212/NXI.0000000000000195 26848486 \n5 Dong-Si T Richman S Wattjes MP Wenten M Gheuens S Philip J \nOutcome and survival of asymptomatic PML in natalizumab-treated MS patients . Ann Clin Transl Neurol (2014 ) 1 :755 –64 .10.1002/acn3.114 25493267 \n6 Berger JR Aksamit AJ Clifford DB Davis L Koralnik IJ Sejvar JJ \nPML diagnostic criteria: consensus statement from the AAN neuroinfectious disease section . Neurology (2013 ) 80 :1430 –8 .10.1212/WNL.0b013e31828c2fa1 23568998 \n7 Lindå H von Heijne A . Presymptomatic diagnosis with MRI and adequate treatment ameliorate the outcome after natalizumab-associated progressive multifocal leukoencephalopathy . Front Neurol (2013 ) 4 :11 .10.3389/fneur.2013.00011 23423248 \n8 Wijburg MT Witte BI Vennegoor A Roosendaal SD Sanchez E Liu Y \nMRI criteria differentiating asymptomatic PML from new MS lesions during natalizumab pharmacovigilance . J Neurol Neurosurg Psychiatry (2016 ) 87 :1138 –45 .10.1136/jnnp-2016-313772 27530808 \n9 Yousry TA Pelletier D Cadavid D Gass A Richert ND Radue EW \nMagnetic resonance imaging pattern in natalizumab-associated progressive multifocal leukoencephalopathy . Ann Neurol (2012 ) 72 :779 –87 .10.1002/ana.23676 23280794 \n10 Wattjes MP Richert ND Killestein J de Vos M Sanchez E Snaebjornsson P \nThe chameleon of neuroinflammation: magnetic resonance imaging characteristics of natalizumab-associated progressive multifocal leukoencephalopathy . Mult Scler (2013 ) 19 :1826 –40 .10.1177/1352458513510224 24192217 \n11 Wattjes MP Wijburg MT Vennegoor A Witte BI Roosendaal SD Sanchez E \nDiagnostic performance of brain MRI in pharmacovigilance of natalizumab-treated MS patients . Mult Scler (2016 ) 22 :1174 –83 .10.1177/1352458515615225 26564995 \n12 Carra-Dalliere C Menjot de Champfleur N Deverdun J Ayrignac X Nerrant E Makinson A \nUse of quantitative susceptibility mapping (QSM) in progressive multifocal leukoencephalopathy . J Neuroradiol (2016 ) 43 :6 –10 .10.1016/j.neurad.2015.08.001 26475668 \n13 Miyagawa M Maeda M Umino M Kagawa K Nakamichi K Sakuma H \nLow signal intensity in U-fiber identified by susceptibility-weighted imaging in two cases of progressive multifocal leukoencephalopathy . J Neurol Sci (2014 ) 344 :198 –202 .10.1016/j.jns.2014.06.018 24972818 \n14 Hodel J Outteryck O Verclytte S Deramecourt V Lacour A Pruvo JP \nBrain magnetic susceptibility changes in patients with natalizumab-associated progressive multifocal leukoencephalopathy . AJNR Am J Neuroradiol (2015 ) 36 :2296 –302 .10.3174/ajnr.A4436 26316568 \n15 Borrelli P Palma G Tedeschi E Cocozza S Comerci M Alfano B \nImproving signal-to-noise ratio in susceptibility weighted imaging: a novel multicomponent non-local approach . PLoS One (2015 ) 10 :e0126835 .10.1371/journal.pone.0126835 26030293 \n16 Palma G Tedeschi E Borrelli P Cocozza S Russo C Liu S \nA novel multiparametric approach to 3D quantitative MRI of the brain . PLoS One (2015 ) 10 :e0134963 .10.1371/journal.pone.0134963 26284778 \n17 Tedeschi E Palma G Canna A Cocozza S Russo C Borrelli P \nIn vivo dentate nucleus MRI relaxometry correlates with previous administration of gadolinium-based contrast agents . Eur Radiol (2016 ) 26 :4577 –84 .10.1007/s00330-016-4245-2 26905870 \n18 Iranzo A Moreno A Pujol J Martí-Fàbregas J Domingo P Molet J \nProton magnetic resonance spectroscopy pattern of progressive multifocal leukoencephalopathy in AIDS . J Neurol Neurosurg Psychiatry (1999 ) 66 :520 –3 .10.1136/jnnp.66.4.520 10201428 \n19 Sinnecker T Othman J Kühl M Mekle R Selbig I Niendorf T \n7T MRI in natalizumab-associated PML and ongoing MS disease activity: a case study . Neurol Neuroimmunol Neuroinflamm (2015 ) 2 :e171 .10.1212/NXI.0000000000000171 26568970 \n20 Sinnecker T Othman J Kühl M Metz I Niendorf T Kunkel A \nProgressive multifocal leukoencephalopathy in a multiple sclerosis patient diagnosed after switching from natalizumab to fingolimod . Case Rep Neurol Med (2016 ) 2016 :5876798 .10.1155/2016/5876798 27994897 \n21 Stuber C Pitt D Wang Y . Iron in multiple sclerosis and its noninvasive imaging with quantitative susceptibility mapping . Int J Mol Sci (2016 ) 17 :100 .10.3390/ijms17010100 26784172 \n22 Zhang Y Gauthier SA Gupta A Chen W Comunale J Chiang GC \nQuantitative susceptibility mapping and R2* measured changes during white matter lesion development in multiple sclerosis: myelin breakdown, myelin debris degradation and removal, and iron accumulation . AJNR Am J Neuroradiol (2016 ) 37 :1629 –35 .10.3174/ajnr.A4825 27256856 \n23 Bagnato F Hametner S Yao B van Gelderen P Merkle H Cantor FK \nTracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla . Brain (2011 ) 134 :3602 –15 .10.1093/brain/awr278 22171355 \n24 Ng S Tse VC Rubinstein J Bradford E Enzmann DR Conley FK . Progressive multifocal leukoencephalopathy: unusual MR findings . J Comput Assist Tomogr (1995 ) 19 :302 –5 .10.1097/00004728-199503000-00025 7890860\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2295",
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"journal": "Frontiers in neurology",
"keywords": "MRI; multiple sclerosis; neuroimmunology; neuroinflammation; progressive multifocal leukoencephalopathy; susceptibility-weighted imaging",
"medline_ta": "Front Neurol",
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"pages": "294",
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"pmid": "28674518",
"pubdate": "2017",
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"title": "Brain Susceptibility Changes in a Patient with Natalizumab-Related Progressive Multifocal Leukoencephalopathy: A Longitudinal Quantitative Susceptibility Mapping and Relaxometry Study.",
"title_normalized": "brain susceptibility changes in a patient with natalizumab related progressive multifocal leukoencephalopathy a longitudinal quantitative susceptibility mapping and relaxometry study"
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"abstract": "Nicotine, a lipid-soluble alkaloid obtained from the dried leaves of Nicotiana, is most frequently encountered in tobacco products for smoking, chewing or sniffing as well as in a limited number of pesticides. Though nicotine is one of the most toxic drugs of abuse, it has rarely led to fatalities. Sudden death can be caused by cardiovascular arrest, respiratory muscle paralysis and/or central respiratory failure. A 42-year-old man was found dead by his wife. He was lying on the floor, next to a box containing many empty bottles of beer and vodka. Some labeled chemical bottles found at the scene contained various substances, including nicotine and brucine. Gross examination of the organs at autopsy revealed no specific findings. The toxicological examination failed to disclose any lethal toxic agents other than a high concentration of nicotine and its primary metabolite cotinine in femoral venous blood (2.2 microg/mL). Blood alcohol was determined to be 2.1 g/L in femoral venous blood. Only a paucity of fatal cases of nicotine poisoning has been reported in the literature so far.",
"affiliations": "Department of Internal Medicine and Public Medicine, University of Bari, Bari, Italy. bisola@tin.it",
"authors": "Solarino|Biagio|B|;Rosenbaum|Frank|F|;Riesselmann|Benno|B|;Buschmann|Claas T|CT|;Tsokos|Michael|M|",
"chemical_list": "D000700:Analgesics; D002492:Central Nervous System Depressants; D005731:Ganglionic Stimulants; D000431:Ethanol; D009538:Nicotine; C083806:brucine; D013331:Strychnine; D003367:Cotinine",
"country": "Ireland",
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"issue": "195(1-3)",
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"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D000700:Analgesics; D002492:Central Nervous System Depressants; D003367:Cotinine; D000431:Ethanol; D053593:Forensic Toxicology; D005731:Ganglionic Stimulants; D008401:Gas Chromatography-Mass Spectrometry; D005766:Gastrointestinal Contents; D006801:Humans; D008297:Male; D009538:Nicotine; D013331:Strychnine",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "e19-22",
"pmc": null,
"pmid": "19954906",
"pubdate": "2010-02-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Death due to ingestion of nicotine-containing solution: case report and review of the literature.",
"title_normalized": "death due to ingestion of nicotine containing solution case report and review of the literature"
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"companynumb": "IT-JNJFOC-20141201966",
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"abstract": "OBJECTIVE\nBRAF-mutant metastatic colorectal cancer (mCRC) forms an aggressive subset of colorectal cancer with minimal response to selective RAF inhibitors. Preclinical data show that reactivation of EGFR signaling occurs in colorectal tumor cells treated with RAF inhibitors and that the addition of an EGFR inhibitor enhances antitumor activity. These data suggest that combined therapy with RAF and EGFR inhibitors could be an effective strategy for treating BRAF V600E mCRC.\n\n\nMETHODS\nWe undertook a pilot trial to assess the response rate and safety of the BRAF inhibitor vemurafenib combined with anti-EGFR antibody panitumumab in patients with BRAF-mutant mCRC. Patients received standard approved doses of panitumumab and vemurafenib.\n\n\nRESULTS\nFifteen patients were treated. Performance status was Eastern Cooperative Oncology Group (ECOG) 0 in 4 patients (27%) and ECOG 1 in 11 patients (73%). All patients had progressed through at least one standard treatment regimen, and 8 (53%) had received previous fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy. Treatment was well tolerated, with less cutaneous toxicity than would be expected with either agent, and no cases of keratoacanthomas/squamous cell carcinomas. Tumor regressions were seen in 10 of 12 evaluable patients with partial responses in 2 patients (100% and 64% regression lasting 40 and 24 weeks, respectively), and stable disease lasting over 6 months in 2 patients.\n\n\nCONCLUSIONS\nCombined RAF and EGFR inhibition is well tolerated, with less cutaneous toxicity than would be expected with either agent, and results in modest clinical activity in this highly aggressive and chemoresistant subset of CRC.",
"affiliations": "Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. yaegerr@mskcc.org.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.",
"authors": "Yaeger|Rona|R|;Cercek|Andrea|A|;O'Reilly|Eileen M|EM|;Reidy|Diane L|DL|;Kemeny|Nancy|N|;Wolinsky|Tamar|T|;Capanu|Marinela|M|;Gollub|Marc J|MJ|;Rosen|Neal|N|;Berger|Michael F|MF|;Lacouture|Mario E|ME|;Vakiani|Efsevia|E|;Saltz|Leonard B|LB|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; D000077544:Panitumumab; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf",
"country": "United States",
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"doi": "10.1158/1078-0432.CCR-14-2779",
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"issue": "21(6)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D015179:Colorectal Neoplasms; D018572:Disease-Free Survival; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D007211:Indoles; D008297:Male; D008875:Middle Aged; D000077544:Panitumumab; D048493:Proto-Oncogene Proteins B-raf; D015398:Signal Transduction; D013449:Sulfonamides; D016896:Treatment Outcome; D000077484:Vemurafenib; D055815:Young Adult",
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "1313-20",
"pmc": null,
"pmid": "25589621",
"pubdate": "2015-03-15",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "22448344;22256804;22446022;21502544;19182786;18316791;24202393;25265492;21285991;23457002;20179705;23406731;19001320;16508002;24737664;20823850;20619739;21639808;19884556;23134356;24024839;15269313;21227396;25265494;19603024;21456008;17470858;22899370;14993230;22281684;22585170;23020132;23685672;19571295;23153539;11325826",
"title": "Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients.",
"title_normalized": "pilot trial of combined braf and egfr inhibition in braf mutant metastatic colorectal cancer patients"
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"companynumb": "US-CIPLA LTD.-2015US00891",
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"abstract": "This multicenter, double-blind, placebo-controlled study examined the efficacy and safety of ipragliflozin, a sodium-glucose co-transporter 2 inhibitor, in combination with metformin in Japanese patients with type 2 diabetes mellitus (T2DM). Patients were randomized in a 2 : 1 ratio to 50 mg ipragliflozin (n = 112) or placebo (n = 56) once daily for 24 weeks, followed by a 28-week open-label extension in which all patients received 50 or 100 mg ipragliflozin, while continuing metformin. The primary outcome was the change in glycated haemoglobin (HbA1c) from baseline to week 24. HbA1c decreased significantly in the ipragliflozin group (-0.87%; adjusted mean difference from placebo: -1.30%; p < 0.001). The overall incidence of treatment-emergent adverse events was similar in both groups, although pollakiuria and constipation were more common in the ipragliflozin group; thus, ipragliflozin significantly improved glycaemic control and reduced body weight without major safety issues in Japanese patients with T2DM.",
"affiliations": "Department of Medicine, Shiga University of Medical Science, Shiga, Japan.",
"authors": "Kashiwagi|A|A|;Kazuta|K|K|;Goto|K|K|;Yoshida|S|S|;Ueyama|E|E|;Utsuno|A|A|",
"chemical_list": "D001786:Blood Glucose; D005960:Glucosides; D006442:Glycated Hemoglobin A; D007004:Hypoglycemic Agents; D010919:Placebos; D013876:Thiophenes; C517652:hemoglobin A1c protein, human; C572941:ipragliflozin; D008687:Metformin",
"country": "England",
"delete": false,
"doi": "10.1111/dom.12331",
"fulltext": "\n==== Front\nDiabetes Obes MetabDiabetes Obes MetabdomDiabetes, Obesity & Metabolism1462-89021463-1326Blackwell Publishing Ltd Oxford, UK 10.1111/dom.12331Research LettersIpragliflozin in combination with metformin for the treatment of Japanese patients with type 2 diabetes: ILLUMINATE, a randomized, double-blind, placebo-controlled study Kashiwagi A 1Kazuta K 2Goto K 2Yoshida S 2Ueyama E 2Utsuno A 21 Department of Medicine, Shiga University of Medical ScienceShiga, Japan2 Astellas Pharma Inc. JapanTokyo, JapanCorrespondence to: Eiji Ueyama, Astellas Pharma Inc. Japan, 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo 103–8411, Japan. E-mail: eiji.ueyama@astellas.com3 2015 31 7 2014 17 3 304 308 10 2 2014 15 3 2014 09 6 2014 © 2014 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.2014This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.This multicenter, double-blind, placebo-controlled study examined the efficacy and safety of ipragliflozin, a sodium-glucose co-transporter 2 inhibitor, in combination with metformin in Japanese patients with type 2 diabetes mellitus (T2DM). Patients were randomized in a 2: 1 ratio to 50 mg ipragliflozin (n = 112) or placebo (n = 56) once daily for 24 weeks, followed by a 28-week open-label extension in which all patients received 50 or 100 mg ipragliflozin, while continuing metformin. The primary outcome was the change in glycated haemoglobin (HbA1c) from baseline to week 24. HbA1c decreased significantly in the ipragliflozin group (−0.87%; adjusted mean difference from placebo: −1.30%; p < 0.001). The overall incidence of treatment-emergent adverse events was similar in both groups, although pollakiuria and constipation were more common in the ipragliflozin group; thus, ipragliflozin significantly improved glycaemic control and reduced body weight without major safety issues in Japanese patients with T2DM.\n\nipragliflozinJapanesemetforminrandomized controlled trialSGLT2type 2 diabetes\n==== Body\nIntroduction\nIpragliflozin, a sodium-glucose co-transporter 2 inhibitor [1], improves glycaemic control by promoting urinary glucose excretion in patients with type 2 diabetes mellitus (T2DM) [2–6]. Western studies have shown that ipragliflozin in combination with metformin improves glycaemic control with a low incidence of adverse events [7,8]. We conducted a 24-week, randomized, double-blind, placebo-controlled trial with a 28-week open-label extension to confirm the efficacy and safety of adding ipragliflozin to metformin to treat Japanese patients with T2DM.\n\nMethods\nThe methods are described in more detail in the Supporting Information. Patients aged ≥20 years with T2DM (≥12 weeks of duration) being treated with metformin (≥6 weeks), with a HbA1c (National Glycohemoglobin Standardization Program) level of 7.4–9.9% and a body mass index of 20.0–45.0 kg/m2 were eligible. All the patients provided written informed consent before participating in this study.\n\nEligible patients entered a 4-week observation period and a 2-week run-in period in which they received placebo, after which they were randomized to either 50 mg ipragliflozin or placebo (2: 1 ratio) for 24 weeks (treatment period 1; Figure S1, Supporting Information). Patients with HbA1c values that had declined from baseline and were <8.4% at the end of treatment period 1 were allowed to enter an open-label extension of 28 weeks (treatment period 2). In treatment period 2, the ipragliflozin dose could be increased to 100 mg, if HbA1c was ≥7.4% at week 20. Patients were followed up for 4 weeks after study completion or treatment withdrawal. The study was approved by the institutional review board at each participating site. The study was conducted in accordance with Good Clinical Practice, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, as well as local laws and regulations. The study was registered at http://ClinicalTrials.gov (identifier NCT01135433).\n\nThe primary efficacy variable was the change in HbA1c from baseline to week 24. The secondary efficacy variables included body weight, waist circumference, fasting plasma glucose (FPG), fasting serum insulin (FSI), plasma leptin, and adiponectin levels. Homeostasis model assessment of insulin resistance (HOMA-R) and homeostasis model assessment of β-cell function (HOMA-β) were also measured. Safety outcomes included vital signs, physical examination, 12-lead ECG, haematology, biochemistry, urine analysis and adverse events.\n\nResults\nThis study was conducted between May 2010 and November 2011 across 34 sites in Japan. The disposition of patients is summarized in Figure S2. Overall, 56 patients were treated with placebo and 112 with ipragliflozin, of whom 42 and 110, respectively, completed treatment period 1. The baseline characteristics of patients in both groups were generally similar (Table 1) except that patients in the ipragliflozin group had lower FPG and less frequently used hypoglycaemic agents other than metformin than patients in the placebo group before the start of the study. The mean duration of exposure in treatment period 1 was shorter in the placebo group (147.3 ± 41.79 days; mean ± standard deviation) than in the ipragliflozin group (168.3 ± 7.12 days), reflecting the higher discontinuation rate in the placebo group. Of 96 patients in the ipragliflozin group who entered treatment period 2, 90 completed this period.\n\nTable 1 Patient characteristics (full analysis set)\n\n\tPlacebo\tIpragliflozin\t\t\nCharacteristic\t(n = 56)\t(n = 112)\tp-value\t\nSex, n (%)\t\n Male\t33 (58.9)\t66 (58.9)\t1.000*\t\n Female\t23 (41.1)\t46 (41.1)\t\t\nMean age, years (s.d.)\t57.7 (9.24)\t56.2 (10.67)\t0.379†\t\nMean BMI, kg/m2 (s.d.)\t25.47 (3.092)\t25.96 (4.410)\t0.462†\t\nMean duration of diabetes, months (s.d.)\t96.6 (61.93)\t89.9 (68.10)\t0.536†\t\nHistory of hypertension, n (%)\t27 (48.2)\t54 (48.2)\t1.000*\t\nDyslipidaemia, n (%)\t38 (67.9)\t81 (72.3)\t0.591*\t\nMean HbA1c, % (s.d.)\t8.38 (0.738)\t8.25 (0.719)\t0.277†\t\nMean FPG, mmol/l [mg/dl] (s.d.)\t9.70 (1.380) [174.5 (24.84)]\t8.98 (1.663) [161.6 (29.93)]\t0.006†\t\nTreatment with hypoglycaemic drugs other than metformin within 12 weeks before screening, n (%)\t29 (51.8)\t39 (34.8)\t0.045*\t\nBMI, body mass index; FPG, fasting plasma glucose; HbA1c, glycated haemoglobin; s.d., standard deviation.\n\n* Fisher's exact test.\n\n† t-test.\n\nThe changes in HbA1c from baseline to the end of treatment period 1 are presented in Table 2 and Figure S3A. HbA1c decreased in the ipragliflozin group by 0.87% but increased in the placebo group, resulting in a statistically significant adjusted mean difference of −1.30% (95% confidence interval: −1.501, −1.095) between the two groups. At the start of treatment, HbA1c was <8.0% in 32.1% (18/56) and 40.2% (45/112) of patients in the placebo and ipragliflozin groups, respectively; none of the patients in either group had an HbA1c of <7.0%. At week 24, 17.9% (10/56) and 86.6% (97/112) of patients in the placebo and ipragliflozin groups, respectively, achieved HbA1c <8.0%; and 0% (0/56) and 21.4% (24/112) of patients in the placebo and ipragliflozin groups, respectively, achieved HbA1c <7.0%.\n\nTable 2 Changes in efficacy outcomes from baseline to week 24 (treatment period 1)\n\nA. Efficacy variables\t\n\tPlacebo (n = 56)\tIpragliflozin (n = 112)\t\t\t\nVariable\tBaseline\tWeek 24 (LOCF)\tChange from baseline\tBaseline\tWeek 24 (LOCF)\tChange from baseline\tAdjusted mean difference (95% CI)*\tp-value*\t\nHbA1c, %\t8.38 ± 0.738\t8.76 ± 0.912\t0.38 ± 0.703\t8.25 ± 0.719\t7.38 ± 0.712\t−0.87 ± 0.655\t−1.30 (−1.501, −1.095)\t<0.001\t\nFPG, mmol/l [mg/dl]\t9.70 ± 1.380 [174.5 ± 24.84]\t10.29 ± 1.801 [185.2 ± 32.42]\t0.59 ± 1.526 [10.7 ± 27.46]\t8.98 ± 1.663 [161.6 ± 29.93]\t7.75 ± 1.298 [139.5 ± 23.36]\t−1.23 ± 1.484 [−22.2 ± 26.72]\t−2.19 (−2.609, −1.769) [−39.4 (−46.96, −31.85)]\t<0.001\t\nBody weight, kg\t67.51 ± 11.365\t66.88 ± 11.469\t−0.63 ± 1.679\t68.52 ± 13.864\t66.20 ± 13.836\t−2.33 ± 1.798\t−1.69 (−2.256, −1.117)\t<0.001\t\nWaist circumference, cm\t88.95 ± 7.176\t88.48 ± 7.833\t−0.48 ± 2.723\t90.70 ± 10.736\t88.20 ± 10.609\t−2.39 ± 3.720\t−1.83 (−2.927, −0.725)\t0.001\t\nFSI, µU/ml\t6.71 ± 3.826\t6.10 ± 3.268\t−0.61 ± 2.478\t7.91 ± 5.392\t6.13 ± 3.862\t−1.78 ± 3.301\t−0.67 (−1.412, 0.071)\t0.076\t\nHOMA-R\t2.88 ± 1.718\t2.79 ± 1.552\t−0.08 ± 1.137\t3.16 ± 2.249\t2.12 ± 1.421\t−1.04 ± 1.686\t−0.81 (−1.156, −0.460)\t<0.001\t\nHOMA-β\t23.0 ± 13.97\t19.2 ± 11.10\t−3.8 ± 9.83\t31.2 ± 22.97\t31.2 ± 21.26\t0.0 ± 12.21\t5.8 (2.40, 9.20)\t<0.001\t\nAdiponectin, µg/ml\t6.54 ± 3.075\t7.28 ± 3.909\t0.75 ± 1.971\t5.95 ± 2.981\t7.42 ± 3.443\t1.47 ± 1.224\t0.77 (0.287, 1.255)\t0.002\t\nLeptin, ng/ml\t7.22 ± 4.285\t6.83 ± 4.439\t−0.39 ± 1.822\t7.15 ± 4.723\t6.40 ± 4.070\t−0.74 ± 2.074\t−0.37 (−0.961, 0.222)\t0.220\t\nB. Other variables\t\n\tPlacebo (n = 56)\tIpragliflozin (n = 112)\t\t\nVariable\tBaseline\tWeek 24 (LOCF)\tChange from baseline\tBaseline\tWeek 24 (LOCF)\tChange from baseline\tp-value†\t\nTriglycerides, mmol/l [mg/dl]\t1.459 ± 0.6759 [129.3 ± 59.87]\t1.324 ± 0.5944 [117.3 ± 52.64]\t−0.135 ± 0.5369 [−12.0 ± 47.56]\t1.868 ± 1.3485 [165.4 ± 119.44]\t1.529 ± 1.3320 [135.4 ± 117.98]\t−0.339 ± 1.1288 [−30.0 ± 99.99]\t0.203\t\nTC, mmol/l [mg/dl]\t4.920 ± 0.7161 [190.3 ± 27.69]\t5.155 ± 0.7008 [199.3 ± 27.10]\t0.235 ± 0.5031 [9.1 ± 19.45]\t4.786 ± 0.8660 [185.1 ± 33.49]\t5.074 ± 0.9245 [196.2 ± 35.75]\t0.288 ± 0.6571 [11.1 ± 25.41]\t0.593\t\nHDL-C, mmol/l [mg/dl]\t1.485 ± 0.3437 [57.4 ± 13.29]\t1.612 ± 0.4415 [62.3 ± 17.07]\t0.127 ± 0.2289 [4.9 ± 8.85]\t1.385 ± 0.3481 [53.6 ± 13.46]\t1.613 ± 0.4004 [62.4 ± 15.48]\t0.228 ± 0.2263 [8.8 ± 8.75]\t0.007\t\nLDL-C, mmol/l [mg/dl]\t2.939 ± 0.6569 [113.6 ± 25.40]\t3.110 ± 0.6295 [120.3 ± 24.34]\t0.171 ± 0.440 [6.6 ± 17.17]\t2.792 ± 0.8163 [108.0 ± 31.56]\t2.970 ± 0.8767 [114.9 ± 33.90]\t0.179 ± 0.5771 [6.9 ± 22.32]\t0.933\t\nSBP, mmHg\t125.8 ± 16.11\t128.2 ± 12.89\t2.4 ± 13.70\t126.3 ± 13.56\t125.1 ± 13.65\t−1.2 ± 11.70\t0.074\t\nDBP, mmHg\t75.4 ± 8.35\t76.2 ± 9.61\t0.8 ± 8.25\t75.7 ± 10.13\t74.7 ± 10.82\t−1.0 ± 9.08\t0.206\t\nValues are means ± standard deviation except for adjusted mean differences, which are presented with confidence intervals (CIs). HbA1c, glycated haemoglobin; DBP, diastolic blood pressure; FPG, fasting plasma glucose; FSI, fasting serum insulin; HDL-C, high-density lipoprotein cholesterol; HOMA-R, homeostasis model assessment of insulin resistance; HOMA-β, homeostasis model assessment of β-cell function; LDL-C, low-density lipoprotein cholesterol; LOCF, last observation carried forward; SBP, systolic blood pressure; TC, total cholesterol.\n\n* Analysed using ancova with treatment group as a fixed effect and the baseline value as a covariate.\n\n† The difference in change from baseline between the two groups was analysed using Student's t-test.\n\nThe decreases in FPG, body weight, and waist circumference and the increase in plasma adiponectin levels from baseline to week 24 were significantly greater in the ipragliflozin group than in the placebo group (Table 2, Figure S3B, C). The reductions in FSI and leptin levels were not significantly different between the two groups (Table 2). The increase in high-density lipoprotein cholesterol levels was significantly greater in the ipragliflozin group than in the placebo group, but the changes in the other lipid levels were not significantly different between the two groups. Systolic blood pressure decreased slightly in the ipragliflozin group but it was not significantly different between the two groups.\n\nThere was no change in HOMA-β from baseline to week 24 in the ipragliflozin group but it decreased in the placebo group (Table 2); however, these results should be interpreted with caution and re-evaluated using other methods because HOMA-β is a function of FPG and fasting insulin levels. Efficacy outcomes in treatment period 2 are presented in the Supporting Information (Appendix S2 and Figure S4).\n\nTable S1 shows all the treatment-emergent adverse events (TEAEs) occurring in ≥2% of patients in either group in treatment period 1. The TEAEs were distributed similarly in both groups. None of the patients died during the study. TEAEs leading to discontinuation were less frequent in the ipragliflozin group than in the placebo group. Two patients in each group experienced serious TEAEs (cataract and anal abscess in the placebo group, and worsening of diabetes and carpel tunnel syndrome in the ipragliflozin group).\n\nThe incidence rates of pollakiuria and constipation, events possibly related to osmotic diuresis, were higher in the ipragliflozin group than in the placebo group (5.4 vs. 1.8% and 4.5 vs. 1.8%, respectively). Cystitis was less frequent in the ipragliflozin group than in the placebo group and genital infection was not reported. There were no episodes suggestive of hypoglycaemia in either group. Safety outcomes in treatment period 2 are presented in the Supporting Information (Table S2). The total daily dose of metformin at screening did not influence the incidence of TEAEs in either treatment period (Tables S3 and S4).\n\nDiscussion\nThe present study showed that ipragliflozin significantly improved glycaemic control in terms of HbA1c and FPG at 24 weeks and its efficacy was maintained over 52 weeks. Patients treated with ipragliflozin also experienced reductions in body weight and waist circumference, as well as an increase in adiponectin levels. No hypoglycaemic events were reported. The overall incidence of TEAEs was not significantly different between the two groups; however, pollakiuria and constipation were more common in the ipragliflozin group than in the placebo group. The former was probably attributable to drug-induced osmotic diuresis.\n\nOur results support those of Western studies showing the efficacy and safety of ipragliflozin in combination with metformin [7,8]. Likewise, the addition of dapagliflozin or canagliflozin to metformin was reported to reduce HbA1c and body weight without major adverse effects [9,10].\n\nLimitations of the present study include the open-label, non-randomized design of treatment period 2, the increase in ipragliflozin dose in some patients in treatment period 2, and the limited generalization of the study population relative to Japanese patients with T2DM in actual clinical settings.\n\nIn conclusion, adding ipragliflozin to ongoing metformin therapy significantly improved glycaemic control and reduced body weight and waist circumference in Japanese patients with T2DM. Ipragliflozin also had a good safety profile.\n\nThis study was sponsored by Astellas Pharma Inc., Japan. Medical writing and editorial support was funded by Astellas and provided by Dr Nicholas D. Smith and ELMCOM™.\n\nInvestigators were as follows: Hiroki Yokoyama (Jiyugaoka Medical Clinic, Internal Medicine), Hiroaki Seino (Seino Internal Medicine Clinic), Takeshi Osonoi (Naka Kinen Clinic), Hisamoto Kuroda (Green Clinic), Shuichi Fukuda (Wakakusa Clinic), Hideto Ishii (Asano Internal Medicine Clinic, Medical Corporation Yukeikai), Akihiko Okano (Okano Clinic, Medical Corporation Kisyoukai), Madoka Taguchi (Toshiba General Hospital), Mitsutoshi Kato (Kato Clinic of Internal Medicine), Yoshio Ohashi (Tokyo Ekimae-building Clinic), Ikuro Matsuba (Matsuba Clinic), Koutaro Fujimoto (Fujimoto Clinic), Taro Asakura (Tsuruma Kaneshiro Diabetes Clinic), Akira Yamauchi (Medical Corporation Rikeikai Suruga Clinic), Noboru Miyachi (Miyachi Internal Medicine Clinic), Shizuo Kajiyama (Kajiyama Clinic), Toru Takeuchi (Hokusetsu General Hospital, Medical Corporation Senyoukai), Mitsuru Ozaki (Kitade Hospital), Tetsuji Okuno (Nippon Kokan Fukuyama Hospital), Kunihiko Nakamura (Tenjingawa Nakamura Medical Clinic), Katsumi Noda (Clinic Tenjinkita, Medical Corporation Fumidukikai), Makoto Kunisaki (Kunisaki Makoto Clinic, Medical Corporation Shinaikai), Kojiro Ichikawa (Fukutsu Medical Clinic), Hideaki Jinnouchi (Jinnouchi Hospital), Nobuyuki Abe (Abe Diabetes Clinic), Daishiro Yamada (Jiyugaoka Yamada Clinic of Internal Medicine), Masahiro Sugawara (Sugawara Clinic), Toshikatsu Shigihara (Medical Corporation Rikeikai Yamauchi Clinic), Koki Shin (Shin Clinic), Kotaro Kawai (Shimada Municipal Hospital), Emi Kose (Sato Hospital), Sadahiro Sempuku (Sempuku Clinic), Keita Ishii (Chugoku Central Hospital), and Syuichi Otabe (Otabe Internal Medicine Clinic).\n\nConflict of Interest\nA. K. contributed to study design, data analysis, and writing of the manuscript; K. K. contributed to study design, study conduct, data collection and analysis and writing of the manuscript; K. G. contributed to study design, study conduct, data collection and writing of the manuscript; S. Y. contributed to study design, data analysis and writing of the manuscript; E. U. contributed to data analysis and writing of the manuscript; A. U. contributed to study design, data analysis and writing of the manuscript. All authors read and approved the final draft of the manuscript. A. K. serves as a consultant for Astellas Pharma Inc., Japan. K. K., K. G., S. Y., E. U. and A. U. are employees of Astellas Pharma Inc., Japan.\n\nSupporting Information\nAdditional Supporting Information may be found in the online version of this article:\n\nFigure S1. Study design.\n\n Figure S2. Patient disposition.\n\n Figure S3. Time-course of HbA1c (A), FPG (B), and change in BW (C) over 24 weeks.\n\n Figure S4. Time-course of HbA1c over 52 weeks in patients treated with ipragliflozin in both treatment periods according to the ipragliflozin dose in treatment period 2.\n\n Table S1. Treatment-emergent adverse events occurring during the first 24 weeks of the study (treatment period 1).\n\n Table S2. Treatment-emergent adverse events occurring over 52 weeks of treatment with ipragliflozin (treatment periods 1 and 2).\n\n Table S3. Incidence of treatment-emergent adverse events in treatment period 1 according to treatment group and the total daily dose of metformin at screening.\n\n Table S4. Incidence of treatment-emergent adverse events in treatment periods 1 and 2 according to the total daily dose of metformin at screening.\n\n Appendix S1. Supplementary methods (Patients, Study design and treatments, Efficacy and safety outcomes, and Statistical analysis) and references.\n\n Appendix S2. Supplementary results (Efficacy outcomes at week 52 and Safety outcomes at week 52).\n==== Refs\nReferences\n1 Tahara A Kurosaki E Yokono M Pharmacological profile of ipragliflozin (ASP1941), a novel selective SGLT2 inhibitor, in vitro and in vivo Naunyn Schmiedebergs Arch Pharmacol 2012 385 423 436 22139434 \n2 Schwartz SL Akinlade B Klasen S Kowalski D Zhang W Wilpshaar W Safety, pharmacokinetic, and pharmacodynamic profiles of ipragliflozin (ASP1941), a novel and selective inhibitor of sodium-dependent glucose co-transporter 2, in patients with type 2 diabetes mellitus Diabetes Technol Ther 2011 13 1219 1227 21854192 \n3 Smulders RA Zhang W Veltkamp SA No pharmacokinetic interaction between ipragliflozin and sitagliptin, pioglitazone, or glimepiride in healthy subjects Diabetes Obes Metab 2012 14 937 943 22587345 \n4 Veltkamp SA Kadokura T Krauwinkel WJ Smulders RA Effect of ipragliflozin (ASP1941), a novel selective sodium-dependent glucose co-transporter 2 inhibitor, on urinary glucose excretion in healthy subjects Clin Drug Investig 2011 31 839 851 \n5 Kashiwagi A Kazuta K Yoshida S Nagase I Randomized, placebo-controlled, double-blind glycemic control trial of a novel SGLT2 inhibitor ipragliflozin in Japanese patients with type 2 diabetes mellitus J Diabetes Investig 2014 5 382 391 \n6 Kashiwagi A Takinami Y Kazuta K Yoshida S Utsuno A Nagase I Ipragliflozin improves glycemic control in Japanese patients with type 2 diabetes mellitus: the BRIGHTEN study. Diabetol Int 2014; DOI: 10.1007/s13340-014-0164-0 [Epub ahead of print] \n7 Veltkamp SA van Dijk J Collins C van Bruijnsvoort M Kadokura T Smulders RA Combination treatment with ipragliflozin and metformin: a randomized, double-blind, placebo-controlled study in patients with type 2 diabetes mellitus Clin Ther 2012 34 1761 1771 22795925 \n8 Wilding JP Ferrannini E Fonseca VA Wilpshaar W Dhanjal P Houzer A Efficacy and safety of ipragliflozin in patients with type 2 diabetes inadequately controlled on metformin: a dose-finding study Diabetes Obes Metab 2012 15 403 409 23163880 \n9 Bailey CJ Gross JL Pieters A Bastien A List JF Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial Lancet 2010 375 2223 2233 20609968 \n10 Rosenstock J Aggarwal N Polidori D Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes Diabetes Care 2012 35 1232 1238 22492586\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1462-8902",
"issue": "17(3)",
"journal": "Diabetes, obesity & metabolism",
"keywords": "Japanese; SGLT2; ipragliflozin; metformin; randomized controlled trial; type 2 diabetes",
"medline_ta": "Diabetes Obes Metab",
"mesh_terms": "D000368:Aged; D044466:Asians; D001786:Blood Glucose; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005960:Glucosides; D006442:Glycated Hemoglobin A; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin; D008875:Middle Aged; D010919:Placebos; D013876:Thiophenes",
"nlm_unique_id": "100883645",
"other_id": null,
"pages": "304-8",
"pmc": null,
"pmid": "24919820",
"pubdate": "2015-03",
"publication_types": "D016422:Letter; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "21854192;22139434;21877761;25411597;22492586;20609968;22795925;23163880;22587345",
"title": "Ipragliflozin in combination with metformin for the treatment of Japanese patients with type 2 diabetes: ILLUMINATE, a randomized, double-blind, placebo-controlled study.",
"title_normalized": "ipragliflozin in combination with metformin for the treatment of japanese patients with type 2 diabetes illuminate a randomized double blind placebo controlled study"
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"abstract": "To review the current evidence of the safety and efficacy of the use of oral agents for treatment of gestational diabetes (GDM).\n\n\n\nThe use of metformin and glyburide in pregnancy for treatment of GDM has dramatically increased since the early 2000s. Meta-analyses suggest that glyburide may increase the risk for large for gestational (LGA) infants and neonatal hypoglycemia. Conversely, metformin may potentially decrease rates of pregnancy-induced hypertension, LGA, neonatal hypoglycemia, and maternal weight gain. However, recent long-term offspring studies indicate a potential detrimental effect of metformin on fat mass that suggests an effect of such medication on fetal programming. While there have been several novel oral anti-diabetes medications brought to market in the past decade, there is minimal data to guide use and in particular data regarding long-term safety for the exposed offspring of treated women. Most professional societies recommend insulin as first-line treatment of gestational diabetes after failure of lifestyle modification. Both metformin and glyburide cross the placenta and long-term safety data is limited. However, patient satisfaction is substantially higher with use of oral agents, and the current literatures suggest that metformin may reduce several common short-term adverse outcomes related to GDM.",
"affiliations": "Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, The Ohio State University College of Medicine, 395 W 12th Ave., Columbus, OH, USA. matthew.finneran@osumc.edu.;Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, The Ohio State University College of Medicine, 395 W 12th Ave., Columbus, OH, USA.",
"authors": "Finneran|Matthew M|MM|;Landon|Mark B|MB|",
"chemical_list": "D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D005905:Glyburide",
"country": "United States",
"delete": false,
"doi": "10.1007/s11892-018-1093-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1534-4827",
"issue": "18(11)",
"journal": "Current diabetes reports",
"keywords": "Gestational diabetes; Glyburide; Metformin; Oral agents",
"medline_ta": "Curr Diab Rep",
"mesh_terms": "D000284:Administration, Oral; D016640:Diabetes, Gestational; D005260:Female; D005905:Glyburide; D006801:Humans; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D011247:Pregnancy",
"nlm_unique_id": "101093791",
"other_id": null,
"pages": "119",
"pmc": null,
"pmid": "30267230",
"pubdate": "2018-09-28",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "25688819;19295505;11036118;28213841;20542272;7988785;18558430;16579925;29682291;15866611;27752931;16828060;18762242;16021069;23812467;21241070;29959933;17350747;6804245;3552795;12716794;18509858;12082477;16318615;11872206;8569826;23020608;19104375;29995731;15820806;15672015;20350646;29222384;21949222;11836280;28771572;19375570;23524173;29409848;16824464;21631239;25039582;18463376;24326619;24633859;29715355;25822253;21083860;16418696;28619690;19640341;3933984;24807336;25667196",
"title": "Oral Agents for the Treatment of Gestational Diabetes.",
"title_normalized": "oral agents for the treatment of gestational diabetes"
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"abstract": "IgG4-related disease (IgG4-RD) is a fibroinflammatory condition that can affect practically every organ. Although it was first identified in pancreas and salivary glands, major organs like liver, biliary tree, kidney, thyroid glands and lungs are commonly involved, sometimes resulting in organ failure. We describe a case of an 41-year-old man presented with back pain after a rotator cuff injury. A Computed Tomography (CT) revealed incidentally a right lower lobe paravertebral lesion extending across the T5 and T6 vertebral levels and invading into the adjacent pleural surface. The laboratory findings and the CT guided biopsy were inconclusive. Morphological and immunohistochemical findings after a lung biopsy by video-assisted thoracic surgery (VATS) were suggestive to IgG4-related lung disease (IgG4-RLD), which was confirmed with high serum levels of IgG4. This represents the first case of a IgG4-RLD lesion located in the mediastinum and extending to the adjacent pleural surface and vertebrae and should be included in the differential diagnosis of posterior mediastinal masses.",
"affiliations": "Department of Thoracic Surgery, University College London Hospitals (UCLH), London, UK.;Department of Thoracic Surgery, University College London Hospitals (UCLH), London, UK.;Department of Thoracic Surgery, University College London Hospitals (UCLH), London, UK.;Department of Pathology, University College London Hospitals (UCLH), London, UK.;Department of Pathology, University College London Hospitals (UCLH), London, UK.;Department of Thoracic Surgery, University College London Hospitals (UCLH), London, UK.;Department of Thoracic Surgery, University College London Hospitals (UCLH), London, UK.;Department of Thoracic Surgery, University College London Hospitals (UCLH), London, UK.",
"authors": "Stamatopoulos|Alexandros|A|;Patrini|Davide|D|;Koletsis|Efstratios|E|;Borg|Elaine|E|;Khiroya|Reena|R|;Hayward|Martin|M|;Lawrence|David|D|;Panagiotopoulos|Nikolaos|N|",
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"doi": "10.1016/j.rmcr.2016.10.008",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(16)30088-010.1016/j.rmcr.2016.10.008Case ReportIgG4 related lung disease extending to the thoracic vertebrae Stamatopoulos Alexandros aPatrini Davide davide.patrini@uclh.nhs.uka∗Koletsis Efstratios aBorg Elaine bKhiroya Reena bHayward Martin aLawrence David aPanagiotopoulos Nikolaos aa Department of Thoracic Surgery, University College London Hospitals (UCLH), London, UKb Department of Pathology, University College London Hospitals (UCLH), London, UK∗ Corresponding author. Department of Thoracic Surgery, University College London Hospitals (UCLH), 16-18 Westmoreland St., W1G 8PH London, UK.Department of Thoracic SurgeryUniversity College London Hospitals (UCLH)16-18 Westmoreland St.LondonW1G 8PHUK davide.patrini@uclh.nhs.uk07 10 2016 2016 07 10 2016 19 162 165 28 8 2016 25 9 2016 6 10 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).IgG4-related disease (IgG4-RD) is a fibroinflammatory condition that can affect practically every organ. Although it was first identified in pancreas and salivary glands, major organs like liver, biliary tree, kidney, thyroid glands and lungs are commonly involved, sometimes resulting in organ failure. We describe a case of an 41-year-old man presented with back pain after a rotator cuff injury. A Computed Tomography (CT) revealed incidentally a right lower lobe paravertebral lesion extending across the T5 and T6 vertebral levels and invading into the adjacent pleural surface. The laboratory findings and the CT guided biopsy were inconclusive. Morphological and immunohistochemical findings after a lung biopsy by video-assisted thoracic surgery (VATS) were suggestive to IgG4-related lung disease (IgG4-RLD), which was confirmed with high serum levels of IgG4. This represents the first case of a IgG4-RLD lesion located in the mediastinum and extending to the adjacent pleural surface and vertebrae and should be included in the differential diagnosis of posterior mediastinal masses.\n\nKeywords\nIgG4 lung diseaseVertebral invasionLung surgery\n==== Body\n1 Introduction\nImmunoglobulin G4-related disease (also called IgG4-related systemic disease, IgG4-related sclerotic disease, IgG4-positive multiorgan lymphoproliferative syndrome, IgG4-related autoimmune disease, systemic IgG4 plasmatic syndrome, IgG4-associated multifocal systemic fibrosis) was first mentioned as a systemic disease in 2003 by Kamisawa et al. [1], [2], [3]. However, two years later Zen and al firstly reported inflammatory pseudotumors of the lung with high levels of IgG4 [4]. IgG4-RD is usually presented in middle age males as an enlargement or swelling of one or more organs, a fact that raises concern for malignancy [5], [6]. The IgG4-RD's lesion can manifest as pseudotumor and is characterized by dense lymphoplasmacytic inflammation infiltrating within the organs parenchyma, fibrosis, phlebitis and increased levels of IgG4-positive plasma cells [7], [8], [9]. The disease can be present in one or more organs simultaneously or metachronously [9]. The fact that IgG4 lung disease can be asymptomatic (only with abnormal findings on imaging) or can manifest with non-specific clinical symptoms like cough, dyspnea, fever, chest pain and hemoptysis can delay the diagnosis [10], [11]. Herein, we report a case of IgG4-RLD lesion in the mediastinum extending to the adjacent pleural surface and vertebrae which was successfully treated with steroids and rituximab.\n\n2 Illustrative case presentation\nA 41-year-old man working as a chauffeur was presented to his GP with subsequent back pain after rotator cuff injury. Physical examination was unremarkable. In terms of medical history there was no exposure to tuberculosis, he had a 20 pack year history of smoking and there was no relevant surgical history. Although his chest X-ray was normal, the back pain insisted. A MRI of the chest was performed revealing a right paravertebral mass (Fig. 1b). In order to better define the lesion and exclude any other organ involvement, a computed tomography (CT) of thorax and abdomen (with contrast) was performed. The CT confirmed a 3 cm right lower lobe paravertebral soft tissue density mass lesion, invading into the adjacent pleural surface (Fig. 1a). Lymphadenopathy of station 2R and station 4R was noted. An extension across the T5 and T6 vertebral levels with frank destruction of the right T6 costovertebral joint and some enlargement of the right neural foramina were also found. Lungs, pleural spaces, mediastinum, thoracic esophagus and abdomen structures were of normal appearance. In order to specify the histopathology of the lesion, a CT guided biopsy was performed but it was not diagnostic. After multidisciplinary meeting and after written consent was obtained from the patient a right 3 ports VATS biopsy of the mediastinal mass was performed. The postoperative course was unremarkable and the patient was discharged in stable condition on the 3rd postoperative day. With regard to the treatment plan, the patient received initially 60mg of enteric-coated corticosteroids (Prednisolone) that have been gradually tapered after 4 weeks due to patient's steroid-related psychosis. These were replaced with rituximab at a 1 g IV dose every 15 days for a total of two doses. The PET/CT scan performed 3 months later showed that the paravertebral lesion was resolved, with only minimal activity. The visualized part of the musculoskeletal system including the spine showed physiological distribution of fluorodeoxyglucose (FDG). There were no FDG avid lymphadenopathy or other organ involvement.\n\n3 Histology report\nSubsequent histological examination of the specimen was performed. The macroscopic description of the lesion was characterized by multiple fragments of firm dark brown and cream colored nodular tissue measuring 15 × 15 × 3 mm aggregate. It was firmly adhered to the lung and was highly vascularized. With reference to the microscopic description, sections of lung parenchyma and adjacent fibrous tissue showed a dense lymphoplasmacytic infiltration predominantly located in the lung parenchyma (Fig. 2a, b, c). The fibrotic areas adjacent to the lung parenchyma showed a similar but less pronounced lymphoplasmacytic inflammatory infiltration. Within the lung parenchyma there were foci suggested but not diagnostic for obliterative phlebitis (Fig. 2d). The alveolar spaces showed occasional pneumocyte metaplasia with no cytological atypia. Immunohistochemistry performed showed (Fig. 3) that the inflammatory infiltration was predominantly composed of CD138 (Fig. 3a) positive plasma cells along with moderate amount of CD3 positive T-lymphocytes and scattered CD20 positive B-lymphocytes (Fig. 3d). Most plasma cells were noted to express IgG (Fig. 3b) and a large proportion of these plasma cells are also noted to co-express IgG4 (Fig. 3c). The IgG4 positive plasma cells, in areas were noted to amount up to more than 150 cells per high power field and amount up to more than 40% of the total plasma cells present. CK7 and TTF-1 highlight the pulmonary parenchymal architecture which was in areas distorted due to marked inflammatory component (Fig. 3f and g). Serum IgG4 levels were also elevated (3,95 g/l) with overall IgG within range of normality. A diagnosis of IgG4-related lung disease was made considering the lymphoplasmacytic inflammatory infiltrate of the lesion, the laboratory findings and the radiological image.\n\n4 Discussion\nThe spectrum of pathologic entities which can appear in the mediastinum is wide and includes neoplastic and non-neoplastic lesions. Most of the non-neoplastic lesions do not extend across the adjacent anatomical structures. [12], [13], [14]. Although there have been reported IgG4-RD lesions of the mediastinum extending to the adjacent pleural surface, the present case indicates that such a lesion can invade to the adjacent vertebrae [21]. IgG4-related disease (IgG4-RD) is an uncommon fibroinflammatory condition that can affect practically every organ, simultaneously or metachronously [9]. IgG4-RD is usually presented in middle age males as an enlargement or swelling of one or more organs, a fact that raises concern for malignancy [5], [6], [11]. It was first mentioned as a systemic disease in 2003 by Kamisawa et al. [1], [2], [3]. However, the first who reported inflammatory pseudotumors of the lung with high levels of IgG4 were Zen and al [4]. Intrathoracic IgG4-RD lesions usually coexist with autoimmune pancreatitis and retroperitoneal fibrosis [10], [15], [22]. In most cases (75%) it is presenting as an asymptomatic lesion which is found incidentally by abnormal findings on imaging [16], [17]. In some patients can manifest with non-specific clinical symptoms like cough, dyspnea, fever, chest pain and hemoptysis a fact that can delay the diagnosis [10], [11]. Depending on the radiologic findings, IgG4-related lung lesions can be divided into four groups: solid nodular, round-shaped GGO, alveolar interstitial, and bronchovascular [10]. The IgG4-RD's lesion is characterized by dense lymphoplasmacytic inflammation infiltrating within the organ's parenchyma, fibrosis, phlebitis and increased levels of IgG4-positive plasma cells [7], [8], [9]. Moreover, in most cases it is reported an elevation of serum IgG4 concentration (more than 135 mg/dl). Recently there have been diagnostic criteria established for IgG4-RD which include: (a) swelling or masses in one or multiple organs; (b) serum IgG4 concentrations > 135 mg/dl; and (c) histopathologic examination showing infiltration and fibrosis by lymphocytes and plasmatocytes or infiltration of IgG4 + plasma cells ratio of IgG4 + /IgG + cells > 40% and >10 IgG4 plasma cells/high power fields (HPF) [18]. However, diagnostic criteria should be established for each organ that can be affected. With reference to the treatment, glucocorticoids appear to be effective in most of the patients [10]. Treatment with rituximab can be an effective alternative choice [19], [20].\n\nIn conclusion, this case report demonstrated the existence of a posterior mediastinal IgG4-RD lesion extending to the adjacent pleural surface and vertebrae. To the best of our knowledge there has not been reported a similar case. The pathogenesis and the relation with malignancy of this disease are to be further investigated.\n\nConflict of interest\nThe authors declare that there is no conflict of interest regarding the publication of this paper.\n\nFig. 1 (a) CT scan with contrast revealed a 3 cm right lower lobe paravertebral lesion extending across the T5 and T6 vertebral levels and invading into the adjacent pleural surface (arrow) (b) MRI revealing a right paravertebral mass (arrow).\n\nFig. 1Fig. 2 IgG4-related lung disease photomicrographs (a) Heavily inflamed lung parenchyma (Hematoxylin-eosin stain, original magnification,×25) (b,c) Dense lymphoplasmacytic inflammatory infiltrate within the lung parenchyma (Hematoxylin-eosin stain, original magnification in b, ×100; and in c,×200) (d) Focus of obliterative phlebitis (Hematoxylin-eosin stain, original magnification, ×200).\n\nFig. 2Fig. 3 Immunohistochemistry shows that the inflammatory infiltration is predominantly composed of (a) CD138 positive plasma cells along with moderate amount of (b) CD3 positive T-lymphocytes and scattered (c) CD20 positive B-lymphocytes. Most plasma cells were noted to express (d) IgG and a large proportion of these plasma cells are also noted to co-express (e) IgG4. (f) CK7 and (g) TTF-1 highlight the pulmonary parenchymal architecture which was in areas distorted due to marked inflammatory component.\n\nFig. 3\n==== Refs\nReferences\n1 Umehara H. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details Mod. Rheumatol. Jpn. Rheum. Assoc. 22 1 Feb. 2012 1 14 \n2 Kamisawa Terumi Egawa Naoto Nakajima Hitoshi Autoimmune pancreatitis is a systematic autoimmune disease Am. J. Gastroenterol. 98.12 Dec 2003 2811 2812 14687846 \n3 Kamisawa T. Funata N. Hayashi Y. Eishi Y. Koike M. Tsuruta K. Okamoto A. Egawa N. Nakajima H. A new clinicopathological entity of IgG4-related autoimmune disease J. Gastroenterol. 38 10 Jan. 2003 982 984 14614606 \n4 Zen Y. Kitagawa S. Minato H. Kurumaya H. Katayanagi K. Masuda S. Niwa H. Fujimura M. Nakanuma Y. IgG4-positive plasma cells in inflammatory pseudotumor (plasma cell granuloma) of the lung Hum. Pathol. 36 7 Jul. 2005 710 717 16084938 \n5 Khosroshahi A. Stone J.H. A clinical overview of IgG4-related systemic disease Curr. Opin. Rheumatol. 23 1 2011 57 66 21124086 \n6 Zen Y. Nakanuma Y. IgG4-related disease: a cross-sectional study of 114 cases Am. J. Surg. Pathol. 34 12 Dec. 2010 1812 1819 21107087 \n7 Chen G. Cheuk W. Chan J.K. IgG4-related sclerosing disease: a critical appraisal of an evolving clinicopathologic entity Zhonghua bing li xue za zhi Chin. J. Pathol. 39 12 Dec. 2010 851 868 \n8 Masaki Y. Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders Ann. Rheum. Dis. 68 8 Aug. 2009 1310 1315 18701557 \n9 Guma M. Firestein G.S. IgG4-related diseases Best Pract. Res. Clin. Rheum. 26 2012 425 438 \n10 Zen Y. Inoue D. kitao A. Onodera M. Abo H. Miyayama S. Gabata T. Matsui O. IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases Am. J. Surg. Pathol. 33 2009 1886 1893 19898222 \n11 Inoue D. Zen Y. Abo H. Immunoglobulin G4-related lung disease: CT findings with pathologic correlations Radiology 251 2009 260 270 19221056 \n12 Juanpere S. Cañete N. Ortuño P. Martínez S. Sanchez G. Bernado L. A diagnostic approach to the mediastinal masses Insights Imaging 4 1 2013 29 52 23225215 \n13 Davis R.D. Oldham H.N. Sabiston D.C. Primary cysts and neoplasms of the mediastinum: recent changes in clinical presentation, methods of diagnosis, management, and results Ann. Thorac. Surg. 44 1987 229 237 2820323 \n14 Macchiarini P. Ostertag H. Uncommon primary mediastinal tumours Lancet Oncol. 5 2004 107 118 14761815 \n15 Shigemitsu H. Koss M.N. IgG4-related interstitial lung disease: a new and evolving concept Curr. Opin. Pulm. Med. 15 2009 513 516 19550328 \n16 Umeda M. Fujikawa K. Origuchi T. Tsukada T. Kondo A. Tomari S. Inoue Y. Soda H. Nakamura H. Matsui S. Kawakami A. A case of IgG4-related pulmonary disease with rapid improvement Mod. Rheumatol. Jpn. Rheum. Assoc. 22 6 Nov. 2012 919 923 \n17 Lighaam L. Aalberse R. Rispens T. IgG4-Related fibrotic diseases from an immunological perspective: regulators out of control? Int. J. Rheumatol. 2012 2012 789164 22701488 \n18 Umehara H. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011 Mod. Rheumatol. Jpn. Rheum. Assoc. 22 1 Feb. 2012 21 30 \n19 Khosroshahi A. Bloch D.B. Deshpande V. Stone J.H. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease Arthritis Rheum. 62 6 Jun. 2010 1755 1762 20191576 \n20 Khosroshahi A. Carruthers M.N. Deshpande V. Unizony S. Bloch D.B. Stone J.H. Rituximab for the treatment of IgG4-related disease: lessons from 10 consecutive patients Medicine 91 1 Jan. 2012 57 66 22210556 \n21 Fei Y. Shi J. Lin W. Chen Y. Feng R. Wu Q. Gao X. Xu W. Zhang W. Zhang X. Zhao Y. Zeng X. Zhang F. Intrathoracic involvements of immunoglobulin G4-related sclerosing disease Medicine 94 50 Dec. 2015 e2150 26683924 \n22 Palazzo E. Palazzo C. Palazzo M. IgG4-related disease. Joint, bone, spine Rev. Du. Rhum. 81 1 2013 27 31\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "19()",
"journal": "Respiratory medicine case reports",
"keywords": "IgG4 lung disease; Lung surgery; Vertebral invasion",
"medline_ta": "Respir Med Case Rep",
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"pages": "162-165",
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"pmid": "27766198",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
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"title": "IgG4 related lung disease extending to the thoracic vertebrae.",
"title_normalized": "igg4 related lung disease extending to the thoracic vertebrae"
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"abstract": "Chronic infection by hepatitis C virus (HCV) is one of the main risk factors for the development of liver cirrhosis and hepatocellular carcinoma. However, the emergence of hepatocellular carcinoma (HCC) in non-cirrhotic HCV patients, especially after sustained virological response (SVR) is an unusual event. Recently, it has been suggested that HCV genotype 3 may have a particular oncogenic mechanism, but the factors involved in these cases as well as the profile of these patients are still not fully understood. Thus, we present the case of a non-cirrhotic fifty-year-old male with HCV infection, genotype 3a, who developed HCC two years after treatment with pegylated-interferon and ribavirin, with SVR, in Brazil.",
"affiliations": "Universidade Federal de Ciências da Saúde de Porto Alegre, RS, Brazil.;Universidade Federal de Ciências da Saúde de Porto Alegre, RS, Brazil.;Universidade Federal de Ciências da Saúde de Porto Alegre, RS, Brazil.;Universidade Federal de Ciências da Saúde de Porto Alegre, RS, Brazil.;Universidade Federal de Ciências da Saúde de Porto Alegre, RS, Brazil.",
"authors": "Mattos|Angelo Alves de|AA|;Marcon|Patrícia dos Santos|Pdos S|;Araújo|Fernanda Schild Branco de|FS|;Coral|Gabriela Perdomo|GP|;Tovo|Cristiane Valle|CV|",
"chemical_list": "D000998:Antiviral Agents; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a",
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"fulltext": "\n==== Front\nRev Inst Med Trop Sao PauloRev. Inst. Med. Trop. Sao PaulorimtspRevista do Instituto de Medicina Tropical de São Paulo0036-46651678-9946Instituto de Medicina Tropical 10.1590/S0036-46652015000600011Case ReportHEPATOCELLULAR CARCINOMA IN A NON-CIRRHOTIC PATIENT WITH SUSTAINED\nVIROLOGICAL RESPONSE AFTER HEPATITIS C TREATMENT Carcinoma hepatocelular em paciente não cirrótico com resposta\nvirológica sustentada após tratamento para hepatite C de MATTOS Angelo Alves MARCON Patrícia dos Santos de ARAÚJO Fernanda Schild Branco CORAL Gabriela Perdomo TOVO Cristiane Valle Post-Graduation Course: Hepatology at Universidade Federal de Ciências da\nSaúde de Porto Alegre (UFCSPA), RS, BrazilCorrespondence to: Patrícia dos Santos Marcon, Prof. Annes Dias 295,\nHospital Santa Clara, 7º andar, Serviço de Gastroenterologia, Complexo Hospitalar\nSanta Casa, Centro Histórico, 90020-090 Porto Alegre, RS, Brazil. Telephone number:\n+55 (51) 95115656. E-mail: patekapel@hotmail.comNov-Dec 2015 Nov-Dec 2015 57 6 519 522 30 12 2014 01 4 2015 This is an open-access article distributed under the terms of the Creative\nCommons Attribution LicenseChronic infection by hepatitis C virus (HCV) is one of the main risk factors for the\ndevelopment of liver cirrhosis and hepatocellular carcinoma. However, the emergence\nof hepatocellular carcinoma (HCC) in non-cirrhotic HCV patients, especially after\nsustained virological response (SVR) is an unusual event. Recently, it has been\nsuggested that HCV genotype 3 may have a particular oncogenic mechanism, but the\nfactors involved in these cases as well as the profile of these patients are still\nnot fully understood. Thus, we present the case of a non-cirrhotic fifty-year-old\nmale with HCV infection, genotype 3a, who developed HCC two years after treatment\nwith pegylated-interferon and ribavirin, with SVR, in Brazil.\n\nA infecção crônica pelo vírus da hepatite C é um dos principais fatores de risco para\no desenvolvimento de cirrose hepática e carcinoma hepatocelular. Entretanto, o\nsurgimento do carcinoma hepatocelular em pacientes portadores de hepatite C na\nausência de cirrose, especialmente após o tratamento e a obtenção de resposta\nvirológica sustentada, é um evento incomum. Recentemente tem sido sugerido que o\ngenótipo 3 do vírus da hepatite C possa ter um mecanismo oncogênico particular, mas\ntodos os fatores envolvidos nestes casos, assim como o perfil destes pacientes, ainda\nnão estão totalmente esclarecidos. Deste modo, apresentamos o caso de um paciente\nmasculino de 50 anos de idade, com infecção pelo vírus da hepatite C genótipo 3a, não\ncirrótico, que desenvolveu carcinoma hepatocelular dois anos após ter atingido\nresposta virológica sustentada com o tratamento com interferon peguilado e\nribavirina.\n\nHepatocellular carcinomaHepatitis CGenotype 3Sustained virological responseNon-cirrhotic liver\n==== Body\nINTRODUCTION\nChronic infection by hepatitis C virus (HCV) is one of the main risk factors for liver\ncirrhosis and hepatocellular carcinoma (HCC) worldwide6\n,\n11\n,\n14. In recent decades, the incidence of HCC seems\nto be changing, especially in areas previously considered at low prevalence. This seems\nlikely to be associated with the increase in the number of cases of HCV-related\ncirrhosis in these regions5\n,\n9. In Brazil, about 54% of HCC are associated to\nHCV-related cirrhosis, according to a national survey5. In contrast with the hepatitis B virus (HBV) infection, the emergence of\nHCC in non-cirrhotic HCV patients is an unusual event9\n,\n10. In chronic HCV patients, the risk of HCC is\nproportionate to the liver fibrosis stage, with an annual rate of 0.5-10% of developing\nHCC in a cirrhotic liver, according to the region studied11\n,\n14\n,\n17. \n\nThe introduction of interferon (IFN) and ribavirin (RBV) in the management of HCV\nprovided a significant advance in the attempt to modify the natural course of liver\ndisease in patients with chronic HCV infection17.\nSeveral studies have examined the effect of this therapy on the incidence of HCC14\n,\n15\n,\n17\n,\n20. Current data indicate that patients treated\nwith antiviral therapy, who achieve sustained virological response (SVR) have a\nreduction in all-cause mortality, including progression of liver disease9\n,\n14. Furthermore, patients with SVR present an\nimportant improvement in hepatic inflammation and fibrosis, and consequently a reduction\nin the risk of developing HCC 3\n,\n14\n,\n17\n,\n18. However, the presence of HCC in non-cirrhotic\npatients with SVR is possible and Asia practically monopolizes existing accounts,\nespecially Japan1\n,\n12\n,\n16. The factors involved in these cases as well\nas the profile of these patients are still not fully understood. Thus, we deem it\nrelevant to describe an unusual case of HCC in a non-cirrhotic patient after HCV\ntreatment with pegylated IFN (pegIFN) and RBV, years after SVR, in Brazil.\n\nCASE REPORT\nA Caucasian fifty-year-old male had HCV infection diagnosis in routine exams in 2007.\nFurther evaluation showed a genotype 3a, with a viral load of 156.789 IU/mL by HCV-RNA\nquantitative PCR (real time - polymerase chain reaction, reference value < 12 UI/mL)\n, baseline gamma-glutamyl transferase (gGT) levels of 90 U/L (normal value: 8-61 U/L)\nand elevated aminotransferase levels - serum alanine aminotransferase (ALT) 110 U/L\n(normal value: 7-56 U/L) and aspartate aminotransferase (AST) 192 (normal value: 5-40\nU/L). The additional laboratory exams showed normal liver function markers (albumin,\nbilirubin and prothrombin), negative serum markers for HBV, absence of abnormalities in\nblood glucose values and normal hematologic counts. The physical examination revealed a\neutrophic patient and no signs of chronic liver disease. The abdominal ultrasound (US)\nwas normal and without signs of advanced chronic liver disease or portal hypertension.\nThere were no reports of comorbidities like diabetes, obesity, other infections, or\nalcohol abuse. Liver biopsy was performed and considered representative. A total of two\nfragments and 11 portal tracts were analyzed; the length and width of the greatest\nfragment was 1.0 x 0.3 cm, respectively. This biopsy showed chronic hepatitis with\nintense interface activity and a few fibrous septa (Fig.\n1- A and B), classified as Metavir2\nA3-F2. There was no hepatic steatosis or other relevant findings, like siderosis, small\ncell change, or even dysplasia. As soon as possible, he began the treatment with pegIFN\nand RBV for six months, achieving SVR and normalizing ALT and AST. He remained with\nnegative HCV-RNA evaluated by real-time PCR, normal aminotransferases, and asymptomatic\nfor two years, when nonspecific abdominal pain appeared, without other symptoms or alarm\nsignals. A new abdominal US showed portal vein thrombosis. Thrombophilia was ruled out,\nand an abdominal CT scan was performed. Surprisingly, it demonstrated a portal vein\nthrombosis with arterial enhancement, associated with nonspecific hypodense nodules in\nthe right hepatic lobe (Fig. 2). The magnetic\nresonance imaging evidenced the same characteristics of portal thrombosis, besides\nseveral nodular images of different sizes, the largest one with 1.8 cm, without typical\nvascular pattern6. The alpha-fetoprotein level\nwas 4.5U/L. We decided to do a tomography to guide a biopsy of the lesion in the right\nlobe and a biopsy away of the lesion, in the left hepatic lobe. The biopsy evidenced a\nmoderately differentiated HCC with trabecular pattern (Fig. 1 - C and D). There was no vessel or stromal invasion documented in the\nsample. The non-tumorous liver tissue remained without evidence of cirrhosis - Metavir\nA1-F1 (Fig. 1 - E and F). Further to this, we\nperformed immunohistochemistry to confirm the histogenesis of this neoplasia, that\nshowed positivity for typical antibodies related to hepatocellular carcinoma10 which were hepatocyte-specific antigen (HSA) and\ncanalicular staining of: pCEA, CD10 and Villin (Fig.\n1 - G and H). These features, associated with the presence of vascularization\nin the portal thrombus, led to the conclusion that the portal thrombosis corresponded to\nmacrovascular tumor invasion and Sorafenib was prescribed. Despite this, the patient\ndeveloped jaundice, signs of portal hypertension, with ascites and variceal bleeding,\nprogressing to death in four months. \n\n\nFig. 1 \n- Histological images. A - Pretreatment liver biopsy:\ninterface activity (hematoxylin-eosin, 100x). B - Pretreatment\nliver biopsy: fibrous septa (Masson's trichrome, 100x). C - Liver\nsection from the tumor: moderately differentiated HCC (hematoxylin-eosin, 100\nx). D - Liver section from the tumor: moderately differentiated\nHCC in detail (hematoxylin-eosin, 400x). E - Post treatment liver\nbiopsy: non-tumoral tissue with mild activity (hematoxylin-eosin, 40 x).\nF - Post treatment liver biopsy: portal fibrosis (Masson's\ntrichrome, 40x). G - HCC, immunohistochemistry:\nhepatocyte-specific antigen (400 x). H - HCC,\nimmunohistochemistry: CD 10, canalicular staining (400 x).\n\n\n\n\nFig. 2 \n- Abdominal computadorized tomography scan in different sections:\nnote the portal vein thrombosis and nonspecific hypodense nodules in the right\nhepatic lobe.\n\n\n\nDISCUSSION\nThe incidence of HCC in patients without advanced hepatic fibrosis, years after\ntreatment for HCV and with SVR, has been reported in Asian patients, particularly in\nJapanese ones1\n,\n9\n,\n12\n,\n18, where HCV infection is endemic and the\nprevalence of HCC is high. In the Occident, we found few similar cases published in the\nliterature3\n,\n19, one of the reasons why we deem important to\npresent this case. \n\nIn the United States, when LOK et al.11 assessed the role of maintaining reduced doses of pegIFN in patients with\nchronic HCV liver disease, in order to prevent complications, they demonstrated the\nexistence of HCC in patients without cirrhosis, but emphasizing the importance of the\npresence of advanced fibrosis. The case presented here is relevant since it shows an HCC\nthat affects a patient with HCV and without advanced fibrosis, two years after SVR, and\nwith documented fibrosis regression outside the tumor area. Previous studies have\nstrongly suggested that SVR can minimize the histological and clinical deterioration,\nresulting in improvement of liver histology7. The\nbenefits of successful antiviral therapy in chronic HCV has been recently reaffirmed by\nMOON et al.13 in a study that\nretrospectively reviewed 463 patients who underwent pegIFN and RBV therapy, where\npatients without cirrhosis and with SVR had a significant lower risk of progression to\ncirrhosis compared to non-SVR and, moreover, SVR was related to reduction in the risk of\nHCC development. As in the present case, MOON et al.13 also found two patients with SVR and no evidence\nof cirrhosis before HCC diagnosis. However, the exclusion of cirrhosis in these two\npatients was made based on clinical criteria, which is not a reliable method to assess\nif advanced fibrosis has already been detected histologically. In the presented case,\ntwo biopsies at different times, including the diagnosis of HCC, have pointed to the\nabsence of significant fibrosis.\n\nIt is suggested that the risk factors for the development of HCC in the absence of\nadvanced fibrosis in HCV pretreatment patients are male gender, advanced age,\npersistently elevated aminotransferases, hepatic steatosis, diabetes, and alcohol\nabuse3\n,\n9. The frequent association of HCV, especially\ngenotype 3, with steatosis deserves mention in this context, as this parameter\ncorrelates with HCC8. In this case, despite being\nmale and genotype 3, the patient had none of the other afore mentioned risk factors,\nincluding absence of steatosis on pretreatment and tumor biopsies.\n\nIn HCV eradicated patients, risk factors for the development of HCC remain not entirely\nclear. SATO et al.17 reported\nthat in their experience, men with documented advanced liver fibrosis, and low levels of\nserum albumin and elevated pretreatment alpha-fetoprotein, are more likely to develop\nHCC within five years of HCV eradication. All these findings suggest a possible more\nadvanced liver disease as the basis for development of HCC; however, these features\ncuriously did not occur in the present case.\n\nRecently, other risk factors for the development of HCC, independent of the degree of\nhepatic fibrosis, have been studied. HUANG et al.9, in a prospective cohort of 642 individuals, found an interesting\nassociation between high baseline gGT levels before IFN-based anti-HCV therapy using a\ncut-off value of 75U/L and development of HCC in non-cirrhotic patients with SVR, but\nthe pathophysiological mechanism of this association remains unclear. Furthermore, the\npossibility that the genotype 3 HCV might have a particular oncogenic process has been\nconsidered, possibly by means of alteration in chromosome 10, causing disturbances in\ntumor suppression and increasing the incidence of HCC, which could remain even after HCV\nclearance and independent of the fibrosis degree8. In the present case, the hypothesis that genotype 3 may have an important\nrole in the emergence of HCC should be considered, as well as high baseline gGT levels,\nespecially in this context of lack of significant fibrosis.\n\nIn current literature, recommendations for monitoring and surveillance of these patients\nwith chronic HCV without cirrhosis are scanty and conflicting. The American Association\nfor the Study of Liver Diseases4 describes that\nthe benefit of maintaining surveillance in patients with HCV and Metavir F3 is\nuncertain, not routinely recommended. On the other hand, the European Association for\nthe Study of the Liver6 recommended that patients\nwith chronic HCV and Metavir F3 should be included in surveillance programs, since the\ntransition to cirrhosis cannot be accurately defined. These same authors also recommend\nmaintaining surveillance in patients treated for HCV who have advanced fibrosis, even\nafter SVR.\n\nIn conclusion, the possibility of developing HCC in patients without advanced fibrosis\nsuggests the existence of other factors that are still unclear in the pathogenesis of\nHCV, raising questions regarding the need to perform the follow-up of these patients,\neven after SVR. The new evidence that HCV genotype 3 has become a problem in hepatitis C\npatients either by the response rate to IFN-free therapy regimens or the possibility of\nindependent mechanisms of carcinogenesis8, a\npoint that needs further studies. \n\nABBREVIATIONS\nHCV - Hepatitis C virus\n\nHCC - Hepatocellular carcinoma\n\nHBV - Hepatitis B virus\n\nIFN - Interferon\n\nRBV - Ribavirin\n\nSVR - Sustained virologic response\n\npegIFN - Pegylated interferon\n\nPCR - Polymerase chain reaction\n\ngGT - Gamma-glutamyl transferase\n\nALT - Alanine aminotransferase \n\nAST - Aspartate aminotransferase\n\nUS - Ultrasound\n\nHSA - Hepatocyte-specific antigen\n==== Refs\nREFERENCES\n1 Al Nozha OM Al Ashgar H Khan M Al Mana H Hepatocellular carcinoma in the absence of liver cirrhosis in a\ntreated hepatitis C virus patient Ann Saudi Med 2009 29 235 236 19448362 \n2 Bedossa P Poynard T An algorithm for the grading of activity in chronic hepatitis\nC The METAVIR Cooperative Study Group. Hepatology 1996 24 289 293 \n3 Bertolini E Bassi F Fornaciari G Development of hepatocellular carcinoma in a non-cirrhotic, long-term\nresponder to antiviral therapy, chronic hepatitis C patients: what kind of\nsurveillance? Ann Gastroenterol 2013 26 80 83 24714548 \n4 Bruix J Sherman M American Association for the Study of Liver Diseases Management of hepatocellular carcinoma: an update Hepatology 2011 53 1020 1022 21374666 \n5 Carrilho FJ Kikuchi L Branco F Gonçalves CS Mattos AA Brazilian HCC Study Group Clinical and epidemiological aspects of hepatocellular carcinoma in\nBrazil Clinics 2010 65 1285 1290 21340216 \n6 European Association for the Study of the Liver, European Organization for\nResearch and Treatment of Cancer EASL-EORTC clinical practice guidelines: management of hepatocellular\ncarcinoma J Hepatol 2012 56 908 943 22424438 \n7 George SL Bacon BR Brunt EM Mihindukulasuriya KL Hoffmann J Di Bisceglie AM Clinical, virologic, histologic, and biochemical outcomes after\nsuccessful HCV therapy: a 5-year follow-up of 150 patients Hepatology 2009 49 729 738 19072828 \n8 Goossens N Negro F Is genotype 3 of the hepatitis C virus the new\nvillain? Hepatology 2014 59 2403 2412 24155107 \n9 Huang CF Yeh ML Tsai PC Hsieh MH Yang HL Hsieh MY Baseline gamma-glutamyl transferase levels strongly correlate with\nhepatocellular carcinoma development in non-cirrhotic patients with successful\nhepatitis C virus eradication J Hepatol 2014 61 67 74 24613362 \n10 Karabork A Kaygusuk G Ekinci C The best immunohistochemical panel for differentiating hepatocellular\ncarcinoma from metastatic adenocarcinoma Pathol Res Pract 2010 206 572 577 20400233 \n11 Lok AS Seeff LB Morgan TR Di Bisceglie AM Sterling RK Curto TM Incidence of hepatocellular carcinoma and associated risk factors in\nhepatitis C-related advanced liver disease Gastroenterology 2009 136 138 148 18848939 \n12 Miyano S Togashi H Shinzawa H Sugahara K Matsuo T Takeda Y Case report: occurrence of hepatocellular carcinoma 4 5 years after successful treatment with virus clearance for chronic hepatitis\nC. J Gastroenterol Hepatol 1999 14 928 930 10535477 \n13 Moon C Jung KS Kim do Y Baatarkhuu O Park JY Kim BK Lower incidence of hepatocellular carcinoma and cirrhosis in hepatitis\nC patients with sustained virological response by pegylated interferon and\nribavirin Dig Dis Sci 2015 60 573 581 25236421 \n14 Morgan RL Baack B Smith BD Yartel A Pitasi M Falck-Ytter Y Eradication of hepatitis C virus infection and the development of\nhepatocellular carcinoma: a meta-analysis of observational studies Ann Intern Med 2013 158 329 337 23460056 \n15 Ng V Saab S Effects of a sustained virologic response on outcomes of patients with\nchronic hepatitis C Clin Gastroenterol Hepatol 2011 9 923 930 21699815 \n16 Nojiri K Sugimoto K Shiraki K Kusagawa S Tanaka J Beppu T Development of hepatocellular carcinoma in patients with chronic\nhepatitis C more than 10 years after sustained virological response to interferon\ntherapy Oncol Lett 2010 1 427 430 22966320 \n17 Sato A Sata M Ikeda K Kumada T Izumi N Asahina Y Clinical characteristics of patients who developed hepatocellular\ncarcinoma after hepatitis C virus eradication with interferon therapy: current\nstatus in Japan Intern Med 2013 52 2701 2706 24334571 \n18 Sewell JL Stick KM Monto A Hepatocellular carcinoma after sustained virologic response in\nhepatitis C patients without cirrhosis on a pretreatment liver\nbiopsy Eur J Gastroenterol Hepatol 2009 21 225 229 19212213 \n19 Tabibian JH Landaverde C Winn J Geller SA Nissen NN Hepatocellular carcinoma in a hepatitis C patent with sustained viral\nresponse and no fibrosis Ann Hepatol 2009 8 64 67 19221537 \n20 Zhang CH Xu GL Jia WD Li JS Ma JL Ge YS Effects of interferon treatment on development and progression of\nhepatocellular carcinoma in patients with chronic virus infection: a meta-analysis\nof randomized controlled trials Int J Cancer 2011 129 1254 1264 21710498\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0036-4665",
"issue": "57(6)",
"journal": "Revista do Instituto de Medicina Tropical de Sao Paulo",
"keywords": null,
"medline_ta": "Rev Inst Med Trop Sao Paulo",
"mesh_terms": "D000998:Antiviral Agents; D006528:Carcinoma, Hepatocellular; D004359:Drug Therapy, Combination; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D016898:Interferon-alpha; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; D016896:Treatment Outcome",
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"pages": "519-22",
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"pmid": "27049708",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21374666;19072828;19221537;10535477;25236421;24334571;18848939;24613362;20400233;21699815;23460056;19448362;8690394;22966320;21710498;21340216;24155107;24714548;19212213;22424438",
"title": "HEPATOCELLULAR CARCINOMA IN A NON-CIRRHOTIC PATIENT WITH SUSTAINED VIROLOGICAL RESPONSE AFTER HEPATITIS C TREATMENT.",
"title_normalized": "hepatocellular carcinoma in a non cirrhotic patient with sustained virological response after hepatitis c treatment"
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"abstract": "A 24-year-old man was referred to our hospital emergency department due to a sudden onset of convulsions after drinking. On arrival he presented status epilepticus and was managed by artificial ventilation. He had no brainstem signs or meningeal irritation. Head MRI showed an old infarction-like lesion in the left occipital lobe, but no abnormal signals on diffusion-weighted images. The patient showed acute rhabdomyolysis (CK 18,000 IU/l) and renal failure, and hemodialysis was started. On 18 day after admission, he was transferred to our department with mild proximal limb muscle weakness and bilateral sensorineural hearing impairment. Electroencephalography demonstrated diffuse intermittent slow wave activities. We suspected a mitochondrial disease because of a significant increase in the lactate/pyruvate ratio (24.1) in the spinal fluid, and identified A3243G mutations in mitochondrial DNA (heteroplasmy 20%) in peripheral white blood cells. We diagnosed his illness as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). This is a rare case presenting an acute onset of rhabdomyolysis following alcohol intake related to A3243G mitochondrial mutation without preceding stroke-like episodes.",
"affiliations": "Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University.",
"authors": "Yokoyama|Jun|J|;Yamaguchi|Hiroo|H|;Shigeto|Hiroshi|H|;Uchiumi|Takeshi|T|;Murai|Hiroyuki|H|;Kira|Jun-ichi|J|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.5692/clinicalneurol.cn-000834",
"fulltext": null,
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"issn_linking": "0009-918X",
"issue": "56(3)",
"journal": "Rinsho shinkeigaku = Clinical neurology",
"keywords": null,
"medline_ta": "Rinsho Shinkeigaku",
"mesh_terms": "D006801:Humans; D017241:MELAS Syndrome; D008297:Male; D017240:Mitochondrial Myopathies; D064847:Multimodal Imaging; D012206:Rhabdomyolysis; D055815:Young Adult",
"nlm_unique_id": "0417466",
"other_id": null,
"pages": "204-7",
"pmc": null,
"pmid": "26960270",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A case of rhabdomyolysis after status epilepticus without stroke-like episodes in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.",
"title_normalized": "a case of rhabdomyolysis after status epilepticus without stroke like episodes in mitochondrial myopathy encephalopathy lactic acidosis and stroke like episodes"
} | [
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"companynumb": "JP-UCBSA-2017037483",
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"abstract": "Uncontrolled cancer pain is a significant problem in palliative medicine. Opioids are often first-line treatment that increase risks of analgesic tolerance and hyperalgesia. Topical ketamine with other adjuvant pain medications is an often-overlooked treatment, yet may be most effective in difficult-to-treat cancer pain. We report a case series of hospice patients with uncontrolled cancer pain who were suboptimally treated with opioids and nerve blocks, whose symptoms responded to topical ketamine with other adjuvants. We review the pronociceptive properties of opioids and how topical multimodal treatment of cancer pain can be more effective than standard opioids, other topical adjuvant medications, and nerve blocks. We discuss the shortcomings of the World Health Organization (WHO) stepladder for the treatment of cancer pain and suggest an adjuvant treatment algorithm, directing physicians to appropriate adjuvant pain agents based on pain type and distinct receptor actions. This is a retrospective case series of patients who responded to topical multimodal pain treatment with implementation of findings into an addendum to the WHO stepladder. Subjects were from a case series of community-based hospice patients with previously uncontrolled cancer pain. Measurement was made by self-report of pain levels using the 10-point numeric pain rating scale. Patients' pain was controlled with topical adjuvant medications with return to previously lost function and prevention of otherwise escalating opioid dosing. These patient cases reveal how ketamine-based topical treatment for cancer pain can be more effective than standard opioids, other topical adjuvant medications, and nerve blocks with no noted side effects and observed reduction in opioid consumption.",
"affiliations": "Department of Medicine, The Medical Team Hospice, Livonia, Michigan, USA.;Department of Public Health and Community Medicine, Pain Research, Education and Policy Program, Tufts University School of Medicine, Boston, Massachusetts, USA.;Department of Public Health and Community Medicine, Pain Research, Education and Policy Program, Tufts University School of Medicine, Boston, Massachusetts, USA.",
"authors": "Winegarden|Jennifer A|JA|;Carr|Daniel B|DB|;Bradshaw|Ylisabyth S|YS|",
"chemical_list": "D000700:Analgesics; D000701:Analgesics, Opioid; D007649:Ketamine",
"country": "United States",
"delete": false,
"doi": "10.1089/jpm.2019.0618",
"fulltext": "\n==== Front\nJ Palliat Med\nJ Palliat Med\njpm\nJournal of Palliative Medicine\n1096-6218 1557-7740 Mary Ann Liebert, Inc., publishers 140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA \n\n10.1089/jpm.2019.0618\n10.1089/jpm.2019.0618\nOriginal Articles\nTopical Ketamine with Other Adjuvants: Underutilized for Refractory Cancer Pain? A Case Series and Suggested Revision of the World Health Organization Stepladder for Cancer Pain\nWinegarden et al.Cancer Pain Topical Ketamine Adjuvants AlgorithmWinegarden Jennifer A. DO, MS1 Carr Daniel B. MD2 Bradshaw Ylisabyth S. DO, MS2 1 Department of Medicine, The Medical Team Hospice, Livonia, Michigan, USA.\n2 Department of Public Health and Community Medicine, Pain Research, Education and Policy Program, Tufts University School of Medicine, Boston, Massachusetts, USA.\nAddress correspondence to: Jennifer A. Winegarden, DO, MS, The Medical Team Hospice, 17197 N. Laurel Park Drive, Suite 521, Livonia, MI 48152, USA jwinegarden@medteam.com\n01 9 2020 September 2020\n19 8 2020 \n19 8 2020 \n23 9 1167 1171\n28 1 2020 Accepted January 28, 2020© Jennifer A. Winegarden, Daniel B. Carr, and Ylisabyth S. Bradshaw, 2020; Published by Mary Ann Liebert, Inc.2020Jennifer A. Winegarden, Daniel B. Carr, and Ylisabyth S. BradshawThis Open Access article is distributed under the terms of the Creative Commons 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.Background: Uncontrolled cancer pain is a significant problem in palliative medicine. Opioids are often first-line treatment that increase risks of analgesic tolerance and hyperalgesia. Topical ketamine with other adjuvant pain medications is an often-overlooked treatment, yet may be most effective in difficult-to-treat cancer pain.\n\nObjective: We report a case series of hospice patients with uncontrolled cancer pain who were suboptimally treated with opioids and nerve blocks, whose symptoms responded to topical ketamine with other adjuvants. We review the pronociceptive properties of opioids and how topical multimodal treatment of cancer pain can be more effective than standard opioids, other topical adjuvant medications, and nerve blocks. We discuss the shortcomings of the World Health Organization (WHO) stepladder for the treatment of cancer pain and suggest an adjuvant treatment algorithm, directing physicians to appropriate adjuvant pain agents based on pain type and distinct receptor actions.\n\nDesign: This is a retrospective case series of patients who responded to topical multimodal pain treatment with implementation of findings into an addendum to the WHO stepladder.\n\nSubjects: Subjects were from a case series of community-based hospice patients with previously uncontrolled cancer pain.\n\nMeasurement: Measurement was made by self-report of pain levels using the 10-point numeric pain rating scale.\n\nResults: Patients' pain was controlled with topical adjuvant medications with return to previously lost function and prevention of otherwise escalating opioid dosing.\n\nConclusions: These patient cases reveal how ketamine-based topical treatment for cancer pain can be more effective than standard opioids, other topical adjuvant medications, and nerve blocks with no noted side effects and observed reduction in opioid consumption.\n\nadjuvantscancerketaminepaintopical\n==== Body\nIntroduction: Problems with Opioids and the WHO Cancer Pain Treatment Stepladder\nAmong other safety and efficacy concerns1 with the use of opioids in hospice and palliative care are the linked phenomena of analgesic tolerance and hyperalgesia. Other concerns involve the accumulation of bioactive metabolites of opioids, particularly when high opioid doses are given chronically. For example, morphine-3-glucuronide is pronociceptive and can lead to liver and kidney toxicity.2,3 Hyperalgesia during ongoing opioid usage reflects opioids' activation of the N-methyl-d-aspartate receptor (NMDAR), as well as stimulation of astrocytes.4,5 Because opioids play a central role in the World Health Organization's (WHO's) stepwise approach to cancer pain control, clinicians and researchers6 have been eager to explore nonopioid adjuvants or alternatives to opioids. A byproduct of shifting to opioid alternatives is the reduction of unmonitored at-home storage and administration of opioids, in which context they may be diverted and contribute to the current epidemic of opioid use disorder.\n\nIn light of the undesired effects of chronically administered opioids, and the need to balance responses to opioid tolerance and uncontrolled pain by increasing opioid doses with the risks of opioid hyperalgesia, clinicians struggle to provide analgesia for severe cancer pain in the face of otherwise shrinking options. We describe three hospice patients in whom adherence to the WHO analgesic ladder proved inadequate for pain control despite escalating doses of strong opioids, who showed prompt and dramatic analgesic responses after the addition of topical ketamine coformulated with other adjuvant pain medications.\n\nThe WHO Analgesic Ladder: Critique\nIn 1986, the WHO developed a three-step “analgesic ladder” to meet the therapeutic challenges presented by severe cancer pain.7 Recognition of the already described mechanisms of opioid adverse effects and their clinical correlation occurred after the development and promulgation of this ladder.\n\nAnother weakness of this stepladder is a failure to differentiate different mechanisms of pain experienced in cancer and to describe adjuvant medications and routes most appropriate for each type. Thus, physicians have long depended on their familiarity with opioids, underutilizing other treatment options such as adjuvant pain medications. Descriptors of the quality, potential source, and mechanism of the pain, not just its severity, guide the choice of adjuvant medications.8,9\n\nKetamine: A Valuable Adjuvant\nOf the available adjuvant medications, ketamine is a powerful NMDAR antagonist. It also reduces production of inflammatory mediators; blocks uptake of dopamine, serotonin, and noradrenaline; decreases activation of microglia; blocks ion channels; and binds opioid receptors.10 Although developed as an anesthetic, ketamine at subanesthetic doses can reverse pain crises in patients taking opioid medications11 and also reverses opioid-induced neurotoxicity.12 Through multiple routes, with and without other adjuvant pain medications, ketamine's varied actions have been exploited to optimize cancer pain control.\n\nIncorporating Ketamine and Other Adjuvants into the WHO Ladder\nIntegrating adjuvant pain medications in routine practice may be facilitated by amending a familiar clinical decision aid such as the WHO ladder. Although other authors have suggested modification of this ladder,13 their suggestions have emphasized inclusion of costly high-tech interventions such as intrathecal pumps, rhizotomy, and neurolytic blocks.14 Advantages in using ketamine include its ability to inhibit spinal windup and central sensitization, providing a stabilizing and even preventative intervention; in addition, its cost is modest, particularly compared with more interventional procedures. The coadministration with other adjuvants, such as clonidine and gabapentin, can provide a more robust response, and formulation in Lipoderm base increases transdermal penetration.15\n\nCase Series\nCase 1\nCK, a 98-year-old Caucasian female, was diagnosed with squamous cell vulvar cancer in July 2016. Her treatment was regional radiotherapy. After treatment, her physicians reported that the cancer was cured, and the patient experienced several months of only minimal discomfort attributed to radiotherapy. However, six months later, the patient began experiencing increased pain in the vulvar region. Although the patient was convinced that the cancer had returned, her treating physicians told her that was highly unlikely. As a result, the patient did not receive further evaluation until the recurrent cancer had extended dorsally to the rectum and superiorly to the bowel, when she was referred for palliative care.\n\nThe patient's pain had steadily increased, particularly in the superficial areas of the vulva, perineum, and rectal regions. Upon examination, the area was excoriated and had malignant-appearing lesions. As the patient was not a candidate for further aggressive therapy, her treatment focused upon pain relief. Tramadol provided minimal relief and intolerable dyspepsia. Hydrocodone-acetaminophen was poorly effective and caused hallucinations. The patient saw a pain specialist who performed a neurolytic ganglion impar nerve block with 10% phenol. This provided good short-term relief of pain but by three months later her pain returned. A subsequent right pudendal nerve block with 0.25% bupivacaine and 40 mg of methylprednisolone provided no relief. Topical benzocaine gel was ineffective. Lidocaine 5% gel applied to her perineum every one to two hours reduced her pain intensity slightly, but it was still severe (“9/10”). The pain was so severe that the patient attempted suicide by overdose of tramadol with an uncomplicated recovery in the hospital. Sitting upright or standing were hindered by pain. Toileting resulted in a searing pain persisting as long as hours.\n\nThe patient experienced progressive weakness, poor appetite, weight loss, vulvodynia, and pudendal neuralgia. In May 2018, the patient was admitted to hospice services. The lidocaine 5% gel was discontinued, and the patient was started on a topical Lipoderm cream containing ketamine 10%, clonidine 0.2 mg/mL, and gabapentin 6 mg/mL. The patient applied 3 mL of the cream to the affected area every 8 hours. She obtained near-complete pain relief within the first 30 minutes of applying the compound; however, the pain relief only lasted for 1–2 hours. Morphine sulfate immediate release (MSIR) was initiated at a dose of 7.5 mg PO (by mouth) every 4 hours as needed. This provided no analgesic benefit and made the patient feel “groggy.” The compounded cream was then increased to a frequency of 3 mL every 4 hours. Again, the patient experienced pain relief but had symptom breakthrough at two hours after application. Oxycodone 5 mg PO q 4 hours was added, in the place of the MSIR, but the patient experienced the side effect of disorientation without providing significant pain relief.\n\nIt was clear that the patient could achieve pain control through topical adjuvant pain medications, but that longer acting agents were needed. Based upon the availability of a longer acting local anesthetic (bupivacaine) and opioid (methadone), a modified Lipoderm cream was compounded with ketamine 10%, clonidine 0.2 mg/mL, gabapentin 6 mg/mL, bupivacaine 0.2 mg/mL, and methadone 0.2 mg/mL; 3 mL to be applied to the perineum every 4 hours. Within 30 minutes after the first application, this augmented medication provided nearly complete relief with a pain intensity <3 out of 10. She was able to resume normal posturing, toileting, and other activities of daily living without any pain. Comfort was maintained in the perineum and all adjoining involved areas, throughout the remainder of the patient's hospice course of 17 days. The patient's and family goals of care were achieved with use of the topical cream including comfort whether seated, lying, or standing, and with toileting.\n\nCase 2\nJG, a 69-year-old Caucasian male, was admitted to hospice services with adenocarcinoma of the prostate diagnosed 2 years earlier, as stage IV (Gleason score 9), with diffuse metastases to bones including axial skeleton and the skull. The patient had received 6 cycles of docetaxel and 10 fractions of radiation therapy to the left posterior ribs. After completing these initial treatments, he continued with oral hormone-based chemotherapy, bicalutamide, and an injectable monoclonal antibody, denosumab, for bone lesion control and comfort. Despite these therapies, the patient's cancer continued to progress.\n\nOver the six months before hospice admission, the patient had increasing pain, weakness, and fatigue. He had a 6-month weight loss of 21 kg, from initial weight of 77 kg, and was profoundly weak. He had daily symptoms of pain, nausea, flushing, depression, and insomnia. On admission to hospice, the patient was spending much of the day in bed with increasing hip and back pain, and fatigue. He was taking morphine sulfate extended release 30 mg orally every 12 hours, and oxycodone 5 mg orally every 6 hours as needed for pain. His pain was self-reported as between “8–10/10.” It was not uncommon for the patient to state his pain was “excruciating.” He described his pain as “deep,” “aching,” and “shooting.” He stated it was in the bilateral hips, low back, and pelvis. The patient did not have specific treatment for bone pain, despite diffuse bony metastases; therefore, oral dexamethasone was started immediately at 2 mg daily, given with his first meal, upon hospice admission.18,19 The patient noted significantly improved comfort and enjoyed increased activity and appetite.\n\nThe patient's pain then varied over the next seven months on hospice requiring multiple titrations to his oral pain regimen. His dexamethasone had been increased incrementally to a final oral dosing of 8 mg daily, given with his first meal, with continued control of bony pain. His baseline opioid was changed from morphine sulfate extended release 30 mg BID (twice daily) to methadone (for continued mu-agonism and partial NMDAR antagonism)17 with a final dose of 30 mg QID (4 times daily) in the final 2 weeks of his life. The patient's oxycodone/acetaminophen was increased from 5/325 to 10/325 and was given 1–2 PO q 4 hours in the final 2 weeks of his life. In addition, the patient admitted that he had existential pain but continued to refuse spiritual care counseling throughout his hospice course.\n\nDuring this seven-month period, the patient was developing symptoms of cognitive impairment and severe bony pain of the left mandibular and orbital regions. The major contributors to his pain and suffering were multiple masses originating from below the left mandible and left cheek. He could no longer tolerate dentures and was placed on a liquid diet due to odynophagia. Then a topical Lipoderm cream of ketamine 10%, clonidine 0.2 mg/mL, and gabapentin 4 mg/mL was initiated with a schedule of 1.0 mL to the affected area every 8 hours. The patient had rated his pain intensity as “8/10” at the time of the first application of cream. At 30 minutes after administration, the patient described “some improvement.” By 60 minutes after the first dose, the patient rated his pain intensity at “4/10” with this intervention alone. Between the 8-hourly applications of cream, his mandibular pain would reach a maximum of “4–5/10” but application of the next dose would reduce the pain to “2–3/10.” The patient resumed eating and denied mandibular pain.\n\nTwo weeks after the painful masses noted in the left mandible and cheek, additional masses grew at the inferior and right side of the mandible. The cream was then applied at 1.0 mL bilaterally TID with good relief of pain symptoms.\n\nIn the last 2 weeks of his life, the frequency of cream application was increased to 1.0 mL every 4 hours bilaterally. This controlled the mandibular and facial pain throughout his end of life, allowing the patient to eat and achieve goals of care.\n\nCase 3\nMZ, a 72-year-old Caucasian female, was admitted to hospice services with ovarian carcinosarcoma diagnosed 3 years prior as stage IIIC, with disseminated malignant metastases to the retroperitoneum, peritoneum, and colon. She underwent radical debulking surgery and chemotherapy with carboplatin and five cycles of Taxol followed by carboplatin and docetaxel for eight cycles. She achieved a short remission. Four months later, the ovarian cancer returned with left adnexal mass, and the patient had surgical removal with a colostomy placed and further debulking surgical procedures. The patient was then treated with 5 cycles of ifosfamide and paclitaxel with 14 days of palliative radiation therapy for severe “10/10” pain of the coccyx. After 2 years of continued cancer presence, the patient presented to hospice services with a recurrence of the ovarian carcinosarcoma, and an additional primary cancer of the right upper lung with likely metastasis to the left axilla, and new metastasis to the coccyx: all within the previous 12 months. The patient was admitted to hospice with symptoms of anorexia-cachexia syndrome, nausea, intermittent shortness of breath, and pain.\n\nThe patient's pain was mainly movement related. She was taking pregabalin 50 mg twice daily and using a fentanyl 50 mcg/hour patch but was suffering with upper back pain; a sharp radiating pain initiating in the right back and wrapping around to the anterior ribs, as well as lower extremity chemotherapy-induced polyneuropathy. The patient started methadone 5 mg BID and the fentanyl patch and pregabalin were discontinued 5 days later. The patient's baseline pain improved but she had intermittent breakthrough pain. The methadone was increased to TID after five days with good results initially. For improved coverage of neuropathic and nociceptive pain, oral ketamine was added to the methadone 2 weeks later at 10 mg BID. The ketamine was helpful, but again the patient had ongoing breakthrough pain episodes. The oral ketamine was increased to 10 mg TID but the patient experienced one distressing vivid dream. The oral ketamine was then reduced to 5 mg TID, which was effective for her localized (back) and generalized pain.\n\nAt the time of hospice admission, the left axillary nodule was <2 cm. It was asymptomatic initially; however, it was doubling in size every one to two weeks. As the lesion grew rapidly beyond 3 cm, the patient developed lesion-associated severe pruritis, which was understood to be a pain equivalent. A Lipoderm cream of ketamine 10%, clonidine 0.2 mg/mL, and gabapentin 4 mg/mL was prescribed for the axillary lesion initially: 1.0 mL TID. The pruritis-associated discomfort decreased from “severe” to “none,” or “mild.”\n\nThe patient also developed a severely painful lesion of the left labium for which a work-up was declined. The lesion grew rapidly and was accompanied by vaginal bleeding, with severe sharp and burning pain, and was assumed to be malignant. During a vaginal pain crisis, the ketamine, clonidine, and gabapentin cream being used in the treatment of the left axilla area was also applied to the perineal region. The pain of the labial lesion decreased from “10/10” to “6/10” within 20 minutes after the cream was applied. At that point, the treatment was increased to 1.0 mL TID applied to both the left axillary and left labial mass. The dosing remained at this level until 10 days before the patient's death when it was increased to six times daily to both areas with control of the left axillary pruritis and the left labial pain.\n\nFinally, as the axillary mass grew to a size of ∼14 × 8 × 5 cm, the patient developed a nonpruritic pain that was not improved by the ketamine, clonidine, and gabapentin cream; therefore, the cream was discontinued to the axilla but remained effective for the labial pain.\n\nAs the patient neared death, her “all over” pain again increased to 5/10. In the final three days her pain medication was titrated again. Her final doses were methadone 10 mg PO QID, ketamine oral solution 5 mg PO TID, and hydromorphone 2 mg PO every 2 hours PRN (as needed), with excellent control of generalized pain. The ketamine, clonidine, and gabapentin cream remained at 1.0 mL every 4 hours to the left labia with pain controlled despite continued growth of the labial mass. The patient died peacefully at home, with relief of symptoms, as was her wish.\n\nDiscussion: The Need to Recognize Topical Adjuvant Analgesics in the WHO Method\nIn light of the increasing obstacles to opioid availability and the undesired side effects of chronically administered opioids for any diagnosis, clinicians struggle to provide analgesia for severe cancer pain. We suggest an addendum to the WHO stepladder to choose adjuvant medications based on efficacy, mechanisms of action, and routes of administration. An expanded treatment algorithm may be beneficial as an aid to clinical decision making for practitioners to select appropriate adjuvant pain agents based on their distinct receptor actions. Choices include three of the most commonly used topical analgesics for chronic neuropathic pain: ketamine, clonidine, and gabapentin, with ketamine having the highest absorption rate.15\n\nClonidine has been used as an adjuvant pain medication successfully in postoperative and chronic pain. As a relatively nonspecific α2-agonist, it acts to hyperpolarize nerve cell membranes, diminishing nociceptive function, and lowering circulating levels of catecholamines.\n\nGabapentinoids, through their action on the α2δ-1 C terminus of the NMDAR, modulate synaptic transmission, reversing the synaptic NMDAR hyperactivity caused by neuropathic pain, and normalizing nerve injury-induced activity of the spinal dorsal horn.16\n\nThis small case series describes topical treatment for neuropathic, nociceptive, and inflammatory pain in patients with end-stage cancer. For these patients, topical treatment allowed for control of symptoms where standard opioids, other topical adjuvant medications, and nerve blocks had failed. These findings are consistent with results in our noncancer palliative care patients with similar pain issues.\n\nConclusions: Topical Multimodal Pain Therapies Effective in Uncontrolled Cancer Pain\nGiven our consistent findings in palliative care cases with cancer-related pain, the following recommendation to the current WHO stepladder for cancer-related pain is suggested (Fig. 1). This algorithm provides suggestions for clinicians based on the type/descriptor of the pain, its location related to body surface, and correlation of the medication therapies to the patient's pain experience. These recommendations will help clinicians more accurately and confidently create patient-specific treatment plans that are inclusive of both traditional opioid treatment and multimodal adjuvant pain therapy. This alternative ladder may be best evaluated in a more formal way prospectively or tried when adherence to the WHO ladder fails to achieve a good effect/adverse effect ratio.\n\nFIG. 1. Addendum to the 1986 WHO cancer pain relief stepladder. WHO, World Health Organization.7,10,13,15,17–19\n\nIn light of the continued opioid crisis, randomized controlled trials are needed in the use of ketamine as a supplement or substitute for systemic opioids. These studies should explore topical routes where primary afferent neurons are easily accessible and acquire data to allow identification of patients more or less likely to benefit. There is a need for a systematic multicenter site trial to further assess the efficacy and safety of ketamine, with or without other adjuvant medications, for topical analgesia in uncontrolled cancer-related pain.\n\nFunding Information\nNo funding was received for the study.\n\nAuthor Disclosure Statement\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1. \nMcNicol E : Opioid side effects and their treatment in patients with chronic cancer and noncancer pain\n. J Pain Palliat Care Pharmacother \n2008 ;22 :270 –281\n21923311 \n2. \nLee KA , Ganta N , Horton JR , Chai E : Evidence for neurotoxicity due to morphine or hydromorphone use in renal impairment: A systematic review\n. J Pall Med \n2016 ;19 :1179 –1187\n\n3. \nAtici S , Cinel I , Cinel L , et al. : Liver and kidney toxicity in chronic use of opioids: An experimental long term treatment model\n. J Biosci \n2005 ;30 :245 –252\n15886461 \n4. \nMao J , Sung B , Ji RR , Lim G : Neuronal apoptosis associated with morphine tolerance: Evidence for an opioid-induced neurotoxic mechanism\n. J Neurosci \n2002 ;22 :7650 –7661\n12196588 \n5. \nWatkins LR , Milligan ED , Maier SF : Glial activation: A driving force for pathological pain\n. Trends Neurosci \n2001 ;24 :450 –455\n11476884 \n6. \nSutherland S : NIH announces HEAL initiative to combat opioid crisis\n. Pain research forum. https://www.painresearchforum.org/news/97040-nih-announces-heal-initiative-combat-opioid-crisis (Last accessed 6 5 , 2018 )\n7. \nMercadante S , Fulfaro Fl : World Health Organization guidelines for cancer pain: A reappraisal\n. Ann Oncol \n2005 ;16 :132 –135\n15598950 \n8. \nPatel R , Kucharczyk M , Montagut-Bordas C , et al. : Neuropathy following spinal nerve injury shares features with the irritable nociceptor phenotype: A back-translational study of oxcarbazepine\n. Eur J Pain \n2019 ;23 :183 –197\n30091265 \n9. \nDemant DT , Lund K , Vollert J , et al. : The effect of oxcarbazepine in peripher neuropathic pain depends on pain phenotype: A radomised, double-blind, placebo-controlled phenotype-stratified study\n. Pain \n2014 ;155 :2263 –2273\n25139589 \n10. \nSawynok J : Topical and peripheral ketamine as an analgesic\n. Pain Med \n2014 ;119 :170 –178\n\n11. \nSchwenk ES , Viscusi ER , Buvanendran A , et al. : Consensus guidelines on the use of intravenous ketamine infusions for acute pain management from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists\n. Reg Anesth Pain Med \n2018 ;43 :456 –466\n29870457 \n12. \nWinegarden J , Carr DB , Bradshaw YS : Intravenous ketamine for rapid opioid dose reduction, reversal of opioid-induced neurotoxicity, and pain control in terminal care: Case report and literature review\n. Pain Med \n2015 ;17 :644 –649\n\n13. \nNersesyan H , Slavin KV : Current approach to cancer pain management: Availability and implications of different treatment options\n. Ther Clin Risk Manag \n2008 ;3 :381 –400\n\n14. \nVargas-Schaffer G : Is the WHO analgesic ladder still valid?\n\nCan Fam Phys \n2010 ;56 :514 –517\n\n15. \nBassani AS , Banov D : Evaluation of the percutaneous absorption of ketamine HCL, gabapentin, clonidine HCL, and baclofen, in compounded transdermal pain formulations, using the franz finite dose model\n. Pain Med \n2016 ;17 :230 –238\n26352507 \n16. \nChen J , Lingyong L , Chen S-R , et al. : The α2δ-1-NMDA receptor complex is critically involved in neuropathic pain development and gabapentin therapeutic actions\n. J Obstet Gynecol \n2008 ;112 :579 –585\n\n17. \nLeppert W : Pain management in patients with cancer: Focus on opioid analgesics\n. Curr Pain Headache Rep \n2011 ;15 :271 –279\n21479998 \n18. \nAhmad I , Ahmed MM , Absraf MF , et al. : Pain management in metastatic bone disease: A literature review\n. Cureus \n2018 ;10 :e3286 30443456 \n19. \nLeppert W , Buss T : The role of corticosteroids in the treatment of pain in cancer patients\n. Curr Pain Headache Rep \n2012 ;16 :307 –313\n22644902\n\n",
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"journal": "Journal of palliative medicine",
"keywords": "adjuvants; cancer; ketamine; pain; topical",
"medline_ta": "J Palliat Med",
"mesh_terms": "D000700:Analgesics; D000701:Analgesics, Opioid; D000072716:Cancer Pain; D006801:Humans; D007649:Ketamine; D009369:Neoplasms; D010148:Pain, Intractable; D012189:Retrospective Studies; D014944:World Health Organization",
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"title": "Topical Ketamine with Other Adjuvants: Underutilized for Refractory Cancer Pain? A Case Series and Suggested Revision of the World Health Organization Stepladder for Cancer Pain.",
"title_normalized": "topical ketamine with other adjuvants underutilized for refractory cancer pain a case series and suggested revision of the world health organization stepladder for cancer pain"
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"abstract": "Drug survival reflects a drug's effectiveness, safety, and tolerability. We assessed the drug survival of biologics used to treat psoriasis in a prospective national pharmacovigilance cohort (British Association of Dermatologists Biologic Interventions Register (BADBIR)). The survival rates of the first course of biologics for 3,523 biologic-naive patients with chronic plaque psoriasis were compared using survival analysis techniques and predictors of discontinuation analyzed using a multivariate Cox proportional hazards model. Data for patients on adalimumab (n=1,879), etanercept (n=1,098), infliximab (n=96), and ustekinumab (n=450) were available. The overall survival rate in the first year was 77%, falling to 53% in the third year. Multivariate analysis showed that female gender (hazard ratio (HR) 1.22; 95% confidence interval (CI): 1.09-1.37), being a current smoker (HR 1.19; 95% CI: 1.03-1.38), and a higher baseline dermatology life quality index (HR 1.01; 95% CI: 1.00-1.02) were predictors of discontinuation. Presence of psoriatic arthritis (HR 0.82; 95% CI: 0.71-0.96) was a predictor for drug survival. As compared with adalimumab, patients on etanercept (HR 1.63; 95% CI: 1.45-1.84) or infliximab (HR 1.56; 95% CI: 1.16-2.09) were more likely to discontinue therapy, whereas patients on ustekinumab were more likely to persist (HR 0.48; 95% CI: 0.37-0.62). After accounting for relevant covariates, ustekinumab had the highest first-course drug survival. The results of this study will aid clinical decision making when choosing biologic therapy for psoriasis patients.",
"affiliations": "Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. Electronic address: christopher.griffiths@manchester.ac.uk.;St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. Electronic address: zenas.yiu@manchester.ac.uk.;Centre for Pharmacoepidemiology and Drug Safety, Manchester Pharmacy School, The University of Manchester, Manchester, UK.;St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Department of Dermatology, Western Infirmary, Glasgow, UK.;Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester, UK.;Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester, UK.;Division of Applied Medicine, University of Aberdeen, Foresterhill, Aberdeen, UK.;Department of Dermatology, East Lancashire Hospitals NHS Trust, Royal Blackburn Hospital, Blackburn, UK.;Dermatological Sciences, Institute of Cellular Medicine, Medical School, Newcastle University, and Department of Dermatology, Royal Victoria Infirmary, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.;Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. Electronic address: christopher.griffiths@manchester.ac.uk.",
"authors": "Warren|Richard B|RB|;Smith|Catherine H|CH|;Yiu|Zenas Z N|ZZN|;Ashcroft|Darren M|DM|;Barker|Jonathan N W N|JNWN|;Burden|A David|AD|;Lunt|Mark|M|;McElhone|Kathleen|K|;Ormerod|Anthony D|AD|;Owen|Caroline M|CM|;Reynolds|Nick J|NJ|;Griffiths|Christopher E M|CEM|",
"chemical_list": "D001688:Biological Products; D000069285:Infliximab; D000069549:Ustekinumab; D000068879:Adalimumab; D000068800:Etanercept",
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"journal": "The Journal of investigative dermatology",
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"medline_ta": "J Invest Dermatol",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D001688:Biological Products; D001691:Biological Therapy; D015331:Cohort Studies; D003880:Dermatology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000068800:Etanercept; D005260:Female; D006801:Humans; D000069285:Infliximab; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011565:Psoriasis; D012042:Registries; D012955:Societies, Medical; D000069549:Ustekinumab",
"nlm_unique_id": "0426720",
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"pages": "2632-2640",
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"pubdate": "2015-11",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": "19209224;19356232;25028371;15649103;25213131;23621374;24841895;22356636;23848131;24807471;24821852;23981051;18237359;20071701;24206025;23921949;20157022;18810241;23647206;15231615;22508869;25132294;25088451;24304288;21219290;21801162;24117023;21781016;24673245",
"title": "Differential Drug Survival of Biologic Therapies for the Treatment of Psoriasis: A Prospective Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR).",
"title_normalized": "differential drug survival of biologic therapies for the treatment of psoriasis a prospective observational cohort study from the british association of dermatologists biologic interventions register badbir"
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"abstract": "BACKGROUND\nIn ineffective erythropoiesis, hepcidin synthesis is suppressed by erythroid regulators, namely erythroferrone and growth differentiation factor-15. For the first time, the hypothesis that iron overload in megaloblastic anemia may be related to ineffective erythropoiesis is explored by describing the kinetics of hepcidin, erythroferrone, and growth differentiation factor-15 levels in a patient diagnosed with megaloblastic anemia associated with iron overload.\n\n\nMETHODS\nAn 81-year-old Caucasian male was admitted for fatigue. He had type-2 diabetes previously treated with metformin, ischemic cardiac insufficiency, and stage-3 chronic kidney disease. Vitiligo was observed on both hands. Biological tests revealed normocytic non-regenerative anemia associated with hemolysis, thrombocytopenia, and elevated sideremia, ferritin, and transferrin saturation levels. Megaloblastic anemia was confirmed with undetectable blood vitamin B12 and typical cytological findings like hyper-segmented neutrophils in blood and megaloblasts in bone marrow. The patient received vitamin B12 supplementation. At 3 months, biological parameters reached normal values. Hepcidin kinetics from diagnosis to 3 months inversely correlated with those of erythroferrone and growth differentiation factor-15.\n\n\nCONCLUSIONS\nThis case suggests that iron-overload mechanisms of dyserythropoietic anemias may apply to megaloblastic anemias.",
"affiliations": "Department of Hematology and Cell Therapy, Tours University Hospital, 2 Boulevard Tonnellé, 37044, Tours Cedex, France.;Department of Biochemistry and Molecular Biology, Tours University Hospital, Tours, France.;Department of Biochemistry, CHU Rennes, Rennes, France.;Department of Biological Hematology, Tours University Hospital, Tours, France.;Department of Biological Hematology, Tours University Hospital, Tours, France.;Department of Internal Medicine, Tours University Hospital, Tours, France.;Department of Hematology and Cell Therapy, Tours University Hospital, 2 Boulevard Tonnellé, 37044, Tours Cedex, France.;Department of Biochemistry and Molecular Biology, Tours University Hospital, Tours, France.;Department of Internal Medicine, Tours University Hospital, Tours, France.;Department of Biological Hematology, Tours University Hospital, Tours, France.;Department of Hematology and Cell Therapy, Tours University Hospital, 2 Boulevard Tonnellé, 37044, Tours Cedex, France. emmanuel.gyan@univ-tours.fr.",
"authors": "Vallet|Nicolas|N|;Delaye|Jean-Baptiste|JB|;Ropert|Martine|M|;Foucault|Amélie|A|;Ravalet|Noémie|N|;Deriaz|Sophie|S|;Chalopin|Thomas|T|;Blasco|Hélène|H|;Maillot|François|F|;Hérault|Olivier|O|;Gyan|Emmanuel|E|",
"chemical_list": "D007501:Iron",
"country": "England",
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"doi": "10.1186/s13256-021-03065-0",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n3065\n10.1186/s13256-021-03065-0\nCase Report\nMegaloblastic anemia-related iron overload and erythroid regulators: a case report\nVallet Nicolas 1\nDelaye Jean-Baptiste 2\nRopert Martine 3\nFoucault Amélie 45\nRavalet Noémie 45\nDeriaz Sophie 6\nChalopin Thomas 1\nBlasco Hélène 2\nMaillot François 6\nHérault Olivier 45\nGyan Emmanuel emmanuel.gyan@univ-tours.fr\n\n15\n1 grid.411167.4 0000 0004 1765 1600 Department of Hematology and Cell Therapy, Tours University Hospital, 2 Boulevard Tonnellé, 37044 Tours Cedex, France\n2 grid.411167.4 0000 0004 1765 1600 Department of Biochemistry and Molecular Biology, Tours University Hospital, Tours, France\n3 grid.411154.4 0000 0001 2175 0984 Department of Biochemistry, CHU Rennes, Rennes, France\n4 grid.411167.4 0000 0004 1765 1600 Department of Biological Hematology, Tours University Hospital, Tours, France\n5 grid.12366.30 0000 0001 2182 6141 CNRS ERL7001 LNOX, EA 3549, Tours University, Tours, France\n6 grid.411167.4 0000 0004 1765 1600 Department of Internal Medicine, Tours University Hospital, Tours, France\n20 9 2021\n20 9 2021\n2021\n15 46316 12 2020\n16 8 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nIn ineffective erythropoiesis, hepcidin synthesis is suppressed by erythroid regulators, namely erythroferrone and growth differentiation factor-15. For the first time, the hypothesis that iron overload in megaloblastic anemia may be related to ineffective erythropoiesis is explored by describing the kinetics of hepcidin, erythroferrone, and growth differentiation factor-15 levels in a patient diagnosed with megaloblastic anemia associated with iron overload.\n\nCase presentation\n\nAn 81-year-old Caucasian male was admitted for fatigue. He had type-2 diabetes previously treated with metformin, ischemic cardiac insufficiency, and stage-3 chronic kidney disease. Vitiligo was observed on both hands. Biological tests revealed normocytic non-regenerative anemia associated with hemolysis, thrombocytopenia, and elevated sideremia, ferritin, and transferrin saturation levels. Megaloblastic anemia was confirmed with undetectable blood vitamin B12 and typical cytological findings like hyper-segmented neutrophils in blood and megaloblasts in bone marrow. The patient received vitamin B12 supplementation. At 3 months, biological parameters reached normal values. Hepcidin kinetics from diagnosis to 3 months inversely correlated with those of erythroferrone and growth differentiation factor-15.\n\nConclusions\n\nThis case suggests that iron-overload mechanisms of dyserythropoietic anemias may apply to megaloblastic anemias.\n\nKeywords\n\nVitamin B12\nIron overload\nErythropoiesis\nErythroferrone\nGDF15\nCase report\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nIron overload related to hemolysis and ineffective erythropoiesis is a feature of megaloblastic anemia. The latter mechanism is yet to be explored [1, 2]. In ineffective erythropoiesis, hepcidin synthesis is suppressed by erythroid regulators, namely erythroferrone (ERFE) [3] and growth differentiation factor-15 (GDF15) [4]. Hepcidin is essential for iron homeostasis, as it induces the endocytosis of ferroportin, lowering iron absorption and circulating iron levels through iron sequestration by hepatocytes, macrophages, and duodenal enterocytes [5]. Herein, we describe the kinetics of hepcidin, ERFE, and GDF15 levels in a patient diagnosed with megaloblastic anemia associated with iron overload. We hypothesized that ineffective erythropoiesis was associated with high levels of ERFE and GDF15 at the time of diagnosis, possibly associated with suppressed hepcidin, thus explaining the iron overload.\n\nCase presentation\n\nAn 81-year-old Caucasian male was referred to emergency department for fatigue associated with profound anemia. He had type-2 diabetes previously treated with metformin, ischemic cardiac insufficiency, and stage-3 chronic kidney disease (CKD, CKD-Epidemiology Collaboration [CKD-EPI] estimated glomerular filtration rate: 32 mL/minute/1.73 m2). There were no clinical signs of infectious or tumoral disease. Vitiligo was observed on both hands. First biological tests revealed normocytic non-regenerative anemia associated with hemolysis, thrombocytopenia, and elevated sideremia, ferritin, and transferrin saturation (TSAT) levels. Vitamin B12 was undetectable, whereas vitamin B9 and C-reactive protein levels were normal (Table 1). He received one pack of red blood cells (RBC), then was admitted to internal medicine department. A peripheral blood smear showed hypersegmented neutrophils, and a bone-marrow smear showed hypercellularity and clear signs of dyserythropoiesis and blocked maturation of erythroid cells (Fig. 1a, b). Stomach endoscopy and biopsies showed chronic gastritis and fundic atrophy. Though metformin may have participated in this condition [1], a diagnosis of megaloblastic anemia caused by pernicious anemia was preferred considering the profound anemia and vitiligo, even if blood antiparietal cells or anti-intrinsic-factor antibodies were not detected. After two other packs of RBC and five daily intramuscular vitamin B12 injections, he was discharged and continued oral vitamin B12 supplementation. Three-month (M3) biological control revealed that platelet count and hemoglobin, sideremia, and TSAT levels normalized (Table 1). Ferritin returned to normal values at 7 months (361 µg/L).Table 1 Peripheral blood characteristics at diagnosis and 3 months after vitamin B12 supplementation\n\nBiological parameters\tUnit\tAt diagnosis\t3 months later\tLaboratory reference range\t\nHemoglobin\tg/L\t57\t129\t129–170\t\nMean corpuscular volume\tfL\t99\t90\t80–100\t\nReticulocytes\t109/L\t16\t94\tNA\t\nAbsolute neutrophil count\t109/L\t2.2\t5.4\t1.5–7.5\t\nPlatelets\t109/L\t89\t240\t150–400\t\nCreatinine\tµmol/L\t171\t200\t59–104\t\nEstimated glomerular filtration rate (CKD-EPI formula)\tmL/minute/1.73 m2\t32\t26\tNA\t\nTotal bilirubin\tµmol/L\t31\t9\t2–24\t\nIndirect bilirubin\tµmol/L\t20\t5\t2–17\t\nHaptoglobin\tg/L\t0.4\t1.8\t0.5–2.0\t\nLactate dehydrogenase\tU/L\t910\t164\t135–225\t\nSideremia\tµmol/L\t36\t13\t5.8–34.5\t\nFerritin\tµg/L\t537\t437\t30–400\t\nTransferrin\tg/L\t1.60\t2.10\t2.0–3.6\t\nTransferrin saturation coefficient\t%\t88\t25\t25–40\t\nReactive C protein\tmg/L\t1.2\t0.9\t0.3–5.0\t\nVitamin B9\tnmol/L\t21\t–\t8.8–60.8\t\nVitamin B12\tpmol/L\t<111\t743\t145–569\t\nErythropoietin\tmUI/mL\t43.9\t8.6\t2.6–18.5\t\nGDF15\tpg/mL\t> 8000\t2,240\t1080–3700*\t\nErythroferrone\tng/mL\t14.44\t0.53\t0.01–1.92*\t\nHepcidin†\tnmol/L\t10.6\t28.7\t4–30\t\nCKD-EPI indicates chronic Kidney Disease Epidemiology Collaboration. *Reference range was defined with healthy controls matched for age. †To convert hepcidin from nmol/L to ng/mL, multiply by 2.76\n\nFig. 1 Proposed integrative interpretation of the results obtained from this case report. a May–Grünwald Giemsa staining of a bone-marrow smear showing hypercellularity (left) and intense basophilic megaloblasts (right, arrows). b Peripheral blood smear revealing increased neutrophil cell volume with a hypersegmented nucleus. c Hypothetical mechanism of the pathogenesis of iron overload in megaloblastic anemia. Relative changes in the size of the protein names represent their down- or upregulation. ERFE erythroferrone, GDF15 growth differentiation factor-15\n\nWe tested our hypothesis by analyzing the samples at the time of diagnosis and at M3 after receiving informed consent of the patient. Serum hepcidin, ERFE, and GDF15 levels were assessed by ELISA (hepcidin-25: S-1337, Peninsula; ERFE: ERF-001, Intrinsic LifeSciences; GDF15: DGD150, R&D Systems). Serum erythropoietin (EPO) was measured by chemiluminescence (UniCel DxL, Beckman Coulter).\n\nERFE and GDF15 levels were higher than those of age-matched healthy controls (HC) at diagnosis, dropping to HC levels at M3, supporting our hypothesis. The level of hepcidin was lower at the time of diagnosis than M3 but remained within reference levels, and its kinetics from diagnosis to M3 inversely correlated with those of EPO, ERFE, and GDF15 (Table 1).\n\nDiscussion and conclusions\n\nGiven the high level of TSAT, the level of hepcidin at diagnosis was inappropriately low, suggesting suppression by an erythroid regulator. The influence of CKD [6, 7] and metformin [8] may explain why the hepcidin levels were comparable to those of HC, but its range is consistent with that found in CKD patients [7]. A metabolic syndrome may also explain high ferritin levels. But these potential biases were internally controlled by comparing two time points before and after vitamin B12 and hemoglobin normalization, when comorbidities and treatments were comparable. ERFE and GDF15 levels were higher than in HC from our institution and previous studies [9, 10]. ERFE levels at diagnosis were comparable to those of patients with pyruvate-kinase deficiency but lower than those with β-thalassemia [9]. The inverse correlation of EPO and ERFE kinetics is consistent with that observed in EPO-treated healthy humans [3] and CKD mouse [6] models. The GDF15 level at diagnosis was comparable to that of congenital dyserythropoietic anemia type-1 [11]. Despite the undetectable vitamin B12 levels and typical cytological abnormalities that define megaloblastic anemia, the mean corpuscular volume (MCV) was unexpectedly not macrocytic [1]. The patient had no history of iron deficiency, inflammation, or red-blood-cell transfusion. GDF15 was recently shown to stimulate erythroid precursor growth in mice [12]. Cell-cycle acceleration in erythroid precursors may have hidden macrocytosis, but whether high levels of GDF15 may have affected the MCV remains to be demonstrated. Intramedullary hemolysis, suggested by bilirubin, lactate dehydrogenase, and haptoglobin levels, can also explain iron overload [2]. However, hemolysis alone cannot explain the higher ERFE and GDF15 levels. In sickle-cell diseases (SCD), in which hemolysis is dominant compared with dyserythropoiesis, the ERFE and GDF15 levels and their correlation with hepcidin levels were not comparable to those observed in β-thalassemia [13]. Additionally, the hepcidin level was inappropriately low relative to that at M3 when TSAT was normal, reinforcing the hypothesis that an erythroid regulator suppressed hepcidin synthesis.\n\nERFE suppresses hepcidin synthesis by sequestering bone morphogenetic protein (BMP) receptor ligands [5]. Its synthesis starts upon EPO stimulation through the JAK2-STAT5 pathway in erythroblasts [14]. ERFE levels are elevated in human congenital or acquired dyserythropoietic diseases associated with iron overload [3, 15]. GDF15 was shown to suppress hepcidin synthesis in the context of β-thalassemia [4] and congenital dyserythropoietic anemia [11]. GDF15 is produced by erythroblasts, but its mechanisms of synthesis and hepcidin suppression are not fully understood [4, 10].\n\nIn conclusion, we found the kinetics of hepcidin, ERFE, and GDF15 to be comparable to those described in iron overload associated with ineffective erythropoiesis (Fig. 1c). This case broadens the spectrum of iron-overload mechanisms in dyserythropoietic anemias to vitamin B12 deficiency, in which hepcidin levels inversely correlate with those of erythroid regulators, suggesting suppression by ERFE and GDF15.\n\nAbbreviations\n\nBMP Bone morphogenetic protein\n\nCKD Chronic kidney disease\n\nEPO Erythropoietin\n\nERFE Erythroferrone\n\nGDF15 Growth differentiation factor-15\n\nM3 Three months\n\nMCV Mean corpuscular volume\n\nRBC Red blood cells\n\nSCD Sickle cell disease\n\nTSAT Transferrin saturation\n\nAcknowledgements\n\nFig. 1 was created using illustrations from Servier Medical Art by Servier, licensed under a Creative Commons Attribution 3.0 Unported License. http://smart.servier.com.\n\nAuthors’ contributions\n\nEG and NV designed the study and wrote the paper. JBD designed the study and performed the ERFE and GDF15 assays. MR performed the hepcidin assays, and AF performed the cytological analysis. All authors critically reviewed the paper, and read and approved the final version of the manuscript.\n\nFunding\n\nNot applicable\n\nAvailability of data and materials\n\nThe dataset analyzed during the current study is available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nPatient and controls gave their consent to participate. Analyses were conducted according to Helsinki declaration.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Green R Vitamin B12 deficiency from the perspective of a practicing hematologist Blood 2017 129 19 2603 2611 10.1182/blood-2016-10-569186 28360040\n2. Ho C-H You J-Y Chau W-K Diagnostic value of serum transferrin receptor and glycosylated hemoglobin on hemolytic anemia Ann Hematol 2003 82 4 228 230 10.1007/s00277-003-0623-3 12707725\n3. Ganz T Jung G Naeim A Immunoassay for human serum erythroferrone Blood 2017 130 10 1243 1246 10.1182/blood-2017-04-777987 28739636\n4. Tanno T Bhanu NV Oneal PA High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin Nat Med 2007 13 9 1096 1101 10.1038/nm1629 17721544\n5. Camaschella C Nai A Silvestri L Iron metabolism and iron disorders revisited in the hepcidin era Haematologica 2020 105 2 260 272 10.3324/haematol.2019.232124 31949017\n6. Hanudel MR Rappaport M Chua K Levels of the erythropoietin-responsive hormone erythroferrone in mice and humans with chronic kidney disease Haematologica 2018 103 4 e141 e142 10.3324/haematol.2017.181743 29419424\n7. Coll AP Chen M Taskar P GDF15 mediates the effects of metformin on body weight and energy balance Nature 2020 578 7795 444 448 10.1038/s41586-019-1911-y 31875646\n8. Ashby DR Gale DP Busbridge M Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease Kidney Int 2009 75 9 976 981 10.1038/ki.2009.21 19212416\n9. van Vuren AJ Eisenga MF van Straaten S Interplay of erythropoietin, fibroblast growth factor 23, and erythroferrone in patients with hereditary hemolytic anemia Blood Adv 2020 4 8 1678 1682 10.1182/bloodadvances.2020001595 32324886\n10. Theurl I Finkenstedt A Schroll A Growth differentiation factor 15 in anaemia of chronic disease, iron deficiency anaemia and mixed type anaemia Br J Haematol 2010 148 3 449 455 10.1111/j.1365-2141.2009.07961.x 19863534\n11. Casanovas G Swinkels DW Altamura S Growth differentiation factor 15 in patients with congenital dyserythropoietic anaemia (CDA) type II J Mol Med 2011 89 8 811 816 10.1007/s00109-011-0751-5 21475976\n12. Hao S Xiang J Wu D-C Gdf15 regulates murine stress erythroid progenitor proliferation and the development of the stress erythropoiesis niche Blood Adv 2019 3 14 2205 2217 10.1182/bloodadvances.2019000375 31324641\n13. Mangaonkar AA Thawer F Son J Regulation of iron homeostasis through the erythroferrone-hepcidin axis in sickle cell disease Br J Haematol 2020 189 6 1204 1209 10.1111/bjh.16498 32030737\n14. Kautz L Jung G Valore EV Rivella S Nemeth E Ganz T Identification of erythroferrone as an erythroid regulator of iron metabolism Nat Genet 2014 46 7 678 684 10.1038/ng.2996 24880340\n15. Bondu S Alary A-S Lefèvre C A variant erythroferrone disrupts iron homeostasis in SF3B1-mutated myelodysplastic syndrome Sci. Transl. Med. 2019 10.1126/scitranslmed.aav5467 31292266\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "15(1)",
"journal": "Journal of medical case reports",
"keywords": "Case report; Erythroferrone; Erythropoiesis; GDF15; Iron overload; Vitamin B12",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D000740:Anemia; D000749:Anemia, Megaloblastic; D004920:Erythropoiesis; D006801:Humans; D007501:Iron; D019190:Iron Overload; D008297:Male",
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"pmid": "34538261",
"pubdate": "2021-09-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24880340;32324886;17721544;31949017;29419424;19863534;31875646;31292266;12707725;31324641;32030737;28360040;21475976;19212416;28739636",
"title": "Megaloblastic anemia-related iron overload and erythroid regulators: a case report.",
"title_normalized": "megaloblastic anemia related iron overload and erythroid regulators a case report"
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"abstract": "OBJECTIVE\nCommunicate the activity of telemedicine, from its opening, between a hospital consultation of infectious diseases and a penitentiary center.\n\n\nMETHODS\nDescriptive study of the tele-consultation of infectious diseases of the Alcorcón Foundation University Hospital with the Navalcarnero penitentiary center from 2013 to 2017, which is carried out by videoconference. The reason and number of consultations, diagnosis of HIV, antiretroviral treatment (ART), immunovirological situation, diagnosis of hepatitis C virus (HCV= and intervention performed by the infectious expert were analyzed.\n\n\nRESULTS\nA total of 75 patients were evaluated in a total of 168 consultations (in the first year 11 consultations and in the fifth year 62). The index of successive / new consultations was 1.24 and 85% of the patients required less than 1 year of follow-up. 84% of patients did not move to the hospital. 99% of patients accepted this modality. 96% were HIV positive, 94% of them took ART and 85% had undetectable viral load with 532 CD4/mL of medium. 90% had positive serology for HCV. 72% of the consultations were for the assessment of HCV treatment, which was sofosbuvir/ledipasvir by 63%. 40% changed their ART (70% to avoid interactions).\n\n\nCONCLUSIONS\nMost of the evaluated patients have HIV infection. This type of consultation has a growing demand, is efficient (avoids transfers and is decisive) and has high acceptance. The most frequent reason for consultation was the treatment of HCV and more than a third of patients required ART change.",
"affiliations": "Antonio Blanco Portillo, Hospital Universitario Fundación Alcorcón. C/Budapest, 1 28922 Alcorcón, Madrid. Spain. blanco131187@hotmail.com.",
"authors": "Blanco Portillo|A|A|;Palacios García-Cervigón|G|G|;Pérez Figueras|M|M|;Navarro Jiménez|G|G|;Jiménez Galán|G|G|;Velasco Arribas|M|M|;Moreno Núñez|L|L|;Hervás Gómez|R|R|;Martín Segarral|O|O|;Guijarro Herraiz|C|C|;García Berriguete|R|R|;Losa García|J E|JE|",
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"fulltext": "\n==== Front\nRev Esp QuimioterRev Esp QuimioterSociedad Española de QuimioterapiaRevista Española de Quimioterapia0214-34291988-9518Sociedad Española de Quimioterapia 31642638revespquimioter-32-539OriginalTelemedicina, centros penitenciarios y enfermedad por VIH Telemedicine, prison and illness associated with HIV Portillo Antonio Blanco 1García-Cervigón Gregorio Palacios 1Figueras Manuel Pérez 1Jiménez Gema Navarro 1Galán Germán Jiménez 2Arribas María Velasco 1Núñez Leonor Moreno 1Gómez Rafael Hervás 1Segarral Oriol Martín 1Herraiz Carlos Guijarro 1Berriguete Rosa García 2García Juan E Losa 11 Hospital Universitario Fundación Alcorcón. C/Budapest, 1 28922 Alcorcón, Madrid.2 Centro Penitenciario Madrid IV. Carretera N-V, Km 27.7, 28600 Navalcarnero, MadridCorrespondencia: Antonio Blanco Portillo Hospital Universitario Fundación Alcorcón. C/Budapest, 1 28922 Alcorcón, Madrid. Spain E-mail: blanco131187@hotmail.com11 12 2019 2019 32 6 539 544 01 7 2019 02 9 2019 03 9 2019 03 9 2019 © The Author 20192019This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/).RESUMEN\nObjetivos\nComunicar la actividad de telemedicina, desde su apertura, entre una consulta hospitalaria de enfermedades infecciosas y un centro penitenciario.\n\nMaterial y métodos\nEstudio descriptivo de la teleconsulta de enfermedades infecciosas del Hospital Universitario Fundación Alcorcón con el centro penitenciario de Navalcarnero desde 2013 hasta 2017, que se lleva a cabo mediante videoconferencia. Se analizó motivo y número de consultas, diagnóstico de VIH, tratamiento antirretroviral (TAR), situación inmunovirológica, diagnóstico del virus de la hepatitis C (VHC) e intervención realizada por el experto en infecciosas.\n\nResultados\nSe valoraron 75 pacientes en un total de 168 consultas (en el primer año 11 consultas y en el quinto 62). El índice de consultas sucesivas/nuevas fue de 1,24 y el 85% de los pacientes requirió menos de 1 año de seguimiento. El 84% de los pacientes no se trasladó al hospital. El 99% de los pacientes aceptó esta modalidad. El 96% era VIH positivo, el 94% de estos tomaba TAR y el 85% tenía carga viral indetectable con 532 CD4/μL de mediana. El 90% tenía serología positiva para VHC. El 72% de las consultas fue para la valoración de tratamiento del VHC, que fue sofosbuvir/ledipasvir en un 63%. Un 40% cambió de TAR (70% para evitar interacciones).\n\nConclusión\nLa mayoría de los pacientes valorados tienen infección por VIH. Esta modalidad de consulta tiene una demanda creciente, es eficiente (evita traslados y es resolutiva) y tiene elevada aceptación. El motivo de consulta más frecuente fue el tratamiento del VHC y más de la tercera parte de los pacientes precisó cambio de TAR.\n\nABSTRACT\nObjectives\nCommunicate the activity of telemedicine, from its opening, between a hospital consultation of infectious diseases and a penitentiary center.\n\nMaterial and methods\nDescriptive study of the teleconsultation of infectious diseases of the Alcorcón Foundation University Hospital with the Navalcarnero penitentiary center from 2013 to 2017, which is carried out by videoconference. The reason and number of consultations, diagnosis of HIV, antiretroviral treatment (ART), immunovirological situation, diagnosis of hepatitis C virus (HCV= and intervention performed by the infectious expert were analyzed.\n\nResults\nA total of 75 patients were evaluated in a total of 168 consultations (in the first year 11 consultations and in the fifth year 62). The index of successive / new consultations was 1.24 and 85% of the patients required less than 1 year of follow-up. 84% of patients did not move to the hospital. 99% of patients accepted this modality. 96% were HIV positive, 94% of them took ART and 85% had undetectable viral load with 532 CD4/μL of medium. 90% had positive serology for HCV. 72% of the consultations were for the assessment of HCV treatment, which was sofosbuvir/ledipasvir by 63%. 40% changed their ART (70% to avoid interactions).\n\nConclusion\nMost of the evaluated patients have HIV infection. This type of consultation has a growing demand, is efficient (avoids transfers and is decisive) and has high acceptance. The most frequent reason for consultation was the treatment of HCV and more than a third of patients required ART change.\n\nPalabras clave\nTelemedicinaPrisionesVIHVHCKey-words\nTelemedicineReferral and ConsultationPrisonsCommunicable DiseasesHIVHCV\n==== Body\nINTRODUCCIÓN\nLa telemedicina es la práctica de la medicina sin el habitual contacto personal entre las unidades o participantes involucradas en el proceso y que en términos genéricos se podría definir como el acto médico-paciente donde ambas partes están en diferentes localizaciones geográficas y cuya comunicación es posible mediante tecnologías de telecomunicación [1]. Sus objetivos son mejorar los cuidados sanitarios agilizando y facilitando el acceso, facilitando el seguimiento de los pacientes y la colaboración entre sanitarios, y aumentando así la eficiencia y la calidad de vida de los pacientes [2-6], y siempre sin la intención de sustituir la imprescindible asistencia directa al paciente, puesto que la dificultad de la exploración física no se ha conseguido eliminar mediante esta metodología [7].\n\nLas nuevas tecnologías en la asistencia sanitaria han creado un medio (‘teleconsulta’) que posibilita ejercer la telemedicina de manera eficiente y segura con vistas a asegurar tratamientos, realizar seguimientos, favorecer el empoderamiento de los pacientes e incluso disminuir los traslados de pacientes presos [2, 8]. Los pacientes reclusos son una parte de la población que se beneficia de la telemedicina [4, 9] por las circunstancias de aislamiento que les rodean y la tipología de enfermedad que presentan para seguimiento, en concreto las enfermedades infecciosas.\n\nLas enfermedades infecciosas que requieren un seguimiento crónico o tratamiento prolongado, como el VIH, el VHC o la tuberculosis, generan un aumento del número de consultas y en consecuencia un detrimento en la calidad de vida de los pacientes, y una sobrecarga de los especialistas, cuya valoración es indispensable para obtener los mejores resultados, adherencia, y supervivencia [10-13]. Por ello surge como indispensable el uso de la teleconsulta de enfermedades infecciosas para dar el mejor cuidado a determinados pacientes, la cual se ha evaluado en procesos agudos, programas de optimización de antibióticos [7], seguimiento ambulatorio tras el alta hospitalaria [14], seguimiento de pacientes con VIH [3], tratamientos directamente observados para tuberculosis [5] y VHC [9], aunque no hay estudios que hayan evaluado el uso de los antivirales de acción directa (AAD) mediante telemedicina ni para el seguimiento del tratamiento del VHB.\n\nEn nuestro hospital la telemedicina lleva desde 2013 siendo una realidad y el objeto de este estudio es describir la actividad de la teleconsulta de enfermedades infecciosas que llevamos a cabo con un centro penitenciario, el cual es el primer estudio de estas características que se hace en España.\n\nMÉTODOS\nSe trata de un estudio descriptivo realizado en el Hospital Universitario Fundación Alcorcón, localizado al sur de Madrid en la localidad de Alcorcón, que es hospital de referencia del centro penitenciario de Navalcarnero donde desde 2013 se lleva colaborando mediante telemedicina. La plataforma técnica de telemedicina del hospital (figura 1) y el centro penitenciario se han creado expresamente para este motivo. Múltiples especialidades colaboran con el centro penitenciario mediante este sistema, entre ellas la unidad de infecciosas del servicio de Medicina Interna.\n\nFigura 1 Equipo de telemedicina usado desde una sala del hospital.\n\n1. Pantalla desde la que se puede visualizar información remitida desde el centro penitenciario. 2. Pantalla desde la que se puede acceder al sistema informático SELENE® para acceder a la historia clínica del paciente. 3. Pantalla, con videocámara asociada en el borde superior, en la que se puede visualizar al paciente y médico en el centro penitenciario. 4. Pantalla en la que se pueden ver radiografías del paciente con mejor resolución.\n\nLa teleconsulta de infecciosas se realiza a petición y juicio del médico responsable del centro penitenciario mediante solicitud virtual y esta es programada en la agenda específica de telemedicina. El mecanismo de la teleconsulta se basa en la videoconferencia del especialista de infecciosas del hospital de un lado y del paciente y médico responsable de la atención en el centro penitenciario del otro lado. Además, se pueden ver pruebas complementarias realizadas en el centro incluso con anterioridad a la consulta. En caso de querer explorar al paciente, éste puede ser explorado por el médico presente en el centro y referirnos los hallazgos en directo. La videoconferencia es encriptada mediante el sistema de seguridad elaborado y los datos personales del paciente quedan recogidos en la historia clínica electrónica en la plataforma SELENE®, de manera que no pueda existir acceso desde otras localizaciones.\n\nPara el estudio se recopilaron mediante el sistema informático SELENE® todos los números de historias clínicas de pacientes que habían sido atendidos en nuestras consultas de infecciosas de telemedicina, hubieran o no terminado el seguimiento, desde su apertura en 2013 hasta 2017 incluido. De cada paciente se recogieron datos demográficos, centro de procedencia, motivo de consulta, número de consultas, seropositividad de VIH, así como carga viral (definimos carga viral (CV) indetectable todos aquellos que tuvieran <50 copias/ ml) y recuento de CD4 al inicio de la interconsulta (en caso de ser seropositivo), terapia antirretroviral (TAR), seropositividad de VHC con genotipo, carga viral y afectación hepática medida con elastografía (Fibroscan® con valores de referencia de Carrión et al [15]) al inicio de la interconsulta , así como el tratamiento antiviral realizado y la respuesta a éste. También se recogió la asistencia o introducción o cambios en la terapia realizados por parte del especialista de infecciosas con motivo de la interconsulta.\n\nLos datos se recogieron en una base de datos en Excel® y se analizaron con el mismo sistema. Los datos se muestran en medianas y rangos o proporciones, según el tipo de variable. La identificación de los pacientes se realizó a través de códigos para preservar su anonimato. El estudio fue aprobado por el Comité Ético de Investigación Clínica del hospital.\n\nRESULTADOS\nEn el periodo estudiado se evaluaron 75 pacientes, todos ellos varones comprendidos entre los 30 y los 59 años (mediana de 46 años). En cuanto a los hospitales de referencia, el 20% eran de la zona correspondiente a nuestro hospital (Alcorcón y Móstoles), el 57% eran de otras áreas de la Comunidad de Madrid y el 23% restante no se conocía su hospital de referencia.\n\nSe realizaron un total de 168 consultas de telemedicina en los 75 pacientes valorados, siendo 75 primeras consultas y 93 revisiones con una media de ratio revisiones/primeras de 1,24 (tabla 1 y figura 2). La mediana de consultas realizadas por paciente fue de 2 (mínima de 1; máxima de 8). Con respecto al tiempo de seguimiento, el 85% de los pacientes necesitaron menos de 1 año de seguimiento y el 15% necesitaron de 1 a 5 años de seguimiento.\n\nTabla 1 Número de primeras consultas y revisiones por año e índice de revisiones/primeras.\n\nAño\t1ª consulta\tRevisiones\tRevisiones/primeras\t\n2013\t5\t6\t1,2\t\n2014\t4\t13\t3,25\t\n2015\t13\t20\t1,54\t\n2016\t21\t24\t1,14\t\n2017\t32\t30\t0,94\t\nTOTAL\t75\t93\t1,24\t\nFigura 2 Número de primeras consultas, revisiones y acumulados de primeras consultas a lo largo del tiempo.\n\nSe evitó el traslado a estancias hospitalarias en el 83% de los casos y 13 pacientes tuvieron que ser trasladados por algún motivo: 3 pacientes necesitaron ingresar para estudio (diagnóstico de leishmaniosis visceral, transfusión de hematíes por anemia y encefalopatía por virus BK), 9 pacientes necesitaron realización de pruebas hospitalarias (RMN, ecografía hepática, espirometrías, colonoscopias, broncoscopia y biopsia cutánea) y 1 paciente porque rechazó valoración mediante telemedicina.\n\nEl 96% de los pacientes eran VIH positivos y de estos el 94% recibía TAR (1 rechazaba el TAR, 2 eran ‘naive’ y 1 era controlador de élite). El 85% tenía CV indetectable (<50 copias/mL) con 532 CD4/μL de mediana (78 1669). El 15% tenía fracaso virológico (FV) por: resistencias por mutaciones reconocidas (1), falta de adherencia (2), toxicidad (1) y causas no especificadas (6). Con respecto al TAR, el 12% estaba con doble terapia y (todos con CV indetectable) y el 88% estaba con triple terapia (83% con CV indetectable) (figura 3). Respecto al FV y el tipo de tratamiento, 8 fracasaron con TDF/FTC y 2 fracasaron con ABC/3TC. En el tercer fármaco, 4 fracasaron con IP/p, 3 fracasaron con ITINN, y 3 fracasaron con INI.\n\nFigura 3 Tipos de TAR pautados.\n\nTAR: Terapia Antirretroviral; ITIAN: Inh. Transcr. Inversa Análogo de Nucleósidos; ITINN: Inh. Transcr. Inversa No-análoga de Nucleósidos; IP/p: Inhibidor de la proteasa potenciado con ritonavir (r) o cobicistat. INI: Inh. de la Integrasa; TDF/FTC: Tenofovir Disoproxil Fumarato/Emtricitabina; ABC/3TC: Abacavir/Lamivudina.\n\nEl 72% fue derivado para valorar inicio de tratamiento frente al VHC (tabla 2). Entre los que iniciaban tratamiento VHC había 1 paciente para valorar también inicio de TAR frente al VIH. Las sospechas de toxicidad por el TAR consultadas fueron ginecomastia, nefropatía y sudoración y diarrea (TDF/ FTC/LPV-R, TDF/FTC/RPV y ABC/3TC/RAL, respectivamente). Otros motivos de consulta fueron para valorar tuberculosis e inicio de antituberculosos, valorar seguimiento de serológico (RPR) en lúes tratada previamente y revisar infección protésica precoz. Sólo hubo 1 paciente que se negó a ser valorado por telemedicina y había sido remitido para seguimiento de VIH.\n\nTabla 2 Motivos de remisión a telemedicina.\n\nMotivo de consulta\tn\t%\t\nTratamiento del VHC y seguimiento\t56\t74\t\nSeguimiento VIH\t10\t13\t\nToxicidad TAR\t4\t5\t\nInicio TAR\t3\t4\t\nOtros\t3\t4\t\nLos 68 pacientes con antecedentes de serología positiva para VHC estaban coinfectados con VIH. El 59% eran genotipo 1 (29 con subtipo 1a, 6 genotipo 1b y 5 desconocidos), el 3% eran genotipo 2, el 15% eran genotipo 3 (6 con subtipo 3a), el 16% eran genotipo 4 y del 7% se desconoce el genotipo. La carga viral recogida al diagnóstico del VHC era de una mediana de 3.200.000 copias/ml (620-27.000.000 copias/ml). En cuanto al grado de fibrosis que presentaban previamente a la valoración de las consultas el 41% tenía grado F0-1, el 18% tenía grado F2, el 19% tenía grado F3, el 19% tenía grado F4 y en el 3% se desconocía el grado de fibrosis. El 10% ya tenía previamente respuesta viral sostenida (RVS) del VHC y el 90% restante estaba coinfectado con VHC en el momento de la valoración.\n\nDe los que tenían ARN positivo de VHC, en el 23% no se inició tratamiento para el VHC (3 estaban remitidos por otro motivo y se desconocía situación del VHC, 3 se curaron espontáneamente antes de las consultas, 6 fueron remitidos a su centro de referencia por estar próxima su libertad del centro penitenciario, 1 consta como ‘evadido’ del centro penitenciario y 1 rechazó el tratamiento) y en el 77% restante se inició tratamiento con la pauta y duración recomendadas ofrecidas en la consulta de telemedicina (35 de ellos eran ‘naive’) y que se resume en la tabla 3.\n\nTabla 3 Tratamientos de VHC y tipo de seguimiento (entre paréntesis los que se trataron además con ribavirina).\n\nTipo de tratamiento\tSeguimiento posterior por:\t\nCentro penitenciario (n= 29)\tTelemedicina (n= 18)\t\nSFB/LDP (+RBV)\t17 (1)\t14 (1)\t\nSFB/VLP\t6\t0\t\nSFB/DCV (+RBV)\t0\t1 (1)\t\nSFB + RBV\t0\t1\t\nEBV/GZP (+RBV)\t4 (2)\t1\t\nGLE/PIB\t2\t0\t\nSMV + RBV + IFN\t0\t1\t\nDCV: Daclatasvir. EBV: Elbasvir. GLE: Glecaprevir. GZP: Grazoprevir. IFN: Interferón. LDP: Ledipasvir. PIB: Pibrentasvir. RBV: Ribavirina. SFB: Sofosbuvir. SMV: Simeprevir. VLP: Velpatasvir.\n\nEn total se objetivó una RVS del 90%, con un 8% de pérdidas y el 2% restante hace referencia al único paciente que no consiguió RVS y que además perdió el seguimiento (genotipo 1a, 7 millones de copias/ml, naive, F4, y, por tanto, candidato a triple terapia con ribavirina, pero por falta de recursos en el centro penitenciario se trató con sofosbuvir/ledipasvir durante 12 semanas). No ha habido ninguna reinfección documentada.\n\nHubo 27 pacientes que tuvieron cambios en el TAR y en el 70% de los casos fue para evitar interacciones con el tratamiento del VHC iniciado. El 44% de los fármacos cambiados fueron IP potenciado y el 66% fueron cambiados a un INI. Hubo 9 cambios de TDF/FTC a ABC/3TC y 1 cambio de ABC/3TC a TAF/FTC (tabla 4).\n\nTabla 4 Cambios de TAR y motivos de cambio\n\nMotivo del cambio\tTAR inicial (3º fármaco)\tTAR final (3º fármaco/doble terapia)\tn\t\nInteracción con el tratamiento VHC\tIP potenciado\tINI\t10\t\nITINN\t2\t\nITINN\tINI\t3\t\nITINN\t4\t\nInteracción con IBP\tIP potenciado\tINI\t1\t\nEfectos secundarios\tIP potenciado\tIP potenciado\t1\t\nITINN\tINI\t1\t\nITINN\tITINN + INI\t1\t\nINI\tINI\t1\t\nFracaso virológico\tITINN\tINI\t1a\t\nINI\tINI + IP potenciado\t2\t\nTAR: Terapia Antirretroviral; ITINN: Inhibidor transcriptasa inversa no-análoga de nucleósidos; IP: Inhibidor de la proteasa; INI: Inhibidor de la integrasa; IBP: Inhibidores de Bomba de Protones.\n\na Este paciente también iniciaba tratamiento para VHC por lo que estaba contraindicado el uso de IP potenciados.\n\nDISCUSIÓN\nNuestro estudio muestra que la telemedicina está creciendo cada vez más en nuestro medio debido al aumento del número de consultas solicitadas, mostrándose de esta forma como un elemento confiable por los pacientes y por los médicos que lo solicitan. Además, es una consulta que está resultando ser muy resolutiva. En los 3 primeros años se realizaron un menor número de primeras consultas con respecto a revisiones, lo cual puede ser debido a la cada vez mayor experiencia en dicha consulta y las facilidades encontradas para el seguimiento por parte del centro penitenciario. Esto nos hace pensar que en el futuro la consulta mostrará mayor resolución que lo hacen los datos ahora.\n\nSe evitó trasladar a un 83% de los pacientes, lo cual indica una mayor eficiencia y seguridad dada la condición de presos que tienen nuestros pacientes atendidos. León et al encontró un 2% de pacientes que se negaron a la consulta de telemedicina frente a nuestro 1% y en este mismo estudio un 85% lo seguirían usando en el futuro y, aunque no fue objeto de nuestro estudio, nos pareció interesante que un 32% vió que la re lación con el médico se dificultaba, lo cual habría que tener en cuenta pues se pudiera deteriorar la relación médico-paciente en estos pacientes a más largo plazo [3].\n\nEl 96% de nuestros pacientes estaban infectados por el VIH y de estos no se cumplía el objetivo 90-90-90 de Onusida en la primera valoración en consulta porque sólo el 85% de los que recibían tratamiento tenían carga viral indetectable (aunque esto depende del corte de carga viral puesto que el 92% de nuestros pacientes tenían <200 copias/mL), al igual que tampoco se cumplía en el estudio estadounidense de Young et al, donde previo a la telemedicina sólo tenían supresión viral un 58% y que tras el uso de la telemedicina la proporción de pacientes con carga viral indetectable llegó al 92% [4].\n\nPor tanto, podríamos considerar las prisiones uno de los nichos de VIH a tener en cuenta a la hora de optimizar los recursos y la asistencia sanitaria y, de hecho, en diversos estudios en EE.UU. se ha objetivado que personas con características similares a las personas encarceladas (minorías raciales o étnicas, alcoholismo, usuarios de drogas vía parenteral, menor número de consultas al año, vivir eventos estresantes, perfiles psicosociales desfavorables), suelen tener un diagnóstico más tardío, un estadío más avanzado e inician TAR más tarde con un abandono más frecuente, lo cual ha motivado programas sanitarios específicos en esas poblaciones [12, 16-22]. En estos casos la telemedicina podría promocionarse como un complemento óptimo a la hora de conseguir el objetivo de erradicar la epidemia de VIH dadas las evidencias arrojadas.\n\nEn cuanto al VHC, la asistencia de un especialista en infecciosas en estos pacientes consiguió pautar tratamientos adecuados con los que conseguir altas tasas de RVS, aunque en ocasiones no se inició el tratamiento más indicado por falta de fármacos en las instalaciones del centro penitenciario y el único caso en el que no se consiguió RVS fue por este motivo (ausencia del combo ombitasvir, paritaprevir, ritonavir, dasabuvir con ribavirina).\n\nSe inició TAR en un 3% y se cambió en un 40%, porcentajes algo diferentes comparándolo con el estudio de León et al [3] donde el 7% inició el TAR y el 28% de los pacientes cambiaron de TAR, en parte porque el 70% de los cambios en nuestro estudio fue por el inicio de AAD.\n\nCon los datos del estudio parece evidente que el manejo de estos pacientes por telemedicina es posible sin aumentar efectos adversos, aumentando la eficiencia al disminuir costes en transporte y personal de seguridad y aumentando la seguridad ciudadana al evitar el transporte entre centros. Además, este estudio permite llegar a pensar que el seguimiento de estas infecciones crónicas podría llegar a hacerse adecuadamente desde atención primaria mediante telemedicina con un especialista en infecciosas dado el progresivo aumento de volumen de pacientes infectados (1.000 nuevos pacientes al año en Madrid, siendo 15 en Alcorcón) y la disminución de complejidad y comorbilidad de estos pacientes dada la eficacia de la TAR.\n\nEl estudio realizado tiene las limitaciones propias de un estudio descriptivo basado en una cohorte retrospectiva de donde no podemos extraer conclusiones definitivas. Tampoco pudimos extraer todos los datos de las historias, y además hubo pacientes que se perdieron en el seguimiento y lo cual imposibilita tener los datos exactos en lo que a tasa de RVS se refiere.\n\nFinalmente, podemos afirmar que en nuestra experiencia la mayoría de los pacientes del centro penitenciario atendidos en la teleconsulta de enfermedades infecciosas tienen infección por VIH. Esta modalidad de consulta tiene una demanda creciente, evita traslados al hospital y cumple criterios de elevada resolución. El motivo de consulta más frecuente fue sobre el tratamiento del VHC y más de la tercera parte de los pacientes precisó cambio de TAR.\n\nAGRADECIMIENTOS\nA todo el servicio de Medicina Interna del Hospital de Alcorcón por su entrega, dedicación y apoyo.\n\nFINANCIACIÓN\nLos autores declaran que no han recibido financiación para la realización de este trabajo.\n\nCONFLICTOS DE INTERESES\nNinguno.\n==== Refs\n1 Bashshur RL , Timothy GR , Shannon GW \nTelemedicine: A new health care delivery system . Annu Rev Public Health . 2000 ; 21 :613 -37 . doi:10.1146/annurev.publhealth.21.1.613 10884967 \n2 Gras G \nUse of telemedicine in the management of infectious diseases . Med Mal Infect . 2018 ; 48 (4 ) 231 –7 . doi:10.1016/j.med-mal.2018.01.005 29452936 \n3 León A , Cáceres C , Fernández E , Chausa P , Martin M , Codina C et al \nA new multidisciplinary home care telemedicine system to monitor stable chronic human immunodeficiency virus-infected patients: a randomized study . PloS One . 2011 ; 6 (1 ): e14515 . doi:10.1371/journal.pone.0014515 21283736 \n4 Young JD , Patel M , Badowski M , Mackesy-Amiti ME , Vaughn P , Shicker L et al \nl. Improved virologic suppression with HIV subs-pecialty care in a large prison system using telemedicine: an observational study with historical controls . Clin Infect Dis \n2014 ;59 (1 ):123 –6 . doi:10.1093/cid/ciu222 24723283 \n5 Wade VA , Karmon J , Eliott JA , Hiller JE \nHome videophones impro-ve direct observation in tuberculosis treatment: a mixed methods evaluation . PloS One \n2012 ;7 (11 ): e50155 . doi:10.1371/journal.po-ne.0050155 23226243 \n6 Whitten P , Love B \nPatient and provider satisfaction with the use of telemedicine: overview and rationale for cautious enthusiasm . J Postgrad Med . 2005 ; 51 (4 ):294 -300 .16388172 \n7 Parmar P , Mackie D , Varghese S , Cooper C \nUse of telemedicine te-chnologies in the management of infectious disease: A review . Clin Inf Dis . 2015 ; 60 (7 ):1084 -94 . doi:10.1093/cid/ciu1143 \n8 Eron L \nTelemedicine: The future of outpatient therapy? \nClin Inf Dis . 2010 ; 51 (S2 ): S224 -S230 . doi:10.1086/653524 \n9 Arora S , Thornton K , Murata G , Deming P , Kalishman S , Dion D et al \nOutcomes of treatment for hepatitis C virus infection by pri-mary care providers . N Engl J Med . 2011 ; 364 (23 ): 2199 -207 . doi:10.1056/NEJMoa1009370 21631316 \n10 Kitahata MM , Koepsell TD , Deyo RA , Maxwell CL , Dodge WT , Wag-ner EH \nPhysicians’ experience with the acquired immunodeficien-cy syndrome as a factor in patients’ survival . N Engl J Med \n1996 ; 334 :701 –6 . doi:10.1056/NEJM199603143341106 8594430 \n11 Laine C , Markson LE , McKee LJ , Hauck WW , Fanning TR , Turner BJ \nThe relationship of clinic experience with advanced HIV and survi-val of women with AIDS . AIDS . 1998 ; 12 :417 –24 .9520172 \n12 Delgado J , Heath KV , Yip B , Marion S , Alfonso V , Montaner JS et al \nHighly active antiretroviral therapy: physician experience and en-hanced adherence to prescription refill . Antivir Ther \n2003 ; 8 :471 –8 .14640395 \n13 Landon BE , Wilson IB , McIness K , Landrum MB , Hirschhorn LR , Marsden PV et al \nPhysician specialization and the quality of ca-re for human immunodeficiency virus infection . Arch Intern Med \n2005 ; 165 :1133 –9 . doi:10.1001/archinte.165.10.1133 15911726 \n14 Eron L , King P , Marineau M , Yonehara C \nTreating acute infections by telemedicine in the home . Clin Infect Dis . 2004 ; 39 :1175 -81 . doi:10.1086/424671 15486842 \n15 Carrión JA \nUtilidad del fibroscan para evaluar la fibrosis hepática . Gastroenterol Hepatol . 2009 ; 32 : 415 -23 . doi:10.1016/j.gastro-hep.2009.01.178 19477552 \n16 CDC \nLate versus early testing of HIV, 16 sites, United States, 2000–2003 . MMWR Morb Mortal Wkly Rep \n2003 ; 52 :581 –6 .12836626 \n17 Keruly JC , Moore RD \nImmune status at presentation to care did not improve among antiretroviral-naive persons from 1990 to 2006 . Clin Infect Dis \n2007 ; 45 :1369 –74 . doi:10.1086/522759 17968837 \n18 Lemly DC , Shepherd BE , Hulgan T , Rebeiro P , Stinnette S , Blackwell RB et al \nRace and sex differences in antiretroviral therapy use and mortality among HIV-infected persons in care . J Infect Dis \n2009 ; 199 :991 –8 . doi:10.1086/597124 19220139 \n19 Gebo KA , Fleishman JA , Conviser R , Reilly ED , Korthuis PT , Moore RD et al \nRacial and gender disparities in receipt of highly active antiretroviral therapy persist in a multistate sample of HIV patients in 2001 . J Acquir Immune Defic Syndr \n2005 ; 38 :96 –103 .15608532 \n20 Palacio H , Kahn JG , Richards TA , Morin SF \nEffect of race and/or ethnicity in use of antiretrovirals and prophylaxis for opportunis-tic infection: a review of the literature . Public Health Rep \n2002 ; 117 :233 –51 ; discussion 231–2. doi:10.1093/phr/117.3.233 12432135 \n21 Li X , Margolick JB , Conover CS , Badri S , Riddler SA , Witt MD et al \nInterruption and discontinuation of highly active antiretroviral therapy in the Multicenter AIDS Cohort Study . J Acquir Immune Defic Syndr \n2005 ; 38 :320 –8 .15735452 \n22 Pence BW , Ostermann J , Kumar V , Whetten K , Thielman N , Mu-gavero MJ \nThe influence of psychosocial characteristics and race/ ethnicity on the use, duration, and success of antiretroviral thera-py . J Acquir Immune Defic Syndr \n2008 ; 47 :194 –201 . doi:10.1097/QAI.0b013e31815ace7e 17971712\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0214-3429",
"issue": "32(6)",
"journal": "Revista espanola de quimioterapia : publicacion oficial de la Sociedad Espanola de Quimioterapia",
"keywords": null,
"medline_ta": "Rev Esp Quimioter",
"mesh_terms": "D000328:Adult; D015658:HIV Infections; D019698:Hepatitis C, Chronic; D006801:Humans; D008297:Male; D008875:Middle Aged; D011330:Prisons; D012189:Retrospective Studies; D017216:Telemedicine",
"nlm_unique_id": "9108821",
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"pages": "539-544",
"pmc": null,
"pmid": "31642638",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": "21631316;15735452;15486842;19477552;17971712;10884967;21283736;16388172;8594430;12432135;19220139;24723283;25516192;20731581;23226243;12836626;15911726;9520172;29452936;17968837;15608532;14640395",
"title": "Telemedicine, prison and illness associated with HIV.",
"title_normalized": "telemedicine prison and illness associated with hiv"
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"abstract": "BACKGROUND\nMooren ulcer has been considered as an idiopathic autoimmune keratitis. However, it has been in some cases suggested to be associated with hepatitis C, although the evidence is very vague.\n\n\nMETHODS\nWe present a case of a man who was diagnosed with a primary Mooren ulcer in his right eye. The eye became blind despite of intensive treatment with local medications and extensive surgical procedures. After 10 years, the patient was diagnosed with the same disease, now in his left, previously healthy eye. There was no history that would suggest a secondary Mooren ulcer, but a chronic hepatitis C infection was detected. Treatment was targeted against hepatitis C (ribavirin and interferon) in addition to immunosuppressive medical and surgical treatment which resulted in a full and more than 6 years lasting remission of the disease.\n\n\nCONCLUSIONS\nWhether the immunomodulatory and immunosuppressive medication against hepatitis C was the key reason for the good results in the treatment of the second eye, remains elusive. The causality of hepatitis C with respect to the pathogenesis of Mooren ulcer on this patient remains open, but should be considered as one of the possible etiological factors of the disease.",
"affiliations": "Department of Ophthalmology, Turku University Hospital, PO Box 52, FIN-20521, Turku, Finland. vesa.aaltonen@tyks.fi.;Department of Ophthalmology, Turku University Hospital, PO Box 52, FIN-20521, Turku, Finland.;Department of Rheumatology, Division of Medicine, Turku University Hospital, Box 52, FIN-20521, Turku, PO, Finland.;Department of Ophthalmology, Turku University Hospital, PO Box 52, FIN-20521, Turku, Finland.;Department of Ophthalmology, Turku University Hospital, PO Box 52, FIN-20521, Turku, Finland.",
"authors": "Aaltonen|Vesa|V|http://orcid.org/0000-0002-0136-9999;Alavesa|Mari|M|;Pirilä|Laura|L|;Vesti|Eija|E|;Al-Juhaish|Mohammad|M|",
"chemical_list": "D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C417083:peginterferon alfa-2b",
"country": "England",
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"doi": "10.1186/s12886-017-0633-x",
"fulltext": "\n==== Front\nBMC OphthalmolBMC OphthalmolBMC Ophthalmology1471-2415BioMed Central London 63310.1186/s12886-017-0633-xCase ReportCase report: bilateral Mooren ulcer in association with hepatitis C http://orcid.org/0000-0002-0136-9999Aaltonen Vesa +358 2 313000vesa.aaltonen@tyks.fi 12Alavesa Mari mari.alavesa@tyks.fi 1Pirilä Laura laura.pirila@tyks.fi 34Vesti Eija eija.vesti@tyks.fi 12Al-Juhaish Mohammad mohammad.al-juhaish@tyks.fi 11 0000 0004 0628 215Xgrid.410552.7Department of Ophthalmology, Turku University Hospital, PO Box 52, FIN-20521 Turku, Finland 2 0000 0001 2097 1371grid.1374.1Department of Ophthalmology, University of Turku, FIN-20014 Turku, Finland 3 0000 0004 0628 215Xgrid.410552.7Department of Rheumatology, Division of Medicine, Turku University Hospital, Box 52, FIN-20521 Turku, PO Finland 4 0000 0001 2097 1371grid.1374.1Department of Internal Medicine, University of Turku, FIN-20014, Turku, Finland 6 12 2017 6 12 2017 2017 17 23912 3 2017 27 11 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nMooren ulcer has been considered as an idiopathic autoimmune keratitis. However, it has been in some cases suggested to be associated with hepatitis C, although the evidence is very vague.\n\nCase presentation\nWe present a case of a man who was diagnosed with a primary Mooren ulcer in his right eye. The eye became blind despite of intensive treatment with local medications and extensive surgical procedures. After 10 years, the patient was diagnosed with the same disease, now in his left, previously healthy eye. There was no history that would suggest a secondary Mooren ulcer, but a chronic hepatitis C infection was detected. Treatment was targeted against hepatitis C (ribavirin and interferon) in addition to immunosuppressive medical and surgical treatment which resulted in a full and more than 6 years lasting remission of the disease.\n\nConclusions\nWhether the immunomodulatory and immunosuppressive medication against hepatitis C was the key reason for the good results in the treatment of the second eye, remains elusive. The causality of hepatitis C with respect to the pathogenesis of Mooren ulcer on this patient remains open, but should be considered as one of the possible etiological factors of the disease.\n\nKeywords\nMooren ulcerKeratitisHepatitis CImmunomodulationImmunosuppressionFinnish Eye Foundationissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nMooren ulcer is a rare, unilateral or bilateral, painful and chronic corneal ulcer. It begins with an inflammation of conjunctiva and episclera and a peripheral corneal ulcer near the limbus. The ulcer then progresses circumferentially and centrally and may destroy the corneal stroma leaving behind only a thin fibrovascular membrane and an intact Descemet’s membrane. As a devastating complication, Mooren ulcer frequently results in a perforation of the eye [1]. The etiological factors leading to Mooren ulcer are not understood. Corneal surgery, trauma, infection, and also parasitic infections and hepatitis C has been suggested in the literature to take part in the cascade leading to Mooren ulcer [1–8]. However, there is clear evidence that suggests that Mooren ulcer is an autoimmune disorder, directed against the cornea [1]. In general, the medical treatment of Mooren ulcer typically includes first topical and systemic immunosuppression. Additional surgical approaches often include a conjunctival excision, but different types of keratoplasty and keratotomy have also been used, together with different types of patches.\n\nCase presentation\nThe patient is a 72 years old male with a previous medical history showing dermatitis herpetiformis which, with gluten-free diet remained asymptomatic. He had been diagnosed with a Mooren ulcer in his right eye in 2000 (Fig. 1a) with devastating end results. At that time, an internist was consulted but no etiological explanations were found. Initial medical interventions for the right eye included p.o. and topical cyclosporine, p.o. prednisolone, chloramphenicol-hydrocortisone caproate drops and aprotinin drops. Since the ulcer continued to progress (Fig. 1b), a tarsorrhaphy and subsequently a conjunctival flap were performed to cover the ulcer. As these failed (Fig. 1c), a corneoscleral transplantation combined with cataract extraction was performed 6 months after the first symptoms. A fistula developed postoperatively, which was operated a total of 29 times including re-suturations and different types of patches (tissue glue, amniotic membrane and scleral transplants) during early 2002. Later in 2002, a sterile ulcer and a spontaneous perforation developed and a lamellar corneal transplantation was performed without complications (Fig. 1d). However, in 2004, the patient’s right eye spontaneously perforated which was treated with re-suturation and amniotic membrane transplantation. The end-stage was phthisis and visual acuity (VA) of only faint sense of light in March 2006 (Fig. 1e).Fig. 1 Clinical photographs of the (a-e) right and (f-j) left eye of the same patient showing developing Mooren ulcer (a-b and f-h) and the end results after different treatment strategies for right (c-e) and left (i-j) eyes. Arrows point to the peripheral ulcer ends and arrowheads point to deeper ulcers threatening to perforate the cornea\n\n\n\n\nThe patient arrived to the hospital again in January 2010 reporting redness and pain in his previously healthy left eye. He had VA 0.7 and biomicroscopy showed an oval ulcer with sharp borders in the nasal cornea near limbus, with slight local chemosis in the conjunctiva of the left eye. Bacterial cultures were negative, and there was no preceding trauma. Despite of the patient’s medical history, a marginal ulcer was diagnosed. Dexamethasone-chloramphenicol (D-C) drops and Chloramphenicol ointment were prescribed. Plasma aspartate aminotransferase and alanine aminotransferase were slightly elevated. After 3 weeks from the onset of the symptoms, the ulcer had progressed circumferentially and centrally as a crescent shaped ulcer with steep central borders. In the center of the ulcer there was another deeper ulcer with steep margins and an epithelial defect. The stroma had melted to the level of Descemet membrane and limbus. There was conjunctival inflammation, but the sclera was intact. A senior ophthalmologist reached the diagnosis of Mooren ulcer (Fig. 1f). The diagnosis of Mooren ulcer was established by elimination of other etiologies for peripheral ulcerative keratitis (PUK). There was no evidence of microbial etiology, trauma, or exposure keratopathy and no findings suggesting rosacea (blepharitis or rash). Terrien marginal degeneration was excluded since the location of that degeneration is in superior cornea, ulcus does not exist, and it does not progress centrally. Also, in Fuchs superficial marginal keratitis, the epithelium is not affected. Pellucid marginal degeneration is located in inferior cornea and, like in Senile furrow degeneration, there is no inflammation. Rheumatoid arthritis may cause similar findings as in the presented patient, but sclera was not involved, and there was no evidence of this condition in clinical evaluation. In addition, other PUK’s typically spare the limbus, which is involved in Mooren ulcer as was in the presented case also. Other systemic etiologies were ruled out by clinical evaluation by an internist and negative laboratory results. Systemic conditions associated with PUK, include infections (tuberculosis, syphilis, gonorrhea, borreliosis, bacillary dysentery, herpes zoster, AIDS, and hepatitis C), rheumatoid arthritis, systemic lupus erythematosus, Wegener granulomatosis, polyarteritis nodosa, relapsing polychondritis, scleroderma, progressive systemic sclerosis, Sjögren syndrome, Beçhet’s disease, sarcoidosis, α1-antitrypsin deficiency, malignancy and inflammatory bowel disease [9, 10].\n\nThe treatment continued with D-C drops and artificial tears. Unfortunately the patient did not come to the controls. After 5 weeks from the onset the patient eventually showed up. There was a large curved vertical ulcer in the nasal cornea which included a deep 2.5 × 1.7 mm ulcer extending to the Descemet membrane (Fig. 1g).\n\nA conjunctival resection was performed during the same day. Further therapy included a therapeutical contact lens, 0.05% cyclosporine drops q6h., D-C drops q6h., ofloxacin drops q6h., methotrexate 10 mg and folic acid 5 mg weekly, and i.v. prednisolone 500 mg for three days, and subsequently p.o. prednisolone 60 mg daily. As a result of cortisone treatment the patient developed hyperglycemia which was treated with s.c. Detemir and Aspart Insulins. At this point, further therapy with systemic adalimumab or infliximab was considered.\n\nAs described above, the autoimmune diseases were excluded by clinical examination and serological tests. However, the patient’s current laboratory results showed an active hepatitis C infection (quantitative RNA 1.25 × 106 IU/ml, genotype 1b). The source of the infection was considered to be a blood transfusion during a surgery in 1977. The possible association of hepatitis C with Mooren ulcer was ignored in 2000 when the patient’s right eye was diagnosed and treated. Thus, the patient was not tested for hepatitis C at that time.\n\nAs the hepatitis C was confirmed, a gastroenterologist was consulted. He did not suggest treatment of hepatitis C because of high age of the patient and lack of typical hepatitis symptoms. However, since Hepatitis C has been considered as an etiological factor in Mooren ulcer, we decided to discontinue methotrexate which the patient had had only one weekly dose, and asked gastroenterologist to start the treatment for hepatitis C. This took place 6.5 weeks after onset of the symptoms in the left eye. The treatment included peginterferon alfa-2b (PegIntron) 100 μg weekly and ribavirin (Copegus) 1000 mg derived into two doses (400 mg + 600 mg) daily, which is a normal regime used for Hepatitis C treatment. Therapeutic contact lens, cyclosporine drops, D-C drops and ofloxacine drops were continued and oral prednisolone was reduced 5 mg every 4 days. In the control after 12 days from the first dose of interferon the nasal ulcer was deeper (Fig. 1h). During the same day, an amniotic membrane was sutured to cover the ulcer, and the oral prednisolon was raised to 60 mg and later tapered more slowly. As a side effect of the treatments, the patient developed neutropenia which was treated with pegfilgrastim (Neulasta). The patient did not respond fully to the combination treatment with interferon and ribavirin since after 24 weeks of treatment the hepatitis C quantitative RNA result was 0.36 × 106 IU/ml (in the beginning of treatment was 1.25 × 106 IU/ml). However, the above mentioned procedures rapidly and permanently stabilized the ulcer (Fig. 1i and j) and the systemic and topical drugs could be terminated. After 6 years of follow up, the eye is still healthy.\n\nDiscussion and conclusions\nIn conclusion, the only major difference in the initial treatment strategies between the patient’s right and left eye was interferon combined with ribavirin. The treatment of the right eye was unsuccessful despite of exhaustive efforts. In contrast, the left eye rapidly and permanently recovered with the treatment. The hepatitis C persisted, albeit with reduced viral count. Previously, Wilson et al. described two patients with Mooren type ulceration in association of chronic hepatitis C infection. In both patients, the corneal disease improved when interferon alpha-2b treatment for chronic active hepatitis. In one of these patients, the corneal disease worsened when the treatment was discontinued, and improved again when the treatment continued again [3]. Furthermore, Moazami et al. described a patient with Mooren ulcer and hepatitis C and showed an improvement of the ulcer which correlated with normalization of the patient’s liver function test [4]. Interestingly, Erdem et al. reported two Mooren ulcer patients who were treated with topical Interferon alpha-2a, and the lesions resolved within 10 days without recurrence. It was not reported whether the patients had Hepatitis C or not [11]. This result may suggest that it is possible that the positive improvement may be due to direct immunomodulation by interferon. However, this does not exclude the possibility of association of Hepatitis C with Mooren ulcer, or improvement of the lesion with the Hepatitis C treatment. Thus, the causality of hepatitis C with respect to the pathogenesis of Mooren ulcer in our patient remains open but possible. Since autoimmune mechanisms may be involved in the pathogenesis of Mooren ulcer [6, 7], the successful treatment results were possibly directly due to immunomodulatory properties of interferon combined with immunosuppression with cortisone and cyclosporine.\n\nAbbreviations\nD-CDexamethasone-chloramphenicol\n\nRNARibonucleic acid\n\nVAVisual acuity\n\nAcknowledgements\nNot applicable.\n\nFunding\nGrants from the Finnish Eye Foundation.\n\nAvailability of data and materials\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nAuthors’ contributions\nVA was responsible for obtaining consent, discussion with ethics committee, acquiring the data and drafting the manuscript. MA, LP, EV and MJ established the clinical diagnosis with VA and assisted in drafting and critically revised the manuscript. All authors approved the final version of the manuscript.\n\nEthics approval and consent to participate\nEthics committee of Turku University Hospital waived the need for formal approval in this case since no ethical assessment or approval by an independent review board is mandatory for a case report in Finland (Medical Research Act 1999/488, revised by 2004/295 and 2010/794). Verbal and written consent has been obtained from the patient.\n\nConsent for publication\nVerbal and written consent has been obtained from the patient for the publication of this case report and all accompanying images.\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. Srinivasan M Zegans ME Zelefscky JR Kundu A Lietman T Whitcher JP Clinical characteristics of Mooren’s ulcer in South India Br J Ophthalmol 2007 5 570 575 10.1136/bjo.2006.105452 \n2. Wilson SE Lee WM Murakami C Weng J Moninger GA Mooren’s corneal ulcer and hepatitis virus infection (letter) N Engl J Med 1993 329 62 10.1056/NEJM199307013290118 8505955 \n3. Wilson SE Lee WM Murakami C Weng J Moninger GA Mooren-type hepatitis C virus-associated corneal ulceration Ophthalmology 1994 101 736 745 10.1016/S0161-6420(94)31291-7 7512254 \n4. Moazami G Auran JD Florakis GJ Wilson SE Srinivasan DB Interferon treatment of Mooren's ulcers associated with hepatitis C Am J Ophthalmol 1995 119 365 366 10.1016/S0002-9394(14)71182-1 7532917 \n5. Pluznik D Butrus SI Hepatitis C-associated peripheral corneal ulceration. Rapid response to intravenous steroids Cornea 2001 20 888 889 10.1097/00003226-200111000-00023 11685073 \n6. Kafkala C Choi J Zafirakis P Baltatzis S Livir-Rallatos C Rojas B Mooren ulcer: an immunopathologic study Cornea 2006 25 667 673 10.1097/01.ico.0000214216.75496.7e 17077658 \n7. Tandon R Chawla B Verma K Sharma N Titiyal JS Outcome of treatment of mooren ulcer with topical cyclosporine a 2% Cornea 2008 27 859 861 10.1097/ICO.0b013e3181702d0c 18724142 \n8. Tsoumani A Theopistos V Katsanos K Asproudis I Tsianos EV Treatment and non-treatment related ocular manifestations in patients with chronic hepatitis B or C Eur Rev Med Pharmacol Sci 2013 17 1123 1131 23661529 \n9. Sangwan VS Zafirakis P Foster CS Mooren’s ulcer: current conceps in management Indian J Ophthalmol 1997 45 7 17 9475006 \n10. Dana MR Qian Y Hamrah P Twenty-five-year panorama of corneal immunology: emerging concepts in the immunopathogenesis of microbial keratitis, peripheral ulcerative keratitis, and corneal transplant rejection Cornea 2000 19 625 643 10.1097/00003226-200009000-00008 11009315 \n11. Erdem U Kerimoglu H Gundogan FC Dagli S Treatment of Mooren’s ulcer with topical administration of interferon alfa 2a Ophthalmology 2007 114 446 449 10.1016/j.ophtha.2006.09.024 17198731\n\n",
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"medline_ta": "BMC Ophthalmol",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D003229:Conjunctival Diseases; D003320:Corneal Ulcer; D015828:Eye Infections, Viral; D006526:Hepatitis C; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008297:Male; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin",
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"title": "Case report: bilateral Mooren ulcer in association with hepatitis C.",
"title_normalized": "case report bilateral mooren ulcer in association with hepatitis c"
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"abstract": "We report a case of acyclovir encephalopathy in a 77-year-old man who was introduced to peritoneal dialysis three years earlier. He developed herpes zoster and was treated with acyclovir (ACV) at 800 mg daily per oral. Two days later, he developed consciousness disturbance, hallucinations and asterixis. Acyclovir was stopped and continuous ambulatory peritoneal dialysis (CAPD) was switched to hemodialysis, which resulted in the resolution of his symptoms. Because the optimal dose of ACV varies among individuals depending on the bioavailability of ACV and metabolic enzyme activity, ACV encephalopathy can occur even when the acyclovir dose is modified according to the renal function of the affected patient. Because CAPD provides a poorer ACV clearance than hemodialysis, CAPD patients tend to have a higher risk of developing ACV encephalopathy and to recover more slowly. If CAPD patients develop ACV encephalopathy, a temporary change in the type of dialysis to hemodialysis should be considered.",
"affiliations": "Department of Neurology, Toranomon Hospital Kajigaya.;Department of Neurology, Toranomon Hospital Kajigaya.;Nephrology Center, Toranomon Hospital Kajigaya.;Nephrology Center, Toranomon Hospital Kajigaya.;Department of Neurology, Toranomon Hospital Kajigaya.;Department of Neurology, Toranomon Hospital Kajigaya.",
"authors": "Kawabe Matsukawa|Miho|M|;Suzuki|Yuya|Y|;Ikuma|Daisuke|D|;Suwabe|Tatsuya|T|;Uesaka|Yoshikazu|Y|;Sugimoto|Izumi|I|",
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"title": "Acyclovir encephalopathy in a peritoneal dialysis patient despite adjusting the dose of oral acyclovir: a case report.",
"title_normalized": "acyclovir encephalopathy in a peritoneal dialysis patient despite adjusting the dose of oral acyclovir a case report"
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"abstract": "Unusual Cause of Acute Kidney Failure in a Patient with Metastatic Bladder Carcinoma Undergoing Palliative Chemotherapy Abstract. Tumour lysis syndrome is a potentially life-threatening complication of cancer and its treatment. It mostly occurs in highly proliferative haematological neoplasms under cytotoxic therapy but can also be seen spontaneously and in solid neoplasms, particularly with high tumour burden and/or high chemosensitivity. The present case report describes a tumour lysis syndrome in a patient with metastatic bladder cancer with an elevated lactate dehydrogenase as only potential correlate of a high tumour burden.",
"affiliations": "Universitätsspital Zürich.;Kantonsspital St. Gallen.;Kantonsspital Münsterlingen.;Kantonsspital Münsterlingen.",
"authors": "Müller|Julia|J|;Kalbermatten Magaya|Natalie|N|;Traichel|Birgit|B|;Taverna|Christian|C|",
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"keywords": "Risikofaktoren; Tumorlysesyndrom; Tumour lysis syndrome; Urothelkarzinom; bladder cancer; risk factors; solid tumours; solide Tumoren",
"medline_ta": "Praxis (Bern 1994)",
"mesh_terms": "D058186:Acute Kidney Injury; D000970:Antineoplastic Agents; D006801:Humans; D010166:Palliative Care; D015275:Tumor Lysis Syndrome; D001749:Urinary Bladder Neoplasms",
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"references": null,
"title": "Unusual Cause of Acute Kidney Failure in a Patient with Metastatic Bladder Carcinoma Undergoing Palliative Chemotherapy.",
"title_normalized": "unusual cause of acute kidney failure in a patient with metastatic bladder carcinoma undergoing palliative chemotherapy"
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"abstract": "Early-onset sarcoidosis (EOS) and Blau syndrome are rare auto-inflammatory diseases characterized by a triad of skin rash, granulomatous uveitis, and symmetrical polyarthritis occurring in early childhood. In this paper, we describe a case report very interesting for the multidisciplinary management (pediatric rheumatologist and ophthalmologist), the challenging diagnosis and the difficult choice of the best treatment. We describe a case report of an 8-year old with recurrent episodes of acute uveitis that developed bilateral granulomatous panuveitis initially treated with topical and systemic steroids. Genetic testing for NOD2/CARD15 revealed a heterozygous mutation on exon 4 in the NBD domain (P268S/SNP5). Therefore, an incomplete EOS was suspected. Because uveitis worsening with multifocal chorioretinitis aggravation, intravenous boluses of methylprednisolone were administered. During the steroids tapering, she flared again, and methotrexate was started along with corticosteroids pulse therapy. However, new ocular granuloma appeared, macular oedema with poor visual outcome occurred, and therefore, adalimumab was added to MTX and steroids. After 6 months since the new therapy started, she had a complete visual recovery, and she was able to stop steroid treatment. At 2 years of follow-up, she is still in remission on treatment, and her visual acuity is normal. No side effects were observed. In our patient, we found a heterozygous mutation on exon 4 in the NBD domain (P268S/SNP5) of NOD2/CARD15 gene and an incomplete EOS was hypothesized. The role of this variant is currently under study. Adalimumab use dramatically changed the course of eye disease, prompting to stop steroid treatment and preserving visual acuity.",
"affiliations": "Rheumatology Unit, Department of Paediatrics, Anna Meyer Children's Hospital, University of Florence, Viale Pieraccini 24, 50139, Florence, Italy. achillemarino6@gmail.com.;Rheumatology Unit, Department of Paediatrics, Anna Meyer Children's Hospital, University of Florence, Viale Pieraccini 24, 50139, Florence, Italy.;Rheumatology Unit, Department of Paediatrics, Anna Meyer Children's Hospital, University of Florence, Viale Pieraccini 24, 50139, Florence, Italy.;Ophthalmology Unit, Department of Pediatrics, Anna Meyer Children's Hospital, University of Florence, Florence, Italy.;Ophthalmology Department, Polytechnic University of Marche, Ancona, Italy.;Ophthalmology Department, Polytechnic University of Marche, Ancona, Italy.;Rheumatology Unit, Department of Paediatrics, Anna Meyer Children's Hospital, University of Florence, Viale Pieraccini 24, 50139, Florence, Italy.;Rheumatology Unit, Department of Paediatrics, Anna Meyer Children's Hospital, University of Florence, Viale Pieraccini 24, 50139, Florence, Italy.",
"authors": "Achille|Marino|M|;Ilaria|Pagnini|P|;Teresa|Giani|G|;Roberto|Caputo|C|;Ilir|Arapi|A|;Piergiorgio|Neri|N|;Rolando|Cimaz|C|;Gabriele|Simonini|S|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000068879:Adalimumab",
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"issue": "36(1)",
"journal": "International ophthalmology",
"keywords": "Adalimumab; Blau syndrome; NOD2; Sarcoidosis; Uveitis",
"medline_ta": "Int Ophthalmol",
"mesh_terms": "D000068879:Adalimumab; D000893:Anti-Inflammatory Agents; D001168:Arthritis; D002648:Child; D002833:Choroiditis; D005260:Female; D006801:Humans; D015864:Panuveitis; D012507:Sarcoidosis; D013585:Synovitis; D016896:Treatment Outcome; D014605:Uveitis",
"nlm_unique_id": "7904294",
"other_id": null,
"pages": "129-135",
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"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15459013;12527755;22426692;19645408;17968944;19116920;7485374;18676502;23970817;16461435;22884558;19479837;21596301;17207093;11528384;4056967;24445386;11385577;21278066;21565531;11262655;18718560;24182856;24876985;12051406;11385576;21452272;20230816",
"title": "Successful treatment with adalimumab for severe multifocal choroiditis and panuveitis in presumed (early-onset) ocular sarcoidosis.",
"title_normalized": "successful treatment with adalimumab for severe multifocal choroiditis and panuveitis in presumed early onset ocular sarcoidosis"
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"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
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{
"abstract": "BACKGROUND\nPatients experiencing out-of-hospital cardiac arrest who remain comatose after initial resuscitation are at high risk of morbidity and mortality attributable to the ensuing post-cardiac arrest syndrome. Systemic inflammation constitutes a major component of post-cardiac arrest syndrome, and IL-6 (interleukin-6) levels are associated with post-cardiac arrest syndrome severity. The IL-6 receptor antagonist tocilizumab could potentially dampen inflammation in post-cardiac arrest syndrome. The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after out-of-hospital cardiac arrest of a presumed cardiac cause and thereby potentially mitigate organ injury.\n\n\nMETHODS\nEighty comatose patients with out-of-hospital cardiac arrest were randomly assigned 1:1 in a double-blinded placebo-controlled trial to a single infusion of tocilizumab or placebo in addition to standard of care including targeted temperature management. Blood samples were sequentially drawn during the initial 72 hours. The primary end point was the reduction in C-reactive protein response from baseline until 72 hours in patients treated with tocilizumab evaluated by mixed-model analysis for a treatment-by-time interaction. Secondary end points (main) were the marker of inflammation: leukocytes; the markers of myocardial injury: creatine kinase myocardial band, troponin T, and N-terminal pro B-type natriuretic peptide; and the marker of brain injury: neuron-specific enolase. These secondary end points were analyzed by mixed-model analysis.\n\n\nRESULTS\nThe primary end point of reducing the C-reactive protein response by tocilizumab was achieved since there was a significant treatment-by-time interaction, P<0.0001, and a profound effect on C-reactive protein levels. Systemic inflammation was reduced by treatment with tocilizumab because both C-reactive protein and leukocyte levels were markedly reduced, tocilizumab versus placebo at 24 hours: -84% [-90%; -76%] and -34% [-46%; -19%], respectively, both P<0.001. Myocardial injury was also reduced, documented by reductions in creatine kinase myocardial band and troponin T; tocilizumab versus placebo at 12 hours: -36% [-54%; -11%] and -38% [-53%; -19%], respectively, both P<0.01. N-terminal pro B-type natriuretic peptide was similarly reduced by active treatment; tocilizumab versus placebo at 48 hours: -65% [-80%; -41%], P<0.001. There were no differences in survival or neurological outcome.\n\n\nCONCLUSIONS\nTreatment with tocilizumab resulted in a significant reduction in systemic inflammation and myocardial injury in comatose patients resuscitated from out-of-hospital cardiac arrest. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03863015.",
"affiliations": "Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark (M.A.S.M., S.W., J.G., A.S.P.M., M.F., J.H.T., J.J., J.E.M., J.K., C.H.).;Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark (M.A.S.M., S.W., J.G., A.S.P.M., M.F., J.H.T., J.J., J.E.M., J.K., C.H.).;Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark (M.A.S.M., S.W., J.G., A.S.P.M., M.F., J.H.T., J.J., J.E.M., J.K., C.H.).;Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark (M.A.S.M., S.W., J.G., A.S.P.M., M.F., J.H.T., J.J., J.E.M., J.K., C.H.).;Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark (M.A.S.M., S.W., J.G., A.S.P.M., M.F., J.H.T., J.J., J.E.M., J.K., C.H.).;Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark (M.A.S.M., S.W., J.G., A.S.P.M., M.F., J.H.T., J.J., J.E.M., J.K., C.H.).;Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark (M.A.S.M., S.W., J.G., A.S.P.M., M.F., J.H.T., J.J., J.E.M., J.K., C.H.).;Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark (M.A.S.M., S.W., J.G., A.S.P.M., M.F., J.H.T., J.J., J.E.M., J.K., C.H.).;Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark (M.A.S.M., S.W., J.G., A.S.P.M., M.F., J.H.T., J.J., J.E.M., J.K., C.H.).;Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark (M.A.S.M., S.W., J.G., A.S.P.M., M.F., J.H.T., J.J., J.E.M., J.K., C.H.).",
"authors": "Meyer|Martin Abild Stengaard|MAS|;Wiberg|Sebastian|S|;Grand|Johannes|J|;Meyer|Anna Sina Pettersson|ASP|;Obling|Laust Emil Roelsgaard|LER|;Frydland|Martin|M|;Thomsen|Jakob Hartvig|JH|;Josiassen|Jakob|J|;Møller|Jacob Eifer|JE|;Kjaergaard|Jesper|J|;Hassager|Christian|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1161/CIRCULATIONAHA.120.053318",
"fulltext": "\n==== Front\nCirculation\nCirculation\nCIR\nCirculation\n0009-7322\n1524-4539\nLippincott Williams & Wilkins Hagerstown, MD\n\n33745292\n00004\n10.1161/CIRCULATIONAHA.120.053318\n10055\n10056\nOriginal Research Articles\nTreatment Effects of Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response After Out-of-Hospital Cardiac Arrest (The IMICA Trial)\nA Double-Blinded, Placebo-Controlled, Single-Center, Randomized, Clinical Trial\nMeyer Martin Abild Stengaard MD 1\nWiberg Sebastian MD, PhD sebastian.christoph.wiberg@regionh.dk\n1\nGrand Johannes MD, PhD johannes.grand@regionh.dk\n1\nMeyer Anna Sina Pettersson MD, PhD martin.as.meyer@gmail.com\n1\nObling Laust Emil Roelsgaard MD laust.emil.roelsgaard.obling.01@regionh.dk\n\nFrydland Martin MD, PhD martin.steen.frydland.01@regionh.dk\n1\nThomsen Jakob Hartvig MD, PhD jakob.hartvig.thomsen.01@regionh.dk\n1\nJosiassen Jakob MD jakob.josiassen@regionh.dk\n1\nMøller Jacob Eifer MD, PhD, DMSc jacob.moeller@regionh.dk\n12\nKjaergaard Jesper MD, PhD, DMSc jesper.kjaergaard.05@regionh.dk\n1\nHassager Christian MD, DMSc Christian.Hassager@regionh.dk\n13\n1 Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark (M.A.S.M., S.W., J.G., A.S.P.M., M.F., J.H.T., J.J., J.E.M., J.K., C.H.).\n2 Department of Cardiology, Odense University Hospital, Denmark (J.E.M.).\n3 Department of Clinical Medicine, University of Copenhagen, Denmark (C.H.).\nMartin Abild Stengaard Meyer, MD, Department of Cardiology (Section 2143), Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark. Email martin.abild.stengaard.meyer@regionh.dk\n22 3 2021\n11 5 2021\n143 19 18411851\n19 12 2020\n4 3 2021\n© 2021 The Authors.\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.\n\nSupplemental Digital Content is available in the text.\n\nBackground:\n\nPatients experiencing out-of-hospital cardiac arrest who remain comatose after initial resuscitation are at high risk of morbidity and mortality attributable to the ensuing post–cardiac arrest syndrome. Systemic inflammation constitutes a major component of post–cardiac arrest syndrome, and IL-6 (interleukin-6) levels are associated with post–cardiac arrest syndrome severity. The IL-6 receptor antagonist tocilizumab could potentially dampen inflammation in post–cardiac arrest syndrome. The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after out-of-hospital cardiac arrest of a presumed cardiac cause and thereby potentially mitigate organ injury.\n\nMethods:\n\nEighty comatose patients with out-of-hospital cardiac arrest were randomly assigned 1:1 in a double-blinded placebo-controlled trial to a single infusion of tocilizumab or placebo in addition to standard of care including targeted temperature management. Blood samples were sequentially drawn during the initial 72 hours. The primary end point was the reduction in C-reactive protein response from baseline until 72 hours in patients treated with tocilizumab evaluated by mixed-model analysis for a treatment-by-time interaction. Secondary end points (main) were the marker of inflammation: leukocytes; the markers of myocardial injury: creatine kinase myocardial band, troponin T, and N-terminal pro B-type natriuretic peptide; and the marker of brain injury: neuron-specific enolase. These secondary end points were analyzed by mixed-model analysis.\n\nResults:\n\nThe primary end point of reducing the C-reactive protein response by tocilizumab was achieved since there was a significant treatment-by-time interaction, P<0.0001, and a profound effect on C-reactive protein levels. Systemic inflammation was reduced by treatment with tocilizumab because both C-reactive protein and leukocyte levels were markedly reduced, tocilizumab versus placebo at 24 hours: –84% [–90%; –76%] and –34% [–46%; –19%], respectively, both P<0.001. Myocardial injury was also reduced, documented by reductions in creatine kinase myocardial band and troponin T; tocilizumab versus placebo at 12 hours: –36% [–54%; –11%] and –38% [–53%; –19%], respectively, both P<0.01. N-terminal pro B-type natriuretic peptide was similarly reduced by active treatment; tocilizumab versus placebo at 48 hours: –65% [–80%; –41%], P<0.001. There were no differences in survival or neurological outcome.\n\nConclusions:\n\nTreatment with tocilizumab resulted in a significant reduction in systemic inflammation and myocardial injury in comatose patients resuscitated from out-of-hospital cardiac arrest.\n\nRegistration:\n\nURL: https://www.clinicaltrials.gov; Unique identifier: NCT03863015.\n\nC-reactive protein\nheart arrest\ninflammation\nintensive care units\nmyocardial infarction\nCMECME\nOPEN-ACCESSTRUE\nSDCT\n==== Body\nClinical Perspective\n\nWhat Is New?\n\nSystemic inflammation is a major component of the post–cardiac arrest syndrome that develops after resuscitation from cardiac arrest, and IL-6 (interleukin 6) is associated with severity of post–cardiac arrest syndrome and mortality.\n\nIn the present phase II trial, we investigated whether blocking the IL-6 signaling pathway with tocilizumab, an IL-6 receptor antibody, could lessen systemic inflammation and possibly mitigate organ injury in patients resuscitated from out-of-hospital cardiac arrest.\n\nTocilizumab greatly diminished the levels of C-reactive protein, an unspecific marker of inflammation, during the initial days after resuscitation, and it is important to note that this was accompanied by reductions in troponin T, creatine kinase myocardial band, and N-terminal pro B-type natriuretic peptide.\n\nWhat Are the Clinical Implications?\n\nThis trial demonstrates the feasibility of reducing systemic inflammation after cardiac arrest and shows an apparent cardioprotective effect as seen by reduced levels of biomarkers of myocardial injury and stress in patients treated with tocilizumab.\n\nFurther studies are needed to determine whether these findings translate into clinical benefits for the patients.\n\nPatients resuscitated from out-of-hospital cardiac arrest (OHCA) who remain comatose at hospital admission are at high risk of morbidity and mortality, and the overall 30-day mortality remains at ≈50%.1 This has been attributed to the post–cardiac arrest syndrome (PCAS), which includes the 4 interacting components: systemic ischemia/reperfusion response, cerebral injury, myocardial dysfunction, and the persistent precipitating cause of the arrest.2 Despite emphasis on postresuscitation care by current guidelines,3,4 no specific therapies for mitigating PCAS have been implemented except for targeted temperature management.5 Consequently, research addressing specific components of PCAS is warranted. During cardiac arrest, patients are exposed to whole-body ischemia, which, after return of spontaneous circulation, is followed by reperfusion injury. Both ischemia and reperfusion injury trigger activation of inflammatory cascades leading to a systemic inflammatory response or sepsislike syndrome.6–9 High levels of inflammatory markers,9–11 including CRP (C-reactive protein)9 and IL-6 (interleukin-6),9 have been associated with an unfavorable outcome after OHCA, with IL-6 being associated with the severity of PCAS assessed by sequential organ failure assessment (SOFA) score in unconscious patients with OHCA.8 Levels of IL-6 have been shown to be independently associated with poor outcomes in unconscious patients with OHCA even after the adjustment for known risk markers.9\n\nIL-6 is a pleiotropic cytokine secreted by a variety of cells, including innate immune and endothelial cells, and the effects of IL-6 are abundant.12,13 IL-6 mediates fever and the acute phase response, increases vascular permeability, contributes to activation of the coagulation system, and can cause myocardial dysfunction.14 IL-6 is also involved in a range of pathological processes including tissue hypoxia, disseminated intravascular coagulation, and multiorgan failure,14 all of which represent parts of the systemic inflammatory response syndrome. As for the ischemia-reperfusion injury in myocardial infarction, IL-6 has been associated with the magnitude of myocardial injury, mortality, and adverse events.15–17\n\nBecause of the effect of IL-6 in many inflammatory diseases, pharmacological therapy to limit the function of IL-6 has been developed, including both IL-6 receptor antibodies (IL-6RA) and antibodies directed against IL-6 itself.18 Tocilizumab is an IL-6RA approved for the treatment of various rheumatic diseases and chimeric antigen receptor T cell–induced cytokine release syndrome.14,18 In addition, tocilizumab has been suggested to have beneficial effects against some autoimmune neurological disorders.19–22 Furthermore, in patients presenting with non–ST-segment–elevation myocardial infarction, a 1-hour infusion of 280 mg tocilizumab decreased the inflammatory response assessed by CRP levels, and further decreased myocardial injury assessed by troponin-T (TnT) levels23; it is important to note that no increased risk of adverse events was observed in patients receiving tocilizumab. Results are also awaited from a randomized clinical trial investigating the effects of tocilizumab on myocardial salvage after ST-segment–elevation myocardial infarction.24\n\nIn the IMICA trial (IL-6 Inhibition for Modulating Inflammation After Cardiac Arrest), we therefore studied whether a single 1-hour infusion of the IL-6RA tocilizumab initiated as soon as possible after hospital admission will reduce the systemic inflammatory response syndrome–like response assessed by high-sensitivity CRP (hsCRP) and leukocyte levels in unconscious patients with OHCA and thereby mitigate organ injury.\n\nMethods\n\nTrial Design\n\nThe trial was an investigator-initiated, randomized, placebo-controlled, double-blinded, single-center, clinical phase II trial. After the successful completion of screening procedures, patients were randomly assigned in a 1:1 fashion to receive IL-6RA or placebo after hospital admission. Before initiation, the trial was registered at https://www.clinicaltrials.gov; Unique identifier: NCT03863015. A comprehensive study protocol with in-depth description of trial rationale, design, safety, and statistical analyses plan has previously been published.25 The full protocol and statistical code will be available on reasonable request. Participant-level data will similarly be made available on reasonable request after full publication and approvals from relevant authorities.\n\nPatients and Randomization Procedure\n\nAdmitted patients with OHCA were screened for trial eligibility by the on-call physician and a dedicated team of research personnel, all medical doctors. Inclusion criteria (all required) were the following: OHCA of a presumed cardiac cause, age ≥18 years, unconsciousness (Glasgow Comma Scale<9), and sustained return of spontaneous circulation for >20 minutes. Exclusion criteria (all prohibitive) were the following: >240 minutes from return of spontaneous circulation until randomization, unwitnessed asystole, suspected or confirmed intracranial bleeding or stroke, pregnancy, temperature on admission <30 °C, persistent cardiogenic shock (defined as systolic blood pressure <90 mm Hg despite relevant interventions) that was not reversed within the inclusion window, any known disease making 180-day survival unlikely, known limitations in therapy, known prearrest Cerebral Performance Category of 3 to 4, known allergies to IL-6RA, known infections, and known hepatic cirrhosis.\n\nRandom assignments of eligible patients were performed using a web-based secure electronic Case Report System (Zenodotus eCRF). Blinding to the allocation sequence was upheld for all treating physicians and study coordinators throughout the trial.\n\nIntervention and Concomitant Care\n\nPatients were randomly assigned 1:1 to receive tocilizumab or placebo. Patients being allocated to IL-6RA received a 1-hour infusion of 8 mg of tocilizumab (RoActemra) per kg body weight (maximum dose 800 mg, ie, 40 mL of concentrate), the study drug was suspended in isotonic saline to a total volume of 100 mL. Patients being allocated to placebo received a 1-hour infusion of 100 mL of isotonic saline. The infusion of either IL-6RA or placebo was commenced in a blinded fashion at the earliest possible time after randomization.\n\nDuring the study period, patients received standard of care, including sedation with either propofol or midazolam (in case of profound hemodynamic instability) and fentanyl, at least until the completion of targeted temperature management of 36 °C for 24 hours, vasopressors and inotropes as needed, prophylactic antibiotics (intravenous piperacillin/tazobactam or, in the case of β-lactam allergy, cefuroxime) and any additional treatment at the discretion of the treating physician.\n\nTrial End Points\n\nPrimary Objective\n\nThe primary objective of the trial was to determine the efficacy of tocilizumab compared with placebo on reducing the CRP response in comatose patients resuscitated from OHCA as determined by the end point of daily hsCRP measurements from admission and until 72 hours. We would consider tocilizumab to have an effect on the CRP response, if there was a significant treatment-by-time interaction by mixed-model analysis (power calculation was based on a 30% reduction in CRP for the active group versus placebo; see Statistics). CRP was chosen as the primary end point because CRP levels were considered to reflect the biological effects of circulating IL-6, because IL-6 regulates CRP production.14 Accordingly, in this phase II trial, we rationalized that if CRP production was significantly reduced by treatment with tocilizumab, then the chosen dosage would also be sufficient in comatose patients resuscitated from OHCA to potentially allow for other IL-6–mediated effects to be present.\n\nSecondary Objective\n\nThe secondary objective of the trial was to determine the effects of tocilizumab on the dampening of inflammation, cardioprotection, neuroprotection, clinical end points including intensive care unit (ICU) length of stay, SOFA score (total and cardiovascular score26 on calendar days 1–3), hemodynamic data in the form of cardiac output and pulmonary capillary wedge pressure from right heart catheter, survival and neurological outcome characterized by cerebral performance category and modified Rankin scale at 30, 90, and 180 days (reported as n [%] with a cerebral performance category ≥3 and modified Rankin scale ≥4),27 and safety, as well. The biomarkers measured were inflammation: hsCRP and leukocytes; cardioprotection: TnT, creatine kinase myocardial band (CKMB) representing myocardial infarction/injury, and N-terminal pro B-type natriuretic peptide (NT-proBNP) representing myocardial stress; and neuroprotection: neuron-specific enolase (NSE).\n\nBiomarker Measurement Techniques and Assays\n\nhsCRP, leukocytes, TnT, CKMB, creatinine kinase, NT-proBNP, creatinine, and NSE were measured as routine biochemistry in a DS/EN ISO 15189 standardized laboratory by a COBAS 8000 (hsCRP, TnT, CKMB, creatinine kinase, NT-proBNP, creatinine, and NSE), and Sysmex XN (leukocytes); IL-6 was measured on EDTA samples from biobank that had not been thawed previously, using a BioRad 17-plex human cytokine assay. Biobank samples were spun at 20g for 10 minutes and plasma was then aliquoted and stored at –80 °C.\n\nApprovals and Monitoring\n\nBefore study initiation, the trial protocol, written information, and consent forms were approved by the regional ethics committee of The Capital Region of Denmark (Approval No. H-18037286), and the Danish Medicines Agency (Approval No. 2018-002686-19). A data handling agreement was approved by the legal department of Rigshospitalet (Approval No. VD-2019-26). Because patients were unconscious at the time of screening, a legal surrogate was consulted for informed consent before inclusion in the trial according to national legislation. Patients’ next of kin were informed and asked for consent at the earliest opportunity, as were those patients who survived. A second legal surrogate was also consulted for all patients in the follow-up period.\n\nThe study was conducted in adherence to national and international standards of good clinical practice and was externally monitored by the national good clinical practice unit at the Copenhagen Good Clinical Practice center.\n\nSafety\n\nPatients were followed for 180 days after randomization for the occurrence of adverse events (AEs). The following categories of AE were registered: bleeding, infection, renal impairment (a patient requiring continuous renal replacement therapy or intermittent hemodialysis), electrolytes (hypo- or hyperkalemia), metabolic disorders (hypo- or hyperglycemia), arrhythmia, seizures, and other (including readmissions, death attributable to withdrawal of life-sustaining therapy, and other AEs not covered by specific categories). An AE that resulted in death was life-threatening, required prolonged hospitalization, or resulted in significant disability was classified as a serious adverse event (SAE). All SAEs were evaluated by the sponsor-investigator, including for the possibility of suspected unexpected serious adverse reactions in accordance with national legislation.\n\nStatistics\n\nThe power calculation for the trial was based on a reduction in the primary end point, hsCRP of 30%, that is, 30% lower CRP levels in the active group versus placebo in the period after baseline/tocilizumab infusion.25 Tocilizumab has previously been shown to reduce hsCRP in patients with non–ST-segment–elevation myocardial infarction with a median area under the hsCRP curve reduction of 52%.23 However, because the systemic inflammatory response in a non–ST-segment–elevation myocardial infarction population is limited compared with an OHCA population,8,23 the assumption was made for a somewhat lesser reduction by tocilizumab in the present trial. A power of 0.81 would be achieved, assuming an α-level of 0.05, if 64 patients were included and data were available for all planned time points. Therefore, to account for mortality within the first 3 days, and blood samples missing, we decided to include 80 patients.\n\nReported results are based on the modified intention-to-treat population defined as all randomly assigned patients who received the intervention and for whom the next of kin did not refuse consent to the trial intervention and procedures. Statistical analyses were performed using SAS Enterprise Guide 7.1 (SAS-Institute Inc), and IBM SPSS Statistics 25 (IBM). Markers of inflammation and cardioprotection were log2-transformed and analyzed by baseline corrected repeated measurement mixed models (SAS, PROC MIXED). These values are reported as predicted geometric means and confidence limits after antilog and as relative differences in percent for select group comparisons at specific time points on the basis of the results provided by “lsmeans” in PROC MIXED; observed values for these variables are presented in Figures I–V in the Data Supplement). By default, PROC MIXED estimates missing values based on maximum likelihood inference. For the primary end point (CRP), a prespecified limit of >5% missingness was set for when to perform multiple imputations. The remainder of continuous variables were analyzed by Mann-Whitney U test and reported as median (interquartile range). Categorical variables were analyzed with Fisher exact tests and reported as n (%); for mortality, we applied log-rank test and Kaplan-Meier estimator. A P value of <0.05 was considered statistically significant.\n\nResults\n\nRecruitment and Patient Characteristics\n\nBetween March 4 and December 20, 2019, we screened 117 consecutive patients admitted to the Department of Cardiology, Rigshospitalet after OHCA. Of these, 85 were randomly assigned, and ultimately 80 patients were included in the modified intention-to-treat population (see Figure 1 for consort diagram). There was a balanced randomization with 39 patients randomly assigned to treatment with tocilizumab and 41 assigned to placebo with no major differences in patient baseline characteristics (see Table 1). With respect to the completeness of the data, for the primary end point, data were available for 97.2% of all planned time points (311 available of 320 planned, which also includes projected sampling of patients who died before completion of the sampling period). For the secondary end points, inflammatory and cardiac markers, the completeness was as follows: leukocytes 97%, TnT 95%, CKMB 95%, and NT-proBNP 95%. Because the missingness of data for the primary end point was less than the prespecified limit that would prompt multiple imputations, such were not performed.\n\nTable 1. Patient Characteristics\n\nFigure 1. Consort flow diagram. Adapted from Consort-Statement.org. All analyses were performed on the modified intention-to-treat population as depicted in the diagram. IMICA trial indicates IL-6 Inhibition for Modulating Inflammation After Cardiac Arrest; and incl., including.\n\nSystemic Inflammation\n\nThe primary end point of reducing the CRP response in patients treated with tocilizumab was achieved (Figure 2). In the tocilizumab group, CRP levels were reduced at 24 hours by 84% [90%; 76%] P<0.0001, at 48 hours by 94% [96%; 91%] P<0.0001, and at 72 hours by 96% [97%; 94%] P<0.0001; P<0.0001 for treatment-by-time interaction. Leukocytes were also reduced at 24 hours by 34% [46%; 19%] P = 0.0001, and at 48 hours by 23% [36%; 8%] P=0.004; P=0.0005 for treatment-by-time interaction.\n\nFigure 2. Systemic inflammation. A, CRP. B, Leukocytes. Results are presented as means with [95% confidence limit] based on predicted values from linear mixed-model analysis with baseline correction (PROC MIXED, SAS Institute Inc). *P≤0.0001, †P=0.004 for tocilizumab vs placebo at corresponding time points using the interaction term “group*time.” For additional illustrations of observed values please see Figures I and II in the Data Supplement. CRP indicates C-reactive protein.\n\nMyocardial Infarction/Injury and Myocardial Stress\n\nTnT and CKMB were both significantly reduced at 6 and 12 hours in the tocilizumab group (Figure 3). TnT was reduced at 6 hours by 33% [47%; 14%] P=0.0017, and at 12 hours by 36% [54%; 11%] P=0.0082, P=0.09 for treatment-by-time interaction. CKMB was reduced at 6 hours by 36% [47%; 21%] P<0.0001, and at 12 hours by 38% [53%; 19%] P=0.0006; P=0.0035 for treatment-by-time interaction. Furthermore, there was a trend for lower levels of both TnT and CKMB in the tocilizumab group at 24 hours (P=0.07 and P=0.05, respectively). Last, NT-proBNP was reduced by 65% [–80%; –41%] P=0.0002 in the tocilizumab group at 48 hours (see Figure 4).\n\nFigure 3. Myocardial infarction/injury. A, TnT. B. CKMB. Results are presented as means with [95% confidence limit] based on predicted values from linear mixed-model analysis with baseline correction (PROC MIXED, SAS Institute Inc). *P<0.01, †P<0.001 for tocilizumab vs placebo at corresponding time points using the interaction term “group*time.” For additional illustrations of observed values please see Figures III and IV in the Data Supplement. CKMB indicates creatine kinase myocardial band; and TnT, troponin T.\n\nFigure 4. Myocardial stress: NT-proBNP. Results are presented as means with [95% confidence limit] based on predicted values from linear mixed-model analysis with baseline correction (PROC MIXED, SAS Institute Inc). Shown P value is for tocilizumab vs placebo at 48 hours using the interaction term “group*time.” For additional illustrations of observed values please see Figure V in the Data Supplement. NT-proBNP indicates N-terminal pro B-type natriuretic peptide.\n\nSafety\n\nThe frequency of patients experiencing at least 1 AE or SAE was equal in the 2 groups (see Table 2), with 90% experiencing an AE and 51% experiencing an SAE in the tocilizumab group, and, in the placebo group, this was 98% and 51%, P=0.20 and P=1, respectively. Specifically, there was no group difference with respect to the frequency of an AE of infection (15% for tocilizumab and 24% for placebo, P=0.41). Nor was there a significant difference in the overall fraction of patients with an AE of infection classified as pneumonia. Last, there was no group difference either in the frequency of patients experiencing any of the prespecified SAE categories.\n\nTable 2. Clinical Outcomes and Safety\n\nClinical Outcomes\n\nThere were no group differences with respect to ICU length of stay, ventilator days, or SOFA total score on days 1 to 3. However, the SOFA Cardiovascular score was slightly lower in the tocilizumab group on day 3, with no difference on days 1 and 2. Also, there was a trend toward a lesser occurrence of a temperature >38 °C during the initial 72 hours in the tocilizumab group. Cardiac output and pulmonary capillary wedge pressure, which approximates left atrial pressure, did not differ between groups at 0 or 24 hours. The frequency of patients receiving renal replacement therapy (RRT) during ICU stay was 10 in the tocilizumab group and 3 for placebo, P=0.04 (a new-onset indication for RRT during ICU stay was registered as an AE). The mortality for patients receiving RRT in the ICU was 7 of 10 for tocilizumab and 3 of 3 for placebo. One patient in the placebo group was treated with peritoneal dialysis before OHCA. Surviving patients all regained native renal function and were discharged without dialysis from the ICU.\n\nMortality rates were similar in both groups at 30, 90, and 180 days after OHCA, with all deaths having occurred before 30 days and before discharge in both groups (see Figure 5). Likewise, there was no significant group difference in the frequencies of death or survival with an unfavorable neurological outcome, defined as a cerebral performance category of ≥3 or a modified Rankin scale ≥4, at neither of the investigated time points. The marker of neuronal damage, NSE, did not differ between groups at the measured time points of 48 and 72 hours, P=0.22 and P=0.39, respectively.\n\nFigure 5. Kaplan-Meier plot. Survival stratified by treatment arm from randomization until the end of the follow-up period of 180 days. OHCA indicates out-of-hospital cardiac arrest.\n\nDiscussion\n\nThe primary objective of the trial, a reduction in the CRP response in comatose patients resuscitated from OHCA by treatment with tocilizumab, was achieved. Furthermore, the tocilizumab group experienced a dampening of systemic inflammation as demonstrated by a reduction in leukocytes, and there was an apparent cardioprotective effect with a reduction in myocardial injury and myocardial stress. Also, in the tocilizumab group there was a slightly lower SOFA Cardiovascular score on day 3, and a trend for fewer patients experiencing a temperature >38 °C. There were no group differences in mortality, the distribution of unfavorable neurological outcomes, or in the predefined safety parameters.\n\nIn the present trial, CRP levels were dramatically reduced, and leukocytes approached normal values faster in patients treated with tocilizumab than with placebo. Although reduction in CRP in itself is not considered a therapeutic target, the marked reduction in CRP levels by IL-6 receptor blockage with tocilizumab illustrates that the dosage was of sufficient magnitude to effectively block the IL-6 receptors and limit the synthesis of acute-phase proteins in the liver, including CRP, even after resuscitation from OHCA.14 Before initiating the trial, this was considered a prerequisite for other IL-6–mediated effects to also be sufficiently lessened. Henceforth, the reduction in CRP should rightfully not be considered a reduction in inflammation, although CRP has been suggested to be active in inflammatory processes.28 However, the accompanying reduction in leukocytes suggests that there was an anti-inflammatory effect of IL-6 receptor blockage. This was further illustrated by the trend for a lesser occurrence in the tocilizumab group of a temperature >38 °C after cessation of targeted temperature management, which is a known entity that has been termed “rebound pyrexia.”29\n\nPatients in the tocilizumab group had a substantial lowering of the markers of myocardial injury, because both TnT and CKMB peaked at lower levels than those seen for placebo. A previous study in patients with non–ST-segment–elevation myocardial infarction similarly demonstrated a reduction in TnT release and a lowering of CRP when patients were given an infusion of tocilizumab before coronary angiography.23 Although the exact mechanism is unknown, Kleveland and associates speculated that the reduction in TnT release was related to a reduction in the ischemia/reperfusion injury by treatment with tocilizumab. The levels of TnT and especially CRP in that study were comparatively lower than in the present trial, and, for our patients, the study drug infusion was generally not initiated until ICU admission after coronary angiography (if such was indicated). Ischemia/reperfusion injury is also an important component of PCAS, but here it relates to the whole body and not just the heart.2 In this context, inhaled Xenon as an adjunct to standard of care after OHCA has also been demonstrated to reduce myocardial injury as evaluated by TnT release, possibly by means of a protective postconditioning effect.30 In the present trial, the cardioprotective effect was also illustrated by the finding of a markedly reduced level of NT-proBNP in patients treated with tocilizumab. Whether this is related to a diminished ischemia/reperfusion injury or to another beneficial effect is unknown at the present. Nonetheless, NT-proBNP has previously been shown in a larger study to be predictive of death from a hemodynamic cause after OHCA.31\n\nWe did not find an effect of treatment on ICU length of stay or total SOFA scores for the initial 3 days. The SOFA Cardiovascular score was slightly lower in the tocilizumab group on day 3, illustrating more stable hemodynamics with lesser vasopressor requirements. However, more patients received RRT during ICU stay in the tocilizumab group than in the placebo group. Whether this is a chance finding or is because of an unforeseen side effect of tocilizumab in this setting remains unknown, but none of the survivors had a need for dialysis after ICU discharge, and observational data suggest that tocilizumab as a treatment for rheumatoid arthritis is safe in patients with renal insufficiency.32 Also, in a recent study in a similar patient cohort from our cardiac ICU, the frequency of RRT in the active and placebo group was 24% and 23%, respectively, and thus of the same magnitude as seen in the tocilizumab group in the present study.33\n\nAlthough the study was not powered to detect the effects on clinical end points, no differences in mortality, unfavorable neurological outcomes, or a surrogate marker for cerebral injury (NSE) were found. There is no concluding evidence on whether tocilizumab crosses the blood-brain barrier in humans, neither in health nor during illness. However, an animal study in healthy monkeys revealed a low degree of penetration of the blood-brain barrier after intravenous administration.34 Yet, tocilizumab has been suggested as a possible treatment of autoimmune central nerve system diseases.19–21\n\nThere were no significant group differences in frequencies of patients experiencing a SAE or in patients with AE infection. The observation of no increased risk of infections is a vital finding in these critically ill patients and is in line with a recent study in patients with coronavirus disease-2019 (COVID-19) treated with tocilizumab.35 This contrasts with previous findings where treatment with tocilizumab was associated with increased occurrence of infections.36 Of note, however, all patients in the present trial were treated with prophylactic antibiotics to prevent infections.37\n\nIn summary, resuscitated OHCA is associated with a systemic inflammatory response, the magnitude of which has been associated with increased mortality and poor neurological outcome. In the present trial, inhibiting the IL-6–mediated immune response by infusion of tocilizumab reduced systemic inflammation and exerted apparent cardioprotective effects as evaluated by biomarkers. The trial was not powered to detect changes in survival or neurological outcome, and nor did we find a difference in mortality or unfavorable neurological outcomes. For safety aspects, however, this does seem reassuring in conjunction with the finding of no significant differences in the occurrence of infections.\n\nLimitations\n\nThis trial, which is to be considered a phase II trial, was conducted at a single center and was of limited size, not powered to detect possible group differences in mortality or neurological outcome. In addition, because all patients in the trial had experienced a cardiac arrest of presumed cardiac cause, as per the inclusion criteria, and the vast majority of patients had an initial shockable rhythm, the generalizability to noncardiac causes or initial nonshockable rhythms can be uncertain.\n\nFurther studies are needed before evaluating if treatment with tocilizumab after OHCA confers a clinical benefit.\n\nConclusions\n\nTreatment with tocilizumab resulted in a significant reduction in systemic inflammation and myocardial injury in comatose patients resuscitated from OHCA. Further studies are warranted to evaluate if tocilizumab or similar agents should be implemented as standard of care in this setting.\n\nSources of Funding\n\nThe study was supported by funding from: The Danish Heart Foundation (Reference No. 19-R135-A9302-22125), “Region Hovedstadens Forskningsfond til sundhedsforskning” (Capital Region Research Foundation, Denmark; Reference No. A6030), “Hjertecenterets Forskningsudvalg” (The Heart Center Research Council, Rigshospitalet), NovoNordisk Foundation (unrestricted research grant for Dr Kjaergaard, NNF17OC0028706), Lundbeck Foundation (Reference No. R186-2015-2132).\n\nDisclosures\n\nNone.\n\nSupplemental Materials\n\nData Supplement Figures I–V\n\nSupplementary Material\n\nSources of Funding, see page 1850\n\nhttps://www.ahajournals.org/journal/circ\n\nContinuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.\n\nThe Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.120.053318.\n==== Refs\nReferences\n\n1. Søholm H Wachtell K Nielsen SL Bro-Jeppesen J Pedersen F Wanscher M Boesgaard S Møller JE Hassager C Kjaergaard J . Tertiary centres have improved survival compared to other hospitals in the Copenhagen area after out-of-hospital cardiac arrest. Resuscitation. 2013;84 :162–167. doi: 10.1016/j.resuscitation.2012.06.029 22796541\n2. Neumar RW Nolan JP Adrie C Aibiki M Berg RA Böttiger BW Callaway C Clark RSB Geocadin RG Jauch EC . Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication a consensus statement from the International Liaison Committee on Resuscitation. Circulation. 2008;118 :2452–2483.18948368\n3. Callaway CW Donnino MW Fink EL Geocadin RG Golan E Kern KB Leary M Meurer WJ Peberdy MA Thompson TM . Part 8: post–cardiac arrest care. 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Anstensrud AK Woxholt S Sharma K Broch K Bendz B Aakhus S Ueland T Amundsen BH Damås JK Hopp E Rationale for the ASSAIL-MI-trial: a randomised controlled trial designed to assess the effect of tocilizumab on myocardial salvage in patients with acute ST-elevation myocardial infarction (STEMI). Open Heart. 2019;6 :e001108. doi: 10.1136/openhrt-2019-001108 31673391\n25. Meyer MAS Wiberg S Grand J Kjaergaard J Hassager C . Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response after Out-of-Hospital Cardiac Arrest (IMICA): study protocol for a double-blinded, placebo-controlled, single-center, randomized clinical trial. Trials. 2020;21 :868. doi: 10.1186/s13063-020-04783-4 33081828\n26. Vincent JL Moreno R Takala J Willatts S De Mendonça A Bruining H Reinhart CK Suter PM Thijs LG . The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. 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Ann Rheum Dis. 2015;74 :627–630. doi: 10.1136/annrheumdis-2014-206695 25561361\n33. Meyer ASP Johansson PI Kjaergaard J Frydland M Meyer MAS Henriksen HH Thomsen JH Wiberg SC Hassager C Ostrowski SR . “Endothelial Dysfunction in Resuscitated Cardiac Arrest (ENDO-RCA): Safety and efficacy of low-dose Iloprost, a prostacyclin analogue, in addition to standard therapy, as compared to standard therapy alone, in post-cardiac-arrest-syndrome patients.” Am Heart J. 2020;219 :9–20. doi: 10.1016/j.ahj.2019.10.002 31710844\n34. Nellan A McCully CML Cruz Garcia R Jayaprakash N Widemann BC Lee DW Warren KE . Improved CNS exposure to tocilizumab after cerebrospinal fluid compared to intravenous administration in rhesus macaques. Blood. 2018;132 :662–666. doi: 10.1182/blood-2018-05-846428 29954750\n35. Stone JH Frigault MJ Serling-Boyd NJ Fernandes AD Harvey L Foulkes AS Horick NK Healy BC Shah R Bensaci AM ; BACC Bay Tocilizumab Trial Investigators. Efficacy of tocilizumab in patients hospitalized with Covid-19. N Engl J Med. 2020;383 :2333–2344. doi: 10.1056/NEJMoa2028836 33085857\n36. Smolen JS Beaulieu A Rubbert-Roth A Ramos-Remus C Rovensky J Alecock E Woodworth T Alten R ; OPTION Investigators. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008;371 :987–997. doi: 10.1016/S0140-6736(08)60453-5 18358926\n37. François B Cariou A Clere-Jehl R Dequin PF Renon-Carron F Daix T Guitton C Deye N Legriel S Plantefève G ; CRICS-TRIGGERSEP Network and the ANTHARTIC Study Group. Prevention of early ventilator-associated pneumonia after cardiac arrest. N Engl J Med. 2019;381 :1831–1842. doi: 10.1056/NEJMoa1812379 31693806\n\n",
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"issn_linking": "0009-7322",
"issue": "143(19)",
"journal": "Circulation",
"keywords": "C-reactive protein; heart arrest; inflammation; intensive care units; myocardial infarction",
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"title": "Treatment Effects of Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response After Out-of-Hospital Cardiac Arrest (The IMICA Trial): A Double-Blinded, Placebo-Controlled, Single-Center, Randomized, Clinical Trial.",
"title_normalized": "treatment effects of interleukin 6 receptor antibodies for modulating the systemic inflammatory response after out of hospital cardiac arrest the imica trial a double blinded placebo controlled single center randomized clinical trial"
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"abstract": "BACKGROUND\nObjectives were to describe the reliability and validity of a new paediatric-specific mucositis scale, the Children's International Mucositis Evaluation Scale (ChIMES).\n\n\nMETHODS\nIn a multi-centre prospective study, children aged 0 to ≤18 years were eligible if they were receiving any of the following: myeloablative stem cell transplantation (SCT), ≥60 mg m(-2) course(-1) doxorubicin or ≥12 g m(-2) methotrexate. Multiple measures of mucositis were included along with ChIMES. Respondents were parent proxy report for children aged <12 years, and child self-report for children aged 12-18 years and 8 to <12 years. Mucositis diaries were completed at baseline and on Days 7-17 following chemotherapy/conditioning. On Day 14, the respondent reported presence of mucositis and change since the previous day.\n\n\nRESULTS\nThe 185 respondents included parents (N=98), children aged 12-18 years (N=66) and children aged 8 to <12 years (N=21). Test-retest reliability was excellent for ChIMES Total Score and ChIMES Percentage Score with r>0.8 for all respondent types. Criteria for construct validation were met across all measures. ChIMES also demonstrated responsiveness with significant differences between baseline and Day 14.\n\n\nCONCLUSIONS\nChIMES is a paediatric-specific measure of mucositis with favourable psychometric properties. It exhibits reliability, construct validity and responsiveness. ChIMES should be incorporated into clinical trials of mucositis prevention and treatment in paediatric cancer and SCT.",
"affiliations": "Center for Cancer and Blood Disorders, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC 20111, USA.",
"authors": "Jacobs|S|S|;Baggott|C|C|;Agarwal|R|R|;Hesser|T|T|;Schechter|T|T|;Judd|P|P|;Tomlinson|D|D|;Beyene|J|J|;Sung|L|L|",
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"doi": "10.1038/bjc.2013.618",
"fulltext": "\n==== Front\nBr J CancerBr. J. CancerBritish Journal of Cancer0007-09201532-1827Nature Publishing Group bjc201361810.1038/bjc.2013.61824129238Clinical StudyValidation of the Children's International Mucositis Evaluation Scale (ChIMES) in paediatric cancer and SCT Validation of ChIMESJacobs S 1Baggott C 2Agarwal R 3Hesser T 4Schechter T 56Judd P 7Tomlinson D 4Beyene J 48Sung L 456*1 Center for Cancer and Blood Disorders, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC 20111, USA2 School of Nursing, SCUSF Medical Center, Parnassus 2 Koret Way Box 0610, Room N611N, San Francisco, CA 94143, USA3 Pediatric Stem Cell Transplantation, Lucile Packard Children's Hospital at Stanford, 725 Welch Road, Palo Alto, CA 94304, USA4 Child Health Evaluative Sciences, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada5 Division of Haematology/Oncology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada6 Department of Paediatrics, University of Toronto, 27 King's College Cir, Toronto, Ontario M5S 1A1, Canada7 Department of Dentistry, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada8 Population Genomics Program, Department of Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main Street W, Hamilton, Ontario L8S 4L8, Canada* E-mail: lillian.sung@sickkids.ca12 11 2013 15 10 2013 109 10 2515 2522 25 07 2013 13 09 2013 15 09 2013 Copyright © 2013 Cancer Research UK2013Cancer Research UKFrom twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/Background:\nObjectives were to describe the reliability and validity of a new paediatric-specific mucositis scale, the Children's International Mucositis Evaluation Scale (ChIMES).\n\nMethods:\nIn a multi-centre prospective study, children aged 0 to ⩽18 years were eligible if they were receiving any of the following: myeloablative stem cell transplantation (SCT), ⩾60 mg m−2 course−1 doxorubicin or ⩾12 g m−2 methotrexate. Multiple measures of mucositis were included along with ChIMES. Respondents were parent proxy report for children aged <12 years, and child self-report for children aged 12–18 years and 8 to <12 years. Mucositis diaries were completed at baseline and on Days 7–17 following chemotherapy/conditioning. On Day 14, the respondent reported presence of mucositis and change since the previous day.\n\nResults:\nThe 185 respondents included parents (N=98), children aged 12–18 years (N=66) and children aged 8 to <12 years (N=21). Test–retest reliability was excellent for ChIMES Total Score and ChIMES Percentage Score with r>0.8 for all respondent types. Criteria for construct validation were met across all measures. ChIMES also demonstrated responsiveness with significant differences between baseline and Day 14.\n\nConclusion:\nChIMES is a paediatric-specific measure of mucositis with favourable psychometric properties. It exhibits reliability, construct validity and responsiveness. ChIMES should be incorporated into clinical trials of mucositis prevention and treatment in paediatric cancer and SCT.\n\nmucositischildrenhematopoietic stem cell transplantation\n==== Body\nOral mucositis is a common consequence of chemotherapy and stem cell transplantation (SCT) that reduces quality of life and results in morbidity in adults and children with cancer (Sonis, 2011). Prevention of mucositis is important to patients, parents and health-care providers (Ethier et al, 2012). In order to determine the most effective preventive and treatment strategies, outcome measures are needed to reliably quantify the degree of oral mucositis and its resultant morbidity. Considerable effort has resulted in many different mucositis scales being developed for adults, and currently, there are several options for the valid measurement of mucositis among adults receiving chemotherapy and radiotherapy, including those undergoing SCT (Sonis et al, 2004). However, there remains a lack of validated instruments for assessing mucositis in children (Tomlinson et al, 2007).\n\nChildren have unique measurement issues compared with adults. Young children are more difficult to assess due to lack of co-operation with oral cavity examination. In addition, attribution of functional symptoms may not be linkable to an aetiology. For example, if a young child refuses to eat, it may be difficult to know whether this behaviour is related to mucositis, nausea or anorexia. The lack of a feasible, reliable and valid scoring system for mucositis in children has created an obstacle to interventional and epidemiological mucositis research in paediatric cancer (Qutob et al, 2013).\n\nIn order to address this gap in the literature, we formed a multi-disciplinary group with expertise in paediatric mucositis. Our previous work established the need for a new paediatric mucositis scale, generated items, drafted the scale and evaluated early psychometrics with a focus on understandability, content validity and acceptability from parents and children with cancer. Three iterations were required to arrive at the final version of the instrument that was then termed the Children's International Mucositis Evaluation Scale (ChIMES; Tomlinson et al, 2007, 2008a, 2008b, 2009a, 2009b, 2010).\n\nThis manuscript describes the evaluation of reliability and validity of ChIMES in children with cancer or undergoing SCT. We hypothesised that ChIMES would be reliable (test–retest, inter-rater and internal consistency) and valid (convergent validity and responsiveness).\n\nMaterials and Methods\nWe conducted a multi-centre prospective study of children at increased risk of developing oral mucositis in order to evaluate the psychometric properties of ChIMES. We measured oral mucositis at baseline (conducted between day −2 to day 5 when mucositis was not expected) and then daily between Days 7 and 17 (when mucositis was expected) following start of chemotherapy or conditioning. Three groups of respondents were included: parent/guardian proxy respondents for children aged <12 years; child self-respondents aged 12–18 years; and child self-respondents aged 8 to <12 years.\n\nThe Research Ethics Board at The Hospital for Sick Children and all participating institutions approved the study. All participants provided written informed consent or assent as appropriate.\n\nSubjects\nChildren aged 0 to⩽18 years were eligible if they were to receive any of the following treatments: myeloablative SCT, ⩾60 mg m−2 course−1 doxorubicin or ⩾12 g m−2 methotrexate. We excluded respondents unable to read English and those who did not have the cognitive ability to complete instruments. Participants were recruited from: The Hospital for Sick Children, Toronto, ON, Canada; Children's National Medical Center, Washington, DC, USA; and Lucile Salter Packard Children's Hospital at Stanford, Palo Alto, CA, USA.\n\nProcedures\nRespondents were approached in the inpatient or clinic setting before the start of the chemotherapy cycle or SCT procedure. Measures of mucositis were ChIMES, World Health Organisation (WHO) mucositis scale, mucositis visual analogue scale (VAS), National Cancer Institute Common Terminology Criteria (NCI-CTC) v3.0 functional/symptomatic mucositis scale and the Oral Mucositis Daily Questionnaire (OMDQ). The recall period for all instruments was the same day except for the OMDQ, which was the past 24 h.\n\nA study training manual, which detailed standard operating procedures, was circulated to all participating sites to maximise consistency in evaluations. Participants were provided descriptions and pictures of erythema and ulcers. Participants were encouraged to consult with their doctor or nurse if they were unsure about their presence. A standard light source was not used across sites. Timing and conduct of assessments were further standardised to occur before eating or drinking and at approximately the same time every day. The order of evaluations was also standardised. The baseline assessment occurred between 2 days before initiation of chemotherapy or SCT conditioning until 5 days following chemotherapy initiation as mucositis is unlikely to occur within this time frame. Follow-up assessments were then conducted once daily between Days 7 to 17 after starting chemotherapy or conditioning. Responses were recorded in a paper diary. The evaluation of test–retest reliability occurred on Days 13 and 14, when maximum mucositis was expected.\n\nFor children aged <8 years, the parent completed all measures and the child did not participate. On Day 14, the parent answered the following three additional questions: (a) reported whether their child was experiencing any mouth pain or sores that day (yes or no); (b) reported whether oral mucositis had changed since the previous day (Day 13) on a five-point scale consisting of much worse, somewhat worse, no change, somewhat better and much better; and (c) completed the Faces Pain Scale—Revised (Hicks et al, 2001) to explore how this measure is associated with the pain question of ChIMES.\n\nFor children aged ⩾12 years, the child completed all instruments although he/she could request assistance from the parent/guardian if necessary. These older children also completed the three additional Day-14 questions as outlined above. The parent did not participate in daily assessments although on Day 14, the parent or guardian also completed ChIMES so that inter-rater reliability could be examined. For children aged 8 to <12 years, only the parent, only the child or both could participate. In the case of child self-report, the child completed the three additional Day-14 questions and the parent completed Day-14 ChIMES.\n\nOutcome measures\nChIMES\nChIMES (parent version illustrated in Appendix 1) consists of seven elements: (1) Amount of mouth or throat pain (ChIMES1), (2) Effect of mouth or throat pain on swallowing (ChIMES2), (3) Effect of mouth or throat pain on eating (ChIMES3), (4) Effect of mouth or throat pain on drinking (ChIMES4), (5) Receipt of pain medication (ChIMES5), (6) Receipt of pain medication for mouth or throat pain (ChIMES6), and (7) Presence of ulcers (ChIMES7). Because in young children failure to eat or drink may not be attributable to mucositis vs other aetiologies such as nausea or anorexia, the instrument allows the respondent to choose ‘I can't tell' if the respondent is uncertain if the cause of functional impairment is due to oral mucositis. ChIMES1–4 each received a score of 0–5 where 5 is the worst degree of symptoms. ChIMES5 received a score of 1 if the child had received pain medications and ChIMES6 received a score of 1 if the child received pain medications because of mucositis. Otherwise, ChIMES5 and 6 received a score of 0. Finally, ChIMES7 received a score of 1 if oral ulcers were present and 0 if absent. Any question that was scored as missing or ‘I can't tell' was excluded from the total possible score. If all the questions were answered, the maximum score was 23. The ChIMES Total Score was the sum of all scores; ‘I can't tell' responses and missing responses both received a score of 0. The ChIMES Percentage Score was the ChIMES Total Score over the total maximum score taking into account ‘I can't tell' responses (by subtracting these items from the maximum score) multiplied by 100. In other words, the ChIMES Total Score does not take into account ‘I can't tell' or missing responses as they are given a score of 0 and the ChIMES Total Score keeps the weighting of all components constant. In contrast, ChIMES Percentage Score does take into account ‘I can't tell' responses by changing the maximum score possible. Higher scores correspond to worse mucositis.\n\nWHO\nThe WHO scale is based upon the ability to eat and drink combined with objective signs of mucositis, namely erythema and ulceration (World Health Organization, 1979). Visualisation of the oral cavity is critical for scoring, as the presence of oral ulcers delineates a WHO mucositis grade of ⩾2 vs<2. It is one of the most commonly used outcome measures in clinical research (Sonis et al, 2004). WHO grade ranges from 0 to 4 where higher scores correspond to worse mucositis.\n\nVAS\nWe used a horizontal 10-cm VAS anchored at 0 (no mouth or throat pain) and 10 (most severe mouth or throat pain) and asked the respondent to indicate that day's level of pain. We have previously used this outcome measure to validate the Oral Mucositis Assessment Scale (OMAS) and as an outcome measure in a randomised trial (Sung et al, 2007a, 2007b).\n\nNCI-CTC\nThe NCI-CTC is the standard adverse event reporting system used by the National Cancer Institute and it is widely used for grading oral mucositis (National Cancer Institute, 2003). The NCI-CTC v3.0 mucositis functional/symptomatic scale was used. NCI-CTC grade ranges from 0 to 5 where higher scores correspond to worse mucositis.\n\nOMDQ\nThe OMDQ was developed through multiple focus groups and one-on-one interviews with cancer patients (Bellm et al, 2002; Stiff et al, 2006). It consists of seven questions that relate to: (1) Amount of mouth and throat pain (OMDQ1), (2) Effect of pain on sleeping (OMDQ2), (3) Effect on swallowing (OMDQ3), (4) Effect on drinking (OMDQ4), (5) Effect on eating (OMDQ5), (6) Effect on talking (OMDQ6) and (7) Amount of diarrhoea (OMDQ7). The OMDQ has been validated in paediatric cancer by parent proxy report and child self-report for all items other than for the diarrhoea item. Thus, OMDQ7 was not included in this study. Each component of the OMDQ was scored separately as an aggregate score has not been validated. For each component, the score ranges from 0 to 4 where higher scores correspond to worse mucositis.\n\nStatistical considerations\nAll analyses were stratified by respondent type. ChIMES evaluations focused on ChIMES Total Score and ChIMES Percentage Score, but we also illustrated the properties of individual items. To evaluate the test–retest reliability of ChIMES, we calculated the Spearman's correlation coefficient between Days 13 and 14 for those who reported no change in mucositis between these days and for all respondents. We hypothesised an r ⩾0.7. To evaluate the inter-rater reliability of ChIMES, we calculated the Spearman's correlation coefficient between parents and children aged 8 to <12 and 12–18 years on Day 14 and anticipated an r ⩾0.5. We evaluated internal consistency by Cronbach's alpha and anticipated an alpha ⩾0.7 (Streiner and Norman, 1995).\n\nTo evaluate convergent validity of ChIMES, we hypothesised that ChIMES scores would be positively correlated with WHO, VAS, NCI-CTC and OMDQ. For this analysis, we described the Spearman's correlation coefficients using all evaluations but in order to account for the same child providing multiple measures at baseline and on Days 7–17, we obtained the P values using a repeated-measures linear model with Proc Mixed in SAS (Cary, NC, USA). We anticipated a Spearman's correlation of ⩾0.35 based on our previous studies. To evaluate the responsiveness of ChIMES, we compared the ChIMES scores obtained at baseline with Day-14 evaluations in children who had oral mucositis on Day 14 and in all children. These two scores were compared using the Wilcoxon signed-rank test. An exploratory aim was to compare the Faces Pain Scale-Revised and the ChIMES pain question (ChIMES1) on Day 14 to address the question of whether the smiley faces scale used in ChIMES may be confounding pain affect and intensity. These scores were evaluated using the Spearman's correlation coefficient.\n\nThe sample size was based on evaluating the test–retest reliability of ChIMES. Assuming that the r under the null hypothesis was 0.4 and under the alternate hypothesis was 0.7, an α of 0.05 and a β of 0.20, we planned to recruit at least 90 parent respondents to ensure that we had 45 who reported no change in oral mucositis between Days 13 and 14.\n\nResults\nBetween 6 July 2010 and 29 April 2013, 222 potentially eligible respondents were evaluated. Figure 1 outlines the flow of participants; 30 refused and 7 were not evaluable, thus leaving 185 respondents in the final analysis. Of these, 98 were parent/guardian proxy respondents for children aged <12 years, 66 were child self-respondents aged 12–18 years and 21 were child self-respondents aged 8 to <12 years. Of the 34 children aged 8 to <12 years, 14 children agreed to self-report mucositis scores alongside their parents, 13 children refused and only their parents participated and 7 children participated alone without their parents. Table 1 illustrates the demographics of the study cohort stratified by respondent type. Approximately 40–45% of respondents had previous experience with mucositis.\n\nTable 2 and Appendix 2 illustrate the evaluation of test-–retest reliability among respondents who reported no change in mucositis between Days 13 and 14 and among all respondents. Reliability was excellent for ChIMES Total Score and ChIMES Percentage Score with r>0.8 for all respondent types. In particular, among parent respondents reporting no change in mucositis, Spearman's correlation coefficients were r=0.967 and 0.968 for the ChIMES Total and Percentage Scores, respectively. In the evaluation of individual items, the r was>0.7 for all respondents and the majority of items had r>0.9. In the evaluation of internal consistency, Cronbach's α was 0.95 for parent, 0.93 for child respondents aged 12–18 years and 0.95 for child respondents aged 8 to <12 years.\n\nTable 3 demonstrates the evaluation of convergent construct validity and correlation between ChIMES and other measures of mucositis. All r values were>0.5 across all respondent types. Table 4 highlights the evaluation of responsiveness. Among those who reported mucositis on Day 14, the mean difference in ChIMES Total Scores was approximately 10 and the mean difference in ChIMES Percentage Scores was approximately 50. These differences were significantly different across respondent types. Among all respondents and all evaluations, the median (interquartile ranges (IQRs)) for ChIMES Total Scores for WHO=1 was 4.5 (3, 8); WHO=2 was 10 (6, 15); and WHO=3 or 4 was 20 (16, 22). The corresponding median (IQRs) ChIMES Percentages Scores for WHO=1 was 21.7 (13.0, 37.7); WHO=2 was 43.5 (26.1, 65.2); and WHO=3 or 4 was 87.0 (72.7, 95.7).\n\nFor the exploratory evaluation of the correlation between Faces Pain Scale-Revised and ChIMES1, the Spearman's correlation coefficients were 0.906, 0.972 and 1.000 for parent, child respondents aged 12–18 years and child respondents aged 8 to <12 years, respectively.\n\nDiscussion\nWe have demonstrated that ChIMES, a new paediatric-specific measure of oral mucositis, is reliable, valid and responsive to change in children and adolescents with cancer and undergoing SCT. In order to decide whether to incorporate an instrument as an outcome measure in clinical trials, assessment of all of these properties is important. Our data also suggest that ChIMES may be used confidently for child self-report in those aged ⩾12 years and likely for those as young as 8 years of age.\n\nThere are several components of ChIMES that are particularly relevant to children. First, ChIMES focuses on functional elements, as these were considered more clinically important rather than simply the presence of ulcers (Tomlinson et al, 2009b). Second, the assessment of ulcers is limited to a yes/no question rather than a detailed assessment as is conducted for the OMAS. With the OMAS (Sonis et al, 2001), nine sites of the oral cavity are evaluated for erythema and ulceration. Although we found the OMAS to be valid in paediatric cancer patients receiving chemotherapy (Sung et al, 2007b), the correlation coefficients between OMAS with WHO and VAS were much lower (0.56 and 0.37, respectively) compared with ChIMES. We also found OMAS difficult for some children given the time required for oral cavity evaluation. These issues suggest that ChIMES is preferable to OMAS for children, although OMAS is likely to be an excellent outcome measure for adult cancer patients. Third, ChIMES allows ‘I can't tell' responses. With WHO, the inability to attribute symptoms to aetiology and the inability to visualise the oral cavity result in a missing score. Given the importance of avoiding missing scores in clinical trials, these issues suggest that ChIMES may be a better measure for paediatric clinical trials compared with WHO (Little et al, 2012).\n\nWe calculated and evaluated two ChIMES outcomes, the ChIMES Total Score and the ChIMES Percentage Score. Our results suggest that either may be used in clinical trials. However, the incorporation of ‘I can't tell' responses may make the ChIMES Percentage Score preferable.\n\nWe had a limited number of children 8 to <12 years of age who self-reported mucositis scores, and there are several aspects of our trial that merit specific consideration. First, some children reported mucositis alongside their parents; we do not know whether the simultaneous completion of diaries by parents and children may have biased the child responses favourably. Second, we invited 34 children aged 8 to <12 years to our study and only 21 agreed to self-report mucositis scores. Thus, our results may not be generalisable to all 8- to <12-year olds. Third, the evaluation of responsiveness focused on those with mucositis on Day 14, and only six respondents met this criterion within the 8- to <12-year self-report respondent group. Consequently, the failure to show a statistically significant difference for the analysis is more likely related to inadequate power rather than lack of responsiveness in this age range. Further, the magnitude of the differences between baseline and Day 14 is similar to that seen in parent and child respondents aged 12–18 years.\n\nThe major strengths of our study include the multi-centre design, incorporation of multiple measures of mucositis and evaluation of responsiveness in addition to reliability and validity. However, our results must be interpreted in light of its limitations. As previously noted, the 8- to <12-year-old group is likely to be self-selected as a more compliant and motivated group. Second, we only included English speakers in this study. Another limitation is that we have little insight into whether parents were able to accurately assess subjective symptoms in the youngest children using the six-point scale or whether a dichotomous or simpler scale would have been preferable. Finally, another limitation is that we do not have clinically defined thresholds for ChIMES scores that delineate the presence or absence of mucositis or degree of severity (such as mild, moderate and severe).\n\nFuture work should focus on determining whether children aged <8 years can self-report mucositis and parent/guardian evaluation of mucositis in the youngest children. Future work should also focus on identifying clinically meaningful thresholds for ChIMES scores to categorise the presence of mucositis and degree of severity. Additionally, ChIMES should be translated into other languages and evaluated in other cultural contexts. In conclusion, ChIMES is a paediatric-specific measure of mucositis with favourable psychometric properties. It exhibits test–retest reliability, inter-rater reliability, internal consistency, construct validity and responsiveness. ChIMES should be incorporated into mucositis prevention and treatment clinical trials in paediatric cancer and SCT.\n\nThis study was supported by operating grants from the National Institutes of Health (No.1 R21 DE021400-01) and the Canadian Institutes for Health Research (No.102711). LS is supported by a New Investigator Award from the Canadian Institutes for Health Research. We would like to thank Faith Gibson, Karis Cheng, Nathanial Treister, Eleanor Hendershot and Anne Marie Maloney for their contributions to the early development of ChIMES.\n\nAppendix 1\n\n\nAppendix 2\n\n\nThis work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License.\n\nThe authors declare no conflict of interest.\n\nFigure 1 Flow diagram of participants stratified by respondent type.\n\nTable 1 Demographics of the study cohort stratified by respondent type\n \tRespondent type\t\nCharacteristic\tParent proxy report for children aged <12 years (N=98)\tChild self-report aged 12–18 years (N=66)\tChild self-report aged 8 to <12 years (N=21)\t\nParent characteristics\t\nMale (%)\t17 (17.5)\t—\t5 (38.5)\t\nMedian age (IQR) in years\t36.8 (32.8, 41.1)\t—\t41.6 (39.5, 45.1)\t\nAt least college education (%)\t75 (76.5)\t—\t10 (47.6)\t\nChild characteristics\t\nMale (%)\t57 (58.2)\t40 (60.6)\t15 (71.4)\t\nMedian age (IQR) in years\t5.3 (3.0, 8.5)\t14.7 (13.5, 16.6)\t9.8 (9.0, 11.1)\t\nDiagnosis (%)\t\nLeukemia/lymphoma\t34 (34.7)\t28 (42.2)\t8 (38.1)\t\nSolid tumour\t31 (31.6)\t30 (45.5)\t8 (38.1)\t\nBrain tumour\t15 (15.3)\t4 (6.1)\t3 (14.3)\t\nMetabolic\t4 (4.08)\t—\t—\t\nOther\t14 (14.3)\t4 (6.1)\t2 (9.5)\t\nTreatment at enrolment (%)\t\nChemotherapy\t16 (16.3)\t35 (53.0)\t7 (33.3)\t\nStem cell transplantation\t82 (83.7)\t31 (47.0)\t14 (66.7)\t\nTBI containing conditioning\t16/82 (19.5)\t7/31 (22.6)\t6 (42.9)\t\nPrevious history of mucositis (%)\t43 (43.9)\t27 (40.9)\t9 (42.9)\t\nAbbreviations: IQR=interquartile range; TBI=total body irradiation.\n\nTable 2 Test–retest reliability of ChIMES total and percentage scores measured on Days 13 and 14a\nRespondent type\tChIMES total score r (P-value)\tChIMES percentage Score r (P-value)\t\nParent proxy report\t\nReport no change, n=53\t0.967 (<0.0001)\t0.968 (<0.0001)\t\nAll, n=98\t0.941 (<0.0001)\t0.942 (<0.0001)\t\nChild self-report aged 12–18 years\t\nReport no change, n=33\t0.894 (<0.0001)\t0.888 (<0.0001)\t\nAll, n=66\t0.854 (<0.0001)\t0.852 (<0.0001)\t\nChild self–report aged 8 to <12 years\t\nReport no change, n=10\t1.000 (<0.0001)\t1.000 (<0.0001)\t\nAll, n=21\t0.902 (<0.0001)\t0.902 (<0.0001)\t\nAbbreviation: ChIMES=Children's International Mucositis Evaluation Scale.\n\na Table represents Spearman's correlation coefficients with P values in parentheses for ChIMES total and percentage scores measured on 2 consecutive days (Days 13 and 14). Results are presented for those who indicated no change in mucositis between Days 13 and 14 and all respondents.\n\nTable 3 Construct validation of ChIMES total and percentage scoresa\n \tRespondent type\t\n \tParent proxy report for children aged <12 years (N=98)\tChild self-report aged 12–18 years (N=66)\tChild self-report aged 8 to <12 years (N=21)\t\nOther measures of mucositis\tChIMES total score\tChIMES percentage score\tChIMES total score\tChIMES percentage score\tChIMES total score\tChIMES percentage score\t\nWHO Mucositis\t0.847 (<0.0001)\t0.846 (<0.0001)\t0.782 (<0.0001)\t0.785 (<0.0001)\t0.830 (<0.0001)\t0.827 (<0.0001)\t\nVAS Mucositis\t0.854 (<0.0001)\t0.857 (<0.0001)\t0.808 (<0.0001)\t0.809 (<0.0001)\t0.727 (<0.0001)\t0.731 (<0.0001)\t\nCTC Mucositis\t0.862 (<0.0001)\t0.863 (<0.0001)\t0.779 (<0.0001)\t0.781 (<0.0001)\t0.795 (<0.0001)\t0.795 (<0.0001)\t\nOMDQ1b\t0.903 (<0.0001)\t0.906 (<0.0001)\t0.851 (<0.0001)\t0.852 (<0.0001)\t0.813 (<0.0001)\t0.822 (<0.0001)\t\nOMDQ2\t0.723 (<0.0001)\t0.706 (<0.0001)\t0.585 (<0.0001)\t0.587 (<0.0001)\t0.551 (<0.0001)\t0.549 (<0.0001)\t\nOMDQ3\t0.900 (<0.0001)\t0.911 (<0.0001)\t0.882 (<0.0001)\t0.882 (<0.0001)\t0.922 (<0.0001)\t0.917 (<0.0001)\t\nOMDQ4\t0.896 (<0.0001)\t0.908 (<0.0001)\t0.884 (<0.0001)\t0.886 (<0.0001)\t0.928 (<0.0001)\t0.926 (<0.0001)\t\nOMDQ5\t0.908 (<0.0001)\t0.917 (<0.0001)\t0.904 (<0.0001)\t0.905 (<0.0001)\t0.900 (<0.0001)\t0.906 (<0.0001)\t\nOMDQ6\t0.864 (<0.0001)\t0.876 (<0.0001)\t0.724 (<0.0001)\t0.726 (<0.0001)\t0.783 (<0.0001)\t0.780 (<0.0001)\t\nAbbreviations: ChIMES=Children's International Mucositis Evaluation Scale; CTC=National Cancer Institute's Common Terminology Criteria v3.0; WHO=World Health Organisation mucositis scale; VAS=pain visual analogue scale; OMDQ=Oral Mucositis Daily Questionnaire.\n\na Table represents Spearman's correlation coefficients with P values derived from a generalised linear mixed model with repeated measures in parentheses.\n\nb OMDQ items were as follows: (1) Amount of mouth and throat pain (OMDQ1), (2) Effect of pain on sleeping (OMDQ2), (3) Effect on swallowing (OMDQ3), (4) Effect on drinking (OMDQ4), (5) Effect on eating (OMDQ5), and (6) Effect on talking (OMDQ6).\n\nTable 4 Responsiveness of ChIMES total and percentage scores between baseline and day 14a\n \tChIMES total scores\tChIMES percentage scores\t\n \tMean baseline total score±s.d.\tMean day 14 total score±s.d.\tMean difference (95% CI)\nP-value\tMean baseline percentage score±s.d.\tMean day 14 percentage score±s.d.\tMean difference (95% CI)\nP-value\t\nParent proxy report\t\nReport D14 mucositis (n=51)\t1.5±3.6\t13.0±7.5\t11.4 (−1.0, 22.0)\n<0.0001\t6.4±15.8\t58.7±32.6\t51.0 (−4.3, 95.7)\n<0.0001\t\nAll patients (n=98)\t1.5±3.6\t8.0±8.5\t6.6 (−3.0, 22.0)\n<0.0001\t6.4±15.8\t36.0±37.5\t29.5 (−13.0, 95.7)\n<0.0001\t\nChild self-report aged 12–18 years\t\nReport D14 mucositis (n=26)\t0.9±2.2\t10.6±7.2\t9.8 (1.0, 21.0)\n<0.0001\t3.7±9.5\t46.5±31.3\t43.3 (4.3, 91.3)\n<0.0001\t\nAll patients (n=66)\t0.9±2.2\t5.1±7.1\t4.3 (−1.0, 19.0)\n<0.0001\t3.7±9.5\t22.3±31.0\t18.9 (−4.3, 82.6)\n<0.0001\t\nChild self-report aged 8 to <12 years\t\nReport D14 mucositis (n=6)\t0.9±1.5\t12.6±8.9\t12.3 (0.0, 23.0)\n0.063\t3.7±6.5\t54.7±38.7\t53.6 (0.0, 100.0)\n0.063\t\nAll patients (n=21)\t0.9±1.5\t5.1±8.1\t3.7 (−5.0, 23.0)\n0.333\t3.7±6.5\t22.0±35.4\t16.1 (−21.7, 100.0)\n0.363\t\nAbbreviations: ChIMES=Children's International Mucositis Evaluation Scale; 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"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0007-0920",
"issue": "109(10)",
"journal": "British journal of cancer",
"keywords": null,
"medline_ta": "Br J Cancer",
"mesh_terms": "D000293:Adolescent; D002648:Child; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008297:Male; D009061:Mouth Mucosa; D052016:Mucositis; D019653:Myeloablative Agonists; D009369:Neoplasms; D012720:Severity of Illness Index; D033581:Stem Cell Transplantation; D013280:Stomatitis; D011795:Surveys and Questionnaires; D019172:Transplantation Conditioning",
"nlm_unique_id": "0370635",
"other_id": null,
"pages": "2515-22",
"pmc": null,
"pmid": "24129238",
"pubdate": "2013-11-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D023361:Validation Study",
"references": "21947490;19955021;12197238;18842459;18982362;22959949;11304772;15108222;17724620;11427329;16628556;18413699;21709615;17383174;19648790;16415901;22829439",
"title": "Validation of the Children's International Mucositis Evaluation Scale (ChIMES) in paediatric cancer and SCT.",
"title_normalized": "validation of the children s international mucositis evaluation scale chimes in paediatric cancer and sct"
} | [
{
"companynumb": "US-JNJFOC-20131202518",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "To analyze the available literature on papilledema in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), report the first detailed pediatric case, and explore the underlying pathophysiology.\n\n\n\nFirst, we conducted a comprehensive literature review of all cases of papilledema in CIDP. Next, we reviewed each case, incorporating only those including cerebrospinal fluid analysis into the results. Finally, we present our pediatric patient.\n\n\n\nOur literature review yielded a total of 9 adult and no pediatric cases. Cerebrospinal fluid protein and opening pressures were elevated in all cases. They were also elevated in our pediatric case.\n\n\n\nProlonged periods of active immune-mediated inflammation is likely a cause of papilledema in adult CIDP, and possibly also in our pediatric case.",
"affiliations": "Department of Child Neurology, State University of New York at Downstate, Brooklyn, NY, USA.;Department of Child Neurology, State University of New York at Downstate, Brooklyn, NY, USA.;Department of Child Neurology, State University of New York at Downstate, Brooklyn, NY, USA.",
"authors": "Abrams|Aaron W|AW|0000-0002-4607-5740;Sah|Jeetendra P|JP|;Pavlakis|Steven G|SG|",
"chemical_list": "D007136:Immunoglobulins",
"country": "United States",
"delete": false,
"doi": "10.1177/0883073820925302",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-0738",
"issue": "35(10)",
"journal": "Journal of child neurology",
"keywords": "children; intracranial hypertension; neuroimmunology; neuroophthalmology; pediatric",
"medline_ta": "J Child Neurol",
"mesh_terms": "D002420:Cauda Equina; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007136:Immunoglobulins; D008279:Magnetic Resonance Imaging; D010211:Papilledema; D020277:Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; D055815:Young Adult",
"nlm_unique_id": "8606714",
"other_id": null,
"pages": "700-704",
"pmc": null,
"pmid": "32468920",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Papilledema in Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP): A Pediatric Case and Review of the Literature.",
"title_normalized": "papilledema in chronic inflammatory demyelinating polyradiculoneuropathy cidp a pediatric case and review of the literature"
} | [
{
"companynumb": "US-TEVA-2020-US-1827394",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "The Zika epidemic has brought increased attention to congenital microcephaly as a birth outcome. However, little is known about risks for microcephaly unrelated to Zika.\n\n\n\nUsing data from the Slone Epidemiology Center Birth Defects Study from 1993 to 2015, we identified 57 cases of microcephaly alone (\"isolated\") and 109 cases of microcephaly that included other major birth defects (\"non-isolated\"), and considered a large number of potential risk factors including demographic characteristics, illnesses, and medications used during pregnancy. Where numbers permitted, we used logistic regression models to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs).\n\n\n\nSubstantial differences in risk factors were observed for isolated versus non-isolated microcephaly. For isolated microcephaly, risk estimates were elevated for mothers of non-Hispanic, non-White race/ethnicity, and underweight pre-pregnancy body mass index (BMI). The risk for exposure anytime in pregnancy to acetaminophen was null; in contrast, the aOR for NSAIDs was 2.4 (95% CI: 1.3-4.2). This association was weakened (but not eliminated) after excluding those exposed to opioids or illicit drugs, and risk was not present among those reporting less frequent exposures. For non-isolated microcephaly, elevated risk estimates were found for urinary tract infection.\n\n\n\nRisk factors differed for isolated and non-isolated microcephaly. While some findings support previously reported associations, (e.g., smoking, alcohol, underweight BMI), we also identified risk factors not previously described, notably NSAID use for isolated microcephaly and urinary tract infection for non-isolated microcephaly; however, these results should be viewed as hypothesis generating.",
"affiliations": "Slone Epidemiology Center at Boston University, Boston, Massachusetts.;Slone Epidemiology Center at Boston University, Boston, Massachusetts.;Slone Epidemiology Center at Boston University, Boston, Massachusetts.",
"authors": "Kerr|Stephen M|SM|0000-0001-9442-9737;Van Bennekom|Carla M|CM|;Mitchell|Allen A|AA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/bdr2.1443",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "111(2)",
"journal": "Birth defects research",
"keywords": "epidemiology; infections; medications; microcephaly; pregnancy risk factors",
"medline_ta": "Birth Defects Res",
"mesh_terms": "D000328:Adult; D016022:Case-Control Studies; D016208:Databases, Factual; D005260:Female; D006801:Humans; D016015:Logistic Models; D008831:Microcephaly; D009035:Mothers; D016017:Odds Ratio; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D012307:Risk Factors; D055815:Young Adult; D000071244:Zika Virus; D000071243:Zika Virus Infection",
"nlm_unique_id": "101701004",
"other_id": null,
"pages": "96-118",
"pmc": null,
"pmid": "30584689",
"pubdate": "2019-01-15",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Risk factors for congenital microcephaly in the pre-Zika era.",
"title_normalized": "risk factors for congenital microcephaly in the pre zika era"
} | [
{
"companynumb": "US-JNJFOC-20190210781",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
"... |
{
"abstract": "Cryptococcosis is a potentially fatal fungal disease caused by the basidiomycetes yeasts Cryptococcus neoformans and C. gattii with high predilection to invade the central nervous system mainly in immunocompromised hosts. Skin can be secondarily involved in disseminated infection or be exceptionally involved as primary cutaneous infection by inoculation with contaminated materials. We report the first two Libyan cases of cryptococcal meningitis in HIV patients, in which one of them presented a secondary cutaneous involvement due to systemic dissemination. The first patient was a 17-year-old female, had fever, cough, headache and intractable vomiting as well as itchy water bumps on her skin and upper limbs. The cutaneous eruption prompted the accurate diagnosis. Cultures were positive for C. neoformans in both cerebrospinal fluid and skin specimens, as well as cryptococcal antigen was detected in serum. The isolate was identified, by molecular analysis, as C. neoformans AD-hybrid belonging to molecular type VNIII and mating type αAAα, the same genotype found for some environmental isolates recovered from olive trees in Tripoli. The second patient was a 36-years-old male with a long history of HIV on irregular treatment. Cryptococcal antigen in serum was positive and cultures yielded the growth of C. neoformans var. grubii, molecular type VNI and mating type αA. Both patients did not respond adequately to treatment and died of impaired central nervous system function and respiratory failure, respectively.",
"affiliations": "Department of Medical Microbiology and Immunology, Faculty of Medicine, Tripoli University, P.O. Box 13555, Tripoli, Libya.;Department of Medical Microbiology and Immunology, Faculty of Medicine, Tripoli University, P.O. Box 13555, Tripoli, Libya.;Tripoli Medical Center, Department of Infectious Disease, P.O. Box 13555, Tripoli, Libya.;Lab. Micologia Medica, Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Pascal 36, 20133, Milano, Italy. Electronic address: massimo.cogliati@unimi.it.",
"authors": "Ellabib|M S|MS|;Krema|Z A|ZA|;Allafi|A A|AA|;Cogliati|M|M|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1016/j.mycmed.2017.04.104",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1156-5233",
"issue": "27(3)",
"journal": "Journal de mycologie medicale",
"keywords": "Cryptococcus neoformans; HIV; Libya; Meningitis; Skin involvement",
"medline_ta": "J Mycol Med",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000293:Adolescent; D000328:Adult; D003453:Cryptococcosis; D003455:Cryptococcus neoformans; D003881:Dermatomycoses; D017809:Fatal Outcome; D005260:Female; D015658:HIV Infections; D006801:Humans; D016867:Immunocompromised Host; D008002:Libya; D008297:Male; D014376:Tuberculosis; D014505:Urban Population",
"nlm_unique_id": "9425651",
"other_id": null,
"pages": "421-424",
"pmc": null,
"pmid": "28576330",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "First report of two cases of cryptococcosis in Tripoli, Libya, infected with Cryptococcus neoformans isolates present in the urban area.",
"title_normalized": "first report of two cases of cryptococcosis in tripoli libya infected with cryptococcus neoformans isolates present in the urban area"
} | [
{
"companynumb": "LY-GLENMARK PHARMACEUTICALS-2017GMK029223",
"fulfillexpeditecriteria": "1",
"occurcountry": "LY",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GANCICLOVIR"
},
"drugaddition... |
{
"abstract": "Intravenous immunoglobulin (IVIG) is a commonly used and generally well-tolerated medication. Common side effects include flu-like symptoms such as fevers, headaches, myalgia, fatigue, and nausea. One of the more rare side effects is aseptic meningitis, with a reported incidence rate of around 0.067 percent of all IVIG infusions. In this paper, we describe a 47-year-old female patient with a history of myasthenia gravis who presented with a headache, neck pain, and neck stiffness while undergoing IVIG infusions for a myasthenia crisis. On admission day, the patient was afebrile with stable vital signs. A physical examination revealed nuchal rigidity and tenderness with no focal neurological deficits. Cerebrospinal fluid (CSF) cytology noted an elevated white blood cell (WBC) count of 1,138 cells/μL with a neutrophil predominance (96 percent). CSF red blood cell count was unremarkable at 1 cell/μL. The patient's IVIG infusions were stopped, suspecting chemical meningitis. Given the markedly elevated CSF WBC count with neutrophil predominance, she was started on vancomycin and ceftriaxone to also cover for bacterial meningitis. The patient's meningeal signs and symptoms significantly improved 24 hours after admission. Given the clear temporal relationship to IVIG administration and the rapid improvement of symptoms, IVIG-induced aseptic meningitis is strongly suspected. The patient's antibiotics were discontinued. Forty-eight hours after stopping IVIG and 24 hours after discontinuing antibiotics, her meningitis symptoms completely resolved with the use of analgesics alone. The patient was then discharged uneventfully. CSF viral and bacterial studies, including a gram stain and cultures, did not result in anything noteworthy. Our case presents an interesting diagnostic dilemma where drug-induced (IVIG) aseptic meningitis mimics bacterial meningitis clinically and on CSF analysis. The clear temporal relationship to IVIG administration and the rapid resolution of symptoms upon stopping the drug can aid in the diagnosis of this rare event and help doctors avoid the use of unnecessary antibiotic therapy.",
"affiliations": "Department of Internal Medicine, University of South Dakota Sanford School of Medicine.;Department of Internal Medicine, University of South Dakota Sanford School of Medicine.;Department of Internal Medicine, University of South Dakota Sanford School of Medicine.",
"authors": "Patel|Anish|A|;Potu|Kalyan Chakravarthy|KC|;Sturm|Tamera|T|",
"chemical_list": "D016756:Immunoglobulins, Intravenous",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0038-3317",
"issue": "70(3)",
"journal": "South Dakota medicine : the journal of the South Dakota State Medical Association",
"keywords": null,
"medline_ta": "S D Med",
"mesh_terms": "D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008582:Meningitis, Aseptic; D016920:Meningitis, Bacterial; D008875:Middle Aged; D009157:Myasthenia Gravis",
"nlm_unique_id": "101265265",
"other_id": null,
"pages": "119-121",
"pmc": null,
"pmid": "28813773",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A Case of IVIG-Induced Aseptic Chemical Meningitis.",
"title_normalized": "a case of ivig induced aseptic chemical meningitis"
} | [
{
"companynumb": "US-IGSA-SR10005262",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nIn September 2012 the UK's Commission on Human Medicines (CHM) recommended changes in the management of paracetamol poisoning: use of a single '100 mg l(-1) ' nomogram treatment line, ceasing risk assessment, treating all staggered/uncertain ingestions and increasing the duration of the initial acetylcysteine (NAC) infusion from 15 to 60 min. We evaluated the effect of this on presentation, admission, treatment, adverse reactions and costs of paracetamol poisoning.\n\n\nMETHODS\nData were prospectively collected from adult patients presenting to three large UK hospitals from 3 September 2011 to 3 September 2013 (year before and after change). Infusion duration effect on vomiting and anaphylactoid reactions was examined in one centre. A cost analysis from an NHS perspective was performed for 90 000 patients/annum with paracetamol overdose.\n\n\nRESULTS\nThere were increases in the numbers presenting to hospital (before 1703, after 1854; increase 8.9% [95% CI 1.9, 16.2], P = 0.011); admitted (1060/1703 [62.2%] vs. 1285/1854 [69.3%]; increase 7.1% [4.0, 10.2], P < 0.001) and proportion treated (626/1703 [36.8%] vs. 926/1854 [50.0%]; increase: 13.2% [95% CI 10.0, 16.4], P < 0.001). Increasing initial NAC infusion did not change the proportion of treated patients developing adverse reactions (15 min 87/323 [26.9%], 60 min 145/514 [28.2%]; increase: 1.3% [95% CI -4.9, 7.5], P = 0.682). Across the UK the estimated cost impact is £8.3 million (6.4 million-10.2 million) annually, with a cost-per-life saved of £17.4 million (13.4 million-21.5 million).\n\n\nCONCLUSIONS\nThe changes introduced by the CHM in September 2012 have increased the numbers of patients admitted to hospital and treated with acetylcysteine without reducing adverse reactions. A safety and cost-benefit review of the CHM guidance is warranted, including novel treatment protocols and biomarkers in the assessment of poisoning.",
"affiliations": "NPIS Edinburgh & Royal Infirmary of Edinburgh, Edinburgh, UK.",
"authors": "Bateman|D Nicholas|DN|;Carroll|Robert|R|;Pettie|Janice|J|;Yamamoto|Takahiro|T|;Elamin|Muhammad E M O|ME|;Peart|Lucy|L|;Dow|Margaret|M|;Coyle|Judy|J|;Cranfield|Kristina R|KR|;Hook|Christopher|C|;Sandilands|Euan A|EA|;Veiraiah|Aravindan|A|;Webb|David|D|;Gray|Alasdair|A|;Dargan|Paul I|PI|;Wood|David M|DM|;Thomas|Simon H L|SH|;Dear|James W|JW|;Eddleston|Michael|M|",
"chemical_list": "D000931:Antidotes; D000082:Acetaminophen; D000111:Acetylcysteine",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.12362",
"fulltext": "\n==== Front\nBr J Clin PharmacolBr J Clin PharmacolbcpBritish Journal of Clinical Pharmacology0306-52511365-2125BlackWell Publishing Ltd Oxford, UK 2466632410.1111/bcp.12362Human ToxicologyEffect of the UK’s revised paracetamol poisoning management guidelines on admissions, adverse reactions and costs of treatment Bateman D Nicholas 1Carroll Robert 2Pettie Janice 1Yamamoto Takahiro 3Elamin Muhammad E M O 4Peart Lucy 4Dow Margaret 1Coyle Judy 5Cranfield Kristina R 5Hook Christopher 5Sandilands Euan A 1Veiraiah Aravindan 1Webb David 67Gray Alasdair 5Dargan Paul I 38Wood David M 38Thomas Simon H L 4Dear James W 17Eddleston Michael 171 NPIS Edinburgh & Royal Infirmary of EdinburghEdinburgh, UK2 School of Social and Community Medicine, University of BristolBristol, UK3 Guy’s and St Thomas’ NHS Foundation Trust and King’s Health PartnersLondon, UK4 Newcastle Hospitals NHS Foundation TrustNewcastle upon Tyne, UK5 Emergency Medicine Research Group, Department of Emergency Medicine, Royal Infirmary of EdinburghEdinburgh, UK6 Royal Infirmary of EdinburghEdinburgh, UK7 Pharmacology, Toxicology & Therapeutics, University/BHF Centre for Cardiovascular Science, University of EdinburghEdinburgh, UK8 King’s College LondonLondon, UKCorrespondence: Professor D. Nicholas Bateman MD, NPIS Edinburgh & Royal Infirmary of Edinburgh, Edinburgh EH16 3SA, UK., Tel.: +44(0)131 242 1383, Fax: +44(0)131 242 1387, E-mail: drnickbateman@gmail.com9 2014 21 8 2014 78 3 610 618 31 1 2014 09 2 2014 © 2014 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.2014This 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.Aims\nIn September 2012 the UK’s Commission on Human Medicines (CHM) recommended changes in the management of paracetamol poisoning: use of a single ‘100 mg l−1’ nomogram treatment line, ceasing risk assessment, treating all staggered/uncertain ingestions and increasing the duration of the initial acetylcysteine (NAC) infusion from 15 to 60 min. We evaluated the effect of this on presentation, admission, treatment, adverse reactions and costs of paracetamol poisoning.\n\nMethods\nData were prospectively collected from adult patients presenting to three large UK hospitals from 3 September 2011 to 3 September 2013 (year before and after change). Infusion duration effect on vomiting and anaphylactoid reactions was examined in one centre. A cost analysis from an NHS perspective was performed for 90 000 patients/annum with paracetamol overdose.\n\nResults\nThere were increases in the numbers presenting to hospital (before 1703, after 1854; increase 8.9% [95% CI 1.9, 16.2], P = 0.011); admitted (1060/1703 [62.2%] vs. 1285/1854 [69.3%]; increase 7.1% [4.0, 10.2], P < 0.001) and proportion treated (626/1703 [36.8%] vs. 926/1854 [50.0%]; increase: 13.2% [95% CI 10.0, 16.4], P < 0.001). Increasing initial NAC infusion did not change the proportion of treated patients developing adverse reactions (15 min 87/323 [26.9%], 60 min 145/514 [28.2%]; increase: 1.3% [95% CI –4.9, 7.5], P = 0.682). Across the UK the estimated cost impact is £8.3 million (6.4 million–10.2 million) annually, with a cost-per-life saved of £17.4 million (13.4 million–21.5 million).\n\nConclusions\nThe changes introduced by the CHM in September 2012 have increased the numbers of patients admitted to hospital and treated with acetylcysteine without reducing adverse reactions. A safety and cost-benefit review of the CHM guidance is warranted, including novel treatment protocols and biomarkers in the assessment of poisoning.\n\nacetylcysteineadverse effectsparacetamolpoisoningregulation\n==== Body\nWhat is Already Known about this Subject\nManagement of paracetamol poisoning is different in the UK from other countries following a decision by the Commission on Human Medicines (CHM) in 2012, including treatment at the ‘100 mg l−1’ nomogram line, stop risk assessment.\n\nThe impact of this advice on patients is unclear.\n\nThe CHM also advised change in the rate of initial infusion in an attempt to reduce adverse drug reactions (ADRs).\n\n\n\n\nWhat this Study Adds\nThe change has resulted in a highly significant increase in admissions and the proportion of patients treated for paracetamol poisoning (estimated UK effect: 31.1 thousand pre-change; 49.0 thousand post-change).\n\nThe net effect is to treat many low risk patients and in the NHS cost per life saved is £17.4 million.\n\nThe change in initial acetylcysteine infusion does not result in any reduction in ADR frequency.\n\n\n\n\n\nIntroduction\nParacetamol poisoning is the most common acute overdose seen in industrialized countries 1,2. It is estimated that between 82 000 and 90 000 patients present in the UK each year with paracetamol overdose 3–5. Between 150 and 250 deaths occur annually, the vast majority in patients who have presented late, after a staggered overdose or after unintentional therapeutic excess 6–9. Deaths or episodes of liver failure in patients 10 who present and are treated within 8 h of a single acute ingestion are extremely rare 1,5,11.\n\nThe main reason for the relatively low number of deaths is the availability of a highly effective antidote, acetylcysteine (NAC) 12, which has been administered intravenously using the same complex regimen since the 1970s. This has involved three weight-related doses of NAC given intravenously in 5% dextrose over three different time frames: 150 mg kg–1 body weight over 15 min, followed by 50 mg kg–1over 4 h and 100 mg kg–1over 16 h. In other parts of the world, notably North America and Australia, the initial dose is given over 60 min rather than 15 min. In the UK, treatment has been recommended for most patients with acute overdose who have a timed plasma paracetamol concentration above the ‘200 mg l−1’ line on a nomogram (Figure 1) after a single acute ingestion or a dose of 150 mg kg−1 or more within 24 h of a staggered ingestion or where the time of ingestion was unknown 13. Patients with risk factors for hepatotoxicity (poor nutrition, chronic alcohol excess, enzyme inducing drugs) were given NAC if their timed blood paracetamol concentration was above the ‘100’ line, or they had ingested more than 75 mg kg−1 within 24 h 21.\n\nFigure 1 Paracetamol nomogram used in the UK until September 3 2012. , normal treatment line; , high risk treatment line\n\nThe NAC regimen is associated with a high incidence of adverse effects, in particular vomiting and anaphylactoid reactions 8–10,14. Because these occur during or soon after infusion of the first 15 min bag 14,15, this is given over 60 min in some countries in the hope of reducing adverse effects, although the one trial that assessed this question did not find a difference 16. Importantly, anaphylactoid reactions are more frequent when NAC is administered to patients with relatively low concentrations of paracetamol 15,17. Anaphylactoid reactions are unpleasant for patients, result in temporary cessation of therapy, extend treatment and admission duration and sometimes cause doctors to withhold effective treatment from patients who need it 1,18.\n\nIn September 2012, the UK’s Commission on Human Medicines (CHM) reviewed the use of NAC in the management of paracetamol overdose. This followed the case of a patient who had not been treated with NAC at first presentation due to the timed paracetamol concentration being below recommended treatment thresholds, who subsequently developed fatal hepatotoxicity. The review identified nine further UK patients since 1991 who had also died after being initially assessed as not requiring NAC. Three key recommendations arose from the CHM review. First to use a single lower ‘100 mg l−1’ line on the nomogram for all patients with acute overdose and to stop assessing risk factors in deciding their need for treatment, on the basis that use of risk factor assessment was poor and inconsistent, and that many of the risk factors were imprecise and difficult to determine with sufficient certainty in clinical practice 5. Second to treat all patients with staggered overdose or unknown time of ingestion with NAC. Third to change the duration of the initial NAC infusion from 15 to 60 min, in an attempt to reduce the risk of adverse reactions 5. These changes were subsequently endorsed by the UK Departments of Health, but not subjected to formal cost-benefit analysis.\n\nThese changes in management guidance resulted in a lower treatment threshold for paracetamol poisoning in the UK than in most other countries, including the USA, Canada, Australia and New Zealand, where a ‘150’ (Rumack-Matthew) line is used 19. An exception is Denmark, where all patients with a suspected overdose receive antidote 5. Although Ireland has subsequently also introduced the CHM changes, clinical toxicologists in other countries have thus far rejected it 20. Of note, the change increases the number of patients with low blood paracetamol concentrations receiving NAC, potentially increasing the number of patients at risk of developing anaphylactoid reactions. An initial report for the first 6 months after the change in York showed substantial increases in admissions following the change in guidance 4.\n\nWe therefore evaluated the effect of the change (i) on the NHS by examining presentations, admissions, treatment and estimated national cost of treating paracetamol poisoned patients and (ii) on patients in terms of adverse reactions to the antidote, especially in those with low paracetamol concentrations. Costs were related to numbers of lives expected to be saved, according to CHM projections.\n\nMethods\nData for audit of the management of paracetamol overdose are routinely and prospectively collected on databases held within the clinical toxicology units of the Royal Infirmary of Edinburgh, the Royal Victoria Infirmary, Newcastle upon Tyne and Guy’s and St Thomas’ NHS Foundation Trust, London. The use of these databases for audit has approval of the data protection officers/Caldicott Guardians of NHS Lothian Health Board and of the Newcastle Hospitals and Guy’s and St Thomas’ NHS Foundation Trusts.\n\nData on patients presenting to the Emergency Departments and discharged, without admission to the toxicology units, were also recorded. Data on treatment indication and adverse events were collected by specialist toxicology nurses, database scientists, senior medical trainees and consultant clinical toxicologists. In addition, in Edinburgh, use and timing of administration of treatments for anaphylactoid reactions and vomiting following commencement of NAC was routinely extracted from the medication administration record (drug kardex) in combination with the medical notes.\n\nThe data collected included: patient demographics; nature of the overdose (acute or staggered [i.e. repeated excess therapeutic ingestion or repeat overdose, i.e. over more than 60 min]), time from ingestion to presentation for single acute ingestions (0–8 h, >8–24 h, >24 h, and unknown time), plasma paracetamol concentration at time of presentation, history of paracetamol dose, use of NAC, nomogram treatment line 21 and need for additional NAC beyond the original 21 h infusion.\n\nPatients\nAll patients presenting to the Emergency Departments of the three hospitals with paracetamol overdose for 2 calendar years, from 3 September 2011 until and including 3 September 2013 were eligible for inclusion in this study, except those seen or admitted on 3 September 2012, who were excluded as the CHM recommendations were published and implemented that day. Eligible patients were those reporting ingestion of (i) >4 g of paracetamol, alone or in combination with other drugs, as a single ingestion or over any 24 h period, (ii) <4 g where the blood results indicated the need for NAC or (iii) an unknown amount of paracetamol.\n\nIn Edinburgh, 150 patients requiring NAC were recruited to the SNAP randomized clinical trial (RCT) of anti-emetics and a novel regimen of NAC during the study period (starting September 2010, terminating 31 December 2012) 18. These patients were excluded from the adverse reaction analysis since they were included in the RCT. The CHM change in management was introduced on 3 September 2012. Prior to this date, all patients received an initial NAC infusion over 15 min. All patients admitted on or after this date, except for those recruited to the RCT, were treated with an initial acetylcysteine infusion over 60 min.\n\nCost estimation\nBuilding on the work of McQuade and colleagues 3, we estimated costs from an NHS perspective using NHS financial year 2011–12 reference costs (HRG4) for three different diagnostic groups (https://www.gov.uk/government/publications/nhs-reference-costs-financial-year-2011-to-2012). For those discharged home from the emergency department, we used VB08Z [Emergency Medicine, Category 2 Investigation with Category 1 Treatment (Toxicology investigation other treatment)] to give £137 per case. For admitted patients not treated we used VB08Z [Emergency Medicine, Category 2 Investigation with Category 1 Treatment (Toxicology investigation other treatment)] cost (£137) and PA50Z [Ingestion poisoning] in-patient episode cost (£572), giving a total of £709. For those admitted and treated with NAC, we used VB04Z [Emergency Medicine, Category 2 Investigation with Category 4 Treatment (Toxicology investigation with i.v. drug treatment)] cost (£196) and PA50Z [Ingestion poisoning] in-patient episode cost (£572), giving an overall cost of £768 per case. We applied these costs equally across the 2 calendar year periods before and after the change to ensure comparability between time frames.\n\nThe number of patients admitted to hospital in the UK can be taken from hospital activity statistics, but there are no good sources to measure accurately all hospital attendances with paracetamol overdose, as many are discharged and admission rates vary. The MHRA estimated that there are 68–70 000 presentations in England and Wales, and including Scottish data, an estimated 82–90 000 patients are seen per annum with deliberate or accidental paracetamol overdose 5.\n\nStatistical analysis\nDemographic details of patients included in the analysis were illustrated by simple descriptive statistics. Continuous variables were presented as medians and ranges. Categorical variables were compared using chi-squared tests. Differences between proportions were compared by testing for their equality.\n\nIn order to assess as objectively as possible the rates of adverse reactions, the analysis concentrated on the use of medication to treat adverse events normally associated with acetylcysteine use, vomiting or anaphylactoid reactions. Medications were either anti-emetics such as ondansetron or cyclizine, antihistamines (generally chlorphenamine) or bronchodilators such as salbutamol.\n\nRates of treatments for adverse reactions were calculated overall for all patients, and then by the 15 or 60 min treatment groups. Patients were then grouped by both treatment regimens and initial paracetamol concentration (below or above 100 mg l−1) and the rates of medication use in these groups compared.\n\nResults are expressed as totals or proportions (%) of patients who had therapy for adverse effects following therapy. Statistical analysis was conducted using Wilcoxon rank-sum test and measurement of odds ratios (OR) and 95% CIs. Multivariable logistic regression was used to investigate the odds of reaction by infusion type and paracetamol concentration.\n\nResults\nPresentation, admissions, and NAC treatment\nFor the calendar year before and after the change, 3 September 2011 to 3 September 2013, and ignoring the day of the change, 3557 patients with paracetamol poisoning presented to the three participating hospitals (Table 1). A total of 1703 presented in the year before (03/09/11–02/09/12), and 1854 in the year after (04/09/12–03/09/13), a relative increase of 8.9% (95% CI 1.9, 16.2, P = 0.011) (Table 1). This increase remained consistent throughout the following year (Figure 2).\n\nTable 1 Presentations, admissions and use of NAC across three UK hospitals\n\n\tPre\tPost\tChange\t\n\t+/−\t95% CI\tP\t\nPresentations (n)\t\n Centre 1\t990\t1111\t12.2%\t3.0, 22.3\t0.008\t\n Centre 2\t378\t386\t2.1%\t−11.4, 17.6\t0.772\t\n Centre 3\t335\t357\t6.6%\t−8.2, 23.7\t0.403\t\n Overall\t1703\t1854\t8.9%\t1.9, 16.2\t0.01\t\nAdmitted (%)\t\n Centre 1\t54.7 (541/990)\t63.1 (701/1111)\t8.5%\t4.2, 12.7\t<0.001\t\n Centre 2\t79.1 (299/378)\t86.8 (335/386)\t7.7%\t2.4, 13.0\t0.005\t\n Centre 3\t65.7 (220/335)\t69.8 (249/357)\t4.1%\t−2.9, 11.0\t0.251\t\n Overall\t62.2 (1060/1703)\t69.3 (1285/1854)\t7.1%\t4.0, 10.2\t<0.001\t\nTreated with NAC (%)\t\n Centre 1\t39.0 (386/990)\t49.6 (551/1111)\t10.6%\t6.4, 14.8\t<0.001\t\n Centre 2\t30.4 (115/378)\t50.3 (194/386)\t19.8%\t13, 26.7\t<0.001\t\n Centre 3\t37.3 (125/335)\t50.7 (181/357)\t13.4%\t6.2, 20.7\t<0.001\t\n Overall\t36.8 (626/1703)\t50 (926/1854)\t13.2%\t10.0, 16.4\t<0.001\t\nCentre 1 = Royal Infirmary of Edinburgh; centre 2 = Guy’s and St Thomas’ NHS Foundation Trust, London; centre 3 = Royal Victoria Infirmary, Newcastle upon Tyne.\n\nFigure 2 Patients admitted () and treated () for paracetamol poisoning with acetylcysteine in the index hospitals during 2011–2013. Vertical arrow indicates new MHRA guidance\n\nComparing the year after the change with the year before, a greater proportion of patients were admitted to hospital (before 1060/1703 [62.2%], after 1285/1854 [69.3%]; absolute increase 7.1%, 95% CI 4.0, 10.2, P < 0.001) and more patients were treated with NAC (before 626/1703 [36.8%], after 926/1854 [50.0%]; absolute increase 13.2%, 95% CI 10.0, 16.4, P < 0.001) (Table 2, Figure 2).\n\nTable 2 Demographics of patients with paracetamol poisoning\n\n\tPre-change\tPost-change\tTotal\t\n\tn = 1703\tn = 1844\tn = 3547\t\nAge (years) median (range)\t32 (1–95)\t31 (1–98)\t2 (1–98)\t\nBlood paracetamol (mg l−1) median (range)*\t37 (0–587)\t30 (0–660)\t32 (0–660)\t\nAdmitted n (%)\t1060 (62.2)\t1285 (69.3)\t2345 (65.9)\t\nMedian age (years) (% F)\t34 (57.4)\t33 (60.2)\t34 (58.9)\t\nDischarged n (%)\t643 (37.8)\t569 (30.7)\t1212 (34.1)\t\nMedian age (years) (% F)\t30 (59.4)\t29 (58.0)\t30 (58.7)\t\nPresentation times\t\t\t\t\n0–8 h n (%)\t1071 (62.9)\t1077 (58.1)\t2148 (60.4)\t\nMedian age (years) (% F)\t32 (59.7)\t30 (61.5)\t31 (60.6)\t\n>8–24 h n (%)\t177 (10.4)\t188 (10.1)\t365 (10.3)\t\nMedian age (years) (% F)\t28 (62.1)\t30 (62.2)\t29 (62.2)\t\n>24 h n (%)\t92 (5.4)\t92 (5.0)\t184 (5.2)\t\nMedian age (years) (% F)\t32 (57.6)\t35 (56.5)\t34 (57.1)\t\nStaggered n (%)\t309 (18.1)\t435 (23.5)\t744 (20.9)\t\nMedian age (years) (% F)\t36 (50.8)\t34 (54.7)\t36 (53.1)\t\nUnknown n (%)\t54 (3.2)\t62 (3.3)\t116 (3.3)\t\nMedian age (years) (% F)\t37 (57.4)\t42 (54.8)\t40 (56.0)\t\nDeliberate self-harm n (%)\t1483 (88.2)\t1535 (83.8)\t3018 (85.9)\t\nMedian age (years) (% F)\t32 (59.7)\t31 (61.9)\t31 (60.8)\t\nAccidental n (%)\t198 (11.8)\t296 (16.2)\t494 (14.1)\t\nMedian age (years) (% F)\t34 (47.5)\t38 (47.4)\t36 (47.6)\t\nFigures in brackets are 95% CIs or % in the patient group.\n\n* For statistical analysis paracetamol concentrations below the level of detection for the laboratory have been treated as zero.\n\nThere was some evidence to suggest differences in the patterns of poisoning before and after the change (Chi-squared = 15.3, P = 0.003), with fewer presentations 0–8 h after overdose and more staggered presentations. There were also more accidental presentations after the change (Chi-squared = 14.0, P < 0.001) (Table 2). None of the patients in this study was referred for liver unit care.\n\nThere were 1340 (78.7%) acute ingestions before the change and 1357 (73.2%) afterwards, of these 822 were admitted before and 917 afterwards, representing 61.3% and 61.7% of these presentations, respectively, (absolute increase 6.2% (95% CI 2.6, 9.8, P < 0.001). A lower proportion of single ingestions were treated with NAC before the change (32.4%, 435/1340) than afterwards (43.7%, 593/1357) absolute increase 11.2% (95% CI 7.6, 14.9, P < 0.001). For staggered overdoses (including therapeutic excess) there were 309 before the change and 435 afterwards, representing 18.1% and 23.5% of presentations, respectively. Comparing before and after the change, there was no statistical evidence of a difference in the proportion of such cases admitted (215/309 [69.6%] vs. 327/435 [75.2%]; absolute increase 5.6%, 95% CI 0.1, 12.1, P = 0.091). However, the proportion treated with NAC increased (178/309 [57.6%] vs. 300/435 [69.5%]; absolute increase 11.4%, 95% CI 4.3, 18.4, P = 0.001).\n\nThere was no reduction after the change in the number of patients who required extended treatment with NAC on review of the blood results taken around the end of bag three. Based on data from Edinburgh, 43 patients (4.3%, 43/990) required additional NAC before the change compared with 43 (3.9%, 43/1111) after the change (absolute change −0.5%, 95% CI −2.2, 1.2, P = 0.587).\n\nIncidence and timing of adverse drug reactions to acetylcysteine\nThe number of recorded ADRs increased substantially following the change in guidance. However, the proportion of treated patients experiencing ADRs was unchanged (before 87/323 [26.9%], after 145/514 [28.2%]; absolute increase 1.3%, 95% CI −4.9, 7.5, P = 0.682). This was also the case for anaphylactoid reactions (before 29/323 [9.0%], after 55/514 [10.7%]; absolute increase 1.7%, 95% CI −2.4, 5.8, P = 0.426) (Table 3). The time of onset of these reactions following initiation of NAC was later after the change (83.2 min, IQR 50 to 95) compared with before (47.5 min, IQR 20 to 50, Wilcoxon rank-sum, P < 0.001, Tables 4 and 5).\n\nTable 3 Patient demographics and reactions to treatment by infusion rate\n\n\t15 min infusion rate (n = 323)\t60 min infusion rate (n = 514)\t\nAge (years) median (range)\t36 (13–90)\t33 (13–98)\t\nFemale\t184 (57.0)\t325 (63.2)\t\nBlood paracetamol (mg l−1)\t\nMedian (range)\t80 (0–424)\t76.5 (3–660)\t\nAdverse reactions n (%)\t\n 1. Vomiting only\t58 (18.0)\t90 (17.5)\t\n 2. Anaphylactoid only\t13 (4.0)\t38 (7.4)\t\n 3. Both vomiting and anaphylactoid\t16 (5.0)\t17 (3.3)\t\n 4. All vomiting (1 + 3)\t74 (22.9)\t107 (20.8)\t\n 5. All anaphylactoid (2 + 3)\t29 (9.0)\t55 (10.7)\t\n 6. No reaction\t236 (73.1)\t369 (71.8)\t\nFigures in brackets are 95% CIs or % in the patient group.\n\nTable 4 Odds ratios of adverse events to treatment by infusion rate and presenting blood paracetamol\n\n\t\tAll vomiting\tAll anaphylactoid\t\n\t\tEvents / n\tOR\t95% CI\tP\tEvents / n\tOR\t95% CI\tP\t\nInfusion rate1\t\n All patients (n = 8353)\t15 min\t73/321\t1\t–\t–\t29/321\t1\t–\t–\t\n1 h\t107/514\t0.85\t0.61, 1.20\t0.368\t55/514\t1.22\t0.75, 1.98\t0.414\t\n <100 mg l−1 patients (n = 495)\t15 min\t46/185\t1\t–\t–\t26/185\t1\t–\t–\t\n1 h\t56/310\t0.67\t0.43, 1.05\t0.084\t47/310\t1.10\t0.66, 1.86\t0.707\t\n >100 mg l−1 patients (n = 340)\t15 min\t27/136\t1\t–\t–\t3/136\t1\t–\t–\t\n1 h\t51/204\t1.19\t0.69, 2.04\t0.527\t8/204\t2.15\t0.54, 8.55\t0.256\t\nParacetamol concentration2\t\n All patients (n = 8353)\t>100\t78/340\t1.09\t0.78, 1.53\t0.618\t11/340\t0.19\t0.10, 0.37\t<0.001\t\n<=100\t102/495\t1\t–\t–\t73/495\t1\t–\t–\t\n 15 min infusion (n = 321)\t>100\t27/136\t0.77\t0.45, 1.33\t0.354\t3/136\t0.14\t0.04, 0.48\t<0.001\t\n<=100\t46/185\t1\t–\t–\t26/185\t1\t–\t–\t\n 1 h infusion (n = 514)\t>100\t51/204\t1.37\t0.88, 2.12\t0.163\t8/204\t0.21\t0.10, 0.47\t<0.001\t\n<=100\t56/310\t1\t–\t–\t47/310\t1\t–\t–\t\nAge4\t\n All patients (n = 8353)\t<35\t111/412\t1\t–\t–\t45/423\t1\t–\t–\t\n>=35\t69/413\t0.58\t0.42, 0.82\t0.002\t39/414\t0.82\t0.51, 1.30\t0.391\t\nGender5\t\n All patients (n = 8353)\tFemale\t125/507\t1\t–\t–\t51/507\t1\t–\t–\t\nMale\t55/328\t0.66\t0.46, 0.95\t0.025\t33/328\t0.91\t0.60, 1.51\t0.688\t\n 1. Controlling for age, gender and presenting paracetamol concentration. 2. Controlling for age, gender and infusion rate. 3. one patient who had no data on blood paracetamol concentration was excluded. 4. Controlling for gender, infusion rate and presenting paracetamol concentration. 5. Controlling for gender, infusion rate and presenting blood paracetamol concentration.\n\nTable 5 Total number of adverse reactions by time of reaction\n\nTime from start infusion\tPre-change group n (%)\tPost-change group n (%)\t\nn = 87\tn = 145\t\n0–29 min\t29 (33.3)\t11 (7.6)\t\n30–59 min\t32 (36.8)\t34 (23.5)\t\n1–1 h 29 min\t9 (10.3)\t45 (31)\t\n1 h 30 min–2 h\t4 (4.6)\t27 (18.6)\t\n>2 h\t5 (5.8)\t19 (13.1)\t\nUnknown time\t8 (9.2)\t9 (6.2)\t\nAssociation of adverse reactions with infusion duration\nTo determine whether changing the duration of infusion had affected the incidence of adverse reactions, we performed a multivariable analysis, while controlling for the paracetamol concentration, gender and age. The analysis included a total of 837 patients, 323 (215 acute, 105 staggered, three unknown) treated using an initial 15 min infusion of NAC and 514 (325 acute, 177 staggered, 12 unknown) treated using a 60 min initial infusion. The median age and gender ratios did not differ between patients treated at the different infusion rates (Table 4).\n\nRates of use of anti-emetic therapies did not differ between patients receiving 15 min or 60 min infusions of NAC (Table 3). After controlling for age, gender and presenting paracetamol concentration, the odds of being treated with anti-emetics did not differ in patients receiving a 60 min infusion compared with those treated with a 15 min infusion (OR 0.85, 95% CI 0.61, 1.20, P = 0.367). In the 495 patients presenting with blood paracetamol concentrations below 100 mg l−1, the longer infusion duration was not associated with less use of anti-emetic therapy (15 min 46/185 [24.9%] vs. 60 min 56/310 [17.1%); OR 0.67, 95% CI 0.43, 1.05, P = 0.084).\n\nThe odds of an anaphylactoid reaction did not differ according to the infusion duration, when controlled for age, gender and presenting paracetamol concentration: 60 min 55/514 (10.7%) vs. 15 min 29/321 (9.0%, OR 1.22, 95% CI 0.75, 1.98, P = 0.414).\n\nAs seen in previous studies, we did find an excess of anaphylactoid reactions in patients with lower paracetamol concentrations. Patients with presenting blood paracetamol concentrations >100 mg l−1 (11/340) were 80% less likely to experience an anaphylactoid reaction than those with blood paracetamol <100 mg l−1 (73/495; OR 0.19, 95% CI 0.10, 0.37, P < 0.001). This association was replicated in both the 15 min (OR 0.14, 95% CI 0.04, 0.48, P < 0.001) and 60 min (OR 0.21, 95% CI 0.10, 0.47, P < 0.001) treatment groups (Table 4).\n\nCost effects of the change\nBefore the change, an estimated 90 000 patients presented to hospitals across the UK and 45 000 were admitted to hospital 5. We observed an 8.9% (95% CI 1.9, 16.2) increase in presentations over the study period, a 7.1% (95% CI 4.0, 10.2) increase in the proportion of patients admitted, and a 13.2% (95% CI 10.0, 16.4) increase in use of antidote in admitted patients. We estimated the cost implications of each aspect of patient care, including patients not treated with NAC and discharged from the emergency department or admitted, and those admitted for NAC. We calculate that the full annual cost of managing paracetamol overdose was £40.0 million before the change and £48.3 million afterwards, an absolute annual increase of £8.3 million (95% CI 6.4, 10.2 million) (Table 6).\n\nTable 6 Estimating the impact on the cost of estimated change in practice in the UK (with 95% CI)\n\n\t\tBefore\tAfter\t\n\t\ti) National presentations and costs\tii) Estimated change (from data in Table 1)\tiii) Estimated % impact of estimated change nationally\tiv) Estimated numbers of patients nationally\tv) Overall estimated costs\t\n\tCost £/patient\tNumber\tOriginal %*\tCost £\tChange\tLower CI\tUpper CI\tNew %\tLower CI\tUpper CI\tNumber\tLower CI\tUpper CI\tCost £\tLower CI\tUpper CI\t\nOverall\t\t90 000\t–\t–\t8.9%\t1.9%\t16.2%\t–\t–\t–\t98 010\t91 710\t104 580\t–\t–\t–\t\nDischarged from ED\t137\t45 000\t50.0%\t6 165 000\t−7.1%\t−4.0%\t−10.2%\t42.9%\t46.0%\t39.8%\t42 046\t45 085\t39 008\t5 760 302\t6 176 645\t5 344 096\t\nAdmitted and treated\t768\t33 120\t36.8%\t25 436 160\t13.2%\t10.0%\t16.4%\t50.0%\t46.8%\t53.2%\t49 005\t45 869\t52 141\t37 635 840\t35 227 392\t40 044 288\t\nAdmitted and not treated\t709\t11 880\t13.2%\t8 422 920\t–\t–\t–\t7.1%\t7.0%\t7.2%\t6 959\t6 861\t7 057\t4 933 931\t5 003 413\t4 864 449\t\nTotal costs £\t\t\t\t40 024 080\t\t\t\t\t\t\t\t\t\t48 330 073\t46 407 450\t50 252 833\t\nIncrease in costs £\t\t\t\t\t\t\t\t\t\t\t\t\t\t8 305 993\t6 383 370\t10 228 753\t\nNotes: First column costs per episodes (see Methods). Before: (I) Costs applied to national estimates before change. After: (ii) illustrates impact of the changes found in this study as %; (iii) application of these data to the national data in (i) as % change; (iv) impact of estimated changes on total number of presentations, discharged, treated and patients nationally; (v) Total estimated costs post change on patients discharged, treated and untreated.\n\nThe CHM estimated that the reduction in treatment thresholds would save a life every 2.1 years 5. On the basis of this estimate and the data collected in the current study, the cost-per-life saved for this change was estimated to be £17.4 million (95% CI 13.4, 21.5 million) (Table 6).\n\nDiscussion\nThis study provides evidence that the 2012 CHM guidance for the management of paracetamol poisoning has resulted in substantial increases in hospital presentations, hospital admissions and NAC treatment courses, but an apparent improved consistency in the proportion of patients treated (with almost identical rates of 50% treatment in the three participating hospitals compared with a previous range of 31 to 39%). In spite of the slower initial infusion rate, there has been no decrease in the proportion of people developing the more severe adverse reactions to acetylcysteine that require treatment.\n\nThe increase in presentation rate is, at least in part, in patients with chronic therapeutic or staggered paracetamol overdose. The CHM guidance has resulted in a significant increase in calls from NHS public telephone advice services (NHS Direct, NHS111 and NHS24) for advice on suspected paracetamol overdose and hospital referrals 22. Although the CHM guidance defined staggered overdose in terms of duration of consumption, the amount of paracetamol required to constitute an overdose needing acetylcysteine was not defined and this may have increased hospital referrals and treatment for patients with modest overdoses.\n\nModelling of the national impact of the CHM advice relies on the assumption that changes seen in these three hospitals are representative of changes that have occurred across the UK. This seems a reasonable approach, particularly as there was consistency in the proportion of patients treated with acetylcysteine across the three centres. A shorter study elsewhere also found an increase in admissions following the change in advice 4. The increases in hospital activity as a result of the change in guidance are expensive, costing the NHS an estimated £8.3 million every year, with a cost per life saved of £17.4 million.\n\nThe study found that the rates of vomiting requiring anti-emetic therapy and of anaphylactoid reactions were little different with a 60 min infusion as compared with a 15 min infusion, even in patients with low paracetamol concentrations, although they were delayed in patients receiving the 60 min infusion (Table 5). It also confirmed a much higher rate of anaphylactoid reactions in those with lower paracetamol concentrations. The changes to the initial acetylcysteine infusion rate recommended by the CHM have therefore not reduced the rates of adverse reactions. However, the patients affected by the change who have lower paracetamol concentrations and a low risk of hepatic injury and who are now being treated with NAC, have the highest risk of anaphylactoid reactions.\n\nNewer approaches that might reduce rates of anaphylactoid reactions are clinically needed, and this might include the use of different acetylcysteine infusion schedules such as we have recently described 18.\n\nLimitations\nThe data come from three specialist centres, in London, Northern England and Scotland, and may not precisely reflect the whole of the UK. The London centre treated proportionally fewer patients in the pre-change year, and if this is representative of southern England as a whole the cost impact of change is even greater than we show. However, the centres see many paracetamol poisoned patients. Indeed, data from Edinburgh were used by the CHM in its risk assessment. We therefore consider that the changes we have found are likely to reflect national activity. While statistics in England as reflected in hospital activity analysis (available from http://www.hscic.gov.uk/hes) to March 2013 do not show an immediate change, there are several factors that may explain this, particularly coding methodologies, and time delays in actual coding. Coding has previously been shown weak in other types of poisoning 23, and importantly these data sets also do not provide information on proportions treated. In contrast, an 18% increase in annual hospital admissions with paracetamol poisoning (ICD10 T39.1) has been seen in Scotland, comparing the years before and after October 2012, which is similar to the increase reported in this paper (source NSD Scotland 2014).\n\nWe have not accounted for any reduced costs as a result of fewer cases of severe hepatic injury in patients who would have been untreated using the previous management guidelines. However we foresee few savings, as, although costs of hepatic intensive care are very high, serious hepatic injury and death are very rare in this patient group, and mortality in patients not treated with NAC is estimated at one death every 2.1–2.2 years 5. The small increase in the rate of anaphylactoid reactions would have resulted in more treatment interruptions and therefore longer stays in hospital. Since neither of these is reflected in the Healthcare Resource Group costs, they are not included in this cost analysis.\n\nIt should be noted that some deaths previously occurring in patients presenting between the ‘100’ and ‘200’ lines may not be known to the MHRA. If this is the case, the numbers of lives that might be saved by the change in guidance would be underestimated and the costs per life saved overestimated. However, treatment at these lower paracetamol concentration thresholds is unlikely to reach conventional thresholds for cost effectiveness unless the actual numbers of deaths had been underestimated many fold. It is also likely that not all fatal adverse reactions to acetylcysteine have been reported to the MHRA and this would have the opposite effect. As the MHRA is only aware of one death occurring in a patient presenting with a paracetamol concentration between the ‘100’ and ‘150’ lines, treatment of this less severely poisoned subgroup would carry a much higher cost-per-life saved. We acknowledge, however, that considerations of cost-effectiveness of treatments are outside the remit of the CHM and the MHRA.\n\nIn the adverse reactions analysis, we only analyzed cases from one unit (the busiest) that received rescue treatments such as anti-emetics or antihistamines. This will underestimate true adverse reaction rates, as less severe symptoms may not be reported or treated. Of note, adverse reaction rates in the control arm of our prospective clinical trial were significantly greater, with 78% of patients suffering nausea or vomiting, and 30% suffering an anaphylactoid reaction severe enough to require interruption of acetylcysteine infusion or rescue therapy 18.\n\nIn conclusion, we have shown that the CHM changes have resulted in significant increases in rates of hospital presentation and admission, in use of acetylcysteine and in adverse reactions, at substantial cost. None of this cohort of over 3500 patients required liver unit referral before or after the CHM change, emphasizing the rarity of serious liver injury with either management strategy. As we, and others, have previously reported, most episodes of hepatotoxicity occur as a result of late presentation to hospital, and this should be a target for public health intervention 6,11. We believe a full safety/efficacy review of the new CHM recommendations is now needed, together with a detailed cost-effectiveness analysis. In view of the substantial increases in hospital presentations and use of acetylcysteine in patients with staggered overdose or therapeutic excess, this should include better definitions of the amount of paracetamol required to constitute an overdose needing acetylcysteine, potential for use of novel biomarkers 24 and alternative regimens for delivering acetylcysteine that have lower rates of adverse effects 18.\n\nCompeting Interests\nAll authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work and no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; DJW has been a member of the Agency Board at MHRA since 1 September 2013. SHLT is a member of the UK Commission on Human Medicines and was a member of the CHM Paracetamol Expert Group. DNB presented evidence to the CHM Paracetamol Expert Group. SHLT, JD and ME were members of the MHRA ad hoc sub-groups to advise on the implementation of changes to the management of paracetamol overdose and on necessary research. RC is funded by a National Institute of Health Research (NIHR) Doctoral Research Fellowship. ME is a Scottish Senior Clinical Fellow, funded by CSO and Scottish Funding Council, and a Lister Research Prize Fellow. All other authors declare that they have no conflicts of interest.\n\nWe thank all staff at the participating centres who assisted in the care of the patients reported in this study. We are grateful for advice from Andrew Stoddart, Edinburgh’s Health Services Research Unit on NHS costs.\n==== Refs\nReferences\nFerner RE Dear JW Bateman DN Management of paracetamol poisoning BMJ 2011 342 d2218 21508044 \nHeard KJ Acetylcysteine for acetaminophen poisoning N Engl J Med 2008 359 285 292 18635433 \nMcQuade DJ Dargan PI Keep J Wood MD Paracetamol toxicity: what would be the implications of a change in UK treatment guidelines? Eur J Clin Pharmacol 2012 65 1541 1547 22527349 \nThompson G Fatima SB Shah N Kitching G Waring WS Impact of amending the acetylcysteine marketing authorisation on treatment of paracetamol overdose ISRN Toxicol 2013 2013 doi:10.1155/2013/494357 \nMHRA 2012 Benefit risk profile of acetylcysteine in the management of paracetamol overdose. [Internet]. Available at: http://www.mhra.gov.uk/home/groups/pl-p/documents/drugsafetymessage/con184709.pdf (last accessed 13 May 2013) \nPakravan N Simpson KJ Waring WS Bates CM Bateman DN Renal injury at first presentation as a predictor for poor outcome in severe paracetamol poisoning referred to a liver transplant unit Eur J Clin Pharmacol 2009 65 163 168 18958458 \nCraig DG Bates CM Davidson JS Martin KG Hayes PC Simpson KJ Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol-induced hepatotoxicity Br J Clin Pharmacol 2012 73 285 294 22106945 \nWhyte IM Francis B Dawson AH Safety and efficacy of intravenous N-acetylcysteine for acetaminophen overdose: analysis of the Hunter Area Toxicology Service (HATS) database Curr Med Res Opin 2007 23 2359 2368 17705945 \nLynch RM Robertson R Anaphylactoid reactions to intravenous N-acetylcysteine: a prospective case controlled study Accid Emerg Nurs 2004 12 10 15 14700565 \nWaring WS Pettie JM Dow MA Bateman DN Paracetamol appears to protect against N-acetylcysteine-induced anaphylactoid reactions Clin Toxicol 2006 44 441 442 \nBeer C Pakravan N Hudson M Smith LT Simpson K Bateman DN Thomas SH Liver unit admission following paracetamol overdose with concentrations below current UK treatment thresholds QJM 2007 100 93 96 17237484 \nPrescott LF Illingworth RN Critchley JA Stewart MJ Adam RD Proudfoot AT Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine Lancet 1977 2 432 434 70646 \nRoutledge PA Vale JA Bateman DN Johnston GD Jones A Judd A Thomas S Volans G Prescott LF Proudfoot A Paracetamol (acetaminophen) poisoning. No need to change current guidelines to accident departments BMJ 1998 317 1609 1610 9848898 \nPakravan N Waring WS Bateman DN Risk factors and mechanisms of anaphylactoid reactions to acetylcysteine in acetaminophen overdose Clin Toxicol 2008 46 697 702 \nSchmidt L Identification of patients at risk of anaphylactoid reactions to N-acetylcysteine in the treatment of paracetamol overdos Clin Toxicol 2013 51 467 472 \nKerr F Dawson A Whyte IM Buckley N Murray L Graudins A Chan B Trudinger B The Australasian Clinical Toxicology Investigators Collaboration randomized trial of different loading infusion rates of N-acetylcysteine Ann Emerg Med 2005 45 402 408 15795719 \nWaring WS Stephen AF Robinson OD Dow MA Pettie JM Lower incidence of anaphylactoid reactions to N-acetylcysteine in patients with higher acetamonophen concentrations after overdose Clin Toxicol 2008 46 496 500 \nBateman DN Dear JW Thanacoody HKR Thomas SHLT Eddleston M Sandilands EA Coyle J Cooper JG Rodriguez A Butcher I Lewis SC Vliegenthart AD Veiraiah A Webb DJ Gray A Reducing adverse effects from intravenous acetylcysteine treatment of paracetamol poisoning: a randomised controlled trial Lancet 2014 383 697 704 Published online November 28, 2013. http://dx.doi.org/10.1016/S0140-6736(13)62062-0 24290406 \nRumack BH Matthew H Actaminophen poiosning and toxicity Paediatrics 1975 55 871 876 \nGosselin S Hoffman RS Juurlink DN Whyte IM Yarema M Caro J Treating acetaminophen overdose: thresholds, costs and uncertainties Clin Toxicol 2013 51 130 133 \nBNF British National Formulary 2012 64 London BMJ Group and RPS Publishing \nAdams RD Crawford C Perry L Thomas SHL Thompson JP Vale JA Eddleston M Paracetamol excess related to dental pain in adults – NPIS enquiries pre and post MHRA guideline changes Clin Toxicol 2014 52 391 392 \nWood DM Conran CP Dargan PI ICD-10 coding: poor identification of recreational drug presentations to a large emergency department Emerg Med J 2011 28 387 389 20660895 \nAntoine DJ Dear JW Lewis PS Platt V Coyle J Masson M Thanacoody RH Gray AJ Webb DJ Moggs JG Bateman DN Goldring CE Park BK Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital Hepatology 2013 58 777 787 23390034\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0306-5251",
"issue": "78(3)",
"journal": "British journal of clinical pharmacology",
"keywords": "acetylcysteine; adverse effects; paracetamol; poisoning; regulation",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000082:Acetaminophen; D000111:Acetylcysteine; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000931:Antidotes; D002648:Child; D002675:Child, Preschool; D005260:Female; D017048:Health Care Costs; D006760:Hospitalization; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D017410:Practice Guidelines as Topic; D011446:Prospective Studies; D018570:Risk Assessment; D006113:United Kingdom; D055815:Young Adult",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "610-8",
"pmc": null,
"pmid": "24666324",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "15795719;18958458;20660895;21508044;18584360;23697458;70646;17705945;24290406;23473457;18803085;17237484;22527349;1134886;23956882;9848898;23390034;14700565;22106945;18635433",
"title": "Effect of the UK's revised paracetamol poisoning management guidelines on admissions, adverse reactions and costs of treatment.",
"title_normalized": "effect of the uk s revised paracetamol poisoning management guidelines on admissions adverse reactions and costs of treatment"
} | [
{
"companynumb": "GB-JNJFOC-20140824344",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETYLCYSTEINE"
},
"drugadditional": null,
... |
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